Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)(O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:39])(=O)=O>ClCCl.O>[CH:1]([N:14]1[CH2:17][C:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)([Cl:39])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1(c2coc3ccccc23)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: ClC1(c2coc3ccccc23)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzhydryl-3-(benzofuran-3-yl)azetidin-3-ol (760 mg, 2.14 mmol) in dichloromethane (10 mL) was added at 0° C. triethylamine (387 μL, 2.78 mmol) and then dropwise a solution of methanesulfonyl chloride (216 μL, 2.78 mmol) in dichloromethane (3 mL). The reaction mixture was stirred for 1 hour at room temperature, then diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The crude title compound was obtained as a yellow gum (873 mg, 109%) and used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[C:32]([N:35]1[C:44]2[C:39](=[CH:40][C:41]([O:46][CH3:47])=[C:42]([NH2:45])[CH:43]=2)[CH2:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33].Cl.C(=O)(O)[O-].[Na+].[OH-].[K+]>FC(F)(F)CO>[C:32]([N:35]1[C:44]2[C:39](=[CH:40][C:41]([O:46][CH3:47])=[C:42]([NH:45][C:2]3[NH:7][C:6]4=[N:8][CH:9]=[CH:10][C:5]4=[C:4]([NH:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=4[C:24]([NH2:26])=[O:25])[N:3]=3)[CH:43]=2)[CH2:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: COc1cc2c(cc1N)N(C(C)=O)CCC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: OCC(F)(F)F
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(C)=O)CCC2
Temperature: 90 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
A mixture of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (0.20 g, 0.44 mmol), 1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.10 g mg, 0.43 mmol) was dissolved in 2,2,2-trifluoroethanol (10 mL) and hydrochloric acid (1.0 mL, 4.0 mmol, 4M in 1,4-dioxane) was added. The mixture was heated at 90° C. in a sealed tube for 24 h. The reaction was cooled, excess saturated aqueous sodium bicarbonate was added, and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, diluted with tetrahydrofuran (35 mL) and treated with excess 27% aqueous ammonia (20 mL). The reaction was stirred in a sealed tube at 80° C. for 1 h, cooled, and the layers were separated. The organic layer was dried over sodium sulfate, concentrated, and purified by flash silica gel column chromatography (0 to 20% methanol /dichloromethane). “Pure” fractions were isolated, concentrated, dissolved in 1,4-dioxane (7.0 mL), treated with potassium hydroxide (4.0 mL, 20 mmol, 5M in water) and stirred for 24 h at 80° C. The reaction was cooled; the organic layer was separated, dried over sodium sulfate, and purified by flash silica gel column chromatography. Further purification via reverse phase HPLC (5 to 90% acetonitrile/water, 0.05% trifluoroacetic acid) provided 2-[(2-{[1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide (0.03 g, 91% pure, 0.054 mmol, 13% over 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.91 (m, 2 H), 2.15 (s, 3 H), 2.68 (m, 2 H), 3.68 (t, J=6.1 Hz, 2 H), 3.86 (s, 3 H), 6.27 (s, 1 H), 6.85 (m, 1 H), 6.91-6.98 (m, 1 H), 7.02 (m, 1 H), 7.40-7.47 (m, 1 H), 7.52 (s, 1 H), 8.02 (bs, 1 H), 8.08 (bs, 1 H), 8.36-8.41 (m, 1 H), 8.46 (s, 1 H), 10.43 (s, 1 H), 11.44 (bs, 1H); ESIMS (M+H)+=490.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH2:17]([C:19]([CH:21]=[CH2:22])=[O:20])[CH3:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:17][C:19](=[O:20])[CH2:21][CH3:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)CC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound of Example 2 (5.0 g, 0.021 mole) was reacted with ethylvinyl ketone (6.3 ml) and triethylamine (1 ml) in methanol (30 ml) by the method of Example 3 to give the title compound, m.p. ca. 76-79° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=O)[CH2:3][SH:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:23]([NH:31][C:32](=[O:39])[C@H:33]([C@H:35]([CH2:37][CH3:38])[CH3:36])[NH2:34])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:23]([NH:31][C:32](=[O:39])[C@H:33]([C@H:35]([CH2:37][CH3:38])[CH3:36])[NH:34][C:5](=[O:7])[C@H:2]([CH2:3][SH:4])[NH2:1])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)NCCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CS)C(=O)NCCc1ccccc1
Reaction time: 16 h
Yield: 168.9 %

Procedure:
N-(t-Butoxycarbonyl)-S-triphenylmethyl)-L-cysteine (0.26 g, 0.55 mmol) was dissolved in DMF (3 mL) with EDC (0.11 g, 0.55 mmol), HOBT (0.074 g, 0.55 mmol) and L-isoleucine-phenethylamide hydrochloride (0.135 g, 0.5 mmol) at .ambient temperature. The pH of the solution was adjusted to 6.5 with triethylamine (0.15 mL, 1.05 mmol). After stirring for 16 h the solvent was evaporated and the residue was partitioned between EtOAc (20 mL) and H20 (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extract was washed with 10% citric acid solution, aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration gave 0.285 g (87%) of the title compound after chromatography (SiO2, EtOAc: hexane, 1:2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CN(C=O)C>[CH3:11][C@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(=O)N[C@@H](C)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
N—[(S)-3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide (770 mg, 3.72 mmol) and sodium hydride (55% in oil, 243 mg, 5.57 mmol) were stirred in 30 ml of DMF under argon at room temperature for 30 min. Following addition of 2-chloro-5-nitropyridine (648 mg, 4.09 mmol) the mixture was stirred at 80° C. for 1.5 h, concentrated, and mixed with ethyl acetate and water, and the organic phase was separated off and concentrated. The crude product was further reacted without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:30])=[C:13]2[C:17]=1[N:16]=[C:15]1[N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[CH2:19][CH2:20][CH2:21][N:14]21.C(N(CC)CC)C.CC(C)([O-])C.[K+]>O1CCCC1.CO>[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([N:30]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1CCCN1c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
4-Chlorobutanoyl chloride (88.2 mg, 0.626 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine (Example 100, 230 mg, 0.626 mmol) and triethylamine (0.18 mL) in tetrahydrofuran (6.0 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. Methanol (1.0 mL) and potassium t-butoxide (351 mg, 3.13 mmol) were added to the mixture, and the mixture was stirred at 60° C. for 16 hr. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 80-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (85.8 mg, 0.197 mmol, 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]#[N:19])=[N:9]1)([CH3:4])([CH3:3])[CH3:2].CCO.[CH2:24](N)[CH2:25][NH2:26]>C(O)(=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[N:9]=[C:10]([C:18]3[NH:26][CH2:25][CH2:24][N:19]=3)[C:11]=12
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2c(N)ncnc21
Reactant: NCCN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Cn1nc(C2=NCCN2)c2c(N)ncnc21
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of (4-amino-3-cyano-pyrazolo[3,4-d]pyrimidin-1-yl)-acetic acid tert-butyl ester (80 g, 0.291 mol) and EtOH (800 mL) in an ice water bath was added acetic acid (67 mL) and then ethylenediamine (195 mL). The resulting mixture was refluxed for 90 min, cooled to room temperature and filtered. The solid was suspended in water (1 L), filtered and dried in vacuo to give of tert-butyl 2-(4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (84.6 g, 90% yield). MS (ES) m/z 318.1 (M+H+).
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:51])[CH:15]([C:20]1[CH:21]=[C:22]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH:23]=[C:24]([NH:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=2[C:37]([F:40])([F:39])[F:38])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].[OH2:54].OO.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:38][C:37]([F:39])([F:40])[C:28]1[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:34])[F:35])=[CH:32][C:27]=1[NH:26][C:24]1[CH:25]=[C:20]([C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:51])=[O:54])[CH:21]=[C:22]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([F:48])([F:49])[F:50])=[CH:45][CH:46]=2)[CH:23]=1
Reactant: O
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)c1cc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
To a solution of 4-benzyl-3-{2-[5-(2,5-bis-trifluoromethyl-phenylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (2.55 g, 3.53 mmol) in THF (15 mL) was added water (5 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (148 mg, 3.53 mmol) and 30% H2O2 (1.20 mL, 10.59 mmol,) and stirred at 0° C. for 15 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (7.06 mL, 10.59 mmol) and stirred at room temperature for 10 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH=2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×50 mL) and dried (MgSO4). The mixture was concentrated in vacuo to receive a crude mixture which was purified by ISCO silica gel column chromatography to yield (R) 2-[5-(2,5-Bis-trifluoromethyl-phenylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (1.15 g, 58%).
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[N:11]=[CH:12][N:13]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH:14]=2)C=CC=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][N:25]=[CH:26]2>O1CCOCC1.CN(C=O)C>[CH:15]1([N:13]2[CH:14]=[C:10]([NH:9][C:8]([NH:20][C:21]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:22]=3[CH:23]=[CH:24][N:25]=[CH:26]4)=[O:19])[N:11]=[CH:12]2)[CH2:16][CH2:17][CH2:18]1
Reactant: Nc1cccc2cnccc12
Reactant: O=C(Nc1cn(C2CCC2)cn1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Nc1cn(C2CCC2)cn1)Nc1cccc2cnccc12
Temperature: 70 °C
Yield: 51.4 %

Procedure:
To a 1 dram vial with septa screw cap was added (1-cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester (Example 4, 50 mg, 0.19 mmol), 5-aminoisoquinoline (30 mg, 0.21 mmol), and 1:1 dioxane-DMF (1 mL). The reaction mixture was heated at 70° C. for 2 h. The reaction mixture was adsorbed onto silica gel and was purified by silica gel chromatography (40:1 chloroform-methanol) to afford 30 mg (52% yield) of 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea; 1H NMR (400 MHz, CD3OD) δ 9.21 (d, J=1.7 Hz, 1H), 8.45 (d, J=6.2 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 7.98 (d, J=5.4 Hz, 1H), 7.84 (dd, J=2.3, 8.3 Hz, 1H), 7.66 (m, 1H), 7.54 (s, 1H), 7.12 (brs, 1H), 4.66 (m, 1H), 2.5–2.3 (m, 4H), 1.9 (m, 2H); MS (AP/CI): 308.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].CO.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[C:17]1([C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: O=C1CCCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3=CCCC3)c[nH]c2c1
Temperature: 75 °C

Procedure:
A 3 L three-necked flask equipped with a mechanical stirrer was charged with indole 6-carboxylic acid (220 g, 1.365 mole) and KOH pellets (764.45 g, 13.65 mole, 10 equivalents). Water (660 mL) and MeOH (660 mL) were added and the mixture heated to 75° C. Cyclopentanone (603.7 mL, 6.825 mole, 5 equivalents) was added dropwise over 18 h using a pump. The reaction mixture was heated for an additional 3 h (after which the reaction was judged complete by HPLC) and cooled to 0° C. for 1 h. The precipitated potassium salt is collected by filtration, and washed with TBME (2×500 mL) to remove cyclopentanone self-condensation products. The brown solid was re-dissolved in water (2.5 L) and the solution washed with TBME (2×1 L). Following acidification to pH 3 with conc. HCl (425 mL), the beige precipitate was collected by filtration, washed with water (2×1 L) and dried under vacuum at 70° C. The crude product weighed 275.9 g (88.9% mass recovery) and had an homogeneity of 85% (HPLC).
Reaction SMILES: [OH:1][CH2:2][C:3]#[CH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:1][CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-1-propyne and 260 g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooled to 0° C. in an ice bath, is added a solution of 20 mg of para-toluenesulfonic acid in 100 ml of methylene chloride, dropwise. The reaction mixture is stirred at 0° C. for one-half hour, and at ambient temperature for one hour. It is then poured into 200 ml of a 5% solution of sodium bicarbonate, the organic phase is separated, the aqueous phase extracted with 100 ml of methylene chloride, the combined organic phases washed with 100 ml of a solution of brine, dried over sodium sulfate, and evaporated under vacuum (12 mm) at 45° C. to give 300 g of crude product, which is purified by fractional distillation, bp 71°-73° C. (14 mm) to yield 250 g (89%) of a liquid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:16]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[OH-].[Na+]>O.Cl.CCOCC.CCCCCC>[ClH:2].[Cl:2][C:3]1[C:4]([O:10][CH2:11][C:12]([F:14])([F:13])[F:15])=[C:5]([NH:6][NH2:16])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(Cl)c1OCC(F)(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: NNc1cccc(Cl)c1OCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-chloro-2-(2,2,2-trifluoroethoxy)aniline hydrochloride (20 g, 77 mmol), concentrated HCl (50 mL), and H2O (30 mL) was cooled to -10° C. Sodium nitrite (10.7 g, 155 mmol) dissolved in H2O (30 mL) was added dropwise at a rate to maintain the temperature below -5° C. The solution was stirred for an additional 30 minutes. At the end of this time SnCl2.2H2O (65 g, 289 mmol) in 125 mL of 6N HCl was added dropwise over 1 hour at 0° C. When addition was complete the mixture was allowed to warm to room temperature and stirred an additional 18 hours. The reaction was cooled to -5° C. and 50% NaOH solution was added slowly to pH=13. This alkaline solution was extracted with EtOAc (3×500 mL), and the combined organic layers were washed with brine (2×500 mL), dried (MgSO4), and concentrated to yield an orange oil. This residue was dissolved in 100 mL Et2O and saturated with HCl gas, which resulted in a turbid solution. After the addition of hexane (~10 volumes) and cooling, the 3-chloro-2-(2,2,2-trifluoroethoxy)phenylhydrazine hydrochloride 17.1 g (86%) was collected by filtration as a tan solid, m.p. 158°-165° C.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1.[CH3:21][O:22][C:23]1[CH2:24][C:25]2[CH2:26][CH2:27][C@@H:28]3[C@@H:37]([C:38]=2[CH2:39][CH:40]=1)[CH2:36][CH2:35][C@@:33]1([CH3:34])[C@H:29]3[CH2:30][CH2:31][CH:32]1[OH:41].O>C1(C)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:21][O:22][C:23]1[CH2:24][C:25]2[CH2:26][CH2:27][C@@H:28]3[C@@H:37]([C:38]=2[CH2:39][CH:40]=1)[CH2:36][CH2:35][C@@:33]1([CH3:34])[C@H:29]3[CH2:30][CH2:31][C:32]1=[O:41]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(O)CC[C@@H]32)C1
Agent: CC(C)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Solvent: O
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 109 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a stirred solution of 106.3 g (0.52 mmol) of aluminum isopropoxide in 2000 ml of dry toluene 720 ml of cyclohexanone, 0.35 g of 2,6-ditert-butyl-4-methyl-phenol and 100 g (0.307 mol) 3-methoxy-17-hydroxy-estra-2,5(10)-diene were added, then the reaction mixture was stirred at 108-110° C. for 1 h. The reaction was followed by TLC. After completion of the reaction the mixture was cooled to 20-25° C., 200 ml of water was added and the so obtained mixture was stirred for 1 h. The precipitated aluminum hydroxide was filtered off and the filtrate was concentrated to a volume of 250 ml under reduced pressure. A mixture of 200 ml of methanol and 100 ml of water was added to this concentrated warm—about 60° C.—solution, the obtained suspension was cooled to 20-25° C. and stirred for 1 h. The precipitated crystalline product was filtered off and dried below 40° C. in vacuum to yield 76.4 g (87%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.COC1C=CC=CC=1CCC(O)=O.COC1C=CC=CC=1CCC(Cl)=O.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42].[CH3:46][O:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][C:57]=1[O:58][CH3:59])[N:54]=[CH:53][CH:52]=[C:51]2[O:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:46][O:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][C:57]=1[O:58][CH3:59])[N:54]=[CH:53][CH:52]=[C:51]2[O:60][C:61]1[CH:62]=[CH:63][C:64]([NH:65][C:44]([NH:43][C:41](=[O:42])[CH2:40][CH2:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[S:45])=[CH:66][CH:67]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccccc1CCC(=O)N=C=S
Agent: COc1ccccc1CCC(=O)Cl
Agent: COc1ccccc1CCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccccc1CCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methoxyphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methoxyphenyl)propanoyl isothiocyanate was prepared using the resultant 3-(2-methoxyphenyl)propanoyl chloride as a starting compound according to the description of the literature. 3-(2-Methoxyphenyl)propanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 74%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3]1.C(=O)([O-])O.[Na+].Cl[O-].[Na+]>C(Cl)Cl.CC1(C)N(OC)C(C)(C)CCC1>[O:1]=[C:2]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3]1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCC(O)C2)cc1
Agent: CON1C(C)(C)CCCC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC(=O)C2)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
4-[(3-hydroxy-1-pyrrolidinyl)sulfonyl]benzonitrile 23a (17.0 g, 67.3 mmol) was dissolved in DCM (300 ml) and treated at room temp with PS-TEMPO (capacity: 1.17 mmol/g, 400 mg, 0.74 mmol). Then 5% aqueous sodium hydrogencarbonate solution (150 ml) was added and the mixture stirred vigorously while cooling to 10° C. Aqueous sodium hypochlorite (titrated at 7.0 wt % NaOCl*; 77.6 ml, 93.0 g, 87.5 mmol) was added over 40 min, maintaining the temperature below 10° C. Cooling was removed and the reaction mixture stirred vigorously. TLC after 2 h showed no starting material, therefore the stirring was stopped and layers separated. The aqueous layer was extracted with DCM (2×30 ml), and the combined organic layers washed with saturated aqueous sodium thiosulphate (75 ml) then water (150 ml). Each of these aqueous layers were back-extracted with DCM (30 ml) and combined with the main organic extract, which was then filtered through a cotton wool plug and evaporated to dryness, yielding 14.3 g (85%) ketone 4-[(3-oxo-1-pyrrolidinyl)sulfonyl]benzonitrile 23b.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[Li+].CCC[CH2-].C(NC(C)C)(C)C.Cl.C1C[O:33][CH2:32]C1>O.CC(OC)(C)C.C(O)(=O)C.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:32]=[O:33]
Reactant: Fc1cccc(Br)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [CH2-]CCC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-fluorobenzene (17.3 g, 100 mmol) was added over 5 minutes to a solution of lithium diisopropylamide (prepared from the addition of 40 mL of 2.5 N-butyllithium in hexanes to 11.5 g of 0.1 M diisopropylamine at 0° C.) in THF at −70° C. The mixture was stirred cold for 1 hour, after which DMF (8 mL) was added over 10 minutes. The mixture was stirred at −70° C. for an additional 40 minutes, followed by treatment with acetic acid (26 g). The mixture was allowed to warm to ambient temperature and transferred into a mixture of MTBE (200 mL), water (200 mL), and hydrochloric acid (4 N, 150 mL). The layers were partitioned and the organic portion was concentrated under reduced pressure to provide the title compound. MS (DCI/NH3) m/z 202 (M+H)+.