Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>C1COCC1>[CH3:19][N:2]1[N:3]=[N:4][C:5]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[N:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nn[nH]n2)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnc(C2CCNCC2)n1
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
To a solution of tert-butyl 4-(2H-tetrazol-5-yl)piperidine-1-carboxylate (CAS 91419-58-8) (0.98 g, 3.89 mmol) and triphenylphosphine (3.06 g) in THF under a blanket of Ar was added the diisopropyl azodicarboxylate (2.30 ml) and the mixture stirred for 10 minutes. Methanol (473 μl) was added and the reaction was stirred for 18 hours and then the solution was concentrated in vacuo. The residue was purified on silica using a 90 g Biotage cartridge and a gradient elution of 25 to 35% ethyl acetate in hexanes. This semi-pure mixture was partially dissolved in a 4M HCl in dioxane solution and stirred for 1 hour, then concentrated in vacuo. The residue was partially dissolved in DCM (40 ml) and triethylamine (162 μl) and MP-Carbonate (4.17 g, loading 2.8 mmol/g) added and slurry stirred for 64 hours. The resin was filtered off and washed with a 10% solution of methanol in DCM and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on SCX-2 stationary phase using methanol and then a 1M ammonia in methanol solution. Evaporation of the solvent under reduced pressure gave the title compound as a yellow solid (0.502 g); NMR (CDCl3): 1.78 (2H, m), 2.06 (2H, d), 2.77 (2H, m), 3.08 (1H, m), 3.19 (2H, d), 3.08 (3H, s).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][CH3:29])=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[OH:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][O:28][CH3:29])=[CH:25][CH:26]=2)[CH3:20])[CH2:14][CH2:13]1
Reactant: COCc1ccc([C@H](C)N2CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c3ccccc3)OC2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: COCc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(methoxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (7 mg, 0.02 mmol) in EtOAc (5 mL) was added TBAF (26.1 mg, 0.10 mmol) at rt, and the mixture was stirred at rt overnight. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative TLC followed by preparative HPLC to afford (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(methoxymethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1.63 mg). LC-MS Method 3 tR=0.96, min, m/z=406; 1H NMR (CDCl3): 1.39 (m, 1H), 1.49 (m, 3H), 1.71 (m, 1H), 1.89 (m, 3H), 2.01 (m, 1H), 2.18 (m, 2H), 2.75-2.88 (m, 3H), 3.23 (m, 1H), 3.48 (m, 1H), 3.70 (m, 1H) □4.19 (m, 1H), 5.58 (m, 1H), 6.73-6.86 (m, 2H), 7.08-7.29 (m, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[O:10]([C:17]1[CH:18]=[C:19]([CH2:23][CH:24]([CH3:27])[CH2:25]I)[CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:10]([C:17]1[CH:18]=[C:19]([CH2:23][CH:24]([CH3:27])[CH2:25][N:6]2[CH2:7][CH2:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH2:5]2)[CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(CI)Cc1cccc(Oc2ccccc2)c1
Reactant: COCc1cccnc1
Product: COCC1=CCCN(CC(C)Cc2cccc(Oc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 20 %

Procedure:
3-Methoxymethylpyridine (1.75 g) was added to 3-(m-phenoxyphenyl)-2-methylpropyl iodide (1.0 g) at room temperature, and the resultant mixture was stirred at 120° C. for 4 hours. The reaction mixture was cooled to room temperature and washed with diethyl ether three times. Methanol (20 ml) was added thereto, and after addition of sodium borohydride (0.21 g) at room temperature, the resultant mixture was stirred at the same temperature for 15 hours. The resultant mixture was admixed with water (200 ml) and 15% aqueous sodium hydroxide solution (20 ml) and extracted with diethyl ether (50 ml×3). The extracts were combined together, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give N-[3-(m-phenoxyphenyl)-2-methylpropyl]-3-methoxymethyl-1,2,5,6-tetrahydropyridine (0.2 g).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=2)[CH:10]=[C:9]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:8]=1>>[CH:1]1([O:5][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=3)[CH:10]=[C:9]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCC1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Product: COCCOc1cc2c(OC3CCC3)nc(Nc3cc(C)[nH]n3)cc2cc1OC

Procedure:
Similar procedure as described in example 400 was used, starting from cyclobutanol and [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-Cyclobutoxy-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 399(MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][C:11]([C:12]3[N:20]=[C:19]4[C:15]([NH:16][C:17](=[O:26])[N:18]4[C@H:21]([CH3:25])[C:22](O)=[O:23])=[CH:14][N:13]=3)=[C:5]2[CH:4]=1)#[N:2]>C1COCC1>[OH:23][CH2:22][C@H:21]([N:18]1[C:17](=[O:26])[NH:16][C:15]2[C:19]1=[N:20][C:12]([C:11]1[CH:10]=[N:9][N:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=13)=[N:13][CH:14]=2)[CH3:25]
Reactant: C[C@H](C(=O)O)n1c(=O)[nH]c2cnc(-c3cnn4ccc(C#N)cc34)nc21
Solvent: C1CCOC1
Product: C[C@H](CO)n1c(=O)[nH]c2cnc(-c3cnn4ccc(C#N)cc34)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a solution of example 14 (60 mg, 0.17 mmol) in THF (10 mL) at 0° C., 1 M THF borane complex solution in THF (0.69 mL, 0.69 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched with MeOH (10 mL) and the reaction mixture was evaporated under reduced pressure. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH2Cl2/MeOH mixtures of increasing polarity as eluent to afford 4 mg of the desired product (7% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:5]=[C:6]2[C:15]=1[CH:14]=[CH:13][C:12]1[O:11][CH2:10][CH2:9][O:8][C:7]2=1.[C:23](B1OC(C)(C)C(C)(C)O1)([CH3:25])=[CH2:24]>>[CH:23]([C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:5]=[C:6]2[C:15]=1[CH:14]=[CH:13][C:12]1[O:11][CH2:10][CH2:9][O:8][C:7]2=1)([CH3:25])[CH3:24]
Reactant: Cc1cc(Nc2cc3c4c(ccc3c(Cl)n2)OCCO4)n[nH]1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: Cc1cc(Nc2cc3c4c(ccc3c(C(C)C)n2)OCCO4)n[nH]1

Procedure:
Similar procedure as described in example 330 was used, starting from (8-Chloro-2,3-dihydro-1,4-dioxa-7-aza-phenanthren-6-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropenylboronic acid pinacol ester to give (8-Isopropyl-2,3-dihydro-1,4-dioxa-7-aza-phenanthren-6-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 325(MH+).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:9]2([CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C2(CC(Cl)(Cl)Cl)CO2)C=CC=1.FC1C=C(C2(CC(Cl)(Cl)Cl)CO2)C=CC=1.ClC1C=C(C2(CC(Cl)(Cl)Cl)CO2)C=CC=1Cl.C(OC1C=C(C2(CC(Cl)(Cl)Cl)CO2)C=CC=1)C.C(OC1C=C(C2(CC(Cl)(Cl)Cl)CO2)C=CC=1)C1C=CC=CC=1.ClC1C=CC(C2(CC(Cl)(Cl)Cl)CO2)=CC=1.[Br:117]C1C=CC(C2(CC(Cl)(Cl)Cl)CO2)=CC=1>>[Br:117][C:3]1[CH:4]=[C:5]([C:9]2([CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(CC(Cl)(Cl)Cl)CO2)c1
Reactant: ClC(Cl)(Cl)CC1(c2ccc(Br)cc2)CO1
Agent: CCOc1cccc(C2(CC(Cl)(Cl)Cl)CO2)c1
Agent: ClC(Cl)(Cl)CC1(c2cccc(OCc3ccccc3)c2)CO1
Agent: Clc1ccc(C2(CC(Cl)(Cl)Cl)CO2)cc1
Product: ClC(Cl)(Cl)CC1(c2cccc(Br)c2)CO1

Procedure:
2-(m-methoxyphenyl)-2-(2,2,2-trichloroethyl)oxirane; 2-(m-chlorophenyl)-2-(2,2,2-trichloroethyl)oxirane; 2-(m-fluorophenyl)-2-(2,2,2-trichloroethyl)oxirane; 2-(3,4-dichlorophenyl)-2-(2,2,2-trichloroethyl)oxirane; 2-(m-ethoxyphenyl)-2-(2,2,2-trichloroethyl)oxirane; 2-(m-(benzyloxy)phenyl)-2-(2,2,2-trichloroethyl)oxirane; 2-(p-chlorophenyl)-2-(2,2,2-trichloroethyl)oxirane; 2-(p-bromophenyl)-2-(2,2,2-trichloroethyl)oxirane; and 2-(m-bromophenyl)-2-(2,2,2-trichloroethyl)oxirane gave complete control and kill of Trichophyton mentagrophytes, Bacillus subtilis and Mycobacterium phlei.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18]([C:20]1[S:21][C:22]([C:25](O)=[O:26])=[CH:23][CH:24]=1)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[S:21][C:22]([C:25](=[O:26])[NH:15][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][CH:11]=2)[CH3:14])=[CH:23][CH:24]=1)=[O:19]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: CC(N)c1ccc(N2CCOCC2)cc1
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(N3CCOCC3)cc2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 1 from 1-(4-Morpholin-4-yl-phenyl)-ethylamine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH2:15]O)=[C:5]2[C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.ClC1C2C(=CC(Cl)=CC=2)[N:32]=[CH:31]C=1>>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([C:31]#[N:32])[CH:3]=4)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=3[CH3:15])=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: O=C(O)Cn1c(CO)c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc21
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(C#N)ccc2n1CC(=O)O

Procedure:
The sub-title compound was prepared from the product of example 55, step a) and 4,7-dichloroquinoline by the method of example 55, step b).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH-:11].[Na+]>>[OH:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(O)nc1
Temperature: 102 °C
Yield: 60 %

Procedure:
A mixture containing 500 g (3.6 mol) of 2-amino-5-nitropyridine in 2000 ml of 10% sodium hydroxide was refluxed at about 102° C. for 10 hours, cooled and filtered. The filter cake was dissolved in water and neutralized with hydrochloric acid. The product was filtered and dried to give 301.7 g (60%) of product as a white powdery solid, m.p. 188°-190° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[OH:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>C(Cl)Cl>[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([O:6][C:29](=[O:30])[NH:28][C:23]1[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: CN(C)CCC(O)c1ccc(-c2ccncc2)cc1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: CN(C)CCC(OC(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-dimethylamino-1-(4-pyridin-4-yl-phenyl)-propan-1-ol (100 mg, 0.37 mmol) in CH2Cl2 (2 mL) was added 3,5-dichloro-phenylisocyanate (70 mg, 0.37 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to give a light brown oil, which was then purified by silica gel chromatography (5–10% MeOH/DCM gradient) to afford the title compound (3,5-dichloro-phenyl)-carbamic acid 3-dimethylamino-1-(4-pyridin-4-yl-phenyl)-propyl ester as a white solid, 131 mg (91%). 1H NMR (300 MHz, CD3OD): δ 8.77 (dd, 2H), 7.72 (d, 2H), 7.58 (m, 3H), 7.48 (d, 2H), 7.12 (t, 1H), 5.94 (t, 1H), 2.49 (m, 2H). 2.36 (s, 6H), 2.33 (m, 1H), 2.21 (m, 1H); MS(ESI): 444.1 (M+1), 446.1 (M+3).
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([O:25][CH2:26][O:27][CH3:28])[CH:12]=2)=[CH:8][CH:7]=1)=O.[OH-].[K+].[CH2:34]([CH:36]1[O:38][CH2:37]1)Cl>CO>[CH3:28][O:27][CH2:26][O:25][C:13]1[CH:12]=[C:11]([O:10][C:9]2[CH:8]=[CH:7][C:6]([S:5][CH2:34][CH:36]3[CH2:37][O:38]3)=[CH:30][CH:29]=2)[CH:16]=[CH:15][C:14]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: ClCC1CO1
Reactant: COCOc1cc(Oc2ccc(SC(=O)N(C)C)cc2)ccc1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCOc1cc(Oc2ccc(SCC3CO3)cc2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of compound 18 (0.65 g, 1.5 mmol) in anhydrous MeOH (10 mL) was added potassium hydroxide (0.42 g, 7.5 mmol). The mixture was refluxed for 4 h and then cooled to room temperature. Epichlorohydrin (0.21 g, 2.3 mmol) was added dropwise and the mixture was stirred at room temperature for 15 min, after which the solvent was removed under reduced pressure. The concentrate was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the suspension was filtered, followed by concentration of the filtrate in vacuo. Purification by silica gel chromatography (hexanes/EtOAc=4/1) gave 19 in 68% yield (0.43 g) 1H NMR (500 MHz, CDCl3) δ 1.53 (s, 9H), 8.03 (br. s., 1H), 2.47 (dd, J=2.6, 5.0 Hz, 1H), 2.77 (t, J=4.4 Hz, 1H), 2.85 (dd, J=6.1, 13.9 Hz, 1H), 3.12-3.05 (m, 1H), 3.18-3.12 (m, 1H), 5.18 (s, 2H), 3.48 (s, 3H), 6.66 (dd, J=2.6, 8.8 Hz, 1H), 6.92-6.85 (m, 3H), 6.98 (br. s., 1H), 7.44-7.37 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 28.5, 38.2, 47.6, 51.3, 56.5, 80.6, 95.4, 106.8, 113.1, 118.4, 119.4, 125.1, 128.0, 131.8, 133.8, 146.6, 151.2, 152.9, 157.9. HRMS (FAB) calcd for C22H28NO4S (M+H+) 434.1632. found 434.1637.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([CH3:12])[CH2:9][C:10]#[CH:11])(=O)=O.[F:13][C:14]([F:24])([F:23])[CH2:15][CH2:16][S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18].[H-].[Na+].Cl>CS(C)=O>[CH3:12][CH:8]([CH2:9][C:10]#[CH:11])[CH2:7][CH2:6][CH:20]([S:17]([CH2:16][CH2:15][C:14]([F:13])([F:23])[F:24])(=[O:18])=[O:19])[C:21]#[N:22]
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: C#CCC(C)CCOS(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCC(C)CCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1.0 g of 3-methyl-5-hexynyl methanesulfonate and 1.1 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of dimethyl sulfoxide was added 0.2 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was stirred at 60° C. for 3 days and at 90° C. for 2 hours. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.69 g of 5-methyl-2-(3,3,3-trifluoropropylsulfonyl)-7-octynenitrile (hereinafter referred to as the present compound (27)).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CC(O)=O.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O.C1COCC1>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
A 250 mL flask was charged with ethyl 4-oxocyclohexanecarboxylate (5 g, 28.5 mmol, Alfa Aesar) and THF (75 mL). The solution was cooled to about 0° C. and AcOH (2.28 mL, 39.9 mmol) and dibenzylamine (6.18 g, 31.3 mmol) (TCI) were added dropwise, resulting in formation of a thick suspension. Na(OAc)3BH (14.3 g, 64.1 mmol) was added portionwise and the reaction mixture was stirred at ambient temperature for about 72 h. The reaction mixture was cooled to about 10° C. Water (25 mL) was added and the reaction mixture was stirred for about 15 min. Heptanes (50 mL) were added. The layers were separated and the organic layer was washed with 10% aqueous AcOH solution (25 mL) and then with water (10 mL). The organic layer was extracted with 4% HCl solution twice (40 mL and 20 mL). The combined aqueous layer was washed with heptanes (20 mL). To the aqueous layer was slowly added 30% aqueous K2CO3 solution (30 g) to adjust the pH to 10. The aqueous solution was extracted with heptane twice (75 mL and 15 mL). The combined organic layer was washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concd under reduced pressure to give ethyl 4-(dibenzylamino)cyclohexanecarboxylate (7.2 g, 72%) as an oil which solidified upon standing: LC/MS (Table 1, Method a) Rt=3.18 and 3.23 min; MS m/z: 352 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.N[CH2:9][C@@H:10]1CC[CH2:12][N:11]1CC.C(=O)C>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[CH2:9][CH2:10][NH:11][CH3:12]
Reactant: CC1CCC(C)N1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1C(C)CCC1C

Procedure:
By using 2,5-dimethylpyrrolidine (200 mg) as a starting material, the title compound (0.17 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: C([O:4][C:5]1[C:6]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.[OH-].[Na+].Cl>>[Cl:20][C:18]1[CH:17]=[CH:16][C:7]2[S:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:5]([OH:4])[C:6]=2[CH:19]=1
Reactant: CC(=O)Oc1c(-c2ccccc2)sc2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1c(-c2ccccc2)sc2ccc(Cl)cc12

Procedure:
A mixture of 3-acetoxy-5-chloro-2-phenylbenzo[b]thiophene (150 mg, 0.50 mmol) and 20% aqueous sodium hydroxide (5 ml) was stirred at reflux temperature for 1 hour. The cooled reaction mixture was acidified with concentrated hydrochloric acid, the solid that separated out filtered, washed with water, and dried in vacuo over phosphorous pentoxide. Recrystallization from cyclohexane afforded pure 5-chloro-3-hydroxy-2-phenylbenzo[b]thiophene; yield 35 mg (26%); m/z 275 (M+.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C=O)C.[H-].[Na+].[CH:18]([Si:21]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])Cl)([CH3:20])[CH3:19]>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:21]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(I)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Iodo-1H-indole (5.0 g, 20.57 mmol) was dissolved in CH2Cl2 (50 ml) and DMF (1 ml) and cooled to 0° C. Sodium hydride (1.234 g, 30.86 mmol) was added in small portions, and the reaction mixture was stirred for 30 minutes at 0° C. Triisopropylchlorosilane (4.54 ml, 20.57 mmol) was added slowly to the reaction mixture, and stirring was continued for 1 hour. Cold water (200 ml) was added to the reaction mixture, which was extracted twice with ethyl acetate (100 ml).
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:25])[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[N:11][C:10]=2[CH3:26])[N:8]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:25])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[N:11][C:10]=2[CH3:26])[N:8]=1)#[N:2]
Reactant: Cc1nc(NC(=O)CCC(=O)OC(C)(C)C)sc1-c1csc(CC#N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NC(=O)CCC(=O)O)sc1-c1csc(CC#N)n1
Temperature: 25 °C

Procedure:
Tert-butyl 4-{[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]amino}-4-oxobutanoate, Compound (58), (63 mg; 0.16 mmol; 1 eq.), is dissolved in DCM (3 ml). Trifluoroacetic acid (0.16 ml; 2.09 mmol; 13 eq) is added dropwise and the reaction mixture is stirred at RT. The solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (63) as a white-off solid (54 mg; 29%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][C:43]#[C:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42][C:43]#[C:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 71.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (58.9 mg, 0.105 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol), 15-crown-5(10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=19:1, developed once) to give the title compound as a colorless oil (60.2 mg, 72%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+]>Cl>[N:12]1([CH2:11][C:8]2[CH:9]=[C:10]3[C:5]([CH2:4][CH2:3][C:2]3=[O:1])=[CH:6][CH:7]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)C(=O)CC3)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CCc2ccc(CN3CCNCC3)cc21

Procedure:
A solution of Example 871A (0.83 g, 2.50 mmol) in 10% aqueous HCl (4 mL) was stirred at 60° C. for 15 min. The solution was brought to basic pH by the addition of K2CO3, then concentrated in vacuo to give a crude solid.