Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]2)[CH2:18][C@@:17]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:29])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:30]#[N:31])[CH2:3]1.[C:32]([OH:44])(=[O:43])[CH2:33][C:34]([CH2:39][C:40]([OH:42])=[O:41])([C:36]([OH:38])=[O:37])[OH:35]>C(O)C>[OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:25][CH2:24][O:23][C:22]([CH3:26])([CH3:27])[CH2:21]2)[CH2:18][C@@:17]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:29])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:30]#[N:31])[CH2:3]1.[OH:35][C:34]([C:36]([O-:38])=[O:37])([CH2:39][C:40]([O-:42])=[O:41])[CH2:33][C:32]([O-:44])=[O:43]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Solvent: CCO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reaction time: 0.08 h

Procedure:
A mixture of (2β,3α,5α,17β)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)androstane-11-one-17-carbonitrile (500 mg) and citric acid (224 mg) in ethanol (5 ml) was stirred for 5 min. Removal of the solvent under reduced pressure and crystallisation from dichloromethane-diethyl ether afforded (2β,3α,5α,17β)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)androstane-11-one-17-carbonitrile 2-hydroxy-1,2,3-propanetricarboxylate (1:1) salt (427 mg). [α]D +80.8° (c 0.5).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]2[N:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:2]1.[C:24]1([N:34]=[C:35]=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([NH:34][C:35]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]3[N:13]=[C:12]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)[CH:11]=[CH:10][N:9]=3)[CH2:2]2)=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: C1CCOC1
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Nc2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.7 %

Procedure:
To a suspension of 15 mg of 2-[(piperidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (from EXAMPLE 6) in 2 mL of THF was added 11 mg of naphthyl isocyanate. The mixture was stirred at room temperature for 2 days, then concentrated. The residue was purified by flash chromatography, eluting with a gradient system of 2:1 CH2Cl2-acetone to 1:1 CH2Cl2-acetone, to yield 12 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H), 8.25 (br s, 1H) 8.14 (d, J=8.0 Hz, 6.69 (d, J=5.3 Hz, 1H), 4.04 (br s, 1H), 3.85 (br d, J=1.7 Hz, 1H), 3.40-3.55 (m, 2H), 3.12 (br s, 1H), 3.05 (br t, J=9.6 Hz, 1H), 2.36 (br s, 1H), 1.90-2.10 (m, 2H), 1.74-1.85 (m, 1H), 1.56-1.68 (m, 1H), 1.42 (ddt, J=3.9, 10.1, 10.1 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].I[CH3:16]>O1CCCC1>[CH3:16][O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (J. Med. Chem. 2001, 44, 94., 130 mg, 0.75 mmol) in tetrahydrofuran (1.5 mL) was added sodium hydride (60% in mineral oil dispersion, 36 mg, 0.90 mmol) slowly at 0° C. After 30 min., iodomethane (130 mg, 0.90 mmol) was added to the mixture at 0° C. The mixture was gradually warmed to room temperature and stirred overnight. The mixture was concentrated and purified by column chromatography on silica gel eluting with hexane/ethyl acetate (6/1) to afford 110 mg (76%) of the title compound as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([N+:21]([O-])=O)=[CH:13][C:12]=1[N+:24]([O-])=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([NH2:21])=[CH:13][C:12]=1[NH2:24])[C:6](=[O:10])[O:7][CH2:8][CH3:9]
Reactant: CCOC(=O)N(Cc1ccccc1Cl)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N(Cc1ccccc1Cl)c1c(N)cc(N)cc1C(F)(F)F
Reaction time: 7 h
Yield: 95.2 %

Procedure:
Ethyl 2-chlorobenzyl[2,4-dinitro-6-(trifluoromethyl)phenyl]carbamate (103.8 mg) was dissolved in ethyl acetate (20 ml), and to the solution was added 10% Pd—C (105.3 mg). The reaction mixture was stirred under hydrogen atmosphere for 7 hours. The catalyst was filtered, and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound (85.6 mg).
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][N:36]=[C:37]=[S:38]>C(Cl)Cl>[CH:1]1([C@@H:7]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:13]=2[CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:37](=[S:38])[NH:36][CH3:35])[CH2:31][CH2:30]2)=[O:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](NC(=O)c1c(CN2CCNCC2)c(-c2ccccc2)nc2ccccc12)C1CCCCC1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)N[C@@H](C)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
0.4 g (0.87 mmol) of 2-phenyl-3-piperazin-1-ylmethyl-quinoline-4carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (compound of Example 34) were dissolved in 10 ml of methylene chloride and 0.09 g methylisothiocyanate were added. The mixture was stirred for 5 h at room temperature and the solvent was concentrated in vacuo and the residue was purified by flash chromatography on silicagel (EtOAc/heptane: 95/5) to afford 0.43 g (yield 92%) of the title compound as white crystals.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C:9](=O)[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].S(C)C>ClCCl.Cl[Ti](Cl)(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.Cl[Ti](Cl)(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of TiCl4 (1M in dichloromethane, 36 ml, 36 mmol) in dichloromethane (30 ml) at 0° C. was added Ti(OiPr)4 (10.8 ml, 36 mmol). The mixture was then stirred at room temperature for 10 min. To a solution of benzyl (S)-1-((1S,2R)-2-acetamido-4-oxocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (23.25 g, 60 mmol) in dichloromethane (600 ml) was added tert-butylamine (30 ml, 300 mmol) at room temperature, followed by the addition of the TiCl4/Ti(OiPr)4 solution at −50° C. The reaction was allowed to warm slowly to room temperature. The reaction was finished after 2 h (The reaction was monitored on HPLC by quenching an HPLC sample with NaBH4 in methanol). The solution was cooled to 10° C. and BH3.SMe2 (1M in dichloromethane, 66 ml, 66 mmol) was added. The mixture was stirred at room temperature for 5 then quenched with Na2CO3 aqueous solution (300 ml). The precipitate was filtered off. The two layers were separated and the aqueous layer was extracted with dichloromethane (600 ml). The combined dichloromethane layers were extracted with 1N HCl twice (150 ml and 15 ml). (The product and the undesired trans isomer were both in the acidic aqueous phase.) The combined acidic aqueous layers were neutralized with 12 M aqueous solution of NH4OH (12 ml) to pH-8 and extracted with dichloromethane twice (600 ml, 450 ml). (The product was in organic phase, while the trans isomer was still in aqueous layer.) The combined organic layers were washed with NH4Cl aqueous solution 3 times (3×200 ml) until there was no trans isomer left in organic layer. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by crystallization in EtOAc/Hexane(200 ml/800 ml) to give the desired benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (20.80 g, 78% yield) as a white solid with 99.5% purity. 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.76 (s, 1H), 7.27-7.46 (m, 6H), 5.03 (m, 2H), 4.14 (m, 1 H), 4.07 (q, J=8.80 Hz, 1H), 3.83 (m, 1H), 3.36 (m, 2H), 2.91 (s, 1H), 2.18 (m, 1H), 2.04 (m, 1H), 1.78 (s, 3H), 1.41-1.74 (m, 7H), 1.04 (s, 9H). m/z: 445.54 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=1)[C:5]2=[O:29].[C:30](Cl)(=[O:32])[CH3:31].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.N1C=CC=CC=1>[C:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:17][CH:18]=1)[C:5]2=[O:29])(=[O:32])[CH3:31]
Reactant: Cc1nc2ccc(N)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nc(C)n(-c3ccc(OCCCN4CCCCC4)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
6-amino-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone (228 mg, 0.58 mmol) were dissolved in a mixed solvent of dry tetrahydrofuran (5 mL) and dry pyridine (1 mL), and cooled on an ice bath. Acetyl chloride (68 mg, 0.87 mmol) was dripped in, and the mixture stirred at room temperature overnight. Ethyl acetate and 1N sodium hydroxide aqueous solution were added, the mixture was extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (chloroform/methanol=20/1), and the title compound (156 mg, 62%) was obtained as colorless crystals by recrystallization from diethyl ether/heptane.
Reaction SMILES: C(OC([NH:8][C:9]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)([CH3:27])[CH2:10][NH:11][C@:12]([CH3:26])([C:22](OC)=[O:23])[CH2:13][O:14][Si](C(C)(C)C)(C)C)=O)(C)(C)C.C(OC(NC(C1C=C(F)C=C(F)C=1)(C)CN[C@](C)(C(OC(C)C)=O)CO[Si](C(C)(C)C)(C)C)=O)(C)(C)C.S(=O)(=O)(O)O>CCCCO>[F:35][C:30]1[CH:29]=[C:28]([C:9]2([CH3:27])[NH:8][C:13](=[O:14])[C:12]([CH2:22][OH:23])([CH3:26])[NH:11][CH2:10]2)[CH:33]=[C:32]([F:34])[CH:31]=1
Reactant: COC(=O)[C@](C)(CO[Si](C)(C)C(C)(C)C)NCC(C)(NC(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Agent: CC(C)OC(=O)[C@](C)(CO[Si](C)(C)C(C)(C)C)NCC(C)(NC(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CC1(CO)NCC(C)(c2cc(F)cc(F)c2)NC1=O

Procedure:
A 1:1 mixture of methyl N-{2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propyl}-O-[tert-butyl(dimethyl)silyl]-2-methylserinate and propan-2-yl N-{2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propyl}-O-[tert-butyl(dimethyl)silyl]-2-methylserinate from Step C (10.98 g, 20.65 mmol) and sulfuric acid (15.0 mL, 281 mmol) in n-BuOH (516 mL) was heated at reflux for 2 days. Most of the n-BuOH was removed in vacuo and the residual solution was cooled in an ice bath, diluted with EtOAc (200 mL) and quenched by portionwise addition of saturated aqueous NaHCO3 solution (to pH ˜8) with stirring. The layers were separated and the aqueous layer further extracted with EtOAc (200 mL). The combined organic extracts were washed successively with water and brine, and the combined aqueous layers were then saturated with NaCl (s) and further extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2—0:100 to 10:90 afforded the title compound. MS: m/z=271 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28](F)[CH:29]=1)[C:25]#[N:26].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CN1C(=O)CCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:20][C:3]2[CH:4]=[C:5]([CH2:8][N:9]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]3=[O:19])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH:29]=1)[C:25]#[N:26]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)c(O)c1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)cc(Oc2cc(CN3C(=O)c4ccccc4C3=O)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
2-[(4-Chloro-3-hydroxyphenyl)methyl]-1H-isoindole-1,3(2H)-dione (0.50 g, 2.3 mmol), 3-chloro-5-fluorobenzonitrile (0.54 g, 3.5 mmol), K2CO3 (1.0 g, 7.0 mmol) and NMP (5.0 mL) were added to a round bottom flask. The reaction mixture was placed in an oil bath at 110° C. and stirred overnight. The reaction mixture was cooled to RT and aqueous 10% citric acid (25 mL) and EtOAc (25 mL) were added. Additional aqueous 10% citric acid was added until pH ˜4-5, the layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (0.47 g, 81%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.81-7.92 (m, 4H), 7.79 (d, 1H), 7.58 (d, 1H), 7.44 (d, 1H), 7.37 (d, 1H), 7.29 (d, 1H), 7.23 (dd, 1H), 4.77 (s, 2H). MS: m/z 444.9 (M+23).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH2:6]([O:13][C:14]([O:16]NC(=O)CCC(N)=O)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:25][C@@H:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:27]([OH:29])=[O:28]>CC(C)=O.O>[C:7]1([CH2:6][O:13][C:14]([NH:25][C@@H:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:27]([OH:29])=[O:28])=[O:16])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)CCC(=O)NOC(=O)OCc1ccccc1
Reactant: COc1ccc([C@H](N)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1

Procedure:
A suspension of NaHCO3 (184 mg, 2.2 mmol), commercially available N-(benzyloxycarbonyloxy)succinamide (548 mg, 2.2 mmol) and (S)-α-amino-4-methoxybenzeneacetic acid (360 mg, 2 mmol), synthesis described in U.S. Pat. No. 3,517,023, in 1:1 acetone/H2O was stirred for 18 hours at 20° C. After partial concentration and extraction with CH2Cl2, the pH was adjusted to 1.5 and the solution extracted with EtOAc (3×). The EtOAc extracts were washed with brine, dried over MgSO4 and concentrated to yield (S)-α-[N-[(phenylmethoxy)carbonyl]amino]-4-methoxybenzeneacetic acid. A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (608 mg, 3.2 mmol), hydroxybenztriazole (643 mg, 4.76 mmol) and (S)-α-[N-(phenylmethoxy)carbonyl]amino-4-methoxybenzeneacetic acid (1 g, 3.17 mmol) in CH2Cl2 (10 mL) was stirred one hour at 0° C. whereupon N-methylmorpholine (0.7 mL, 6.4 mmol) and t-butylamine (0.5 mL, 4.8 mmol) were added and the reaction stirred at 20° C. for 18 hours. The reaction was diluted with EtOAc, washed with H2O, aq. NaHCO3, brine, dried over MgSO4, and concentrated. Pure (S)-N-(1,1-dimethylethyl)-α-[N-[(phenylmethoxy)carbonyl]amino]-4-methoxybenzeneacetamide was obtained after chromatography on silica gel using 35% EtOAc/hexane as eluant. Hydrogenation of (S)-N-(1,1-dimethylethyl)-α-[N-[(phenylmethoxy)carbonyl]amino]-4-methoxybenzeneacetamide over 10% Pd(OH)2 /C at 1 atom of H2 in 1:1 MeOH/EtOAc generated the title compound which required no further purification following filtration and concentration.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:1][C:2]2[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)C(C)Oc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a mixture of 0.18 g of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}pyridine, 0.19 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene, and 2.0 ml of N,N-dimethylformamide was added 90 mg of potassium carbonate, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrim idin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine as a mixture of diastereoisomers.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1>>[Cl:20][C:17]1[N:16]=[CH:15][C:14]([NH:13][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccc(Cl)nc1)c1ccccc1[N+](=O)[O-]

Procedure:
Using methods substantially equivalent to those described in example 1-A, N-(6-chloropyridin-3-yl)-2-nitrob nzamide (1.24 g, 73%) was prepared from 2-nitro-benzoyl chloride and 3-amino-6-chloropyridine.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[CH3:39][N:40](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:40][CH3:39])=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
To a mixture of 0.06 g (0.14 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-151), 0.08 g (0.21 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.07 mL (0.41 mmole) of diisopropylethylamine. The mixture was stirred at room temperature for 30 minutes. To this was then added 0.21 mL (0.41 mmole) of 2M methylamine in tetrahydrofuran. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hot methanol to give 0.018 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-153).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:2].[H][H]>[Pt]=O.C(O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[N:11]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CN(CCCc1ccc2cccnc2n1)C(=O)OC(C)(C)C
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CN(CCCc1ccc2c(n1)NCCC2)C(=O)OC(C)(C)C

Procedure:
A solution of 2-7 (24.3 g, 65.1 mmol), platinum oxide (4 g) and ethanol (130 mL) was stirred under a balloon of hydrogen gas for 6 h. Following filtration and evaporation, the residue was chromatographed (silica gel, ethyl acetate) to give 2-8 as a yellow oil. TLC Rf =0.35 (silica, 70:25:5 chloroform/ethyl acetate/methanol) 1H NMR (300 MHz, CDCl3) δ 7.05 (d, 1H, J=6 Hz), 6.37 (m, 1H), 4.74 (brs, 1H), 4.18 (q, 2H, J=7 Hz), 3.9 (2s, 2H), 3.32 (m, 4H), 2.63 (m, 2H), 2.51 (m, 2H), 2.72 (m, 4H), 1.43 (m, 9H), 1.26 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][OH:27].[H-].[Na+]>C1COCC1>[CH3:23][O:24][CH2:25][CH2:26][O:27][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1
Reactant: COCCO
Reactant: Cc1cc(C#Cc2cn(-c3cncc(Cl)n3)c(C)n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cncc(-n2cc(C#Cc3ccnc(C)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=350.4 (M+H+) was prepared by treatment of 100 mg 0.32 mmol) 2-chloro-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrazine (27) with 3 equiv. of 2-methoxyethanol and 3 equiv. of sodium hydride in 5 ml of THF (1 h, 50° C.). The compound, after extraction with methylene chloride/water, was purified by chromatography. Yield: 45 mg (0.13 mmol, 40%).
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12](Cl)=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:16]([NH:15][C:12]([C:4]34[CH2:10][CH:8]5[CH2:9][C:2]([NH2:1])([CH2:11][C@@H:6]([CH2:7]5)[CH2:5]3)[CH2:3]4)=[O:13])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: NC12CC3CC(C1)CC(C(=O)Cl)(C3)C2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: NC12CC3C[C@H](C1)CC(C(=O)NC1CCN(CCc4ccc(F)cc4)C1)(C3)C2

Procedure:
1-Aza-5-methyladamantane-3-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-aza-5-methyladamantane-3-carboxamide.