Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]2[C:19]3[C:26]([CH3:27])=[C:25]([C:28]([OH:30])=O)[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH3:31][N:32]([CH3:38])[CH2:33][C:34]#[C:35][CH2:36][NH2:37]>>[CH3:31][N:32]([CH3:38])[CH2:33][C:34]#[C:35][CH2:36][NH:37][C:28]([C:25]1[S:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([NH:17][C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][C@H:7]3[CH2:8][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]3)[C:19]=2[C:26]=1[CH3:27])=[O:30]
Reactant: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Reactant: CN(C)CC#CCN
Product: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCC#CCN(C)C)c(C)c23)C1

Procedure:
Prepared analogously to 35.3 from 0.080 g 4-[2-(trans-3-acetylamino-cyclobutoxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 35.2) and 0.045 g 4-(dimethylamino)-but-2-ynylamin*2HCl.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: Fc1ccc2c(C3CCN(CCN4CCOCC4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2O3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131°-132° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]#[N:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][N:5]([CH3:7])[CH:6]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:18]([CH2:17][NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:8][C:3]1[C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]3)=[CH:38][CH:37]=2)=[CH:6][N:5]([CH3:7])[N:4]=1)#[N:19]
Reactant: CC(C)C[C@H](Nc1nn(C)cc1Br)C(=O)NCC#N
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1nn(C)cc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Temperature: 90 °C

Procedure:
To N2-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N1-(cyanomethyl)leucinamide (250 mg, 0.762 mmol), and 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (350 mg, 1.14 mmol, prepared as described in Example 1) in DMF (8 mL) under dry nitrogen was added aqueous sodium carbonate (2.0 M, 0.9 mL, 1.7 mmol) followed by the catalyst PdCl2(dppf) (20 mg, 0.022 mmol). The reaction was heated to 90° C. for 0.5 hours and an additional aliquot of PdCl2(dppf) (20 mg, 0.022 mmol) was added and the reaction mixture heated for 1½ hour during which time an additional aliquot of PdCl2(dppf) (20 mg, 0.022 mmol) was added. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 6/4 then 8/2) to afford N1-(cyanomethyl)-N2-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1-methyl-1H-pyrazol-3-yl)leucinamide.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:24]5=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]5[N:22]=[C:21]4[CH2:31][CH3:32])=[CH:15][CH:14]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>C1COCC1>[CH2:31]([C:21]1[N:20]([CH2:19][C:16]2[CH:15]=[CH:14][C:13]([NH:12][CH2:11][CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:18][CH:17]=2)[C:24]2=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]2[N:22]=1)[CH3:32]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 82.3 %

Procedure:
Compound 144 (488 mg, 1.12 mmol) was dissolved in THF (7.4 mL), and 5% hydrochloric acid (3.7 mL) was added to the solution, followed by stirring at room temperature for 9 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with ethyl acetate three times. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19). The desired compound was recrystallized from diethyl ether to obtain Compound 148 (360 mg, 0.922 mmol, 82.1%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](F)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:25]#[N:26].[Na+].O.C(OCC)C>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:25]#[N:26])=[C:11]([C:14]([F:15])([F:17])[F:16])[C:10]([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: Fc1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: N#Cc1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
1.95 g (5.1 mmol) of 3-chloro-2-[5-fluor-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine and 0.30 g (6.1 mmol) of sodium cyanide are suspended in 20 ml of acetonitrile and the reaction mixture is then stirred under reflux for 16 hours. After cooling, the reaction mixture is poured onto a water/diethyl ether mixture. The aqueous phase is extracted three times with diethyl ether. The combined organic phases are washed twice with water and once with saturated sodium chloride solution and then dried over magnesium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. The crude product is purified by means of flash chromatography on silica gel. This gives 1.7 g of 3-chloro-2-[5-cyano-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine (84%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]1([CH2:42]/[CH:43]=[CH:44]/B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:44]=[CH:43][CH2:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: OB(O)/C=C/Cc1ccccc1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(C=CCc4ccccc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-3-phenyl-1-propen-1-ylboronic acid (49 mg, 0.3 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(3-phenyl-propenyl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:19][O:20][C:21]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:25]2[CH2:24][CH2:23][C:22]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[C:30]([O:31][CH3:32])[C:21]=3[O:20][CH3:19])[CH2:26]2)[N:3]=1
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Reactant: COc1cc2c(c(OC)c1OC)CCNC2
Product: COc1cc2c(c(OC)c1OC)CCN(c1nc(N)c3cc(OC)c(OC)c(OC)c3n1)C2

Procedure:
The procedure described in Example 1 was followed to prepare the above compound, starting from 4-amino-2-chloro-6,7,8-trimethoxyquinazoline and using 5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline as the regent of choice on the same molar basis as before. In this particular instance, the final product was obtained as the free base compound, m.p. 193°-195° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:27][NH:26][CH2:25]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2].[C:29]1([CH:35]2[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:25][N:26]([CH:38]3[CH2:37][CH2:36][CH:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:40][CH2:39]3)[CH2:27]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Product: CC(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(c4ccccc4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid isopropylamide and 4-phenyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:4])=[O:3].[Cl:19][C:20]1[N:25]=[C:24]([NH:26][C:27]([NH2:29])=[S:28])[CH:23]=[N:22][CH:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:7]=3)=[C:12]([CH3:13])[N:29]=2)[CH:23]=[N:22][CH:21]=1
Reactant: NC(=S)Nc1cncc(Cl)n1
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Product: Cc1nc(Nc2cncc(Cl)n2)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared from 1-(4-methanesulfonyl-3-trifluoromethyl-phenyl) propan-2-one (59c) and 6-chloro-pyrazin-2-yl-thiourea.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[CH3:19])=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:7][C@H:6]2[CH3:19])=[O:4])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)CCl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 94.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.40 g, 1.4 mmol) in 2-butanone (14 mL) was added 4-chloro-2-nitro-phenol (0.25 g, 1.4 mmol), potassium carbonate (0.39 g, 2.8 mmol) and potassium iodide (233 mg, 1.4 mmol). The reaction was refluxed overnight, cooled and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.56 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[O:28][CH3:29])=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(Cl)Cl.FC(F)(F)C(O)=O.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[O:28][CH3:29])=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2 g (5.55 mmol) of (4-fluorophenyl)[2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy) phenyl]methanone in 10 ml methylene chloride and 3 ml trifluoroacetic acid is added 2.1 g (18.0 mmol) of triethylsilane. The solution is stirred overnight at room temperature, then diluted with ether (100 ml) and washed with water, 5% aqueous sodium carbonate, water, dried (CaSO4) and evaporated. The residual oil is flash chromatographed to give 1-[(4-fluorophenyl)methyl]-2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)benzene, m.p. 105°-110°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Reactant: COc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)c1ccc(Cl)c(Br)c1
Reaction time: 12 h

Procedure:
3-Bromo-4-chloro-benzoyl chloride in DCM (200 mL) was cooled in an ice bath and triethylamine (11.1 mol, 80 mmol) was added slowly, followed by the drop-wise addition of o-anisidine (4.5 mL, 40 mmol) in DCM (50 mL). At this time the ice bath was removed and the mixture was stirred for 12 hrs, followed by partition between DCM and water. The organic layer was washed with 1 N HCl, saturated NaHCO3, brine and dried over MgSO4. Concentration of the filtrate yielded 3-bromo-4-chloro-N-(2-methoxy-phenyl)-benzamide as a pinkish solid (13.5 g).
Reaction SMILES: [CH:1]([O:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:47][CH2:48][C:49]1[C:50]([OH:57])=[N:51][C:52]([CH3:56])=[CH:53][C:54]=1[CH3:55]>ClCCl.O>[OH:57][C:50]1[C:49]([CH2:48][NH:47][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH3:6])=[CH:15][CH:14]=2)=[C:54]([CH3:55])[CH:53]=[C:52]([CH3:56])[N:51]=1
Reactant: CC(C)OC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)OC(C)C)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.2 %

Procedure:
To the solution of 4-(1-isopropoxyethyl)benzoic acid (137 mg, 0.66 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) and triethylamine (200 mg, 2 mmol). then the 3-(aminomethyl)-4,6-di methylpyridin-2-ol (100 mg, 0.66 mmol) was added, the solution was stirred at room temperature for 12 hours, water (80 mL) was added and washed 3 times, the organic layer was evaporated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-isopropoxyethyl)benzamide (57 mg, 91%) LRMS (M+H+) m/z: calcd: 342.19. found 342; 1H-NMR (300 MHz, CD3OD) 1H-NMR (300 MHz, CD3OD) δ 7.77 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.10 (s, 1H), 4.64-4.62 (m, 1H), 4.49 (s, 2H), 3.52-3.48 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 1.36 (d, J=6.3 Hz, 3H), 1.15 (d, J=6 Hz, 3H), 1.06 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Yield: 79 %

Procedure:
2 g (8.8 mmol) of 3-benzoylbenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 2.5 g (79%) of the product were obtained.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[C:20]2[CH:27]3[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:29][CH:21]2[CH2:22]4)[CH2:26]3)[O:16][CH2:17][CH2:18][Cl:19])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>C1COCC1>[Cl:19][CH2:18][CH2:17][O:16][C:15](=[C:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2)[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCCl)=C2C3CC4CC(C3)CC2C4)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Oc1cccc(C(OCCCl)=C2C3CC4CC(C3)CC2C4)c1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
##STR35## To a stirred solution of the tert-butyldimethylsilyl protected-alkene 7 shown above (2.0 g, 0.004 mol) in 5 mL of THF was added tetrabutylammonium fluoride trihydrate (TBAF, 1.4 g, 0.004 mol). The resulting solution was stirred for 10 minutes. TLC analysis (ethyl acetate/hexane, 20:80) indicated conversion to a new material. After evaporation of solvent, the crude product was washed with water and taken up in ether. The organic layer was dried over MgSO4 and evaporated to dryness. The oily material was chromatographed on silica gel using (ethyl acetate/hexane, 20:80) to give 1.3 g (100%) of alkene 8: 1H NMR (CDCl3) δ 1.81-1.96 (m, 12H), 2.67 (bs, 1H), 3.34 (bs, 1H), 3.55 (t, 2H, J=5.6 Hz), 3.69 (t, 2H, J=5.6 Hz), 6.77-7.19 (m, 4H); 13C NMR (CDCl3) δ 28.21, 30.24, 32.35, 37.08, 38.92, 39.19, 42.55, 69.05, 114.76, 116.05, 121.92, 129,31, 133.41, 136.62, 140.77, 155.64; MS m/e (rel intensity) 318 (100), 227 (19), 213 (24), 121 (92), 107 (29), 93 (37), 69 (21), 55 (36), 41 (40); MS exact mass: calcd. 318.1386, found 318.1383.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[O:14][CH:15]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])[N:17]=1)[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C.Cl.Cl.C(N1CCNCC1)(C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:26]([N:23]1[CH2:24][CH2:25][N:20]([C:18]([C:16]2[N:17]=[C:13]([CH2:12][NH:7][CH2:8][CH2:9][O:10][CH3:11])[O:14][CH:15]=2)=[O:19])[CH2:21][CH2:22]1)([CH3:28])[CH3:27]
Reactant: COCCN(Cc1nc(C(=O)N2CCN(C(C)C)CC2)co1)C(=O)OC(C)(C)C
Agent: CC(C)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCNCc1nc(C(=O)N2CCN(C(C)C)CC2)co1
Reaction time: 1 h

Procedure:
[4-(4-Isopropyl-piperazine-1-carbonyl)-oxazol-2-ylmethyl]-(2-methoxy-ethyl)-carbamic acid tert-butyl ester. A mixture of the crude material from Step C (1.10 g, 3.67 mmol), 1-isopropyl-piperazine dihydrochloride (0.810 g, 4.03 mmol), 1-hydroxybenzotriazole (0.595 g, 4.40 mmol), and N-methylmorpholine (2.42 mL, 22.0 mmol) in DMF (20 mL) was stirred for 1 h. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.845 g, 4.40 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (3×60 mL). The combined organic extracts were washed with H2O (3×300 mL), dried over Na2SO4, filtered and concentrated to yield the crude title compound (1.30 g). MS (ESI): exact mass calcd. for C20H34N4O5, 410.25; m/z found, 411.5 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C@H:6]([NH:9]C(=O)OCC2C=CC=CC=2)[C:5](=[O:20])[N:4]2[CH2:21][CH2:22][CH2:23][CH2:24][C@H:3]12>CCOC(C)=O.[Pd]>[NH2:9][C@@H:6]1[C:5](=[O:20])[N:4]2[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:3]2[C:2](=[O:1])[NH:8][CH2:7]1
Reactant: O=C(N[C@H]1CNC(=O)[C@H]2CCCCN2C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@H]1CNC(=O)[C@H]2CCCCN2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
Argon was bubbled through a solution of benzyl (4S,10aR)-1,5-dioxodecahydropyrido[1,2-a][1,4]diazepin-4-ylcarbamate (37 mg, 0.11 mmol) in EtOAc (3 mL) for 5 min at rt. Then, 5% Pd/C (30 mg, 0.014 mmol) was added to the solution. The reaction mixture was stirred at rt under hydrogen (50 psi) for 3 hr. The reaction mixture was filtered through CELITE® and the filtrate was concentrated under reduced pressure to give (4S,10aR)-4-aminohexahydropyrido[1,2-a][1,4]diazepine-1,5(2H,7H)-dione (19 mg, 0.096 mmol, 86% yield) as a white solid. Anal. Calcd. for C9H15N3O2 m/z 197.2. found: 198.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=O)OC(C)(C)C)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C1COCC1.[OH-].[Na+]>C1COCC1>[CH3:15][NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccncc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl (1-(pyridin-4-yl)piperidin-4-yl)methylcarbamate (180 mg, 0.618 mmol, 1 eq) in THF (4 ml) was added dropwise at 0° C. to a suspension of LAH (188 mg, 4.94 mmol, 8 eq) in THF (4 ml) and heated for 16 h at boiling temperature. The reaction mixture was hydrolyzed with H2O:THF (9:1, 2 ml) and 10% NaOH solution (0.4 ml) at 0° C., diluted with THF (25 ml) and stirred for 1 h at RT. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure. The resulting amine was used in the following stage without being purified further. Yield: 150 mg.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN1CCCC1=O>[N:25]([C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)CCCn1c(N=[N+]=[N-])nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 110 °C
Reaction time: 12 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 7.40 g, 20.0 mmol) and sodium azide (2.60 g, 40.0 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was stirred at 110° C. for 12 hr. After cooling, water was added to the mixture, which was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (4.90 g, 12.9 mmol, 64%) as a pale yellow solid.