Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[F:46][CH:47]([F:55])[C:48]1[O:52][C:51]([CH2:53][NH2:54])=[CH:50][CH:49]=1>>[F:46][CH:47]([F:55])[C:48]1[O:52][C:51]([CH2:53][NH:54][C:40]([C:36]2[S:35][C:34]([N:31]3[CH2:32][CH2:33][N:29]([CH2:28][C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:45][CH:44]=4)[C:30]3=[O:43])=[N:38][C:37]=2[CH3:39])=[O:41])=[CH:50][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(C(F)F)o1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(C(F)F)o1
Yield: 47 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (5-(difluoromethyl)furan-2-yl)methylamine, the title compound was obtained as a white powder in 47% yield: mp 173-174° C. (diethyl ether): 1H NMR (300 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.05-6.99 (m, 2H), 6.59-6.56 (m, 1H), 6.55 (t, JH-F=54.4 Hz, 1H), 6.32-6.29 (m, 1H), 6.01 (t, J=5.4 Hz, 1H), 4.56 (d, J=5.4 Hz, 2H), 4.43 (s, 2H), 4.08-4.02 (m, 2H), 3.46-3.40 (m, 2H), 2.58 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 164.2, 162.3, 160.9, 157.5, 155.4, 153.6, 153.3, 146.2, 130.3, 116.9, 115.8, 111.3, 108.4, 105.3, 47.3, 42.0, 41.7, 36.6, 17.3: MS (ES+) m/z 465.3 (M+1).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:4]1([CH2:3][CH2:2]/[CH:1]=[CH:14]/[C:13]([O:12][CH3:11])=[O:34])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/CCc1ccccc1

Procedure:
A solution of hydrocinnamaldehyde (13.42 g, 0.1 mol) and methyl(triphenylphosphoranylidene)acetate (33.44 g, 0.1 mol) in THF was stirred at reflux for 20 hours. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography using hexane:EtOAc::9:1. The desired product was obtained as a clear, pale yellow oil (8.0 g, 0.042 mol, 42%); 1H NMR (300 MHz, CDCl3) δ 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 7.1-6.9 (m, 1H), 5.85 (d, 1H, J=5.8 Hz), 3.75 (s, 3H), 2.8 (t, 2H, J=7.7 Hz), 2.55 (q, 2H, J=7.4 Hz); MS (NH3 -DCI) 191 (M+H)+.
Reaction SMILES: O[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH2:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+]>C(Cl)Cl.CCO.CC(O)=O>[F:23][C:20]([F:21])([F:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC1(O)c1ccccc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: FC(F)(F)c1ccccc1C1CCCN1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 2-hydroxy-2-(2-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate (I-27) (0.44 g, 1.6 mmol) in DCM (20 mL) was added TFA (10 mL). The reaction was stirred at room temperature until complete by LCMS then reduced to dryness. The crude mixture was dissolved in EtOH:AcOH (10:1, 8 mL) and was added NaCNBH3 (0.17 g, 2.7 mmol). The reaction was stirred for 1 hour then partitioned with EtOAc and saturated aqueous NaHCO3. The organic layer was separated, dried over MgSO4, filtered and reduced to dryness to afford 2-(2-(trifluoromethyl)phenyl)pyrrolidine (I-28) as a clear oil. MS m/z 216.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C:15](OC)=[O:16])=[CH:12][N:11]=[C:10]1[S:19][CH2:20][CH2:21][CH3:22].CO.C(O)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][OH:16])=[CH:12][N:11]=[C:10]1[S:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCSc1ncc(CC(=O)OC)n1Cc1ccccc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCCSc1ncc(CCO)n1Cc1ccccc1Cl
Yield: 83 %

Procedure:
A solution of methyl 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]acetate (2.1 g, 6.2 mmol) in dry tetrahydrofuran (150 mL) was cooled to -78° C. for 1.5 hours and at ambient temperature for 1 8 hours. Methanol was added followed by 5% aqueous acetic acid. The mixture was concentrated in vacuo, the residue was extracted with methylene chloride, and the organic extract was washed with 5% aqueous sodium carbonate solution, dried, and concentrated to give 2.33 g of crude product. This was chromatographed over silica gel with ethyl acetate to give 1.6 g (84%) of 1-[(2-chlorophenyl)methyl]-5-(2-hydroxy)ethyl-2-propylthio-1H-imidazole as an oil.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].[Li].[H-].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(CCO)c1ccccc1
Reaction time: 0.5 h

Procedure:
3-Methyl-3-phenylbutanoic acid (0.90 9) was dropwise added to a suspension of lithium alminum hydride (0.2 g) in 15 ml of tetrahydrofuran at room temperature and the mixture was stirred for 30 minutes. To the reaction mixture was added a saturated aqueous solution of sodium bicarbonate under ice cooling, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride,, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (20 g). Elution with a hexane ethyl acetate (5:1) mixture gave 0.75 g of 3-metyl-3-phenylbutanol.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=2)[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH:6]=1)[CH3:2].[Li].N.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C@@H:3]1[CH2:20][C@@H:19]2[C@H:14]([CH2:15][CH2:16][C:17](=[O:21])[CH2:18]2)[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH:6]=1)[CH3:2]
Reactant: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H]2CC(=O)CC[C@@H]2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
A solution of (7α,17β)-7-ethyl-17-hydroxyestra-4,14-dien-3-one (Example 1a; 0.67 g) in dry tetrahydrofuran (13 ml) was added to a refluxing solution of lithium (0.31 g) in liquid ammonia (44 ml). After 30 min. stirring at −40° C., solid ammonium chloride was added and the ammonia was allowed to evaporate. Water was added and the product was extracted into ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of ammonium chloride and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (5α,7α,17β)-7-ethyl-17-hydroxyestr-14-en-3-one (0.21 g), 1H-NMR (CDCl3) δ 5.02 (s, 1H), 3.98 (t, 1H, J=8.4 Hz), 0.99 (s, 3H), 0.89 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15](Cl)=[N:16][C:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22](Cl)[CH:21]=3)=[N:18][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+]>CO>[CH2:19]([C:17]1[N:16]=[C:15]([O:29][CH3:28])[C:12]2[CH2:13][CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][C:11]=2[N:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1cccc(Cc2nc(Cl)c3c(n2)CCN(Cc2ccccc2)CC3)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2

Procedure:
2,7-dibenzyl-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of Step B (86 mg, 0.23 mmol) was dissolved in methanol (10 ml) and sodium methoxide (25 mg, 0.47 mmol) was added. The reaction was refluxed under nitrogen for 16 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was separated, washed with brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo to afford a colourless oil, 75.5 mg, 89%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[C:7]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:6]=1[F:24])(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:6]=1[F:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(OCc2ccccc2)ccc(OC(C)=O)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(O)ccc(OC(C)=O)c1F

Procedure:
Following General Procedure G and using acetoxymethyl-4-benzyloxy-2-fluoro-phenyl acetate (Compound 20, 0.75 g, 2.26 mmol), ethyl acetate (15 mL) and 10% palladium on carbon (0.08 g), the title compound was obtained as an oil (0.48 g, 88%). 1H-NMR (300 MHz, CDCl3): δ2.09(s, 3H), 3.62(s, 2H), 5.75(s, 2H), 6.48-6.54 (m, 2H), 7.02(d, J=8.4 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]2=[O:19])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(S(=O)(=O)N2CCCCC2=O)cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
2 g of product obtained in stage A are heated to reflux for 2 hours with 2 g of sodium acetate in 20 cm3 of acetic anhydride. The mixture is cooled to room temperature and evaporated to dryness, the residue is taken up in a mixture of chloroform and water, the organic phase is separated and dried and, after removal of the solvents, 1.8 g of expected crude product are obtained. M.p. 118°-120° C. After crystallization in isopropanol, 1.2 g of pure product are obtained. M.p. 122°-123° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OC(C)(C)C)[C:24]5=[O:37])[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:29][C@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([N:16]3[C:10]4[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[N:22]=2)[C:24]1=[O:37]
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3=O)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](N)C3=O)n2)n1
Yield: 39.2 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-2-oxo-3-piperidyl]carbamate (140 mg, 0.280 mmol) in dichloromethane 4.0 ml and trifluoroacetic acid (0.80 ml, 10 mmol) was stirred at RT 3 h. The reaction was concentrated and diluted with water then extracted with EtOAc. The aqueous layer was basified with 1M NaOH to pH 10 then extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was submitted for reverse phase HPLC to give 225 (44 mg, 39% yield). MS (ESI) m/z: 401.1. 1H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.05 (t, J=8.1 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 4.46-4.33 (m, 1H), 4.14-4.02 (m, 1H), 3.58 (dd, J=10.8, 6.4 Hz, 1H), 2.65 (s, 3H), 2.24 (dt, J=11.4, 5.3 Hz, 1H), 2.19-2.00 (m, 2H), 1.77 (ddd, J=23.0, 10.6, 5.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:14][C:15](=[O:33])[CH:16]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:17](=O)[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:11](=O)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl.CN(C=[O:47])C>>[CH2:1]([O:8][CH2:9][CH:10]([C:11]#[N:12])[NH:14][C:15](=[O:33])[CH:16]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:17][C:18]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C(COCc1ccccc1)NC(=O)C(CC1CCCCC1)C(=O)CN1CCOCC1
Reactant: CN(C)C=O
Agent: Clc1nc(Cl)nc(Cl)n1
Product: N#CC(COCc1ccccc1)NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
N-(2-Benzyloxy-1-carbamoyl-ethyl)-2-cyclohexylmethyl-4-morpholin-4-yl-oxo-butyramide (0.22 g, 0.48 mmol) was dissolved in 4 mL of DMF and cooled to 0° C. with an ice-water bath. To this solution was added cyanuric chloride (0.089 g, 0.48 mmol) and the reaction mixture was stirred for one h. The reaction was quenched with cold water (2 mL), extracted with EtOAc (3×100 mL), and the organic layers were combined and washed with 100 mL brine. The organic layer was dried over MgSO4, filtered and concentrated by rotary evaporation to give the crude residue. The residue was purified by chromatography (SiO2, 35% hexane in EtOAc) to give the title compound as a clear oil (0.12 g, 57%); 1H NMR (CDCl3) 7.35 (5H, m), 7.02-7.08 (1H, m), 5.01-5.09 (1H, m), 4.52-4.63 (2H, m), 3.72-3.34 (10H, m), 2.96-2.83 (1H, m), 2.78-2.62 (1H, m), 2.18-2.30 (1H, m), 1.75-1.51 (6H, m), 1.30-1.07 (5H, m), 0.95-0.73 (2H, m). MS: m/z=442 M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.69 mmol) was dissolved in 30 mL dichloromethane. Powdered molecular sieves (3 A, 200 mg), 4-chlorobenzene boronic acid (216 mg, 1.38 mmol) and [Cu(OH)TMEDA]2Cl2 (113 mg, 0.24 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 minutes and stirring was continued at room temperature overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 100:0→3:2 gradient) and by recrystallization from diisopropylether. The desired compound was obtained as a white solid (42 mg, 19%), MS: m/e=329.2 (M+H+).
Reaction SMILES: [Cl:1]CCC[N:5](C)C(=O)C(C1C=CC(Cl)=CC=1C(=O)C1C=CC=CC=1)=O.[I-].[Na+].N1CCOCC1.Cl.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][N:44]([CH3:64])[C:45](=[O:63])[C:46]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=2[C:55](=O)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=O)[CH2:37][CH2:36]1>CC(CC)=O>[ClH:1].[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][N:44]([CH3:64])[C:45]([C:46]2[NH:5][C:55]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[C:49]3[C:48]=2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50]3)=[O:63])[CH2:37][CH2:36]1
Reactant: CN(CCCCl)C(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CN(CCCN1CCOCC1)C(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: C1COCCN1
Product: CN(CCCN1CCOCC1)C(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
A solution of 7.6 g. of o-benzoyl-p-chlorophenylglyoxylic acid (3-chloropropyl)methylamide in 40 ml. of ethyl methyl ketone is treated with 3.0 g. of sodium iodide and 3.5 g. of morpholine and the mixture is boiled at reflux for 30 hours. After concentration under reduced pressure, the residue is partitioned between water and methylene chloride, the organic phase washed with water, dried over sodium sulfate and concentrated to dryness. The residual oily base is purified on 500 g. of aluminum oxide using methylene chloride/ethyl acetate (4:1) for the elution, dissolved in diethyl ether and treated with excess ethereal hydrochloric acid. The hydrochloride which crystallizes out is recrystallized from isopropanol/diethyl ether, and there is obtained 4.9 g. of o-benzoyl-p-chlorophenylglyoxylic acid [3-(morpholino)propyl] methylamide hydrochloride in the form of light yellow crystals having a melting point of 169°-172° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[C:25]([O-])=[O:26].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25][OH:26]
Reactant: COc1ccc(Cn2nc(C(=O)[O-])c3cc(OC)c(OC)cc32)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(CO)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
5,6-Dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazole-3-carboxylate (205.0 g) was ground in a mortar and suspended in tetrahydrofuran (1500 ml) at room temperature. Then sodium borohydride (96.8 g) was added thereto and the mixture was stirred at room temperature. Methanol (300 ml) was slowly added dropwise thereinto within 30 minutes. After the completion of the addition, the reaction mixture was heated to 50° C. and stirred for 5 hours. After adding sodium borohydride (19.4 g) and methanol (60 ml), the mixture was stirred at room temperature overnight. Then the reaction mixture was added in portions into a mixture of conc. hydrochloric acid (200 ml), water (5000 ml) and ice (1 kg) under stirring (pH 1-2). To this aqueous layer, a saturated aqueous solution of sodium bicarbonate was added with stirring at room temperature until the pH became about 8. As a result, a colorless solid was precipitated. This precipitate was collected by filtration, washed with water (500 ml×2), dissolved in chloroform (10000 ml), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Thus a colorless solid (185.2 g) was obtained. This solid product was used in the subsequent reaction without purification.
Reaction SMILES: C(O)C.[O:4]=[C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]=2[CH2:8][CH2:7][CH2:6]1.[BH4-].[Na+]>CC(C)=O>[OH:4][CH:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cccc2c1CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc2c1CCCC2O
Reaction time: 4 h

Procedure:
To 200 ml. of ethanol is added 10.9 g. of ethyl 1,2,3,4-tetrahydro-1-oxo-5-naphthoate and while the solution is stirred at room temperature, 950 mg. of sodium borohydride is added. The mixture is stirred for 4 hours, after which 2 ml. of acetone is added. The mixture is further stirred for 30 minutes and, then, the solvent is distilled off under reduced pressure. Following the addition of 30 ml. of 2N hydrochloric acid, the residue is extracted with ethyl ether. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the oily residue is purified by column chromatography on silica gel(100 g. silica gel; eluted with chloroform). The described procedure gives ethyl 1-hydroxy-1,2,3,4-tetrahydro-5-naphthoate as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:22]#[N:23].[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C.[OH-].[Na+]>N1C=CC=CC=1>[C:22]([C:3]1[C:2]([NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:14])[CH3:15])[CH2:9]2)=[C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:4]=1)#[N:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(C)[C@H]1CCN(c2cc(N)c(C#N)cc2-c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)[C@H]1CCN(c2cc(NC(=O)C(C)(C)C)c(C#N)cc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
4-Amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]biphenyl-3-carbonitrile (I-243) (300 mg, 0.98 mmol) was dissolved in pyridine (3 ml), and under nitrogen atmosphere at room temperature, pivaloyl chloride (181 μl, 1.47 mmol) was added. After stirring at room temperature for 3 days, the reaction liquid was fractionated with ethyl acetate and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:methanol=98:2) to obtain the entitled compound (364 mg, 95%) as a pale yellow gel.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])=[O:3].[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:13]#[CH:14]>>[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])=[O:3])[CH2:17][CH2:16]1)[C:13]#[CH:14]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)Oc1ccccc1Cl
Product: C#CCC1CCN(C(=O)Oc2ccccc2Cl)CC1

Procedure:
2-(chloro)phenyl chloroformate (5.00 g, 26.2 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.50 g, 20.2 mmol) according to general procedure 1. Yield=4.56 g, 82%. m/z MH+=278.13. HPLC rt=9.3 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CN(C)C=O>[O:7]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=CCBr
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCOc1ccccc1
Reaction time: 4 h
Yield: 7.4 %

Procedure:
A mixture of phenol (18.8 g) and sodium hydroxide (8 g) was stirred at 60°-70° in dimethylformamide (162 ml) and water (18 ml) while 1-bromo-3-methylbut-2-ene (VII, R1 =R2 =CH3, Hal=Br) (29.8 g) was added dropwise over 11/2 h. The mixture was stirred at 60° for 4 h after the addition was complete. It was then poured into water (800 ml) and extracted with ether (3×300 ml). The ether extract was washed with 10% sodium hydroxide (200 ml) and then with water (3×200 ml) before drying over anhydrous sodium sulphate. The solvent was removed in vacuo, and the residue distilled to give 1-phenoxy-3-methylbut-2-ene (2.4 g, yield 75%) as a clear liquid b.p. 116°-118°/18 mm. Hg.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1.[Br:24][CH2:25][C:26](=O)[CH3:27]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([CH3:27])[CH2:25][Br:24])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Reactant: CC(=O)CBr
Product: CC(CBr)=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-(trifluoromethyl) -2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with bromopropanone to give 7-(trifluoromethyl)-2-[ (2-bromo-1-methylethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.