Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=CN(C2C=CC(OCCN3CCCCC3)=CC=2)C(=O)C=1)C1C=CC=CC=1.[F:31]C1C=CC(COS(C)(=O)=O)=CN=1.[CH2:44]([O:51][C:52]1[CH:57]=[CH:56][N:55]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH2:65][CH2:66][N:67]3[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]3)=[CH:60][N:59]=2)[C:54](=[O:73])[CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.FC1C=CC(CBr)=CC=1>>[F:31][C:48]1[CH:49]=[CH:50][C:45]([CH2:44][O:51][C:52]2[CH:57]=[CH:56][N:55]([C:58]3[CH:63]=[CH:62][C:61]([O:64][CH2:65][CH2:66][N:67]4[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]4)=[CH:60][N:59]=3)[C:54](=[O:73])[CH:53]=2)=[CH:46][CH:47]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OCCN2CCCCC2)cn1
Reactant: CS(=O)(=O)OCc1ccc(F)nc1
Agent: Fc1ccc(CBr)cc1
Agent: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OCCN2CCCCC2)cc1
Product: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc(OCCN2CCCCC2)cn1

Procedure:
Example 25 was repeated except that 4-benzyloxy-1-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1H-pyridin-2-one and 2-fluoro-5-methanesulfonyloxymethylpyridine were replaced with 4-benzyloxy-1-[5-(2-piperidin-1-ylethoxy)pyridin-2-yl]-1H-piridin-2-one (Example 20) and 4-fluorobenzyl bromide, to provide the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([Cl:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].[NH:32]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]1>CC(O)C.CCOC(C)=O>[Br:10][C:11]1[C:12]([N:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([Cl:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
DIPEA (190 μL, 1.1 mmol) was added to a solution of 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2, 206 mg, 0.5 mmol) and (S)-pyrrolidin-3-ol (52.3 mg, 0.6 mmol) in iPrOH (500 μL) in a vial, which was sealed and heated at 140° C. for 1 h. After cooling at RT, the RM was dissolved in EtOAc, washed with 0.5 M aq. HCl and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 20% to 100% EtOAc) to afford the title compound as a white crystalline powder. HPLC (Condition 4) tR=5.59 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=462.0/464.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[C:8]([CH:21]=O)=[CH:7]2.[BH4-].[Na+].S(Cl)(Cl)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C1COCC1.O.C(Cl)(Cl)Cl>[N:29]([CH2:21][C:8]1[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN=[N+]=[N-]
Reaction time: 1 h

Procedure:
To a stirred solution of 8-chloro-2-(5-fluoro-2-methoxyphenyl)quinoline-3-carb-aldehyde (385.4 mg, 1.221 mmol) in THF (6.0 mL) was added sodium borohydride (1.831 mmol) at rt. The solution was stirred 1 hour then diluted with water, and extracted with EtOAc to provide a crude solid after solvent removal, which was used without further purification. To the crude alcohol in CHCl3 (6 mL) was added thionyl chloride (0.445 mL, 6.103 mmol) at r.t. and stirred overnight. After 14 h the solvents were removed (TLC indicates complete.) The solid was dissolved in DMF (6 mL) then sodium azide (2.441 mmol) was added at once, and stirred 1 hour, poured into water and extracted EtOAc to give a crude material: 373.3 mg Chromatography, gradient 89/9/1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH3:10][NH2:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:11][CH3:10])=[CH:4][CH:3]=1
Reactant: CN
Reactant: BrCc1ccc(Br)cc1
Product: CNCc1ccc(Br)cc1
Yield: 93.7 %

Procedure:
Following the procedure outlined for Example 488, 1-bromo-4-(bromomethyl)benzene (1.0 g, 4.0 mmol) was reacted with methanamine (620 mg, 20 mmol) to afford the desired product (750 mg, 93%) as a brown solid: ESI MS m/z 201 [C8H10BrN+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[C:13]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=3)(=[O:31])=[O:30])[N:12]=2)[CH:8]=[CH:7][N:6]=1)=O.[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>CCO.C1COCC1>[OH:2][CH2:3][C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=3)(=[O:31])=[O:30])[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[C:15]([O:17][CH3:18])[N:16]=2)[CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CO)c2)nc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl ester, product of example 22, were dissolved in a mixture of EtOH/THF (each 15 ml) on gentle warming and subsequently treated with 42 mg of CaCl2 and 28 mg of NaBH4 at RT. The reaction mixture was stirred at RT for 18 h until which time starting material was consumed according to TLC analysis. The mixture was partitioned between diluted HCl and CH2Cl2. The organic layer was dried over Na2SO4 and the solvent removed in vacuo to give 5-methyl-pyridine-2-sulfonic acid [2-(2-hydroxymethyl-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a white solid. ISN mass spectrum, m/e 508.3 (M−1 calculated for C24H23N5O6S: 508).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:18])=[C:5]([C:14]([O:16][CH3:17])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C(Cl)Cl.[Br:22]Br>>[Br:22][CH2:18][C:4]1[C:3]([C:1]#[N:2])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][C:5]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: BrBr
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1C
Solvent: ClCCl
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1CBr
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.6 %

Procedure:
To the solution of methyl 4-cyano-3-methyl-5-(morpholin-4-yl)thiophene-2-carboxylate (0.500 g, 1.88 mmol) in anhydrous methylene chloride (15 mL, 230 mmol) was added a solution of bromine (0.409 g, 2.56 mmol) in anhydrous methylene chloride (5.0 mL, 78 mmol). The mixture was stirred at room temperature for 4 days. The mixture was evaporated under reduced pressure and dried in vacuum to give a crude product that was used without further purification (0.658 g, contained 3.4% starting material, yield 96.6%). LC/MS: (FA) ES+ 345, 347. 1H NMR (400 MHz, d-chloroform) δ 4.83 (s, 2H), 3.87 (s, 3H), 3.85 (m, 4H), 3.62 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
4-(4-Nitro-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.4 mmol) was suspended in a 5:1 mixture of ethanol and water (3 ml). To this solution was added iron powder (0.4 g, 0.98 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.114 g, 83% yield) as a yellow solid. Tr=1.37 min, m/z (ES+) (M+Na)+ 363.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5].[C-:20]#[N:21].[Na+]>CS(C)=O>[C:20]([CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5])#[N:21]
Reactant: CC(O)(CCCl)c1ccc(-c2ccc(F)cc2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(O)(CCC#N)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 27.9 g. of 1-chloro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol in 60 ml. of dimethylsulfoxide is added, at 80°, to a solution of 7.6 g. of NaCN in 100 ml. of dimethylsulfoxide. The mixture is warmed to 80°-90° for 6 hours, poured onto ice and worked up in the customary manner to give 1-cyano-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 118°-120°.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][N:4]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:37][C:38]1[C:43]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:48][NH2:49]>ClCCl>[Cl:37][C:38]1[C:43]([C:44]([F:46])([F:47])[F:45])=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:48][NH:49][C:6](=[O:8])[C@@H:5]1[CH2:9][CH2:10][C:11](=[O:12])[N:4]1[CH2:3][C:2]([CH3:1])([CH3:14])[CH3:13]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2,2-dimethylpropyl)-5-oxoproline (0.100 g, 0.5 mmol, prepared as described below) was dissolved in dichloromethane (5 ml) and to this was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.191 g, 1 mmol), and 1-hydroxybenzotriazole (0.135 g, 1 mmol). The mixture was stirred for 30 minutes at room temperature and then {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.209 g, 1 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was then washed sequentially with water, 3N aqueous citric acid, and three more times with water then dried by filtering through a hydromatrix cartridge (Varian 5 g). The solvent was then evaporated and the residue was purified by mass-directed automated HPLC to give pure N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-(2,2-dimethylpropyl)-5-oxoprolinamide.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[CH2:14][C:15]([NH:17][CH:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[O:20][CH2:19]1)=[O:16])(=O)C>C1COCC1.[OH-].[Na+].CCOC(C)=O>[Cl:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([CH2:5][OH:4])[C:7]=1[CH2:14][C:15]([NH:17][CH:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[O:20][CH2:19]1)=[O:16]
Reactant: CC(=O)OCc1cc(Cl)cc(Cl)c1CC(=O)NC1COc2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1c(Cl)cc(Cl)cc1CO)NC1COc2ncccc21
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A mixture of rac-3,5-dichloro-2-(2-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)amino)-2-oxoethyl)benzyl acetate (0.097 mmol) in 0.5 mL THF and 0.24 mL of 2M NaOH solution was stirred at 30° C. for 3 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired compound as white solid.
Reaction SMILES: [Mg].II.Cl[CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].BrCCBr.[C:19](=[O:21])=[O:20].Cl>O1CCCC1.O>[CH3:7][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH2:5][C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: CC(C)(CCl)c1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
While stirring powdery magnesium (9.56 g, 393 mmol) and iodine (one crumb) in tetrahydrofuran (10 ml), a solution of 1-chloro-2-methyl-2-phenylpropane (26.53 g, 157.3 mmol) and 1,2-dibromoethane (29.6 g, 157 mmol) in tetrahydrofuran (100 ml) was dropwise added at a rate permitting the reaction solution to gently reflux. After completion of the dropwise addition, the mixture was stirred at 60° C. for 4 hrs. The reaction solution was cooled to −78° C., and pulverized dry ice (50 g) was carefully added. After completion of the dropwise addition, the reaction solution was gradually warmed to room temperature with stirring. The reaction solution was diluted with water, acidified with conc. hydrochloric acid, and extracted twice with ethyl acetate. The solvent of the recovered organic layer was evaporated under reduced pressure. The obtained residue was mixed with sodium hydroxide (6 g) and water (200 ml). The obtained aqueous solution was washed with diethyl ether-hexane, acidified with conc. hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the objective substance.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=[O:29])=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[OH:33][CH2:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([NH2:47])=[N:44][C:43]=1[CH3:48])(=[O:41])=[O:40])([CH3:37])[CH3:36]>>[OH:33][CH2:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([NH:47][C:28]([C:27]2[CH:26]=[N:25][N:18]3[C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:32])([F:31])[F:1])[CH:6]=4)=[N:16][C:17]=23)=[O:29])=[N:44][C:43]=1[CH3:48])(=[O:41])=[O:40])([CH3:37])[CH3:36]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.C[N:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=C([N+]([O-])=O)C1=O.N>>[CH3:1][CH:2]1[CH2:3][C:4]2[N:10]=[CH:15][C:14]([N+:16]([O-:18])=[O:17])=[CH:13][C:5]=2[CH2:6][CH2:7]1
Reactant: CC1CCCC(=O)C1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Product: CC1CCc2cc([N+](=O)[O-])cnc2C1
Yield: 53.7 %

Procedure:
3-Methylcyclohexanone (0.56 g, 4.99 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone(1.00 g, 5.02 mmol) in 1M methanolic ammonia (50 mL, 50 mmol) and heated at reflux overnight. The solvent was evaporated off and the residue was suspended in CHCl3 and flash chromatographed over silica gel (43 g) eluding with EtOAc/hexane (1:10) to afford a white solid (515 mg, 63% yield): mp 55-56° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH2:11][CH3:12])[N:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:8]([C:7]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:3][C:4]([S:10][CH2:11][CH3:12])=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)N(C)C
Reactant: CCSc1ncc(C#N)c(N)n1
Solvent: Cc1ccccc1
Product: CCSc1ncc(C#N)c(N=CN(C)C)n1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of the product from Example 156A (200 mg, 1.11 mmol) and N,N-dimethylformamide dimethyl acetal (0.15 mL, 1.11 mmol) in toluene (10 mL) was refluxed for 2.5 hours. After cooling to room temperature the solution was concentrated under vacuum to provide the title compound as a colorless solid (260 mg, 100%).
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.) in toluene (200 ml.) is added benzoyl chloride (1.4 g.). The mixture is refluxed for 18 hours, cooled to room temperature and the precipitate collected, washed with hexane and dried to afford 2.8 g. (65% yield) of 3-(3-carbomethoxythioureido)-4-benzamidobenzophenone as a gray solid, m.p. 191°-192° C., dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[CH2:29]([O:28][CH2:27][CH2:26][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=1)=[O:10])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCOCc1ccccc1
Reactant: CN(C)CCOc1ccc(C(=O)Cc2ccc(Cl)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(C(=O)C(CCOCc2ccccc2)c2ccc(Cl)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
The mixture containing 2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]ethanone (6.3 g, 0.020 mol) and TBABr (0.5 g) in toluene (70 ml) is heated to 70° C. and 48% aqueous sodium hydroxide (70 ml) is added. The mixture is stirred for 30 min. and (2-bromoethoxymethyl)benzene (5.5 g, 0.025 mol) is added dropwise at 85-90° C. The reaction mixture is stirred at 95-100° C. for 3 h. The layers are separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with water and the solvent is evaporated. The residual product (9.0 g) is used in the next reaction step without further purification.
Reaction SMILES: C([O:5][C:6]([C@H:8]([C@@H:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25](=[O:28])[N:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]1=[O:36])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[CH2:41]([O:48][NH2:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O1CCCCC1ON>>[CH2:41]([O:48][NH:49][C:6]([C@H:8]([C@@H:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25](=[O:28])[N:24]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:23]1=[O:36])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:5])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: NOCc1ccccc1
Agent: NOC1CCCCO1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1

Procedure:
In an analogous manner to that described in Example 1, parts (vi)-(viii), but using (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-4-methylvaleramide and O-benzylhydroxylamine in place of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-glycinyl-4-methylvalerohydrazide and O-(tetrahydro-2H-pyran-2(RS)-yl)hydroxylamine respectively there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1.Cl.[OH-].[Na+].CCOCC>C1COCC1.C(Cl)Cl>[NH2:11][CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][C:2]([OH:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: N#CCCN1CCC(O)(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCCCN1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 3-(4-hydroxy-4-phenylpiperidin-1-yl)propionitrile (3.71 g, 16.1 mmol, 1.00 equiv) in THF (15 mL) at room temperature was added boranetetrahydrofuran complex (1.0 M in THF, 56.3 mL, 56.3 mmol, 3.50 equiv) dropwise. The mixture was stirred at reflux for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 85 mL) was added and the mixture was stirred at 50-70° C. for 2 hours. The mixture was basified to pH 9-10 by addition of 6 N aqueous NaOH and extracted with EtOAc (75 mL) and CH2Cl2 (3×75 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (75 mL) was added HCl in Et2O (1.0 M, 38 mL, 2.3 equiv). After removal of the solvents, the residue was triturated with Et2O (185 mL). The resulting white solid was collected by filtration and washed with Et2O. Water (50 mL) was added to this solid, and the mixture was basified to pH 10-11 by addition of 1 N aqueous NaOH and extracted with CH2Cl2 (150 mL+2×75 mL). The combined CH2Cl2 solutions were dried over MgSO4 and concentrated to give 3.12 g (83%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: Cl.[CH2:2]([O:9][C@@H]1[C@H](OCC2C=CC=CC=2)CN(CC2CC2)[C@]1(C)OCC1C=CC=CC=1)[C:3]1C=CC=CC=1.[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:47][NH:46][C@@H:45]1[CH2:57][O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ClCCO>>[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:47][N:46]([CH2:3][CH2:2][OH:9])[C@@H:45]1[CH2:57][O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1CC1CC1
Agent: Cl
Agent: OCCCl
Product: OCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1

Procedure:
The title compound was prepared as described for compound 8 using (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.51g, 1.27 mmol) and 2-chloroethanol (0.1ml, 1.49 mmol) as starting material. (2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethyl-1-(2-hydroxyethyl)pyrrolidine was obtained as a golden oil (0.48 g, yield: 85 %).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][CH2:37][O:38]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][CH2:37][OH:38])=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3CCOC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CCO)c1)=N2

Procedure:
The title compound was prepared from (RS)-{5-dimethylamino-2-[3-oxo-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,2,3]triazol-1-yl}-phenyl) -propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M72) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (179 mg).