Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]1([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:29]3[CH2:30][CH2:31][C:27]([CH3:26])([OH:32])[CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC1(O)CCNC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C)(O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-methylpyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-8.01 (m, 2 H), 7.84-7.82 (d, J=7.2 Hz, 1 H), 7.74-7.68 (m, 2 H), 7.57-7.53 (m, 2 H), 5.81 (s, 1 H), 5.26 (s, 2 H), 4.49 (s, 2 H), 4.12-3.31 (m, 3 H), 3.27-3.21 (m, 3 H), 2.44 (s, 3 H), 2.08 (s, 2 H), 1.50 (s, 3 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.[NH:13]([C:20]1[C:25]([Br:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][O:35]CCO)=[CH:30][CH:29]=2)[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(NCC)C>C(Cl)Cl>[NH:13]([C:20]1[C:25]([Br:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][O:35][CH2:2][CH2:1][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])=[CH:32][CH:33]=2)[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: OCCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)CCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Triethylamine (33 ml, 0.241 mmol) and methanesulphonyl chloride (19 ml, 0.241 mmol) were added to a solution of 4-anilino-5-bromo-2-[4-(2-hydroxyethoxy)methylanilino]pyrimidine (Example 31; 100 mg, 0.241 mmol) in DCM (5 ml) at 0° C. The solution was warmed to ambient temperature and left to stand for 1 hour. Diethylamine (2 ml) was added, and the mixture was heated at 50° C. for 3 hours. The solvent was removed by evaporation, and the residue was purified by column chromatography, eluting with 0-2% methanol solution in DCM containing 0.5% aqueous ammonia solution, to give the product as a cream solid (38 mg, 34%). NMR (CDCl3): 1.03 (t, 6H), 2.58 (q, 4H), 2.69 (t, 2H), 3.54 (t, 2H), 4.48 (s, 2H), 7.06 (d, 2H), 7.17 (t, 1H), 7.22 (s, 1H), 7.26 (s, 1H), 7.38 (dd, 2H), 7.49 (d, 2H), 7.58 (d, 2H), 8.15 (s, 1H); MS (MH+): 470.4, 472.4.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:8]([SH:10])[CH3:9]>C(OCC)C>[CH2:8]([S:10][CH:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)[CH3:9]
Reactant: O=C1CCC(O)N1
Reactant: CCS
Solvent: CCOCC
Product: CCSC1CCC(=O)N1

Procedure:
A mixture of 2.8 g of 5-hydroxy-pyrrolidin-2-one in 25 cm3 of ethylmercaptan is made to react for 4 hours at 20° C. with 1.4 g of Amberlite IR 120 H. The mixture is diluted with ethyl ether, the solvent is distilled off, and 2.6 g of the expected product is obtained, m.p. 65°-68° C. after crystallizing from isopropyl ether, m.p. 68°-70° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][OH:12])[C:5]=2[N:6]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1.O>[CH3:20][S:21]([O:12][CH2:11][CH:7]1[C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH2:10][CH2:9][CH2:8]1)(=[O:23])=[O:22]
Reactant: Nc1nc2c(s1)CCCC2CO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCc2sc(N)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol (3.3 mmol) and Et3N (1.4 mL, 10 mmol) in THF (10 mL) was added MsCl (0.3 mL, 3.6 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water (200 mL), filtered, and dried to give the crude product, which was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: NN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(NN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (2.5 g, 14 mmol), 4-aminomorpholine (4.4 g, 40 mmol), and K2CO3 (2.0 g, 14 mmol) in DMF (20 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (150 mL). The crude solid product was collected by filtration, air dried, and purified by flash chromatography (silica gel, 4×15 cm, eluted with 20% ether in CHCl3) to yield the product as a yellow solid (0.7 g, 20%).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5]1(=[O:15])[NH:9][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[K].O>CN(C)C=O>[O:10]=[C:8]1[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:15])[N:9]1[CH2:2][C:3]#[N:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of bromoacetonitrile (22 g) in N,N-dimethylformamide (200 mL) was added potassium phthalimide (34 g) under ice-cooling and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as white crystals (yield 27 g, yield 80%).
Reaction SMILES: Cl.C([O:5][C@@H:6]1[C@@H:10]([C:11]2[O:15][N:14]=[C:13]([CH2:16][CH3:17])[CH:12]=2)[O:9][C@@H:8]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([Cl:38])=[N:22][C:23]=3[NH:27][C@@H:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][OH:30])[C@@H:7]1[O:39]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)(Cl)Cl.C(Cl)Cl.O>[CH2:31]([C@H:28]([NH:27][C:23]1[N:22]=[C:21]([Cl:38])[N:20]=[C:19]2[C:24]=1[N:25]=[CH:26][N:18]2[C@H:8]1[C@H:7]([OH:39])[C@H:6]([OH:5])[C@@H:10]([C:11]2[O:15][N:14]=[C:13]([CH2:16][CH3:17])[CH:12]=2)[O:9]1)[CH2:29][OH:30])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(N[C@H](CO)Cc5ccccc5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(N[C@H](CO)Cc5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of acetic acid (2R,3R,4R,5S)-4-acetoxy-2-[6-((S)-1-benzyl-2-hydroxy-ethyl amino)-2-chloro-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)tetrahydro-furan-3-yl ester hydrochloride (Step AC1) (1.194 g, 2.02 mmol) in MeOH/chloroform (4 at, 3:1 MeOH/chloroform) is treated with saturated potassium carbonate solution (10 mL). After stirring at RT overnight, the reaction mixture is diluted with DCM/water and the organic portion is separated. The organic portion is concentrated in vacuo to afford the title compound. (MH+501)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(CC)cc1
Reaction time: 18 h
Yield: 95.5 %

Procedure:
A mixture of 4-ethylphenol (Aldrich) (14.34 g, 116.20 mmoles), anhydrous potassium carbonate (Aldrich) (20.47 g, 146.63 mmoles), ethyl bromoacetate (Aldrich) (17.01 g, 99.81 mmoles) and dry acetone (Aldrich) (200 mL) was refluxed with stirring under a drying tube for 18 hours. The reaction was cooled, and the volatiles were removed by spin evaporation in vacuo. The white residue was partitioned between ice-cold water (250 mL) and dichloromethane (250 mL). The dichloromethane phase was separated and washed with ice cold water (2×100 mL), an ice-cold solution of 5% aqueous sodium hydroxide (150 mL) and finally with ice-cold water (2×100 mL). The dichloromethane solution was dried over sodium sulfate and spin evaporated in vacuo to give 19.86 g (95% yield) of ethyl 4-ethylphenoxyacetate as a clear liquid, which was one spot on thin layer chromatography.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@@H:9]3[CH2:14][NH:15][CH2:16][C@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:19]([C:21]1[CH:30]=[CH:29][CH:28]=[C:27](C(F)(F)F)[C:22]=1C(OC)=O)=O.C(=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C([O-])(O)=O.[Na+]>[CH2:19]([N:15]1[CH2:16][C@@H:8]2[C@H:9]([NH:10][C:11](=[O:13])[C:12]3[C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=[CH:6][C:7]=32)[CH2:14]1)[C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:22]=1
Reactant: COC(=O)c1c(C=O)cccc1C(F)(F)F
Reactant: O=C1N[C@@H]2CNC[C@H]2c2cccc(C(F)(F)F)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1
Product: O=C1N[C@@H]2CN(Cc3ccccc3)C[C@H]2c2cccc(C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of (±)-trans-6-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one, the free base of Example 10, (161 mg, 0.63 mmol) in 4 mL of 1,2-dichloroethane was added benzaldehyde (0.076 mL, 0.76 mmol), sodium triacetoxyborohydride (267 mg, 1.26 mmol) and 3 drops of glacial acetic acid. The mixture was allowed to stir at ambient temperature for 3 h. The reaction was diluted with sat'd aq NaHCO3 and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 180 mg (83%) of the title compound which was sufficiently pure to be used without purification. LRMS (ESI): 347.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:15]=[C:16]([CH3:17])[C:10]=3[N:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:24][C@@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][OH:27].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:24][C@@H:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][OH:27])[C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:15]=[C:16]([CH3:17])[C:10]=2[N:9]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3Cl)nc12
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3N[C@H](CO)Cc3ccccc3)nc12
Temperature: 80 °C

Procedure:
To a solution of 2-(4,6-dichloro-pyrimidin-5-yl)-6-imidazol-1-yl-4-methyl-1H-benzimidazole (40 mg, 0.16 mmol) in isopropanol (5 mL) was added (S)-(−)-2-amino-3-phenyl-propanol (35 mg, 0.23 mmol) and triethylamine (0.5 mL). The reaction mixture was heated to 80° C. for 4 h, cooled to room temperature and concentrated with high vacuum. The crude product was used for the next step without purification. LCMS (M+H)+ m/z 460 (t=2.13 min.).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:33][CH2:32][CH2:30][OH:31])=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: NCCO
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(NCCO)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(2-hydroxy-ethyl-amino)-nicotinamide was prepared starting from intermediate E and ethanolamine. MS calcd. for C24H21ClN4O3 [(M+H)+] 449.1, obsd. 449.0.
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[CH3:17][N:18]=[C:19]=[O:20]>C(#N)C>[C:1]([C:3]1([NH:9][C:19]([NH:18][CH3:17])=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2]
Reactant: C#CC1(N)CCCCC1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CC1(NC(=O)NC)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g (8 mmol) 1-ethynylcyclohexylamine and 2 mL (15 mmol) triethylamine in 10 mL acetonitrile is combined at ambient temperature with 0.5 g (9 mmol) methylisocyanate. The colourless suspension is stirred overnight at ambient temperature and then evaporated down. The residue is taken up in dichloromethane and washed with aqueous potassium carbonate solution. The organic phase is dried and evaporated down. Yield: 1.4 g (colourless solid)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[C:18]1([C:15]2[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=2)[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:26])=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc(-c2ccccc2)cc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 4-biphenyl isocyanate. m/z (ES+) 340 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]1.C(N(CC)CC)C.CO>O1CCCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH2:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)nc1NCC1CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (1 g, 5.18 mmol)), (tetrahydro-2H-pyran-4-yl)methanamine (1.044 g, 9.07 mmol) and triethylamine (2.167 mL, 15.55 mmol) in tetrahydrofuran (22.83 mL) was stirred at 0° C. for 30 minutes and at ambient temperature for 2 hours. Methanol was added (10 mL) followed by silica gel and the mixture was concentrated and purified by silica gel flash chromatography (Isco®, Redi-Sep® column), eluting with a gradient of 2-30% ethyl acetate/hexane to afford the title compound. MS (ESI) m/z 272 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][O:1][N:30]1[C:34](=[O:35])[C:33]2[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31]1=[O:40]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C1CCCN1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCN1CCON1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 57 %

Procedure:
1-(2-Hydroxy-ethyl)-pyrrolidin-2-one (1.00 g, 7.74 mmol, commercial product), PPh3 (2.07 g, 7.90 mmol), N-hydroxy-phthalimide (1.29 g, 7.90 mmol), and diisopropyl azodicarboxylate (1.60 g, 7.90 mmol) were added to anhydrous THF at 0° C. under a nitrogen atmosphere, and the mixture was stirred. After 4 hours, the reaction mixture was purified by silica gel chromatography to give 2-(2-(2-oxo-pyrrolidin-1-yl)-ethoxy)-isoindol-1,3-dione (1.21 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:7]=3[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:6]2[C:5]3[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[C:7]=2[CH:13]=1
Reactant: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)oc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
3-Hydroxy-8-nitrobenzo[c]chromen-6-one (Reference Compound No. 1-(2), 52.01 g, 202 mmol) was dissolved in methanol (150 mL) N,N-dimethylformamide (600 mL), 10% palladium on charcoal (5.00 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature overnight. After the unsoluble materials were filtered out, the methanol was removed under reduced pressure. Water (2 L) was added to the residue. The precipitated solid was filtered off and dried at 90° C. under reduced pressure to give the titled reference compound (44.02 g) as a pale yellow solid. (Yield 96%)
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[C:17]([C:22](O)=[O:23])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[C:17]([CH2:22][OH:23])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:32][CH:33]=1
Reactant: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3c2c2ccccc2n3Cc2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2c(CO)n(C)c(=O)c3c2c2ccccc2n3Cc2ccc(F)cc2)cc1
Temperature: 70 °C
Yield: 90.4 %

Procedure:
A mixture of methyl 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylate (625 mg, 1.375 mmol) in Methanol (10 mL) and Tetrahydrofuran (THF) (10.00 mL) was treated with 2M LiOH (20 mL, 40.0 mmol) and then refluxed overnight. The mixture was cooled to 0° C., treated with HCl (1M) until pH<2 and then filtered to afford 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylic acid as a white solid (595 mg, 1.35 mmol, 98% yield). A suspension of 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (595 mg, 1.35 mmol) in thionyl chloride (10 mL, 137 mmol) was heated at 70° C. for 2 hours and then concentrated. The residue was dissolved in Tetrahydrofuran (THF) (10.00 mL), treated with sodium borohydride (520 mg, 13.75 mmol) and then heated at 70° C. for 2 hours. Additional NaBH4 (15 eq.) was added and then mixture was heated at 70° C. overnight. The mixture was concentrated, treated with NH4Cl (sat. aq) slowly at 0° C. and then extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated to afford 9-(4-fluorobenzyl)-3-(hydroxymethyl)-2-methyl-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (520 mg, 1.22 mmol, 90% yield) as a white solid which was used in the next step without any further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.30-7.44 (m, 7H) 7.19-7.27 (m, 3H) 6.95 (s, 4H) 6.62-6.70 (m, 1H) 6.14 (s, 3H) 4.57 (s, 2H) 3.92 (s, 3H) 2.52 (s, 3H); LCMS (m/z) ES+=427 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1.N#N>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:10]1[C:9]([CH3:17])=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)=[C:12]([C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 100.6 %

Procedure:
A biphasic solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyl trifluoromethanesulfonate (9.56 g, 26.4 mmol) and (3,5-difluorophenyl)boronic acid (5.00 g, 31.7 mmol) in toluene (100 mL) and saturated NaHCO3 (80 mL) was bubbled with N2 to degas. Tetrakis(triphenylphosphine)palladium(0) (1.22 g, 1.06 mmol) was added. The reaction mixture was bubbled with N2 for an additional 5 minutes and then heated at 80° C. for 2 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting material was purified on silica gel column, eluting with ethyl acetate/hexane, 0-30%, to give the desired product (8.65 g, 100%). LCMS calculated for C15H11ClFF2NO3 (M+H)+: m/z=326.0; Found: 326.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16](I)[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:19]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:20]#[CH:21].O>COCCOC.C(N(CC)CC)C.[Cu]I>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[C:16]([C:21]#[C:20][CH2:19][N:22]2[C:26](=[O:27])[C:25]3[C:24](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]2=[O:32])=[CH:15][N:14]=1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Reactant: Nc1ccc(-c2csc3c(I)cnc(N)c23)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2csc3c(C#CCN4C(=O)c5ccccc5C4=O)cnc(N)c23)cc1
Temperature: 80 °C
Yield: 43.4 %

Procedure:
A suspension of Example 77B (0.6 g, 1.63 mmol) in DME (3 mL) and triethylamine (2 mL) was degassed by bubbling nitrogen through the suspension for 5 minutes, treated with N-propargylphthalimide (0.45 g, 2.45 mmol), PdCl2(PPh3)4 (57 mg, 0.08 mmol), and CuI (15 mg, 0.08 mmol), then heated to 80° C. for 1 hour. The cooled solution was poured into water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 3% methanol/dichloromethane to provide 300 mg (43% yield) of the desired product. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.72 (s, 2H), 5.37 (s, 2H), 5.86 (s, 2H), 6.66 (d, J=8.14 Hz, 2H), 7.07 (d, J=8.14 Hz, 2H), 7.35 (s, 1H), 7.87-7.89 (m, 1H), 7.90 (s, 1H), 7.93 (d, J=4.07 Hz, 2H), 7.96 (d, J=5.76 Hz, 1H); MS (ESI(+)) m/e 425 (M+H)+
Reaction SMILES: CO.O.[BH4-].[Na+].ClCCl.[CH2:9]([N:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[N:16][C@H:15]([CH2:32][C:33]([OH:35])=[O:34])[C:14]1=[O:36])[CH:10]([CH3:12])[CH3:11]>>[CH2:9]([N:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[C@@H:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[NH:16][C@H:15]([CH2:32][C:33]([OH:35])=[O:34])[C:14]1=[O:36])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CN1C(=O)[C@@H](CC(=O)O)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)CN1C(=O)[C@@H](CC(=O)O)N[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
In a mixture solvent (methanol:water=6:1) (0.7 ml) was dissolved (3R)-1-isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid (30 mg) obtained in Example 13. To the solution was added sodium borohydride (10 mg). The reaction mixture was stirred for two hours at room temperature, to which were added dichloromethane (50 ml) and water (50 ml). The aqueous layer was made acid, then the organic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was removed, and the residue was recrystallized from dichloromethane/petroleum ether to give 17 mg of colorless crystals, m.p. 184°-188° C.