Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20].N1C=C[CH:25]=[CH:24][CH:23]=1.ClC1C=CC=CC=1Cl.S(Cl)(Cl)=O>CO>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][C:3]=1[C:19]([O:21][CH:24]([CH3:25])[CH3:23])=[O:20]
Reactant: c1ccncc1
Reactant: Nc1c(C(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CC(C)OC(=O)c1cc(Br)c2c(c1N)C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
While a solution of 100 parts of 1-amino-4-bromoanthraquinone-2-carboxylic acid, 1.6 parts of pyridine and 500 parts of orthodichlorobenzene was stirred at room temperature, 87 parts of thionyl chloride was added thereto dropwise over about 30 minutes. After the completion of the addition, the solution was heated at 100° C. for 2 hours. Afterward, excess thionyl chloride was distilled off under reduced pressure, and 88 parts of isopropyl alcohol was added dropwise to the solution at about 80° C. Reaction was performed at the same temperature as above for 2 hours, and the solution was then cooled to room temperature. Afterward, the solution was introduced into 1,000 parts of methanol, followed by stirring for 30 minutes. The resulting precipitate was collected by filtration, washed with methanol and dried, thereby obtaining 90 parts of isopropyl 1-amino-4-bromoanthraquinone-2-carboxylate. To the thus obtained product were added 34 parts of potassium acetate, 3 parts of copper sulfate, 6 parts of benzyl alcohol, 59 parts of m-toludine and 206 parts of dipropylene glycol, and the solution was then heated up to 135° C. in a nitrogen atmosphere and reaction was carried out for 2.5 hours. Afterward, the solution was cooled to 50° C. and was then introduced into 2,000 parts of methanol, followed by enough stirring for 30 minutes. The resulting precipitate was then collected by filtration, introduced into 2,000 parts of methanol again, stirred, filtered, and dried, so that 89 parts of isopropyl 1-amino-4-m-toluidinoanthraquinone-2-carboxylate (melting point 133°-134° C.) was obtained.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([C:12]#[N:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]#[N:13])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CCc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC[O-]
Agent: [Na+]
Product: N#CC(=C1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a solution sodium ethoxide (prepared by slow addition of 22 g, 0.96 mol Na to dry 800 mL ethanol) was added benzyl cyanide (113 g, 1.05 mol) and N-benzyl-4-piperidone (90 g, 0.48 mol) at room temperature. The reaction mixture was stirred at 85° C. for 3 h and the solvent was evaporated. The residue was poured into a mixture of ice (1 kg) and concentrated hydrochloric acid (200 mL). The pH was then adjusted to 9 addition of solid sodium hydroxide and the mixture was extracted three times with ethyl acetate (500 mL each). Organic phases were pooled and dried with MgSO4. The solvent was evaporated and chromatography on silica gel (hexane, ethyl acetate, triethyl amine 80:20:1) gave (1-benzyl-piperidin-4-ylidene)-phenyl-acetonitrile as yellow crystalls (135 g, 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH2:26])[CH2:23][CH2:22]2.[NH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:36]=O)[C:30]=2[CH:29]=[CH:28]1>>[NH:27]1[C:35]2[C:30](=[C:31]([CH2:36][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:26][CH:24]5[C:25]6[C:21](=[CH:20][CH:19]=[CH:18][C:17]=6[O:16][CH3:15])[CH2:22][CH2:23]5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: COc1cccc2c1C(N)CC2
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1cccc2c1C(Nc1ccc3c(NCc4cccc5[nH]ccc45)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=435.4 (M+H+), was prepared in accordance with the general method of example 43 from 5-nitro-2-chloroquinoline, rac-7-methoxy-indane-1-ylamine and indole-4-carbaldehyde.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3]1>CO>[CH2:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCOC2)CC1
Agent: Cl
Solvent: CO
Product: C1CC2(CCN1)CCOC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
Methanolic hydrogen chloride (3M, 3 mL) was added to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 85, 150 mg, 0.62 mmol) in methanol and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol and passed through Amberlyst 26 ion exchange resin, eluting with methanol. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (77 mg, 88%). m/z (ES+) 142 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[BH4-].[Na+]>O1CCCC1>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(CO)cs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared in Example 1(B)(f), 200 mg, 0.45 mmol) in tetrahydrofuran (3 mL) at 25° C. was slowly treated with sodium borohydride (26.0 mg, 0.68 mmol). The reaction mixture was heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then slowly quenched by the dropwise addition of water. The resulting reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide (44.9 mg, 25%) as a white solid: mp 88-90° C.; EI-HRMS m/e calcd for C18H20Cl2N2O2S (M+) 398.0623, found 398.0631.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:10]([NH:12][NH:13][C:14]([C:16]1[O:17][CH:18]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[O:11].C(N(CC)CC)C.O1CCOCC1>C(OCC)(=O)C>[CH3:37][O:36][C:35]1[CH:34]=[CH:33][C:9]([C:10]([NH:12][NH:13][C:14]([C:16]2[O:17][CH:18]=[C:19]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[O:11])=[CH:8][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylsulfonyl chloride (0.28 ml) was added to a mixture of the compound of Example 41 (0.85 g), triethylamine (0.41 ml) and dioxane (30 ml) at 0° C., allowed to be warmed to 25° C. and stirred overnight. The reaction solution was diluted with ethyl acetate, washed with water and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform), thereby giving 0.95 g of the desired compound. Melting point: 180-182° C. (Recrystallized from ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](Cl)=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=C([C@@H](CC2CCCC2)C(NC2C=CN(CC3C=[C:60]([CH:64]=[CH:65]C=3)[C:61]([NH2:63])=O)N=2)=O)C=CC=1S(C)(=O)=O.NCC1CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:63][CH2:61][CH:60]3[CH2:64][CH2:65]3)=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(N)=O)c3)n2)cc1Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)Cl)c3)n2)cc1Cl
Agent: NCC1CC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)NCC4CC4)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a 0.166 M solution of crude 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoyl chloride in methylene chloride (prepared in example 63, 1.71 mL, 0.28 mmol) was added aminomethyl cyclopropane (20 mg, 0.28 mmol) and the reaction stirred at 25° C. for 30 min. The solution was diluted with methylene chloride (40 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to an off white foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-cyclopropylmethyl-benzamide (60 mg, 36%) as a white powder: ESI-LRMS m/e calcd for C30H35ClN4O4S [M+] 582.21, found 583.33 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.17-0.27 (m, 2H, CH2), 0.39-0.046 (m, 2H, CH2), 0.98-1.17 (m, 3H, CH and CH2), 1.37-1.78 (m, 8H, 4×CH2), 2.02-2.17 (m, 1H, CH), 3.12 (t, J=6.0 Hz, 2H, NCH2), 3.32 (s, 3H, SO2CH3), 3.83-3.91 (m, 1H, CH), 5.22 (s, 2H, NCH2), 6.46 (d, J=2.0 Hz, 1H, Ar), 7.28-7.36 (m, 1H, Ar), 7.39 (t, J=8.0 Hz, 1H, Ar), 7.56 (d, Jo=7.8 Hz, 1H, Ar), 7.65 (d, Jm=1.2 Hz, 1H, Ar), 7.69-7.80 (m, 3H, Ar), 7.97 (d, Jo=8.2 Hz, 1H, Ar), 8.51 (m, 1H, NH), 10.77 (s, 1H, NH).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[NH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[N+:20]([C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:18]=[CH:19][C:2]=1[NH:30][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([C:24]#[N:23])=[CH:26][CH:27]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Reactant: N#Cc1ccc(CN)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 100.4 %

Procedure:
To a mixture of 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (2.0 g, 6.7 mmol) and 4-(aminomethyl)benzonitrile (1.1 g, 8.3 mmol) in DMA (20 mL) was added DIPEA (3.5 mL, 20 mmol) and heated to 100° C. for 16 h. The mixture was cooled and poured into water (400 mL). The resulting solids were collected by filtration to provide 2.76 g of the title compound. The material was used without further purification. MS (ESI): mass calcd. for C24H18N4O3, 410.43; m/z found 411.1 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.O.C([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:14]1([CH2:1][CH:2]2[C:7](=[O:8])[CH:6]3[CH2:9][CH2:10][N:3]2[CH2:4][CH2:5]3)[C:15]2[C:16](=[CH:1][CH:2]=[CH:7][CH:6]=2)[CH2:18][CH2:17]1
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: CCN(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: O=C1C2CCN(CC2)C1CN1CCc2ccccc21
Temperature: 80 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 2-methylene-3-quinuclidinone (0.5 g, 0.0028 mol) in water (6 ml) indoline (0.66 g, 0.0057 mol), triethylamine (0.84 g, 0.0084 mol) and tetra-n-butyl ammonium bromide (90 mg, 0.00028 mol) were added and the reaction mixture were allowed to stir at 80° C. for 18-20 h. The reaction mixture was quenched with ice-cold water (20 ml), extracted with dichloromethane (3×50 ml), the organic layers were washed with brine and dried over sodium sulphate, filtered and concentrated to get the crude product which was purified as greenish yellow solids (125 mg, 17%) by column chromatography on neutral silica gel using chloroform as eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([OH:24])=O)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)CC)C>CN(C=O)C.O>[C:18]([O:17][C:15]([NH:14][CH:13]([C:22]([NH:26][CH3:25])=[O:24])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alanine (10.0 g, 30.0 mmol) in DMF (100 mL) was added HATU (14.0 g, 36.0 mmol). After 2 hours, methylamine (4.1 g, 60 mmol) and triethylamine (15.0 g, 149 mol) were added. After 16 hours, the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give benzyl {2-[(tert-butoxycarbonyl)amino]-3-(methylamino)-3-oxopropyl}carbamate. MS ESI calc'd. for C17H26N3O5 [M+H]+ 352. found 352. 1H NMR (300 MHz, CDCl3) δ 7.33-7.31 (m, 5H), 6.59-6.57 (m, 1H), 5.69-5.66 (m, 1H), 5.42-5.39 (m, 1H), 5.14-5.05 (m, 2H), 4.19-4.16 (m, 1H), 3.63-3.41 (m, 2H), 2.78 (d, J=4.8 Hz, 3H), 1.43 (s, 9H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([CH2:21][C:22]#[N:23])([C:19]#N)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-:24].[Na+]>C(O)(=O)C>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]2([C:19](=[O:24])[NH:23][C:22](=[O:2])[CH2:21]2)[CH2:17][CH2:18]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: N#CCC1(C#N)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Acetic acid (56.8 ml) and sulfuric acid (11.8 ml) are added to 1-benzyl-4-cyanomethyl-piperidine-4-carbonitrile (27.2 g, 0.114 mmol) at ambient temperature. The reaction mixture is stirred at 125 C.° for 1 h, cooled down to the room temperature and added to saturated NaOH aq. to adjust to pH 6.0. The mixture is extracted with dichloromethane. The combined extracts are washed with H2O and brine, dried over sodium sulfate and evaporated down to give 8-benzyl-2,8-diaza-spiro[4.5]decane-1,3-dione (three steps yield: 81.8%).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1.[BH4-].[Na+]>CO>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1
Reactant: N#Cc1ccc(-c2ccc3c(c2)CC(CC=O)O3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2ccc3c(c2)CC(CCO)O3)cc1
Yield: 95.2 %

Procedure:
A solution of Example 67B (0.25 g, 0.95 mmol) and sodium borohydride (0.054 g, 1.42 mmol)in methanol (5 mL) was stirred for 1 hour, cooled on ice and quenched with aqueous NaHCO3 (50 mL). The mixture was extracted with dichloromethane (3×100 mL), the organic extracts combined and washed with water (1×150 mL), brine (1×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound (0.24 g, 95%). 1H NMR (CDCl3): 1.90 (m, 2H), 2.90 (m, 2H), 3.46 (m, 2H), 5.40 (m, 1H), 6.85 (d, J=7 Hz, 1H), 7.38 (m, 2H), 7.65 (m, 4H); MS (DCI) 265 (M+), 283 (M+NH4+).
Reaction SMILES: [C:1]([CH2:4][C:5]#[N:6])(=O)[CH3:2].C(N([CH2:12][CH3:13])CC)C.Cl.Cl.[NH2:16][NH2:17]>C(O)C>[CH3:2][C:1]1[C:4]([C:13]2[CH:12]=[CH:5][CH:4]=[CH:1][CH:2]=2)=[C:5]([NH2:6])[NH:17][N:16]=1
Reactant: CC(=O)CC#N
Reactant: NN
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: Cc1n[nH]c(N)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 176.2 %

Procedure:
To a solution of α-acetylacetonitrile (2 g, 12.6 mmol) in ethanol was added triethylamine (1.05 mL, 7.6 mmol) and hydrazine dihydrochloride (1.6 g, 15.1 mmol). The mixture was heated to 80° C. and stirred for 2 h before cooling to rt. The volatile materials were removed in vacuo. The crude residue was purified by flash chromatography (gradient: 5% methanol in CH2Cl2 to 10% methanol in CH2Cl2) to provide 1.92 g of 3-methyl-4-phenyl-1H-pyrazol-5-amine (11.1 mmol, 88% yield). 1H NMR (400 MHz, CDCl3): δ7.40 (m, 2H), 7.34-7.32 (m, 2H), 7.27-7.23 (m, 1H), 3.71 (br s, 2H), 2.30 (s, 3H); MS (EI) for C10H11N3: 174 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3[CH2:13][S:14][CH2:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.ClC1C=CC2N(C)C(=O)C3CSCC=3NC=2C=1.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: CN1C2=C(CSC2)C(=O)Nc2cc(Cl)ccc21
Agent: CN1C(=O)C2=C(CSC2)Nc2cc(Cl)ccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: O
Product: CN1c2ccc(Cl)cc2NC(=O)c2cscc21

Procedure:
To a suspension of 0.53 g. of the mixture of 7-chloro-4-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 6-chloro-9-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one (prepared as described in Example 17) in 5 ml. of dry pyridine is added, in portions, 0.27 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15-20 minutes, cooled, diluted with water and filtered. The solid is recrystallized from methanol to give a yellow solid which consists of the single isomer of the title, m.p. 244°-246° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH2:21])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH3:21])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: C=Cc1cc(Cl)c2c(c1)CN(Cc1ccc(F)cc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CCc1cc(Cl)c2c(c1)CN(Cc1ccc(F)cc1)C2=O
Yield: 49.7 %

Procedure:
A mixture of 7-chloro-5-ethenyl-2-(4-fluoro-benzyl)-2,3-dihydro-isoindol 1-one (0.134 g, 0.45 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-chloro-5-ethyl-2-(4-fluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.068 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 2.68 (q, 2H), 4.19 (s, 2H), 4.74 (s, 2H), 6.98-7.32 (m, 6H). GC-MS: m/z 303 (M)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11].C(N)CN.ClCCC[Si](OC)(OC)OC>>[NH2:3][CH2:2][CH2:1][NH:4][CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11]
Reactant: NCCN
Reactant: CO[Si](CCCCl)(OC)OC
Product: CO[Si](CCCNCCN)(OC)OC
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A 200-ml, four necked glass flask equipped with a stirrer, reflux condenser, and thermometer was charged with 72.0 g (1.2 mol) of ethylene diamine and heated at 112° to 117° C. From a dropping funnel, 59.6 g (0.3 mol) of 3-chloropropyltrimethoxysilane was added dropwise to the flask over 2 hours (the molar ratio of ethylene diamine/3-chloropropyltrimethoxysilane=4.0). After one hour ripening, the reaction solution was transferred to a separatory funnel and cooled for allowing the solution to separate into two layers. The lower layer of ethylene diamine hydrochloride was separated off. The upper layer containing 3-[N-(2-aminoethyl)]aminopropyltrimethoxysilane was taken out and purified by simple distillation, obtaining 46.8 g of 3-[N-(2-aminoethyl)]aminopropyltrimethoxysilane. The yield was 70.1%. A substantial amount of bis-silyl products was detected.
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[S:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][N:9]=1>C(O)C>[NH:2]([C:5]1[S:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][N:9]=1)[NH2:3]
Reactant: CC(C)(C)c1nnc(Br)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nnc(NN)s1
Yield: 79.6 %

Procedure:
Hydrazine hydrate (12.5 g) was added to a solution of 2-bromo-5-t-butyl-1,3,4-thiadiazole (22.1 g) in ethanol (100 ml), and the mixture was heated under reflux for 2 hours. The solvent was evaporated to give an oily solid which was crystallised from water to give 2-hydrazino-5-t-butyl-1,3,4-thiadiazole (13.7 g, 79%) as white needles, mp 111°-112° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:11]([CH:12]=[N:13][N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:20]Br.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:11]([C:12]([Br:20])=[N:13][N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nncn2CC1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nnc(Br)n2CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a suspension of 4,5,7,8-tetrahydro-1,2,3a,6-tetraaza-azulene-6-carboxylic acid tert-butyl ester (200 mg, 0.839 mmol) in water was added 10N NaOH until a clear solution was formed. Br2 (0.432 mL, 8.39 mmol) was then added slowly while maintaining a pH of 12 by addition of conc. NaOH. The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was then acidified to pH ˜4 with 6 M HCl. The organics were extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid (185 mg, 70% yield).