Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[NH:6][CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][CH:2]1[CH:7]([CH3:8])[N:6]([CH3:21])[CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC1NCCN(C(=O)OCc2ccccc2)C1C
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1C(C)N(C(=O)OCc2ccccc2)CCN1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of phenylmethyl 2,3-dimethyl-1-piperazinecarboxylate (mixture of four stereoisomers) (3.105 g, 12.5 mmol) in dichloromethane (90 mL) at 0° C. was added formaldehyde (1.409 mL, 37% water solution, 18.75 mmol) followed by sodium triacetoxyborohydride (3.445 g, 16.26 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield phenylmethyl 2,3,4-trimethyl-1-piperazinecarboxylate (mixture of all four stereoisomers) (3.04 g, 93%). Phenylmethyl (2R,3R)-2,3,4-trimethyl-1-piperazinecarboxylate (365 mg) and phenylmethyl (2S,3S)-2,3,4-trimethyl-1-piperazinecarboxylate (420 mg) were separated out by a combination of preparative and chiral chromatography. Absolute configuration was assigned using Ab Initio vibrational circular dichroism. LCMS: (M+H)+: 263.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnc(Cl)cc1-c1ccc(F)cc1OC
Product: COc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Yield: 61 %

Procedure:
The title compound was prepared in analogy to Example 90, from [6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 17 hours. The compound was purified by silica gel chromatography using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). The volatiles were evaporated until a precipitate formed. The suspension was filtered and the filter cake was washed three times with a small amount of a mixture of EtOAc:n-heptane (1:4) to give the title compound as a colorless solid (61%). MS (ESI): m/z=517.06 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:25](Cl)(Cl)=[O:26]>C(Cl)Cl>[C:12]([C@H:9]1[CH2:10][O:11][S:25](=[O:26])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[C@@H](CO)NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[C@H]1COS(=O)N1Cc1ccccc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
(S)-2-(Benzylamino)-3,3-dimethylbutan-1-ol (5.77 g, 27.8 mmol) in dry DCM (100 mL) was cooled down to −20° C., DIEA (19.39 ml, 111 mmol) was added, followed by thionyl chloride (2.228 ml, 30.6 mmol) in DCM (10 mL). The reaction mixture was stirred for 1 h at this temperature, then concentrated. The residue was purified by column chromatography to give the title compound (6.26 g) as a diastereomeric mixture. LCMS m/z=254.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]([C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1)#[N:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:24]#[N:25])[CH:27]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(O)c1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3cccc(C#N)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (175 mg, 0.536 mmol) and 3-cyanophenol were reacted as starting materials at 150° C. for 19 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (165 mg, 75.2%). Melting point: 169.9-172.7° C. (ethyl acetate-diethyl ether-hexane).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH:46]([SH:49])[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH:46]([S:49][C:2]2[CH:30]=[CH:29][C:5]3[N:6]([C:10]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=c1oc2cc(Br)ccc2n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(S)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc3c(c2)oc(=O)n3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Tris(dibenzylideneacetone)dipalladium chloroform complex (14 mg, 13.5 □mol) and 1,1′-bis(diphenylphosphino)ferrocene (30 mg, 54.1 □mol) in degassed and dry toluene (2 ml) were stirred at room temperature until the solution turned orange (15 minutes). 6-Bromo-3-trityl -3H-benzooxazol-2-one (0.2 g, 0.44 mmol), Cs2CO3 (0.22 g, 0.68 mmol) and (RS) -3-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.49 mmol) in toluene (0.5 ml) were successively added. After 4 hours stirring at 100° C., the reaction mixture was cooled to room temperature and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1 then 1:1) to provide (RS)-3-(2-oxo-3-trityl-2,3-dihydro-benzooxazol-6-yl-sulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.19 g 7 77%) as a white foam, MS: m/e=596.1 (M+NH4+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](O)(=[O:14])[CH3:13]>>[C:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Product: CC(=O)NNc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C

Procedure:
4-Nitrophenylhydrazine (15.0 g, 0.10 mole) and acetic acid (24.0 g, 0.40 mole) were mixed in a flask equipped with a stirrer and reflux condenser and heated at about 90° C for one hour. The solid mass was collected, washed with water, and then dissolved in hot ethanol. The resulting solution was chilled in ice to give tan needles. Yield 14.4 g (74%), mp 207°-209° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:40])[CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)(Cl)Cl>[CH3:40][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][C:20]([NH:22][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCCCc1nc2cc(N)ccc2n1CCCN(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(NC(=O)c3ccccc3)ccc2n1CCCN(C)C
Temperature: 25 °C

Procedure:
Triethylamine is added to a solution containing Compound 27 in chloroform, and then benzoyl chloride is added thereto while being cooled with ice. The mixture is stirred at room temperature to give the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:42]([NH:41][C:33]2[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:31]([O:30][CH2:29][CH2:28][O:27][CH3:26])[CH:32]=2)=[O:43])[CH:23]=[CH:24][CH:25]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: COCCOc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OCCOC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 76 %

Procedure:
3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from the previous step (102 mg, 0.3 mmol) was reacted with phenyl 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) in the manner described in Example 115C. The final product was purified by column chromatography (25-100% EtOAc/hexanes then 5-10% MeOH/DCM) to give 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (137 mg, 0.23 mmol, 76%). 1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, 1H), 9.04 (s, 1H), 8.56 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.45-7.38 (m, 2H), 7.32-7.26 (m, 2H), 6.96 (d, 1H), 6.87 (s, 1H), 4.37-4.31 (m, 4.19-4.12 (m, 2H), 4.00 (s, 3H), 3.80-3.73 (m, 2H), 3.70-3.63 (m, 2H), 3.36 (s, 3H), 3.31 (s, 3H); LC-MS (ESI) m/z 603 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>C1COCC1.CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(O)(c1ccccc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A solution of 1,5-dimethyltetrazole (29.25 g; 0.298 mole) in dry THF (400 mL) was cooled to -78° C. and treated with n-butyllithium (133 mL of a 2.5M solution in hexane; 0.3325 mole) over 30 minutes. The mixture was stirred at -78° C. for 30 minutes and treated with 4-fluorobenzophenone (50 g; 0.25 mole). The mixture was stirred at -78° C. for 30 minutes and allowed to warm up to 23° C. over 2 hours. The reaction was quenched with 2N HCl (100 mL) and the organic solvent was removed by evaporation. The residue was extracted with CHCl3 (2×100 mL) and the combined organic layers were dried (Na2SO4) and evaporated to afford a brown oil. Purification by chromatography using 20% EtOAc-hexane as eluent afforded the title compound as a white solid (46.3 g; 62%). m.p.=113°-114° C. (crystallized from EtOAc-hexane). MS (CI): m/e=299 for (M+H)+ ;
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br)#[N:2].[N-:11]=[N+:12]=[N-:13].[Na+]>C1COCC1.O>[N:11]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:1]#[N:2])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1CN=[N+]=[N-]
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of 90 g (459 mmol) 2-cyanobenzylbromide in 600 mL THF was added in one portion a solution of 36 g (553 mmol) sodium azide in 100 mL water. The two phase mixture was stirred at 23° C. for 18 hr. The THF layer was separated from the lower water layer and used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:25][C:4]1([CH3:26])[CH2:5][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][O:24][S:34]([C:31]4[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=4)(=[O:36])=[O:35])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3]1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCCO)cc3)n2)CC(C)(C)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1

Procedure:
The title compound was prepared from 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propan-1-ol (Example 189) and p-toluenesulfonyl chloride in pyridine. Yield: 140 mg (45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.S(=O)(=O)(O)O.O.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:19][NH2:20])=[O:12]
Reactant: NN
Reactant: O=C(O)Cc1c(F)cccc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1c(F)cccc1F

Procedure:
70.4 g (0.41 mol) of 2,6-difluorophenylacetic acid, 700 ml of ethanol and 35 ml of concentrated sulphuric acid are heated under reflux for 3 hours. The reaction mixture is then concentrated by evaporation, taken up in dichloromethane and the solution is extracted by shaking in succession with water, 2N sodium carbonate solution and again with water. After drying over magnesium sulphate, the organic phase is concentrated by evaporation. The residue is dissolved in 560 ml of ethanol. After the addition of 30 ml (31 g; 0.62 mol) of hydrazine hydrate, the whole is heated under reflux for 4 days. After cooling, the resulting crystals are filtered off to yield 56.4 g (74% of the theoretical yield) of 2,6-difluorophenylacetic acid hydrazide which melts at 177-178°.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[N:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=4)[C:18]3=[O:31])[C:12]=2[CH2:32][O:33]C(=O)C)=[N:8][C:7]=1[CH3:37])=O)C.[NH3:38].CO>>[C:27]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:31])[N:17]([C:13]1[C:12]([CH2:32][OH:33])=[C:11]([C:9]3[O:10][C:6]([C:4]([NH2:38])=[O:3])=[C:7]([CH3:37])[N:8]=3)[CH:16]=[CH:15][CH:14]=1)[N:26]=[CH:25]2)([CH3:29])([CH3:28])[CH3:30]
Reactant: N
Reactant: CCOC(=O)c1oc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2COC(C)=O)nc1C
Solvent: CO
Product: Cc1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)oc1C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
The above 2-[2-acetoxymethyl-3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-phenyl]-4-methyl-oxazole-5-carboxylic acid ethyl ester was dissolved in 10 mL of NH3/MeOH. The reaction was stirred at room temperature for two days. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1:1) to give 2-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-oxazole-5-carboxylic acid amide (47 mg, yield 68% for two steps) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.20 (dd, J=2.1, 8.4 Hz, 1H), 8.06-8.00 (m, 2H), 7.66-7.58 (m, 2H), 4.73-4.57 (m, 2H), 2.46 (s, 3H), 1.41 (s, 9H). LC-MS calcd for C24H24N4O4 (m/e) 432.18, obsd 433 [M+H]+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.CCOCC>C(O)(=O)C>[Br:1][CH2:12][C:11](=[O:13])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)C(c1ccccc1)c1ccc(F)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(CBr)C(c1ccccc1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
Bromine (14.85 g) in acetic acid (200 ml.) was added dropwise to a solution of 1-p-fluorophenyl-1-phenyl-propan-2-one (20 lg.) in acetic acid (200 ml.) at 60° - 70°. After 30 minutes, the reaction mixture was poured on to ice. Isolation through ether in the usual manner gave crude 3-bromo-1-p-fluorophenyl-1-phenyl-propan-2-one (28 g) which was converted by the procedures described in Example 1 to 3-(N-Benzyl,N-methylamino)-1-p-fluorophenyl-1-phenyl-propan-2-ol (38%), m.p. 61° - 62°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH2:25][CH2:26][CH2:27][NH:28][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of p-methoxybenzoyl chloride (37.8 g, .222 mol) in CH2Cl2 (200 ml) at 0°, is added triethylamine (22.5 g, .222 mol) followed by the slow addition of 3-phenylpropylamine (20 g,.148 mol) dissolved in CH2Cl2 (100 ml). The reaction is allowed to warm to room temperature over several hours. The solvent is removed in vacuo, and the residue is dissolved in EtOAc (500 ml) and 2N HCl (500 ml). The EtOAc is separated, washed with 2NHCl (350 ml), H2O (350 ml), saturated NaHCO3 solution (350 ml), and saturated NaCl solution (350 ml); dried over MgSO4 ; and evaporated. The resulting light brown solid is purified by chromatography (SiO2 ;1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes) yielding N-(3-phenylpropyl)-4-methoxybenzamide as creamy solid.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]([NH:23][C:24]3[C:34]([CH3:35])=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][C:25]=3[CH3:36])=[O:22])[C:18]([CH3:37])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]([NH:23][C:24]3[C:25]([CH3:36])=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][C:34]=3[CH3:35])=[O:22])[C:18]([CH3:37])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc2C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(O)CC3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
To a solution of ethyl 4-[[6-[4-(tert-butyl(dimethyl)silyl)oxy-1-piperidyl]-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (342 mg, 0.650 mmol) in THF (4 ml) is added Bu4NF 1.0 M in THF (0.975 ml, 0.975 mmol) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 12 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 0-40% ethyl acetate in hexanes to afford the title compound (223 mg, 83.3%). Mass spectrum (m/z): 412.2 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]([NH:10][C:11]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].[NH2:20][C@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]([NH:10][C:11]1([C:17]([NH:20][C@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:9]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccco1
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccco2)CCCCC1

Procedure:
2.00 g (7.48 mmol) of 1-[[(2-furanylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid was used instead of 2-benzothiophenecarboxylic acid, and 772 mg (7.48 mmol) of L-valinol was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in the process according to Reference Example 197 to obtain 2.67 g (quantitative) of the title compound and 2.64 g (quantitative) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[CH3:30][C:27]1[CH:26]=[CH:25][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:29][CH:28]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(C)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(C)cc3)c[nH]c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
671 mg (10.3 mmol) of potassium cyanide and 31.5 mg (0.26 mmol) of 4-N,N-dimethylaminopyridine were added to 2.08 g (5.15 mmol) of the compound from Example 109A in 112 ml of DMSO. The mixture was stirred at 120° C. for 1 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.92 g (99% of theory) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[OH:10][CH2:11][C:12]([N+:17]([O-])=O)([CH2:15]O)[CH2:13][OH:14]>>[NH2:17][C:12]1([CH2:13][OH:14])[CH2:11][O:10][CH:4]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH3:2])[O:5][CH2:15]1
Reactant: CCCCC(C=O)CC
Reactant: O=[N+]([O-])C(CO)(CO)CO
Product: CCCCC(CC)C1OCC(N)(CO)CO1
Yield: 95.1 %

Procedure:
Procedure of Example 2 was repeated with 6.41 g of 2-ethylhexanal and 7.56 g of 2-(hydroxymethyl)-2-nitro-1,3-propanediol to give 11 g of 5-nitro-5-hydroxymethyl-1,3-dioxane derivative, which was reduced and distilled at 175°-178° C. to give 8.7 g of the product.
Reaction SMILES: O[C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.C1C=CC(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:28]([C@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc2c1CCC[C@H]2O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cccc2c1CCC[C@@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A stirring solution of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 (3.00 g, 17.32 mmol) in toluene (16 mL) under N2, was cooled to 0° C. DPPA (9.53 g, 34.64 mmol) was added, followed by dropwise addition of DBU (3.16 mL, 20.78 mmol) over 20 min. The mixture was stirred at 0° C. for 4 h then slowly warmed to room temperature over 2 h and then concentrated. The resulting crude mixture was diluted with EA and washed with NaHCO3. The combined organic layers were washed with brine, dried over Na2SO4, and chromatographed (EAI hexane) to provide 2.49 g (72.6%) of (S)-5-azido-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-6 as a white solid. LCMS-ESI (m/z) calculated for C11H10N4: 198.2; found 156.1 [M−N3]+, tR=3.65 min. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=7.6, 1.2 Hz, 1H), 7.56 (dd, J=7.8, 0.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 4.59 (t, J=4.4 Hz, 1H), 3.08 (dt, J=18.0, 5.1 Hz, 1H), 2.99-2.83 (m, 1H), 2.15-1.96 (m, 3H), 2.00-1.81 (m, 1H). 13C NMR (101 MHz, DMSO) δ 141.05, 135.58, 133.47, 132.66, 126.58, 117.43, 113.21, 58.74, 28.28, 27.54, 18.27.