Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:12])=[O:11])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of 500 mg (2.26 mmol) of 3-nitrobenzenesulfonyl chloride in 30 mL of dichloromethane were added 275 μL (2.48 mmol) of N-methylpiperazine and 786 μL (5.64 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with dichloromethane and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with diethyl ether to give 510 mg (79%) of the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:19])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1.Cl>CO.C1COCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH2:6][C:5]([OH:19])=[O:4])=[CH:9][C:10]=1[C:15]([F:16])([F:17])[F:18]
Reactant: COC(=O)CNc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 2 N aqueous NaOH solution (15.0 ml, 30.0 mmol) was added to a solution of (4-bromo-3-trifluoromethyl-phenylamino)-acetic acid methyl ester (4.30 g, 13.8 mmol) in methanol-THF (6:1, 35.0 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was made acidic with hydrochloric acid and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over MgSO4 and concentrated under reduced pressure to give (4-bromo-3-trifluoromethyl-phenylamino)-acetic acid (4.03 g, 98%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
To a solution of N-(3-hydroxypropyl)phthalimide (5.25 g, 24.36 mmol) in DMF (20 mL) was added imidazole (16.6 g, 240 mmol) and tert-butyldimethylsilyl chloride (19 g, 120 mmol). The reaction was stirred at room temperature for 18 hours before the volatiles were removed in vacuo and a portion of the crude product was subjected to column chromatography (SiO2, 1:1 DCM/hexanes) to give 2-[3-(tert-butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione as a clear oil (5 g). 2-[3-(tert-Butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione (5 g, 26.4 mmol) was dissolved in ethanol (50 ml) and methyl hydrazine (2.94 ml, 55.4 mmol) added. The reaction was heated to 75° C. for 8 hours before concentration in vacuo. The crude residue was triturated with a mixture of diethyl ether (150 mL) and hexanes (50 mL) and the resultant solid removed by filtration. The solvents were removed in vacuo to give the title compound as a pale yellow oil (1.8 g, 61%). δH (DMSO-d6) 4.58 (2H, br s), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m), 1.60-1.55 (2H, m), 0.83 (9H, d, J=1.1 Hz), 0.00 (6H, d, J=1.2 Hz). LCMS (ES+) RT 1.77 minutes, 190 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO.[H][H]>O>[Cl:1][CH:2]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Solvent: O
Solvent: CO
Product: CCCC(O)C(Cl)C(=O)OCC
Temperature: 70 °C
Reaction time: 14 h
Yield: 72.3 %

Procedure:
Ethyl 2-chloro-3-oxohexanoate (2.5 g, 13 mmol), methanol (7.5 ml) and water (0.75 ml) were mixed, and nitrogen substitution was carried out after reducing the pressure. The above catalyst solution was added thereto, and hydrogen substitution (3 atmospheres) was carried out under reduced pressure. The mixture was stirred at 70° C. for 14 hours. After the mixture was cooled to room temperature, the solvent was evaporated away under reduced pressure. The concentrated matter was purified by silica gel column chromatography to obtain the title compound as a colorless oil (1.83 g, yield: 72%) ((2S,3R):(2S,3S):(2R,3S):(2R,3R)=6.2:58.5:33.2:2.2).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[N:20]1[C:21]([C:29](O)=[O:30])=[CH:22][N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(N(CC)CC)C.CN(C)C=O>[O:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([O:3][C:2]([F:18])([F:1])[F:19])[CH:5]=2)[C:29]([C:21]2[N:20]=[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]3[CH:22]=2)=[O:30])[CH2:10][CH2:11]1
Reactant: O=C(O)c1cn2ccccc2n1
Reactant: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cn2ccccc2n1)N(Cc1cccc(OC(F)(F)F)c1)C1CCOCC1
Yield: 77.6 %

Procedure:
N-[3-(Trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (242 mg), imidazo[1,2-a]pyridine-2-carboxylic acid (194 mg), EDC.HCl (199 mg), HOBt (138 mg), dimethylformamide (5 mL) and triethylamine (0.33 mL) was stirred overnight at room temperature. The solvents were distilled off under reduced pressure and following extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and, thereafter, the solvents were concentrated. The residue was purified by column chromatography (NH silica gel cartridge; ethyl acetate) to give the titled compound (286 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH:14]=[O:15])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH3:24]>CN(C=O)C>[CH2:23]([O:1][C:2]1[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH:14]=[O:15])[CH:3]=1)[CH3:24]
Reactant: CCI
Reactant: CC1Oc2c(O)cc(C=O)cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Temperature: 23 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a 20 mL screw cap vial was added 8-hydroxy-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 398A (0.619 g, 2.99 mmol) and cesium carbonate (0.973 g, 2.99 mmol). The mixture was suspended in DMF (5.98 mL) and then cooled in an ice bath. Iodoethane (0.241 mL, 2.99 mmol) was added in 2 portions over 5 minutes. The reaction mixture was stirred for 2 hr, slowly warmed to 23° C., and the stirred for 18 hr. The crude material was purified by prep HPLC-MS (30-50% MeCN in water, basic mode) and the fractions were collected and concentrated in vacuo. The resulting solid was isolated by filtration, washed with water and dried in vacuo to give a tan solid (0.404 g, 57% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (t, J=6.95 Hz, 3H) 1.46 (d, J=6.82 Hz, 3H) 4.14 (qd, J=6.99, 1.77 Hz, 2H) 4.72-4.88 (m, 1H) 7.07 (d, J=1.77 Hz, 1H) 7.24 (d, J=1.77 Hz, 1H) 9.82 (s, 1H) 10.92 (s, 1H). ESI-MS: m/z 236.1 (M+H)+.
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13]3([CH3:23])[C:18](=[CH:19][CH2:20][C:11]=2[CH:10]=1)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13]3([CH3:23])[CH:18]([CH2:19][CH2:20][C:11]=2[CH:10]=1)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3
Reactant: CN1C(=O)CCC2(C)C1=CCc1cc(F)ccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CCC2(C)c3ccc(F)cc3CCC12
Temperature: 0 °C
Reaction time: 96 h

Procedure:
Triethylsilane (1 ml; 6.12 mmol) was added to 8-fluoro-4,10b-dimethyl-l,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (500 mg; 2.04 mmol) in CH2Cl2 (15 ml) at room temperature. The reaction mixture was cooled to 0° C. and trifluoroacetic acid (2.6 ml) was added. After stirring at room temperature for four days, the reaction mixture was diluted with CH2Cl2 and treated with saturated NaHCO3. The resulting layers were separated and the organic layer was washed with saturated NaHCO3, dried over MgSO4 and concentrated under vacuum to a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH2:37])[N:28]=1)=[O:26]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[N:37]=[CH:14][C:13]([OH:20])([C:16]([F:18])([F:19])[F:17])[CH2:12][C:11]([C:5]2[C:6]3[O:10][CH2:9][O:8][C:7]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:21])[CH3:22])[N:28]=1)=[O:26]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c2c1OCO2
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3ccc(Cl)c4c3OCO4)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 70 mg (0.21 mmol) of 4-(7-chlorobenzo[1,3]dioxol -4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is reacted with 50 mg (0.25 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 0.5 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%), 60 mg (55% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:7]2=1.[H-].[Na+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([NH:1][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cn1c(=O)c2c(N)nccc2c2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nccc3c2c(=O)n(C)c2cc(Cl)ccc32)cc1
Reaction time: 0.08 h
Yield: 74.6 %

Procedure:
To a stirred solution of 4-amino-8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (30 mg, 0.059 mmol) in DMF (10 mL) at 0° C. was added NaH (7.09 mg, 0.295 mmol) and the reaction was stirred for 5 min. To this mixture, 1-(chloromethyl)-4-methoxybenzene (0.026 mL, 0.191 mmol) was added and stirred at rt for 16 h. The reaction was quenched by addition of ice and the reaction mixture extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (25 mL), dried over sodium sulfate, and concentrated under reduced pressure to yield 8-chloro-4-((4-methoxybenzyl)amino)-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (29 mg, 0.044 mmol, 75% yield). LC/MS (ESI) m/e 380.27 [(M+H)+, calcd for C21H19ClN3O2380.11]; LC/MS retention time (Method D): tR=0.86 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C@H:13]1[C@@H:19]([OH:20])[C@H:18]([OH:21])[C@@H:17]([CH2:22][OH:23])[O:16][CH:14]1[OH:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:28](=[O:30])[CH3:29])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:15][CH:14]1[O:16][C@H:17]([CH2:22][O:23][C:28](=[O:30])[CH3:29])[C@@H:18]([O:21][C:14](=[O:15])[CH3:13])[C@H:19]([O:20][C:10](=[O:11])[CH3:9])[C@@H:13]1[NH:12][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(COCc1ccccc1)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](NC(=O)COCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 192.8 %

Procedure:
A solution of 31 (512 mg, 1.56 mmol) in pyridine (5 mL) was cooled to 0° C. To this solution was added acetic anhydride (2.5 mL, 27 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight and allowed to warm to rt. The resulting light yellow solution was diluted with CH2Cl2 (100 mL) and washed with 1 N HCl (3×50 mL), sat. NaHCO3 (2×50 mL), water (2×50 mL) and sat. NaCl (1×50 mL). The combined aqueous layers were back extracted with 50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:4 to 1:1 EtOAc/hexanes to afford 745 mg (96%) of a light yellow oil. IR (thin film): 3409, 2959, 2357, 1750, 1692, 1520 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.90 (s, 6H), 1.99 (s, 6H), 2.06 (s, 6H), 2.18 (s, 6H), 3.79-3.84 (m, 1H), 3.91-3.99 (m, 1H), 4.02 (d, 2H, J=2.8), 4.04-4.07 (m, 2H), 4.14 (dd, 2H, J=2.7, 17.8), 4.20 (dd, 1H, J=3.9, 9.1), 4.55 (app t, 1H, J=6.3), 4.60-4.65 (m, 4H), 4.66-4.68 (m, 1H), 4.79 (ddd, 1H, J=1.6, 3.8, 13.2), 5.07 (dd, 1H, J=3.9, 9.8), 5.19 (app t, 1H, J=4.7), 5.24 (app t, 1H, J=9.8), 5.35 (dd, 1H, J=4.2, 10.2), 5.90 (d, 1H, J=1.6), 6.03 (d, 1H, J=1.6), 6.89 (d, 1H, J=9.6), 7.03 (d, 1H, J=9.3), 7.32-7.39 (m, 10H). 13C NMR (125 MHz, CDCl3): δ 20.3, 20.4, 20.6, 20.7, 20.8, 48.6, 61.7, 65.1, 65.2, 68.9, 69.1, 69.3, 70.2, 71.3, 73.3, 73.5, 73.6, 77.8, 97.1, 127.8, 127.9, 128.2, 128.3, 128.4, 128.6, 128.7, 136.4, 136.6, 169.4, 169.7, 170.1, 170.5. MS (FAB) m/z 496 (MH+). Anal. Calcd for C23H29NO11: C, 55.75; H, 5.90; N, 2.83; Found: C, 55.54; H, 5.93; N, 2.68.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Al]>C1C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:12]([O:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)nc1
Reaction time: 85 h

Procedure:
To a solution of methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (2.00 g, 13.1 mmol) in 45 mL of benzene was added benzyl bromide (1.86 mL, 15.7 mmol) and silver carbonate (3.96 g, 14.4 mmol). The flask was covered with aluminum foil, and after 85 hr, the mixture was diluted with ethyl acetate, filtered through celite, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to provide methyl 6-(benzyloxy)pyridine-3-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:24]#[N:25])[C:10]([CH3:23])=[C:11]([CH:21]=[O:22])[C:12]=3[N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)[N:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO.ClCCl>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:24]#[N:25])[C:10]([CH3:23])=[C:11]([CH2:21][OH:22])[C:12]=3[N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:20])[CH3:19])[CH2:14]3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C=O)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(CO)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2-Cyclopropyl-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-formyl-5-methyl-1,3-benzoxazole-4-carbonitrile (free form of #88) (120 mg, 0.35 mmol) was dissolved in methanol (2.4 ml) and dichloromethane (0.8 ml), then at 0° C., sodium borohydride (18 mg, 0.43 mmol) was added, followed by stirring at the same temperature for 1 hour. Next, at the same temperature, sodium borohydride (9 mg, 0.22 mmol) was further added, followed by stirring at the same temperature for 1 hour. An aqueous saturated sodium hydrogencarbonate solution was added, followed by farmer stirring for 5 minutes. The solution was extracted three times with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1) to obtain the entitled compound (91 mg) as a roughly-purified product. This was washed with isopropyl ether to obtain the entitled compound (85 mg, 70%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3[N+](=O)[O-])cc12
Temperature: 101 °C
Yield: 67 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-chloro-3-nitropyridine were used. Triethylamine was used as base, p-dioxane was used as solvent, and the reaction was heated at reflux (101° C.) for 3 hours. Chromatography afforded the title compound (67%) as a dark red foam: mp, 59.0°-61.0° C.; 1H NMR (CDCl3) δ 8.66 (br s, 1H), 8.51 (dd, J=8.3 and 1.8 Hz, 1H), 8.41 (dd, J=4.4 and 1.8 Hz, 1H), 7.76 (br s, 1H), 7.30-7.24 (m, 2H), 6.97 (d, J=2.1 Hz, 1H), 6.73 (dd, J=8.3 and 4.4 Hz, 1H), 2.97-2.91 (m, 2H), 2.70-2.63 (m, 2H), 2.36 (s, 6H); 13C NMR (CDCl3) δ 155.7, 151.5, 135.5, 134.5, 129.4, 128.2, 127.9, 122.8, 119.3, 114.4, 114.3, 113.0, 111.5, 60.3, 45.4, 23.7. Anal. calcd for C17H19N5O2.1/3 H2O: C, 61.62; H, 5.98; N, 21.13. Found: C, 61.58; H, 5.65; N, 20.80.
Reaction SMILES: COC([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[S:8][CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:33]1CCC[CH2:34]1>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([NH:10][C:7]2[S:8][C:9]([CH2:34][OH:33])=[CH:5][N:6]=2)=[O:26])=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=C(Nc1ncc(CO)s1)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A solution of 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (prepared as in Example 32, 127.7 mg, 0.31 mmol) in tetrahydrofuran (0.4 mL) was added to a slurry of lithium aluminum hydride (15.0 mg, 0.39 mmol) in tetrahydrofuran (2.24 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction was then quenched by the dropwise addition of water. The reaction was then diluted with more water (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide (63.4 mg, 55.4%) as a white solid: mp 115-117° C.; EI-HRMS m/e calcd for C18H21ClN2O2S (M+) 364.1012, found 364.1004.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[OH-].[Na+].CN(C)[CH:21]=[O:22]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2[nH]cc(C=O)c2c1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To stirred dimethylformamide is added dropwise phosphorus oxychloride. The mixture is stirred for 10 min and a solution of 5-methoxyindole in dimethylformamide is added dropwise. The mixture is heated to 40° C. for 45 min, cooled to room temperature and then treated with a solution of sodium hydroxide in water. The mixture is heated to 50° C. for 10 min, cooled to room temperature, poured onto crushed ice and filtered. The filter cake is recrystallised (methanol) to give the product as a white solid.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:16]12([CH2:26][CH2:27]O)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(C(C)C)CC)(C)C.[CH3:38][O:39][C:40](=[O:63])[C@H:41]([CH2:50][C:51]1[N:55]=[CH:54][N:53](C(OC(C)(C)C)=O)[CH:52]=1)[NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[CH3:38][O:39][C:40](=[O:63])[C@H:41]([CH2:50][C:51]1[N:55]([CH2:27][CH2:26][C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:54]=[N:53][CH:52]=1)[NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cncn1CCC12CC3CC(CC(C3)C1)C2)NC(=O)OC(C)(C)C
Temperature: -55 °C
Reaction time: 24 h

Procedure:
A solution of 11.8 mL trifluoromethanesulfonic anhydride in 70 mL dichloromethane is chilled to -70° C. and treated dropwise with a solution composed of 12.6 g 1-adamantyl-2-hydroxyethane, 12.2 mL diisopropylethylamine and 70 mL dichloromethane. The solution is allowed to warm to -55° C. over 45 min then a solution of 25 g N,1-bis-BOC-histidine methyl ester (J. Chem. Soc., Perkin Trans. I 1982; 1553-61.) in 70 mL dichloromethane is added dropwise. The reaction is then stirred at 25° C. for 24 hr and poured into pH=7, 0.25M potassium phosphate buffer (500 mL), stirring vigorously. The organic layer is separated, washed with the same buffer, dried and concentrated. 3-(2-(1-Adamantyl)ethyl)-N-BOC-histidine methyl ester is isolated by chromatography on silica gel (chloroform-methanol, 99:1) as a gum. NMR (CDCl3) 3.85 (m, 2H, NCH2).
Reaction SMILES: C=O.[NH3:3].Cl[CH2:5][C:6]([NH:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)=[O:7]>CO>[C:13]1([C:11]2[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[NH:8][C:6](=[O:7])[CH2:5][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: O=C(CCl)Nc1ccccc1C(=O)c1ccccc1
Agent: C=O
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1
Yield: 84.7 %

Procedure:
Paraformaldehyde (200 g., 91% flake) is placed in a stirred reactor equipped with a reflux condenser, decanter, and ammonia addition tube. Methanol (575 mls.) is added and then gaseous ammonia below the surface of the reaction mixture. 2-Chloroacetamido-benzophenone (273.7 g.) is then added. With a slow, continuous flow of ammonia to the reaction zone, the mixture is heated at reflux for 5 hours. The crystal slurry obtained is distilled to recover the methanol. Toluene (1350 mls.) is now added to the crystal residue and residual water is removed by azeotropic distillation through the decanter. When dry, the hot toluene solution is filtered, the filtrate is cooled for crystallization, and the product obtained isolated to give 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (200 g., 84.7%) m.p. 180°-181° C. (uncorr.).