Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:20]=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:20]=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[CH:29][C:30]#[N:31])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC=C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Yield: 80.7 %

Procedure:
Bis-benzo[1,3]dioxol-5-yl-methanone (2.41 g, 8.92 mmol), cyanomethylphosphonic acid diethyl ester (2.81 ml, 17.84 mmol) in anhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 17.84 ml, 17.84 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 50% EtOAc in hexane in about 40 min.) to give 3,3-bis-benzo[1,3]dioxol-5-yl-acrylonitrile as an off-white solid (2.11 g, 81%): mp, 126-128° C.; 1HNMR (DMSO-d6) δ 7.07-7.03 (2 ds, J=1.84 and J=8 Hz, 2H, Ar), 6.94 (d, J=8 Hz, 1H, Ar), 6.90 (d, J=1 Hz, 1H, Ar), 6.86 (dd, J=1.76 and J=7 Hz, 1H, Ar), 6.74 (dd, J=1.82 and J=8 Hz, 1H, Ar), 6.13 (s, 1H, double bond proton), 6.12 (s, 2H, CH2), 6.10 (s, 2H, CH2); 13C NMR (DMSO-d6) δ 160.8, 149.4, 148.4, 147.8, 147.3, 132.2, 130.9, 123.8, 123.6, 118.5, 109.4, 108.4, 108.2, 107.7, 101.8, 101.6, 93.8. Anal. Calcd. For C17H11NO4: C, 69.62; H, 3.78; N, 4.78. Found: C, 68.43; H, 3.97; N, 4.37.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([CH2:15][CH3:16])([F:14])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C:12]([CH2:15][CH3:16])([F:14])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:66][CH:63]5[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]5)=[O:30])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and. 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.4 Hz, 3 H) 1.08-2.06 (m, 16 H) 2.20 (s, 3 H) 2.82 (d, J=11.1 Hz, 2 H) 3.25 (s, 4 H) 3.60-3.85 (m, 3 H) 3.95 (s, 3 H) 4.49 (m, 1 H) 7.47 (d, J=8.3 Hz, 1 H) 7.50 (s, 1 H) 7.77 (s, 1 H) 8.01-8.19 (m, 2 H) 8.31 (d, J=8.3 Hz, 1 H). [M+H] calc'd for C30H42FN7O3, 568; found 568.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:36][CH3:37]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH2:36][CH3:37])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCI
Reactant: CCOc1ccc(NC(=O)c2c[nH]c3c2C(=O)CCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(NC(=O)c2cn(CC)c3c2C(=O)CCC3)cc1
Temperature: 85 °C
Yield: 32 %

Procedure:
A mixture of N-(4-ethoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (204 mg, 0.7 mmol), potassium carbonate (188 mg, 1.4 mmol), cesium carbonate (22 mg, 0.1 mmol), and iodoethane (0.08 mL, 1 mmol) in N,N-dimethylformamide was heated at 85° C. for 1 hour. The mixture was cooled and filtered using ethyl acetate. The solid was set aside; the organic layer was washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and triturated with diethyl ether to give N-(4-ethoxyphenyl)-1-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (73 mg). The set-aside solid was slurried in aqueous hydrochloric acid, the precipitate collected, rinsed with water and dried to give additional amide (Compound 58) (94 mg). mp. 209°-210° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:18][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)NCCc1ccc(C(C)=O)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NCCc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
In a round-bottomed flask, N-[2-(4-acetyl-phenyl)-ethyl]-acetamide (7.23 g, 35.2 mmol) was dissolved in methylene chloride (120 ml), and methanol (60 ml). Tetrabutylammonium tribromide (17.0 g, 35.2 mmol) was added to this solution in one portion, and the mixture was allowed to stir overnight at room temperature. The volatiles were then removed in vacuo to afford an oil, which was then resuspended in 100 ml of methylene chloride and extracted with 125 ml of saturated aqueous sodium bicarbonate. The aqueous extracts were reextracted with methylene chloride (3×100 ml), and the combined organic extracts were then washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by column chromatography (silica gel; methylene chloride to 7% methanol/methylene chloride), and the resulting material was washed with 110 ml of water to afford 8.27 g (83% yield) of pure product as a white solid. LRMS ([M−1 ]−)=283.0, 284.9.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]=[CH:12][N:13]([C:52]=2[N:53]=[C:54]([NH:56][C:57](=[O:66])[CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:55]=1)[C@@H:14]1[O:51][C@H:25]([CH2:26][O:27]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]2[N:11]=[CH:12][N:13]([C:52]=2[N:53]=[C:54]([NH:56][C:57](=[O:66])[CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:55]=1)[C@@H:14]1[O:51][C@H:25]([CH2:26][OH:27])[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(OCc5ccccc5)nc(NC(=O)COc5ccccc5)nc43)C[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(OCc4ccccc4)nc(NC(=O)COc4ccccc4)nc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.07 h
Yield: 85 %

Procedure:
A solution of 3% TCA (67.8 mL, 19.9 mmol) in CH2Cl2 is added to a solution of 8 (4.51 g, 4.97 mmol) dissolved in CH2Cl2 (100 mL) and stirred at room temperature for 4 minutes. Et3N (2.77 mL, 19.9 mmol) is added to the solution, and the solvent is removed under reduced pressure. The resulting solid is purified by column chromatography (silica, 90:10 CH2Cl2: EtOAc) to afford 9 as an off-white foam (2.56, 85.0%). 1H NMR (DMSO-d6) δ 10.69 (1H, s, N2H, exchanges with D2O), 8.47 (1H, s, H-8), 7.54 (2H, dd, J=8.4, J=1.6, PAc Ar), 7.42-7.34 (3H, m, Bn Ar), 7.31-7.26 (2H, m, Bn Ar), 6.97-6.92 (3H, m, PAc Ar), 6.33 (1H, t, J=6.8, H-1′), 5.63 (2H, s, CH2-Ph), 5.04 (2H, s, Pac-CH2), 4.94 (1H, t, J=5.4, 5′-OH, exchanges with D2O), 4.60 (1H, ddd, J=5.6, J=2.8, J=2.8, H-3′), 3.84 (1H, ddd, J=4.8, J=4.8, J=2.8, H-4′), 3.57 (1H, ddd, J=11.6, J=5.6, J=5.6, H-5′), 3.51 (1H, J=11.2, J=5.2, J=4.8, H-5′), 2.82 (1H, ddd, J=13.2, J=6.0, J=2.0, H-2′), 2.28 (1H, ddd, J=13.2, J=6.0, J=3.2, H-2′), 0.875 (9H, s, Si—C(CH3)3), 0.094 (3H, s, Si—CH3), 0.088 (3H, s, Si—CH3). Anal. (C31H39N5O6Si) C, H, N.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Cl:13][C:14]1[CH:15]=[N+:16]([O-:43])[CH:17]=[C:18]([Cl:42])[C:19]=1[CH2:20][C@H:21]([O:32][C:33]([C:35]1[S:36][C:37]([CH:40]=O)=[CH:38][CH:39]=1)=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:42][C:18]1[CH:17]=[N+:16]([O-:43])[CH:15]=[C:14]([Cl:13])[C:19]=1[CH2:20][C@H:21]([O:32][C:33]([C:35]1[S:36][C:37]([CH2:40][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([O:3][Si:2]([CH3:12])([CH3:11])[CH3:1])[CH:5]=2)=[CH:38][CH:39]=1)=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Reactant: C[Si](C)(C)Oc1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNc3cccc(O[Si](C)(C)C)c3)s2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-((trimethylsilyl)oxy)aniline (0.14 g, 0.77 mmol) and [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (0.186 g, 0.39 mmol) in DCM (5 mL) was stirred at room temperature for 18 h. NaBH(OAc)3 (0.206 g, 0.97 mmol) and acetic acid (0.043 mL, 0.75 mmol) was added and the reaction mixture was stirred at room temperature for a further 3 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 solution (25 mL). The aqueous phase was further extracted with DCM (10 mL), and the combined organic phases were washed with brine (20 mL), filtered through a phase separator cartridge and the solvent was removed in vacuo, co-evaporated with MeCN to give [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(3-trimethylsilyloxyanilino)methyl]thiophene-2-carboxylate as a light brown gum. A mixture of this material (0.185 g, 0.29 mmol) and (R)-quinuclidin-3-yl carbonochloridate (0.162 g, 0.72 mmol) in MeCN (5 mL) was heated in a microwave at 80° C. for 6 min. Additional (R)-quinuclidin-3-yl carbonochloridate (0.08 g, 0.35 mmol) was added and heated in the microwave at 80° C. for a further 6 min. The solvent was removed in vacuo and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The separated aqueous phase was basified by the addition of saturated aqueous NaHCO3 solution and extracted with EtOAc (2×20 mL). The organic extracts were combined and filtered through a phase separator and the solvent was removed in vacuo. Purification by preparative HPLC gave the title compound as a white solid (0.02 g, 9.6%).
Reaction SMILES: [C-]#N.[K+].[Cl-].[Cs+].CC(C)(O)[C:8]#[N:9].[C:12]([O:16][C:17](=[O:41])[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:39])/[CH:25]=[C:26](\[C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)/[C:27]([F:30])([F:29])[F:28])=[CH:20][C:19]=1[CH3:40])([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1.O>[C:12]([O:16][C:17](=[O:41])[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:39])[CH2:25][C@:26]([C:8]#[N:9])([C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)[C:27]([F:28])([F:30])[F:29])=[CH:20][C:19]=1[CH3:40])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
Potassium cyanide (0.0377 g, 0.578 mmol), cesium chloride (0.0086 g, 0.051 mmol) and acetone cyanohydrin (0.142 ml, 1.55 mmol) were added to a solution of 4-[(E)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.250 g, 0.512 mmol) in toluene (5.0 ml). To this vigorously stirred suspension was added antracen-9-yl-methyl quininium chloride (0.071 g, 0.129 mmol). The reaction mixture was stirred at 90° C. for 18 hours. At this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.197 g, 79%) as a white foam. Chiral HPLC analysis (Chiralpack IB, Heptane:2-propanol=90:10, 1 ml/min, retention time 8.18 minutes (major enantiomer, minor enantiomer not observed), indicated that the reaction proceeded with >99% enantioselectivity.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]5[N:35]=[C:34]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[NH:33][N:32]=5)[CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[N:9][C:10]3[CH:11]=[CH:12][NH:13][C:14](=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:44].CN(C=O)C.C([O-])(O)=O.[Na+]>O>[Cl:44][C:14]1[N:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[NH:35][C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)=[N:33][N:32]=4)[CH2:29][CH2:30]3)=[CH:22][CH:23]=1)=[N:9]2
Reactant: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 130 °C

Procedure:
A mixture of 8-7 (5.5 g, 10.2 mmol) and POCl3 (50.0 g, 326.1 mmol) and DMF (0.3 g, 4.1 mmol) was heated to reflux at 130° C. for 3 hr. The reaction mixture was cooled and concentrated to remove POCl3. 40 mL Toluene was added and concentrated to obtain a solid. To the solid was added 50 mL H2O and 40 mL NaHCO3 (saturated) and 20 mL 1NNaOH to pH=9. The mixture was stirred to precipitate a solid which was collected via filtration as the desired product 8-8. It was washed by water and CH3CN and dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=1>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)cs1
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromo-2-cyanothiophene generally according to the procedures described in examples 82 and 1. A yellowish solid: mp 202-204° C.; 1H NMR (DMSO-d6): δ 10.06 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 7.64-7.7 (m, 2H), 7.55 (d, J=5.0 Hz, 1H), 7.23 (d, J=8.48 Hz, 1H), 6.92-7.03 (m, 2H), 4.06 (d, J=15.52 Hz, 1H), 3.94 (d, J=15.44 Hz, 1H), 3.37 (m, 1H), 2.5 (m, 1H), 0.76 (t, J=6.79 Hz, 1H); MS (ESI) m/z 381 ([M+H]+); MS (ESI) m/z 379 ([M−H]−); Anal. calcd for C20H16N2O2S2: C, 63.14; H, 4.24; N, 7.36. Found: C, 62.53; H, 4.25; N, 7.12.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1
Reactant: C1CSCCN1
Reactant: Fc1ccc(C2=NOC(Cn3ccnn3)C2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(C2=NOC(Cn3ccnn3)C2)ccc1N1CCSCC1

Procedure:
A mixture of (5RS)-3-(3,4-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-4,5-dihydroisoxazole (528 mg, 2 mM), potassium carbonate (414 mg, 3 mM), and thiomorpholine (7.5 ml) was heated under nitrogen at 130° for 40 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic extract was washed with aqueous sodium dihydrogen phosphate (75 ml), sodium bicarbonate (75 ml), and brine (75 ml). After drying (magnesium sulfate) and evaporation, the crude product was then purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient from 50–100% ethyl acetate in isohexane. Relevant fractions were combined to give the desired product (305 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([C:19](=[CH2:21])[CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:23])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([C:19](=[CH2:21])[CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:23])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1C[C@]2(CC)C(=O)C[C@H](O)[C@H]2[C@@H]2CCC3=CC(=O)CC[C@@H]3[C@@H]12
Solvent: c1ccncc1
Product: C=C1C[C@]2(CC)C(=O)C[C@H](OC(C)=O)[C@H]2[C@@H]2CCC3=CC(=O)CC[C@@H]3[C@@H]12
Temperature: 0 °C

Procedure:
2.2 g of 15α-hydroxy-18-methyl-11-methylene-4-estrene-3,17-dione is reacted in 10 ml of pyridine with 2.5 ml of acetic anhydride under argon at room temperature within 2 hours. The solution is introduced into ice/water. The thus-precipitated crude product is vacuum-filtered, dissolved in ethyl acetate, and dried. Chromatography of the crude product on silica gel with 0-20% acetone/hexane yields 1.7 g of 15α-acetoxy-18-methyl-11-methylene-4-estrene-3,17-dione, mp 176.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[I-].[K+].Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(OCCCCl)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 73.6 %

Procedure:
To a solution of 2.58 g of p-chlorophenol in 25 ml of ethanol is added 2.64 g of 85% potassium hydroxide solution, 3.6 g of potassium iodide and 4.6 g of [p-(3-chloropropoxy)phenyl]acetic acid. The mixture is refluxed for 18 hours, diluted with water, acidified with concentrated HCl and filtered to give 4.74 g of crystals. Recrystallization from acetic acid-water gives 3.85 g of white crystals, mp slowly melts 131°-150° C.
Reaction SMILES: C(OC([NH:8][C:9]1[NH:35][CH2:34][C:33]2[CH:36]=[C:37]([Cl:38])[C:30](=[C:31]([Cl:39])[CH:32]=2)[NH:29][C:28](=[O:40])[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=[CH:23][CH2:22][O:21][C:20]2[CH:48]=[CH:49][C:17](=[CH:18][CH:19]=2)[C:16]2[C:12](=[C:13]([CH3:50])[O:14][N:15]=2)[C:11](=[O:51])[N:10]=1)=O)(C)(C)C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[NH2:8][C:9]1[NH:35][CH2:34][C:33]2[CH:32]=[C:31]([Cl:39])[C:30](=[C:37]([Cl:38])[CH:36]=2)[NH:29][C:28](=[O:40])[CH2:27][NH:26][CH2:25][CH:24]=[CH:23][CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:17](=[CH:49][CH:48]=2)[C:16]2[C:12](=[C:13]([CH3:50])[O:14][N:15]=2)[C:11](=[O:51])[N:10]=1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]
Reactant: Cc1onc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CC=CCOc1ccc-2cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1onc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCC=CCOc1ccc-2cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The intermediate (24 mg) from Step 1(C) was dissolved in 2 mL of TFA and DCM mixture (1:1). The resulted solution was stirred at room temperature for 1 h. TFA and DCM were evaporated in vacuo to give a crude product, which was purified by preparative HPLC to give the title compound as a TFA salt (19.9 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])=[O:8])(=[O:3])[CH3:2].[NH2:22][OH:23].Cl>C(N(CC)CC)C>[OH:23][NH:22][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7](=[O:8])[C:6]1[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)CCCCCCC(=O)O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)CCCCCCC(=O)NO
Yield: 43 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50e for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 43% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 7.78 (dd, J=8.1, 1.2 Hz, 1H), 7.47 (m, 1H), 6.96 (dd, J=8.4, 1.2 Hz, 1H), 6.91 (m, 1H), 3.00 (t, J=7.2 Hz, 2H), 2.12 (t, J=7.5 Hz, 2H), 1.59-1.79 (m, 4H), 1.40 (m, 4H); 13C NMR (75.4 MHz, CD3OD/CDCl3=5/1) δ 23.97, 32.51, 37.94, 118.02, 118.84, 119.01, 129.86, 136.09, 161.76, 171.15, 206.79.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH2:20]([Li])CCC.CI>C1COCC1>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:3]1[C:2]([CH3:20])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=1
Reactant: Cn1nc(-c2cc(F)ccc2F)c(Br)c1C(F)(F)F
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(-c2cc(F)ccc2F)nn(C)c1C(F)(F)F
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 10 g of 4-bromo-3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 250 mL anhydrous THF was cooled to -78° C. and stirred with an overhead stirrer. The cold solution was treated with 12 mL of 2.5M n-butyllithium in hexanes never allowing the temperature to exceed -70° C. After stirring for 5 minutes, 1.9 mL of methyl iodide was added quickly. The cooling bath was removed and the solution allowed to warm to room temperature. The solution was diluted with diethyl ether and the combined organic extracts were washed twice with brine, dried over anhydrous magnesium sulfate and concd in vacuo. Chromatographic purification (silica, 5% ethyl acetate in hexanes) gave 5.8 g (72.4%) of 3-(2,5-difluorophenyl)-1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazole as an oil; 1HNMR (CDCl3) δ 2.0 (quintet, 3H, J=2.1 Hz), 3.9 (d, 3H, J=1.2 Hz), 6.9-7.1 (m, 3H). Anal. Calcd for C13H9F5N2: C, 52.18; H, 3.28; N, 10.14. Found: C, 52.20; H, 3.30; N, 10.11.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[Na+].[Na+].[Cl-]>C1COCC1>[NH2:9][CH2:8][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1ncccc1Br
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1ncccc1Br

Procedure:
3-Bromo-pyridin-2-nitrile (14.3 g, 78.0 mmol) was dissolved in 200 mL of dry THF. While stirring the solution, 100 mL of BH3-THF complex (1M) (5 eq) was added drop-wise. The mixture was then stirred overnight and 250 mL 4N HCl were added and the solution was refluxed for additionally 30 min. After that a 2M aqueous solution of NaOH (pH-value=8.0). The mixture was saturated by addition of NaCl. The organic layer was separated and the aqueous solution was again extracted three times by means of 100 mL THF. The organic layers were combined and dried over Na2SO4. After that the solvent was removed and the remaining oil was used without further purification.