Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:27]([CH3:29])[CH3:28])[C:11]2[C:12]([CH3:26])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:14]3[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]=3[CH:21]=2)=[CH:6][CH:5]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH:27]([N:10]([C:11]1[C:12]([CH3:26])=[C:13]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:14]2[O:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]=2[CH:21]=1)[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc(N(c2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(N(c2ccc(C(=O)O)cc2)C(C)C)cc2c(c1C(C)(C)C)OCC2(C)C
Temperature: 80 °C
Yield: 46.6 %

Procedure:
A solution of 4-[isopropyl-(7-t-butyl-3,3,6-trimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid methyl ester (Compound 69, 0.015 g, 0.038 mmol) in 3 mL of ethanol was treated with 1M sodium hydroxide (1.5 mL, 1.5 mmol) and the resulting clear solution was heated at 80° C. for 2 hours. The volatiles were removed by distillation in vacuo and the residue was neutralized with saturated ammonium chloride solution and extracted with diethylether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to afford, after flash column chromatography using 25% ethyl acetate in hexanes as the eluent, the title compound (0.007 g, 48%) as a solid. 1H NMR (300 MHz, CDCl3): δ 7.87 (d, 2H, J=9.1 Hz), 6.61 (s, 1H), 6.43 (d, 2H, J=8.9 Hz), 4.32 (heptet, 1H, J=6.5 Hz), 4.18 (s, 2H), 3.83 (s, 1H), 2.19 (s, 3H), 1.52 (s, 9H), 1.32-1.28 (m, 9H), 0.99 (d, 3H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]([C:6]1[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=[C:13](O)[N:8]2[N:7]=1)([F:5])[CH2:3][CH3:4].P(Cl)(Cl)([Cl:19])=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:19][C:13]1[N:8]2[N:7]=[C:6]([C:2]([F:5])([F:1])[CH2:3][CH3:4])[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=1
Reactant: CCC(F)(F)c1nc2nc(C)cc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCC(F)(F)c1nc2nc(C)cc(Cl)n2n1

Procedure:
A suspension of Intermediate 6 (0.660 g, 2.89 mmol) in phosphorus oxychloride (ALDRICH, 0.404 mL, 43.4 mmol) was heated under reflux for 2 h, the starting material dissolving during the process. The mixture was slowly added to a mixture of water and ice. The resulting solution was neutralized with solid Na2CO3 and extracted with DCM (25 mL). The aqueous layer was further extracted with DCM (2×5 mL) and the combined organic layers were washed with water (20 mL); then with brine (20 mL), and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified (silica gel column, eluting with Hexane/EtOAc mixtures from 100:0 to 40:60%) to afford Intermediate 7 as a pale yellow solid.
Reaction SMILES: C(OC(=O)C[N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH:11]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)(C)(C)C.[C:30]([OH:36])([C:32](F)(F)F)=[O:31]>C(Cl)Cl>[C:30]([O:36][N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH:11]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)(=[O:31])[CH3:32]
Reactant: COC(=O)CC1c2ccccc2C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC1c2ccccc2C(=O)N(OC(C)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl [5-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate 2 (30.5 g, 77.5 mmol) was taken up in 100 ml of CH2Cl2 and, at 0° C., 150 ml of TFA were added, and the mixture was stirred at 0° C. for about 1 h and then at RT. After the reaction was complete, the mixture was evaporated, and mixed with toluene 2× and again evaporated. 33.6 g of a yellowish oil were obtained as crude product; crystallization from acetone afforded 14.8 g of white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[NH2:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>O.CO>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[NH2:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: NC1CCNC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CO
Solvent: O
Product: N[C@@H]1CCNC1
Reaction time: 8 h

Procedure:
D(-)-tartaric acid (17 g) is dissolved in a mixture of water (30 ml) and methanol (120 ml), and to the solution is gradually added (3RS)-3-aminopyrrolidine (19 g), and the mixture is stirred. When exothermic reaction is finished, methanol (60 ml) is added to the mixture, and the mixture is allowed to stand at 0°-2° C. overnight. The precipitated crude (3R)-3-aminopyrrolidine D(-)-tartrate (20.6 g) is taken by filtration. This product is recrystallized from a mixture of methanol-water (2:3) four times to give (3R)-3-aminopyrrolidine D(-)-tartrate (6.8 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]1[CH2:18][C@@H:17]2[C@H:8]([C@H:9]3[C@H:14]([CH2:15][CH2:16]2)[CH2:13][C@:12]2([CH3:24])[C:19]([C:22]#[N:23])=[CH:20][CH2:21][C@H:11]2[CH2:10]3)[CH2:7][CH2:6]1>CCOC(C)=O.[Pd]>[CH3:1][O:2][CH2:3][O:4][C@@H:5]1[CH2:18][C@@H:17]2[C@H:8]([C@H:9]3[C@H:14]([CH2:15][CH2:16]2)[CH2:13][C@:12]2([CH3:24])[C@@H:19]([C:22]#[N:23])[CH2:20][CH2:21][C@H:11]2[CH2:10]3)[CH2:7][CH2:6]1
Reactant: COCO[C@H]1CC[C@@H]2[C@H](CC[C@@H]3C[C@]4(C)C(C#N)=CC[C@H]4C[C@H]32)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCO[C@H]1CC[C@@H]2[C@H](CC[C@@H]3C[C@@]4(C)[C@@H](CC[C@@H]4C#N)C[C@H]32)C1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of compound 8 (180 mg, 0.6 mmol) in EtOAc (40 mL) was added Pd/C (100 mg) and hydrogenation was carried out under 7 atm H2 at room temperature for 3 h. The reaction was filtered through Celite® 545 which was washed with EtOAc (100 mL). Solvents were removed and the residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to afford compound 9 (172 mg, 94%): 1H NMR (CDCl3) δ 4.58 (s, 2H), 3.82-3.79 (m, 1H), 3.29 (s, 3H), 0.84 (s, 3H); 13C NMR (CDCl3) δ 121.4, 94.5, 71.8, 54.9, 48.4, 47.9, 46.7, 44.9, 44.4, 39.7, 38.1, 37.9, 36.6, 33.8, 33.7, 30.0, 28.3, 26.3, 26.2, 23.7, 14.2.
Reaction SMILES: [CH2:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH2:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][N:7]([C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)OC)CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCC1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
A mixture of methyl 4-allylpiperidine-4-carboxylate from Step A (5.30 g, 24.2 mmol), N-(benzyloxycarbonyloxy)succinimide (7.25 g, 29.1 mmol), and N,N-diisopropylethylamine (12.7 mL, 72.7 mmol) in CH3CN (61 mL) was stirred for 16 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and saturated NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (2×100 mL).The combined organic extracts were concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 40:60, to give the title compound. MS: m/z=318 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:19]=[C:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[N:10]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[N:10]=1
Reactant: COC(=O)C(O)=Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution of methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-hydroxy-2-propenoate 23 (0.38 g) in CH3OH (2 ml) is added, at 0° C., NaBH4 (36 mg). The solution is stirred for 5 h. A saturated solution of NaHCO3 and then, a solution of 1 N NaOH are added until pH=11. The aqueous phase is extracted with AcOEt (3×10 ml). The organic phases are washed with brine, dried over MgSO4 and concentrated. The residue is purified over silica gel using AcOEt/petroleum ether 30/70 then 35/65 as eluent to give methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-hydroxypropanoate 55.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]#[C:11][Si](C)(C)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:10]([C:4]1[CH:5]=[CH:6][C:7]([NH2:9])=[N:8][C:3]=1[C:2]([F:1])([F:17])[F:16])#[CH:11]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)nc1C(F)(F)F

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 2.82 g (11.0 mmol) 6-trifluoromethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 757 mg (5.5 mmol) K2CO3 in 25 mL MeOH. The product is purified by chromatography on silica gel using a cyclohexane/ethyl acetate gradient. Yield: 0.9 g (44%).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([S:10][CH3:11])[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:14])=O>>[C:1]([S:4][CH2:5][CH:6]([S:10][CH3:11])[C:7]([Cl:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CSC(CSC(C)=O)C(=O)O
Reactant: O=S(Cl)Cl
Product: CSC(CSC(C)=O)C(=O)Cl

Procedure:
The 3-(acetylthio)-2-(methylthio)propionic acid is refluxed in thionyl chloride for two hours. The reaction mixture is distilled to remove excess thionyl chloride and the product is distilled in vacuo to yield 3-(acetylthio)-2-(methylthio)propionic acid chloride.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([NH:17][C:18]2[N:22]([CH3:23])[C:21]3[CH:24]=[C:25]([N:29]4[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([F:38])([F:37])[F:36])[CH2:30]4)[C:26]([Cl:28])=[CH:27][C:20]=3[N:19]=2)[C:11]=1[Cl:39])(C)(C)C>O1CCOCC1>[Cl:39][C:11]1[C:12]([NH:17][C:18]2[N:22]([CH3:23])[C:21]3[CH:24]=[C:25]([N:29]4[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([F:38])([F:37])[F:36])[CH2:30]4)[C:26]([Cl:28])=[CH:27][C:20]=3[N:19]=2)=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][NH2:8]
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 M HCl in dioxane (38 mL) was added to N-{2,4-dichloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzyl}-carbamic acid tert-butyl ester (5.4 g, 8.9 mmol) in dioxane (300 mL) and stirred at rt overnight. The reaction mixture was concentrated and the resulting residue was diluted with aq. NaHCO3-solution. The aq. phase was extracted with EtOAc, the organic phase was dried with Na2SO4 and concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1.CCOC(C)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([C:16]3[O:17][C:27](=[O:28])[NH:19][N:18]=3)=[CH:20][CH:21]=1)[CH:6]=[CH:5]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccc(-c3ccc4cc(O)ccc4n3)cc2)o1
Temperature: 25 °C
Yield: 11 %

Procedure:
A mixture of 4-(6-hydroxyquinolin-2-yl)benzohydrazide (90 mg, 0.322 mmol) and CDI (454 mg, 3.22 mmol) in DCM (20 mL) was refluxed overnight. The resulting mixture was cooled to room temperature, followed by an aqueous/EtOAc workup. The crude was purified by prep-HPLC (0.1% TFA as additive) to give Compound IV-24 (18 mg, yield 11%). 1H NMR (CD3OD, 400 MHz): δ 8.64-8.48 (m, 1H), 8.38-7.96 (m, 6H), 7.66-7.24 (m, 2H). MS (ESI): m/z 305.7 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](O)=[O:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.C(Cl)(=O)C([Cl:28])=O>ClCCl.CN(C=O)C>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([Cl:28])=[O:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of 0.43 g (1.22 mmol) of 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic acid in 8 ml of dichloromethane was treated at RT with 2 drops of DMF. 0.12 ml (1.34 mmol, 1.1 eq) of oxalyl chloride were added within 5 min and stirring was continued for 2 h. The solution was evaporated and dried under reduced pressure to give 0.45 g of the title compound.
Reaction SMILES: ClC1C=C(C=CC=1[N+]([O-])=O)C[P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([O:31][CH3:32])[C:23]=1[F:33]>>[F:33][C:23]1[C:24]([O:31][CH3:32])=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=[CH:27][C:22]=1[CH2:21][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: COc1c([N+](=O)[O-])ccc(CCl)c1F
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1F)OCC

Procedure:
The title compound was prepared using the procedure from Compound 104C (Diethyl (3-chloro-4-nitrobenzyl)phosphonate) with 1-(chloromethyl)-2-fluoro-3-methoxy-4-nitrobenzene (Compound 147C). 1H NMR (CDCl3, 400 MHz): δ=1.28-1.32 (m, 6H), 3.19-3.31 (m, 2H), 7.14-7.22 (m, 1H), 7.54-7.61 (m, 1H). MS (ES+): m/z 322.08 [MH+] (TOF, polar).
Reaction SMILES: [OH:1]O.[CH2:3]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([OH:15])[N:8]=1)[CH2:4][CH:5]=[CH2:6]>CCO.[OH-].[Na+]>[CH2:3]([C:7]1[CH:14]=[CH:13][C:10]([C:11]([NH2:12])=[O:1])=[C:9]([OH:15])[N:8]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCc1ccc(C#N)c(O)n1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCc1ccc(C(N)=O)c(O)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
Hydrogen peroxide (30 wt. % solution in water, 45 mL) was added to a solution of a1 (12.13 g, 70.2 mmol) in a mixture of EtOH (150 mL) and 10% aqueous NaOH (280 mL) at 23° C. The reaction mixture was heated to 50° C. for 18 h, then was cooled to 23° C. and the volatiles were removed under reduced pressure. The residue was acidified with 12 M HCl to pH 2-3, and the resulting precipitate was filtered, washed with water (2×50 mL), and air-dried to afford b1 as a yellow solid (13.48 g, 100%): mp=195-198° C.; IR (cm−1) 3329, 3134, 1688, 1642; 1H NMR (DMSO-d6) δ 2.31-2.38 (m, 2H), 2.64 (t, 2H, J=7.6), 4.96-5.05 (m, 2H), 5.71-5.84 (m, 1H), 6.29 (d, 1H, J=7.3), 7.45 (s, br, 1H), 8.21 (d, 1H, J=7.3), 9.00 (s, br, 1H), 12.37 (s, br, 1H); Anal. C10H12N2O2·0.15H2O: C, H, N.
Reaction SMILES: FC1C=C(C=CC=1F)[CH2:5][N:6]1C=CC=C(C(NCC2C=C(C3C4C(=NC=C(C(N)=O)C=4)NC=3)C=CC=2)=O)[C:7]1=O.[F:39][C:40]1[CH:41]=[C:42]([CH:73]=[CH:74][C:75]=1[F:76])[CH2:43][N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([NH:52][CH2:53][C:54]2[CH:55]=[C:56]([C:60]3[C:68]4[C:63](=[N:64][CH:65]=[C:66]([C:69]([OH:71])=O)[CH:67]=4)[NH:62][CH:61]=3)[CH:57]=[CH:58][CH:59]=2)=[O:51])[C:45]1=[O:72].CNC.O1CCCC1>>[CH3:5][N:6]([CH3:7])[C:69]([C:66]1[CH:67]=[C:68]2[C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([CH2:53][NH:52][C:50]([C:46]4[C:45](=[O:72])[N:44]([CH2:43][C:42]5[CH:73]=[CH:74][C:75]([F:76])=[C:40]([F:39])[CH:41]=5)[CH:49]=[CH:48][CH:47]=4)=[O:51])[CH:55]=3)=[CH:61][NH:62][C:63]2=[N:64][CH:65]=1)=[O:71]
Reactant: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid dimethylamide was synthesized as per Example 81, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid amide using 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (53 mg, 0.00010 mol) as carboxylic acid and 2.00 M of dimethylamine in tetrahydrofuran (127 uL, 0.254 mmol; Aldrich) as amine, to yield the product. 1H NMR (400 MHz, CDCl3-MeOH-d4) d ppm 8.751 (m, 1H) 8.481 (m, 1H) 8.424 (m, 1H) 7.755 (m, 1H) 7.562 (m, 1H) 7.525 (m, 1H) 7.454-7.379 (m, 2H) 7.342 (m, 1H) 7.138-7.032 (m, 2H) 7.005-6.936 (m, 1H) 6.450 (m, 1H) 5.096 (m, 2H) 4.640 (m, 2H) 3.082 (m, 6H); MS m/z=542.33 M+H.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+].[NH:24]1[CH:28]=[CH:27][N:26]=[N:25]1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([N:25]1[N:26]=[CH:27][CH:28]=[N:24]1)[N:6]2[CH3:16]
Reactant: c1c[nH]nn1
Reactant: Cn1c(Br)nc2c(N)nc(CCCCO)nc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(-n2nccn2)nc2c(N)nc(CCCCO)nc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)butan-1-ol (1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added Cs2CO3 (5.9 g, 18.24 mmol) and then 1H-1,2,3-triazole (1.2 g, 1.0 ml, 17.2 mmol). The mixture was stirred overnight at 90° C. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (DCM/MeOH: 93/7).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21])=[CH:16][CH:15]=1.[CH2:29]([O:36][CH2:37]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CCCCCC.O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:29]([O:36][CH2:37][CH:25]([CH2:24][CH2:23][NH:22][C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=1)=[O:21])[C:26]([OH:28])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(C(=O)NCCCC(=O)O)cc1
Reactant: ClCOCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCCC(COCc2ccccc2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
Under an atmosphere of argon, 1.63M n-butyl lithium in hexane (4.05 ml) was added to a solution of diisopropylamine (0.925 ml) in tetrahydrofuran (5 ml) and hexamethyl phosphoramide (HMPA) (3 ml) at −78° C. The mixture was stirred at −78° C. for 15 minutes. A solution of the compound prepared in Example 2(1) (0.442 g) in tetrahydrofuran (3 ml) was added to this solution at −78° C. The mixture was stirred at room temperature for 30 minutes. Benzyloxymethyl chloride (0.313 g) was added to the reaction mixture at −78° C. The mixture was stirred at −78° C. for 2 hours. To the reaction mixture, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (0.22 g) having the following physical data.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:14][CH:13]=2)[CH:5]=1.[Li+].[OH-]>CO.C1COCC1>[C:38]([N:30]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:42])=[O:2])=[CH:13][CH:14]=2)=[O:19])[C@@H:21]([CH3:41])[CH2:22]1)(=[O:40])[CH3:39]
Reactant: COC(=O)c1cccc(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3cccc(C(=O)O)c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
(2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxymethyl)-benzoic acid methyl ester (93 mg, 0.16 mmol) was dissolved in MeOH/THF (2:1, 3 mL). To this solution was added LiOH (2M in H2O, 2 mL). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to remove MeOH and THF. Then 6N HCl aqueous solution was added to acidify the reaction mixture to pH 2-3. The reaction mixture was extracted with DCM (5 mL×3). The extract was washed with water (15 mL), brine (15 mL) and dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by preparatory HPLC to afford the product (90 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=3Cl)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.COC(C1C2NC(C3C(=O)NC=CC=3NC[C@@H](O)C3C=CC=CC=3)=NC=2C=CC=1)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=3[NH:31][CH2:30][CH2:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2nc(-c3c(Cl)cc[nH]c3=O)[nH]c12
Reactant: NCCc1cccc(Cl)c1
Agent: COC(=O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-Chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid methyl ester was synthesized from 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazole-4-carboxylic acid methyl ester, 2-(3-Chloro-phenyl)-ethylamine, triethylamine, and ACN using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid methyl ester yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:28])[N:14]([CH2:22][C:23]([O:25]CC)=[O:24])[C:15](=[O:21])[N:16]([CH2:18][O:19][CH3:20])[CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:28])[N:14]([CH2:22][C:23]([OH:25])=[O:24])[C:15](=[O:21])[N:16]([CH2:18][O:19][CH3:20])[CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c(=O)c(NS(=O)(=O)Cc2ccccc2)cn(COC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCn1cc(NS(=O)(=O)Cc2ccccc2)c(=O)n(CC(=O)O)c1=O
Temperature: 25 °C

Procedure:
To a cooled (0° C.) suspension of the compound of Example 43 (10.0 g, 24 mmole) in methanol (50 mL) is added 1.0N NaOH (49 mL) over a period of 10 minutes. After the addition is complete, the solution is allowed to warm to room temperature over a period of 1.5 hours. The solvent is reduced under vacuum, residue diluted with water, and washed with ethyl acetate twice. The aqueous layer is acidified with 2.0N HCl to pH 1, extracted with ethyl acetate three times. The combined organic extracts are washed with water, then brine (twice). The solvent is removed to give the title compound.