Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[N:14]O)=[CH:6][CH:5]=1)([O-])=O>CO>[CH:11]1([NH2:14])[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(=NO)CCC2
Solvent: CO
Product: Nc1ccc2c(c1)C(N)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
7-Nitro-3,4-dihydro-2H-naphthalen-1-one oxime (274 mg, 1.33 mmol) was dissolved in methanol (10 mL) and the flask was flushed with N2 (g). 10% Pd—C (50 mg) was added and the reaction was stirred under H2 (1 atm) at room temperature overnight. The reaction was filtered and the filtrate was concentrated to yield 1,2,3,4-tetrahydro-naphthalene-1,7-diamine (207 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 6.61-6.57 (m, 2H), 6.28 (dd, J=8.0, 2.4 Hz, 1H), 4.62 (s, 2H), 3.58 (m, 1H), 2.48-2.44 (m, 2H), 1.78-1.70 (m, 2H), 1.53-1.37 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:12]([O:13][C:14](=[O:16])[CH3:15])[CH:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2([CH2:22]I)[CH2:21][CH:6]1[NH:7][C:8](=[O:24])[O:9]2)(=[O:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:12]([O:13][C:14](=[O:16])[CH3:15])[CH:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2([CH2:22][N:25]=[N+:26]=[N-:27])[CH2:21][CH:6]1[NH:7][C:8](=[O:24])[O:9]2)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC1C2CC(CI)(OC(=O)N2)C(OC(C)=O)C1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC1C2CC(CN=[N+]=[N-])(OC(=O)N2)C(OC(C)=O)C1OC(C)=O

Procedure:
6,7,8-Triacetoxy-1-iodomethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (as described in Example 2 of the Japanese Patent Application No. 144309/1981, pp. 39) (4.5 g) is dissolved in dimethylformamide (15 ml), and sodium azide (1.0 g) is added to the solution, followed by stirring under heating on a bath of the temperature of 130° to 140° C. for 2 hours. The reaction mixture is treated in the same manner as described under (a) of Reference Example mentioned above to produce crystalline 6,7,8-triacetoxy-1-azidomethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (3.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23].[H-].[Na+].Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 13.1 %

Procedure:
To a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.56 mmol) in DMF (4 mL), sodium hydride (60% dispersion in mineral oil, 34 mg, 0.84 mmol) was added. After 25 min, β-bromophenetole (0.15 mL, 1.1 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (17:3) and triturating with hexanes gave 35 mg (13%) of a white solid: mp 175.0-176.0° C.; 1H NMR (400 MHz, DMSO) δ 7.53 (d, J=8.8 Hz, 1H), 7.24 (m, 3H), 6.90 (t, J=7.6 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.81 (d, J=7.9 Hz, 2H), 4.60 (m, 2H), 4.17 (m, 2H), 3.67 (m, 2H), 3.61 (m, 2H), 3.14 (t, J=5.3 Hz, 2H), 1.41 (s, 9H); IR (diffuse reflectance) 2967, 2931, 1676, 1493, 1448, 1422, 1406, 1363, 1298, 1245, 1221, 1167, 1118, 754, 690 cm−1; MS (EI) m/z 474 (M+), 333, 95, 92, 79, 78, 76, 67, 64, 57, 55; HRMS (FAB) calcd for C25H28Cl2N2O3+H 475.1555, found 475.1559; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.47; H, 6.11; N, 5.84.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCOC(=O)c1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCOC(=O)c1ccccc1

Procedure:
To a solution of benzyl 6-benzoyloxy-hexanoate (c) (38.09 g) in ethyl acetate was added 5% Pd/C (3 g) and the resultant mixture was stirred under a hydrogen atmosphere for 24 hours. The crude product obtained by treating in the conventional manner was distilled under reduced pressure (1 mmHg, 182°-192° C.) to give the title compound (d).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH3:11][O:10][C:9]1[CH:8]=[C:5]([CH2:6][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]([O:12][CH3:13])=[CH:3][C:2]=1[OH:1]
Reactant: COc1cc(C=O)c(OC)cc1O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(CN2CCCC2)c(OC)cc1O
Yield: 57.5 %

Procedure:
Intermediate 58, 4-Hydroxy-2,5-dimethoxybenzaldehyde (1.2 g, 6.6 mmol) was added in portions for 30 min to a mixture of pyrrolidine (0.7 mL, 8.2 mmol) and NaB(OAc)3H (1.75 g, 8.2 mmol) in CH2Cl2 (20 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (30 mL) and a 5 N solution of NaHSO4 were added to pH 1. The organic layer was separated and discarded. The aqueous one was alkalized with a saturated solution of K2CO3 to pH 6 and subjected to extraction with chloroform (2×50 mL). The combined extracts were dried with Na2SO4 and evaporated to give the title compound (0.9 g, 58%) as a yellow oil. LCMS data: 238.1 (M+H)+ and 168.0, 167.0 (M-pyrrolidine+H) (calculated for C15H23NO 237.3). 1H NMR data (DMSO-d6): 8.88 (br. s, 1H ArOH), 6.84 (s, 1H, Ar—H), 6.45 (s, 1H, Ar—H); 3.69 (s, 3H, —OCH3), 3.659 (s, 3H, —OCH3), 3.47 (s, 2H, —CH2—), 2.37-2.49 (m, 4H, pyrrolidine (CH2)2N), 1.60-1.73 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([C:17]([O:19]CC)=[O:18])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4].[OH-].[Li+].Cl>O1CCCC1.O>[OH:1][C@H:2]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4]
Reactant: CCOC(=O)c1cccc2c(CCN[C@@H](C)[C@H](O)c3ccc(O)cc3)c[nH]c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NCCc1c[nH]c2c(C(=O)O)cccc12)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a solution of ethyl 3-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-(methyl) ethylamino]ethyl}-1H-indole-7-carboxylate (115 mg, 0.301 mmol) in tetrahydrofuran (10 mL) and water (5 mL) is added lithium hydroxide (36 mg, 1.51 mmol), and the mixture is stirred at room temperature for 15 hours. The pH value of the reaction solution is adjusted to pH 7 with 1N aqueous hydrochloric acid solution, and the solvent is distilled off. The residue is isolated by reversed phase column (octadecylsilyl, water→water-methanol=10:1→9:1→6:1) to give 3-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-(methyl)ethyl-amino]ethyl}-1H-indole-7-carboxylic acid (69.3 mg, 0.195 mmol, 65%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.Cl.[CH2:21]([NH:23][CH2:24]/[CH:25]=[CH:26]/[C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][C:29]([CH3:31])([CH3:32])[C:28]#[C:27]/[CH:26]=[CH:25]/[CH2:24][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:4]=1)[CH2:21][CH3:22]
Reactant: CCNC/C=C/C#CC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
6.0 g of N-(3-bromomethylphenyl)phthalimide [synthesized by brominating N-(m-tolyl)phthalimide with N-bromosuccinimide in carbon tetrachloride] was dissolved in 100 ml of dimethylformamide, and 3.82 g of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 7.87 g of potassium carbonate were added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate-water and the organic layer was separated, and the solvent was evaporated, and then the residue was washed with a small amount of ethyl ether to give 5.5 g (yield 72%) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-phthalimidobenzylamine, m.p. 96°-98 ° C.
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[C:54]1([CH2:60][S:61]([NH2:64])(=[O:63])=[O:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.CCCC(C)C>C(Cl)Cl.CCOC(C)=O.O>[CH2:60]([S:61]([NH:64][C:30](=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:20]1[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:33])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22][CH2:21]1)(=[O:63])=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CCC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCC(C)C
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)NS(=O)(=O)Cc2ccccc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising 7-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid [prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Example 4.3] (100 mg, 0.225 mmol) in dry DCM (5 ml) at RT, under nitrogen, was treated with DMF (1.746 μl, 0.023 mmol) followed by oxalyl chloride (0.022 ml, 0.248 mmol). After stirring at RT for 2 hours, DIPEA (0.157 ml, 0.902 mmol) was added followed by phenylmethane sulfonamide (154 mg, 0.902 mmol). The resulting mixture was stirred at RT for 2 hours and subsequently added to water (30 ml). The mixture was extracted with DCM (×3) and the combined organic extracts were passed through a phase separating column. The organic solvent was removed under reduced pressure and purification of the crude residue by chromatography on silica eluting with 0-40% EtOAc in iso-hexane afforded an orange solid. The solid was dissolved in a minimal volume of EtOAc and treated with an excess of iso-hexane. The resulting suspension was filtered and the solid rinsed with iso-hexane (×3) the afford the titled compound;
Reaction SMILES: [NH2:1][C:2](=[N:37][N+]([O-])=O)[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Pd].C(O)(=O)C>[C:17]1([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]([NH:8][C@@H:7]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=2)=[O:25])[CH2:6][CH2:5][CH2:4][NH:3][C:2](=[NH:1])[NH2:37])=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(CCO)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(CCO)cc1

Procedure:
Prepared analogously to Example 1c) from (R)-N5 -[Amino(nitroimino)methyl]-N2 -(diphenylacetyl)-N-[[4-(2-hydroxyethyl)-phenyl]methyl]-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid.
Reaction SMILES: [C:1]([O:5][PH:6]([CH2:8][CH:9]([CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[C:27]([CH3:29])=[CH2:28].[H-].[Na+].O>C1COCC1.CCOCC>[CH2:32]([O:31][C:26]([CH:27]([CH3:29])[CH2:28][P:6]([CH2:8][CH:9]([CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(CP(=O)(CC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a solution of di-tert-butyl 2-[(tert-butoxyphosphinyl)methyl]pentane-1,5-dioate (13.62 g, 36.0 mmol) and benzyl methacrylate (6.35 g, 36.0 mmol) in THF (100 mL) under nitrogen was added sodium hydride (0.14 g, 60% dispersion in oil, 3.60 mmol). After three hours, the reaction mixture was poured into water (300 mL) and ether (100 mL) was added. The organic layer was separated and retained, and the aqueous layer was washed again with ether (100 mL). The combined organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the product was eluted with 2:3 EtOAc/Hexane. The solvent was removed under reduced pressure leaving a clear oil (10.5 g, 53%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([Cl:12])=[N:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[N+]=[N-]>[Pt]>[Cl:12][C:6]1[C:5]([CH2:4][NH2:1])=[CH:10][C:9]([F:11])=[CH:8][N:7]=1
Reactant: [N-]=[N+]=NCc1cc(F)cnc1Cl
Agent: [Pt]
Product: NCc1cc(F)cnc1Cl

Procedure:
The product of Example 127A was processed according to the method of Example 115B except that Pt/C was used instead of Pd/C as catalyst. MS (ESI+) m/z 161 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:11][CH3:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:13]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:11][CH3:12])[C:8]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: CCC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CCC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 122 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.89–7.74 (br, 1H), 7.48–7.05 (m, 13H), 6.89–6.74 (d, 1H, J=7.2 Hz), 6.46–6.25 (br, 1H), 3.30–3.15 (m, 2H), 3.15–3.01 (m, 2H), 2.38–2.25 (m, 3H), 2.25–2.09 (m, 2H), 1.99–1.78 (m, 3H), 1.78–1.60 (m, 5H), 1.60–1.47 (m, 1H), 1.12–1.01 (m, 2H), 0.90–0.71 (m, 2H), 0.75 (t, 3H, J=7.2 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.BrC1C=NC2C(C=1)=CC=CC=2N1CCN(C)CC1.O.O.[Na+].[C:40]1([S:46]([O-:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.[Cu]I.CO.ClCCl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[N:4]=[CH:3][C:2]([S:46]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:48])=[O:47])=[CH:11]3)[CH2:13][CH2:14]1
Reactant: O=S([O-])c1ccccc1
Reactant: CN1CCN(c2cccc3cc(I)cnc23)CC1
Agent: [Cu]I
Agent: CN1CCN(c2cccc3cc(Br)cnc23)CC1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(c2cccc3cc(S(=O)(=O)c4ccccc4)cnc23)CC1
Temperature: 120 °C
Reaction time: 40 h
Yield: 7 %

Procedure:
A 4:1 mixture of 3-iodo-8-(4-methyl-piperazin-1-yl)-quinoline (D2) and 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1) (1.5 g), phenylsulfinic acid sodium salt dihydrate (2.52 g, 12.6 mmol) and copper (I) iodide (2.4 g, 12.6 mmol) in N,N-dimethylformamide (25 ml) was stirred in an oil bath at 120° C. for 40 h under argon. To the reaction mixture, cooled to ambient temperature, was added 5% sodium hydrogen carbonate solution (100 ml) and dichloromethane (100 ml) with vigorous shaking. The insoluble material was filtered, washed with dichloromethane (3×20 ml) and discarded. The filtrate and washings were transferred to a separating funnel and the layers separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic extracts were washed with water (100 ml), dried (MgSO4) and concentrated in vacuo to an oil (0.9 g). The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford an orange oil (0.28 g, Rf 0.11, methanol/dichloromethane 1:19). This material was further purified by passage through a strong cation exchange (SCX) column eluting firstly with methanol (fractions discarded) and then with methanol/aqueous ammonia-880 (10:1) to give the title compound (D9) as an orange oil (0.152 g, 0.41 mmol, 7% over two steps);
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[O:22]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:27])[N:21]1[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: [K]
Solvent: CN(C)C=O
Product: CN1CC(CCN2C(=O)c3ccccc3C2=O)Oc2ncccc2C1=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 4.92 g (0.02 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)one in 35 ml of dimethylformamide was added 7.55 g (0.041 mole) of potassium phthalimide. The mixture was stirred for 5 hr at 100° C. and left standing at room temperature overnight. Dimethylformamide was removed by rotary evaporation (80° C. vacuum pump). The residue was taken up in 100 ml of chloroform and washed with water (2×30 ml) and 2M potassium hydroxide (2×3 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70° C., water aspirator). The 6.26 g of crude product was recrystallized from isopropyl alcohol to give 2.60 g (36%) white cyrstalline powder, m.p. 146°-47° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.C(O)C.O.[NH2:27]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:15]=[C:16]([C:19]([F:22])([F:20])[F:21])[CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:27]
Reactant: NN
Reactant: NC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 9.1 parts of 2-amino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine, 150 parts by volume of ethanol and 3.6 parts by volume of glacial acetic acid is added 4.5 parts by volume of 100% hydrazine hydrate. The whole mixture is stirred for 30 minutes at room temperature and treated in a similar manner to Example 1, whereby 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine is yielded as a crystalline powder. Melting point: 127° C (sintering), 133° C to 135° C (effervescence).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]1)[C:5](=[O:24])[N:6]2C(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]1)[C:5](=[O:24])[NH:6]2
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Temperature: 75 °C
Yield: 48 %

Procedure:
A mixture of 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one (5.38 g, 9.96 mmol), triethylsilane (7.93 mL, 49.8 mmol) and trifluoroacetic acid (25.9 mL, 348 mmol) was heated at 75° C. for 8 h. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo. The residue was triturated in diethyl ether, purified by column chromatography and eluted with a 0% to 25% gradient of ethyl acetate in dichloromethane to afford 4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.79 g, 48%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.53 (s, 1H), 5.98 (s, 1H), 5.63 (ABq, 2H), 4.20-4.12 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 148.7, 145.1, 144.3, 139.1, 133.0, 128.7, 126.8, 120.0, 112.6, 112.2, 110.2, 105.4, 87.7, 77.6, 64.7, 64.3; MS (ES+) m/z 359.6 (M+1), 361.6 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:63]=[C:62]4[C:58]([CH:59]=[N:60][NH:61]4)=[C:57]([NH:64][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=4[O:11][CH3:12])[CH:56]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: COc1c(C)cccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(C)cccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
DMF (1 ml) was added to 3-methyl-2-(methyloxy)benzoic acid (134 mg, 0.81 mmol) (Apin Chemicals), HATU (306 mg, 0.81 mmol) and DIPEA (0.422 ml, 2.417 mmol). The reaction was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (100 mg, 0.403 mmol). The reaction was stirred under nitrogen at RT overnight, then it was loaded onto a PS-aminopropyl cartridge and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH:DMSO (2 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. The solvent was dried under a stream of nitrogen to give title compound (6 mg).