Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-1H-benzo[d]imidazole (10 g) and NaH (60% in oil, 3.15 g) in DMF (150 mL) was added ethyl bromoacetate (11.0 mL) at 0° C. After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The precipitate was crystallized from AcOEt/hexane to give the title compound (12 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:27](=[O:28])[N:13]3[CH2:14][CH2:15][CH2:16][N:17](CC4C=CC=CC=4)[C:18](=[O:19])[C:12]3=[C:11]([CH3:29])[CH:10]=2)[CH:3]=1.OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:27](=[O:28])[N:13]3[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:29])[CH:10]=2)[CH:3]=1
Reactant: Cc1cc(Nc2cc(N)ncn2)c(=O)n2c1C(=O)N(Cc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: Cc1cc(Nc2cc(N)ncn2)c(=O)n2c1C(=O)NCCC2
Temperature: 150 °C

Procedure:
A vial was charged with 8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione (9, 0.3 g, 76.9 mmol) and triflic acid (7.0 mL) was added. The reaction mixture was heated under microwave at 150° C. for 20 min. TLC showed completion of the reaction and the mixture was cooled to ambient temperature. This was then basified with aqueous sodium bicarbonate solution and extracted with 5% methanol/dichloromethane (3×200 mL). The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to afford 8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione (Cpd. No. 217) as a brown solid. Yield: 0.06 g, 26%; MS (ESI) m/z 301.15 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.36-8.20 (m, 2H), 8.15 (s, 1H), 6.52 (brs, 2H), 6.13 (s, 1H), 5.05 (brs, 1H), 3.26-3.04 (m, 2H), 2.95-2.80 (m, 1H), 2.13 (s, 3H), 1.87 (brs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-])=O)[C:3]=1[Cl:17].O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:14][C:4]1[C:3]([Cl:17])=[C:2]([Br:1])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2
Reactant: O=c1[nH]c2cc(Br)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)c(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A suspension of 7-bromo-6-chloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (50 mg, 0.16 mmol) and tin (II) chloride dihydrate (176 mg, 0.780 mmol, Aldrich, used as received) in ethanol (5 mL) was refluxed for 7 h. It was then cooled to r.t. and poured into ice (10 g). The suspension was then basified with 10% aq. NaHCO3 (25 mL) to pH 8-8.5 (pH paper) and extracted with ethyl acetate (50 mL). The ethyl acetate extract was washed with water and brine, dried over Na2SO4 and evaporated to give a solid which was dried under high vacuum to furnish 28 mg (62%) of pure title compound as a brown powder, m.p.>350° C.; 1H NMR (DMSO-d6) δ5.888 (br s, 2H), 6.075 (s, 1H), 11.286 (s, 1H), 11.827 (s, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:5].[CH3:17][Mg]I.C(OCC)C>C1COCC1.C(=O)=O>[N:14]1[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH3:17])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Mg]I
Reactant: CON(C)C(=O)c1cccc2cccnc12
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cccc2cccnc12
Temperature: -78 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Quinoline-8-carboxylic acid methoxy-methyl-amide (2.16 g, 10 mmol) was dissolved in anhydrous THF (40 mL) and cooled to −78° C. The 3 M methyl magnesium iodide solution in diethyl ether (4.0 mL, 12 mmol, Aldrich) was slowly added to the reaction solution in dry ice bath. The reaction mixture was allowed to stir under nitrogen at room temperature for overnight then the reaction was cooled at ice bath and quenched with saturated aqueous ammonium chloride (40 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated via vacuo to give crude title compound as light yellow solid in 83% yield (1.42 g, 8.3 mmol).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[N:26]=[CH:25]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[N:26]=[CH:25]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)OCc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](OCc1ccccc1)[C@@H](CCc1cccc2ccccc12)n1cnc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of methyl 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)- 3-pentyl]imidazole-4-carboxylate (obtained in Example 3(20))(97 mg) and sodium hydroxide (12 mg) in ethanol (2 ml) and water (0.2 ml) was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in a mixture of ethyl acetate and water. The aqueous layer was separated, acidified to pH 3 with hydrochloric acid, and extracted with ethyl acetate. The extract was dried and evaporated to give a pale brown powder of 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxylic acid (84.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12](Br)[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].O.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: COC(Cn1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(Cn1cc(-c2ccccc2)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (70 mg) obtained in Example 161, Step 2 in dimethoxyethane (1.4 ml)-water (0.7 ml) were successively added phenylboronic acid (32 mg), tetrakis(triphenylphosphine)palladium(0) (31 mg) and sodium carbonate (42 mg), and the mixture was stirred at 80° C. for 2 hr. After cooling to room temperature, the mixture was purified by silica gel column chromatography (ethyl acetate:hexane=1:3–1:1) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-phenyl-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (56 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH:15]([OH:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:14]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20])[O:25][CH2:10][C:9]1=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CN(Cc1ccccc1)C(=O)CCl)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1OCC(=O)N(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of N-benzyl-N-[(2RS,3RS)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,4-dichlorophenyl)-3-hydroxybutyl]-2-chloroacetamide (44.7 g) in THF (450 ml) was added sodium methoxide (5.46 g) at 0° C. The mixture was stirred at room temperature for 2 hr, water was added, and methanol was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (10%-50%)) to give the title compound (40.6 g) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>CN(C)C=O>[CH2:24]([O:23][C:21]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a suspension of 1-(4-hydroxyphenyl)piperazine (50 g) and potassium carbonate (46.5 g) in N,N-dimethylformamide (100 ml) was added dropwise benzyl chloroformate (47.86 g) at 0 to 10° C., and stirred for 4 hours at ambient temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (30:1) to give 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid benzyl ester (60.8 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[C:28]([Cl:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][N:24]=1>>[Cl:29][C:28]1[C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[N:24][CH:25]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:27]=1
Reactant: FC(F)(F)c1cnc(Br)c(Cl)c1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2ncc(C(F)(F)F)cc2Cl)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-3-chloro-5-trifluoromethyl-pyridine.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:16]=[C:15]4[CH:34]=O)[C:9]([CH3:36])=[C:8]([F:37])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=3)[CH:16]=[C:15]4[CH2:34][N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[C:9]([CH3:36])=[C:8]([F:37])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(C=O)c2c1
Reactant: CN1CCNCC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(CN3CCN(C)CC3)c2c1

Procedure:
The title compound was prepared by the method of Example 59 step iv) using product of example 112 step i) and 1-methyl-piperazine.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:50]=[CH:51][C:52]5[C:53](=[N:63][N:64]([CH2:66][CH3:67])[CH:65]=5)[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:50]=[CH:51][C:52]5[C:53](=[N:63][N:64]([CH2:66][CH3:67])[CH:65]=5)[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CCn1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCn1cc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(2-ethyl-6-oxo-8-phenyl-2,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.5 mL), water (3.5 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (30.3 mg, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.53 (br s, 3H), 7.74 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.49-7.38 (m, 7H), 7.32 (d, J=8.1 Hz, 2H), 4.58 (q, J=7.3 Hz, 2H), 2.62-2.49 (m, 4H), 2.23-2.13 (m, 1H), 1.86-1.75 (m, 1H), 1.55 (t, J=7.3 Hz, 3H). LCMS (Method E): RT=3.36 min, [M+H]+=436.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH2:27][CH2:26][C:25]([C:35](O)=[O:36])=[CH:24][C:23]=3[CH:38]=2)=[CH:15][CH:14]=1)[CH2:7][CH3:8].S(Cl)(Cl)=O>O1CCCC1>[CH3:3][N:2]([CH2:4][C:19]1[CH:20]=[CH:21][C:22]([NH:28][C:35]([C:25]2[CH2:26][CH2:27][N:28]([CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:22]3[CH:21]=[CH:20][C:19]([C:16]4[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][O:9][CH2:6][CH2:7][CH3:8])=[CH:14][CH:15]=4)=[CH:38][C:23]=3[CH:24]=2)=[O:36])=[CH:23][CH:38]=1)[CH:1]1[CH2:7][CH2:6][O:9][CH2:10][CH2:11]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccs2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccs2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-propoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (240 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (184 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (137 mg) and triethylamine (629 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 59) (152 mg) as yellow crystals.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[S:24]1[CH:28]=[CH:27][C:26]([C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]3[N:6]([CH:8]=[N:9][N:10]=3)[CH:7]=2)=[CH:25]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cn3cnnc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccsc3)cn3cnnc23)CC1
Yield: 99.5 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(6-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (1.0 g, 2.6 mmol), thiophen-3-ylboronic acid (0.50 g, 3.9 mmol), Pd(PPh3)4 (0.30 g, 0.26 mmol), Cs2CO3 (1.27 g, 3.9 mmol), 1,4-dioxane (25 mL) and water (25 mL). The resulting mixture was refluxed under N2 overnight. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). Work-up: the reaction mixture was extracted with EtOAc (50 mL). The organic solution was washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 1.0 g (99%) of the product as a yellow solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[C:24]1([O:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Product: O=C1Nc2ccccc2C1=CNc1ccc(S(=O)(=O)Oc2ccccc2)cc1
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from 3-hydroxymethylene-1,3-dihydro-indol-2-one and phenyl 4-aminobenzenesulfonate according to
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].Br[CH2:25][C:26]([NH2:28])=[O:27].[OH-].[Na+]>C(#N)C.O.C(=O)([O-])[O-].[Ca+2]>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:1][CH2:25][C:26]([NH2:28])=[O:27])=[C:3]([S:21]([CH3:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1NCC(N)=O
Temperature: 25 °C
Yield: 15.5 %

Procedure:
To a solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (0.5 g) in acetonitrile was added 2-bromoacetamide (0.18 g) in water and calcium carbonate (0.13 g). The mixture was heated under reflux for 1.5 hours, cooled to 25° C. and a solution of sodium hydroxide (0.05 g) in water added. This was then heated under reflux for one hour, evaporated and the residue purified by preparative thin-layer chromatography eluting first with 20% methanol in dichloromethane to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-5-[(aminocarbonylmethyl)amino]-1H-pyrazole-3-carbonitrile (0.089 g), m.p.155-157° C.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3]>C(OCC)(=O)C.[Pt]=O>[CH:8]1[CH:9]=[CH:10][C:11]2[O:1][C:2](=[O:3])[CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: O=c1ccc2ccccc2o1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2O1

Procedure:
Coumarin (30 g, 0.205 moles) is reduced on the Parr apparatus in 200 ml ethyl acetate with 1 g platinum oxide at 40 psi. When the uptake ceased (ca. 1 hr.) the catalyst is removed by filtration and the filtrate evaporated to give a quantitate yield of dihydrocoumarin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=O)O[CH:14]=2)=[CH:5][CH:4]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:18])[CH:11]=[C:12]3[C:15](=[O:17])[NH:24][CH2:21][CH2:22][N:23]3[CH:14]=2)=[CH:19][CH:20]=1
Reactant: NCCN
Reactant: COc1ccc(COc2coc(C(=O)O)cc2=O)cc1
Solvent: O
Product: COc1ccc(COc2cn3c(cc2=O)C(=O)NCC3)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
The mixture of 5-((4-methoxybenzyl)oxy)-4-oxo-4H-pyran-2-carboxylic acid (Example 2b) (5.24 g, 18.21 mmol), ethane-1,2-diamine (1.830 mL, 27.3 mmol) in water (80 mL) was stirred at 60° C. for 1 h and then 80° C. for 20 h. Yellow solid precipitated from the reaction when heating. After cooling, white precipitate was filtered off, washed with 20 mL of cold water/acetone (v:v=1:1) and dried to give 7-((4-methoxybenzyl)oxy)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione (4.15 g, 13.82 mmol, 76% yield) as white solid, which was used in the next step without further purification. LCMS (M+H)+: 301.2
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@:10]3([O:28][C@H:11]3[CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:27])[CH2:9]1>C1COCC1>[CH3:19][C@:18]12[CH2:20][CH2:21][C@H:22]3[C@@H:13]([CH2:12][CH2:11][C@:10]4([OH:28])[C@:23]3([CH3:26])[CH2:24][CH2:25][C@H:8]([OH:7])[CH2:9]4)[C@@H:14]1[CH2:15][CH2:16][C@@H:17]2[OH:27]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1CC[C@@H]2O
Yield: 74 %

Procedure:
To a stirred suspension of LiAlH4 (0.247 mg) in THF under N2 (10.5 mL), a solution of 3β-hydroxy-5α,6α-epoxyandrostane-17-one (0.64 g) in THF (20 mL) was added dropwise and the mixture was stirred at reflux for 8 h. The suspension was cooled with an ice bath and then quenched by careful addition of H2O (1 mL) and 4N NaOH (0.20 mL). The mixture was filtered through a Celite pad and the filter cake was washed with THF (3×10 mL). The filtrate was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 40/30/30) to give androstane-3β,5α,17β-triol (0.48 g, 74%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.37 (1H, d), 4.19 (1H, d), 3.78 (1H, m), 3.62 (1H, s), 3.39 (1H, m), 1.87-0.80 (21H, m), 0.86 (3H, s), 0.59 (3H, s).