Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH3:2].[SH:3][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[N:6][N:5]=1.[OH-].[Na+]>CO>[CH3:2][S:3][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[N:6][N:5]=1
Reactant: CI
Reactant: CCCCn1cnnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cnnc1SC

Procedure:
Iodomethane (9.05 g. or 0.0637 mole) was added to a solution of 10 g. of 3-mercapto-4-n-butyl-1,2,4-triazole, methanol (100 ml.), and sodium hydroxide (2.55 g. or 0.0637 mole). This solution was then refluxed for 2 hours. The solvent was then removed in vacuum and the residue was dissolved in benzene. This solution was washed with water, dried and the benzene removed in vacuum. The residual oil was distilled to give 3-methylmercapto-4-n-butyl-1,2,4-triazole, b.p. 128°-131° C./ 2 mm. The structure was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[Cl:8].[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:16][C:14]1[N:13]=[C:12]([OH:17])[CH:11]=[C:10]([CH3:9])[N:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1ncsc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2scnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A mixture of 5-(bromomethyl)-4-chloro-1,3-thiazole (8.4 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (850 mg, 6.0 mmol), and triethylamine (3.5 mL, 25 mmol) in absolute ethanol (45 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness and then co-evaporated with EtOAc (20 mL). The residue was treated with water (100 mL). The solid material was recovered by filtration and washed with water (3×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL). The solid material was dried in vacuo. The crude product was purified by flash chromatography (0-4% MeOH/DCM), affording the title compound (491 mg, 31% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 4.62 (s, 2H), 6.05 (s, 1H), 8.82 (s, 1H); M+274.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1)=O.Cl.[OH-].[NH4+:17]>[Ni].CO>[F:12][C:11]([F:14])([F:13])[O:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:17])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: [NH4+]
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Agent: [Ni]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(N)c1cccc(OC(F)(F)F)c1
Yield: 63 %

Procedure:
A mixture of 3-trifluoromethoxyacetophenone, oxime, Preparation 14 (3.08 g, 12.36 mmol), Raney nickel (1 mL) in methanol (50 mL) and ammonium hydroxide (5 mL) was hydrogenated (H2, 50 psi) for 16 hours. The reaction mixture was filtered through Celite and the resultant filtrate was concentrated in vacuo. The suspension obtained was acidified with hydrochloric acid (6N) (100 mL). The aqueous layer was washed with diethyl ether (2×50 mL). The aqueous layer was then made basic with sodium hydroxide (10 N) (with cooling). The basic aqueous layer was then extracted with CH2Cl2 (2×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the resultant filtrate was concentrated in vacuo to provide the title compound (1.82 g, 63%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:7][C:6]=1[NH2:18])=[O:4].[Cl:19][C:20]([Cl:27])([Cl:26])[C:21]([N:23]=[C:24]=[O:25])=[O:22]>C1COCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[S:7][C:6]([NH:18][C:24]([NH:23][C:21](=[O:22])[C:20]([Cl:27])([Cl:26])[Cl:19])=[O:25])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=2)=[CH:11][CH:12]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)sc1N
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)sc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 2-Amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid methyl ester (7.15 g, 27.2 mmol) in anhydrous THF (150 mL) was added trichloroacetyl isocyanate (6.4 mL, 54 mmol) slowly over a period of 5 min. After the addition was complete, a precipitate formed and the reaction stirred for an additional 1 h. The desired product was obtained by filtration to give 6.9 g (56%) an off-white solid. The product was used in the next step without purification 1H NMR (d6-DMSO δ 12.3, br s, 1H; δ 12.2, s, 1H; δ 7.46, d, 2H; δ 7.32, s, 1H; δ 6.85, d, 2H; δ 3.75, s, 3H; δ 3.66, s, 3H), LC/MS (APCI, ES, M+H=451).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:33])[CH2:17][CH2:18][NH:19][C:20](=[O:32])[C:21]3[C:29]([CH3:30])=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[CH3:31])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.C1C=C[C:56]2N(O)N=[N:59][C:57]=2[CH:58]=1.C(N)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:57]([NH:59][C:25](=[O:26])[C:24]1[CH:28]=[C:29]([CH3:30])[C:21]([C:20]([NH:19][CH2:18][CH2:17][C@H:16]([N:13]2[CH2:12][CH2:11][CH:10]([N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][C:40]=3[CH3:41])[CH2:15][CH2:14]2)[CH3:33])=[O:32])=[C:22]([CH3:31])[CH:23]=1)([CH3:58])[CH3:56]
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C(=O)O)cc3C)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C(=O)NC(C)C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
N-((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-terephthalamic acid (0.050 g, 0.09 mmol), EDCI (0.019 g, 0.10 mmol) and HOBT (0.013 g, 0.10 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added isopropylamine (8 μL, 0.10 mmol) followed by DIPEA (19 μL, 0.11 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 93:5:2, v/v/v) afforded N′-isopropyl-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-terephthalamide (0.046 g, 86%) as a white foam. 1H NMR (CDCl3) δ 0.97 (d+m, 4H), 1.18 (d+m, 7H), 1.55 (m, 1H), 1.72 (m, 3H), 2.08 (br t, 1H), 2.26 (s, 6H), 2.30 (s, 3H), 2.42 (br t, 1H), 2.67-2.81 (m, 3H), 3.14 (m, 1H), 3.31 (m, 1H), 3.72 (s, 3H), 3.78 (m, 1H), 3.99 (s, 2H), 4.23 (m, 1H), 6.57 (d, 1H, J=6.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 6.73 (d, 2H, J=9.0 Hz), 7.00 (d, 1H, J=3.0 Hz), 7.45 (s, 2H), 7.83 (s, 1H), 8.29 (s, 1H), 8.31 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 13.7, 19.0, 19.6, 23.1, 29.7, 30.4, 31.3, 39.6, 42.2, 44.2, 47.7, 49.2, 51.9, 55.9, 59.6, 60.0, 114.8, 118.2, 121.4, 125.3, 126.5, 134.0, 134.8, 135.1, 141.2, 143.3, 145.2, 148.1, 149.4, 154.5, 166.5, 169.8. ES-MS m/z 600 (M+H). Anal. Calcd. for C36H49N5O3.0.1 CH2Cl2: C, 71.28; H, 8.15; N, 11.51. Found: C, 71.26; H, 8.18; N, 11.41.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][N:29]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:28]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CC[C@H](N(C)C)C3)cn2)c1O
Reaction time: 8 h
Yield: 46.2 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50.0 mg, 0.156 mmol), (S)—N,N-dimethylpyrrolidin-3-amine (26.7 mg, 0.234 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (44.9 mg, 0.234 mmol) in DMF (1561 μl). HOBT (35.9 mg, 0.234 mmol) and DIPEA (136 μl, 0.781 mmol) were added. The reaction was allowed to stir overnight. Then 1N aqueous hydrochloric acid (21 ML) was added and reaction mixture was then purified using preparative HPLC eluting with 0.1% formic acid in water and 5-30% acetonitrile to give the title compound (30 mg, 0.072 mmol, 46.1%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-1.88 (m, 1 H) 2.24 (br. s., 3 H) 2.36 (br. s., 3 H) 2.42 (s, 3 H) 2.88-3.05 (m, 2 H) 3.59-3.81 (m, 4 H) 7.58 (d, J=7.83 Hz, 1 H) 7.64 (s, 1 H) 7.95 (d, J=7.83 Hz, 1 H) 8.01 (s, 1 H) 8.11 (d, J=9.09 Hz, 1 H) 8.43 (d, J=8.84 Hz, 1 H) 8.62 (s, 1 H); ESI-MS m/z (M+H)+ calc'd for C23H24N6O2, 417.20; found 417.5.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)=O>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][C@H:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)OC(=O)N1CCC(C(C)Oc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: O=C=O
Solvent: CO
Product: CC(C)OC(=O)N1CCC([C@H](C)Oc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1

Procedure:
The racemic 1-methylethyl 4-[1-({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)ethyl]-1-piperidinecarboxylate (prepared as in Example 140) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 80% CO2: 20% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 280 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as a white foam with Tr of 13.23 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:3]([OH:20])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.2 %

Procedure:
A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (0.55 g, 2.0 mmol) in tetrahydrofuran/water (10 mL, 3:1) was treated with lithium hydroxide (185 mg, 4.40 mmol). The reaction was stirred at 25° C. for 48 h. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (25 mL) and extracted with ether (1×20 mL). The aqueous layer was acidified to pH=2 with a 3N aqueous hydrochloric acid solution. The product was extracted into methylene chloride (3×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid (0.48 g, 91.9%) as a tan solid: mp 95-99° C.; EI-HRMS m/e calcd for C14H17NO4(M+) 263.1157, found 263.1156.
Reaction SMILES: CSC(=S)NN=CC1N=C(C2C=CC=CC=2)NC=1C.C[S:21][C:22](=S)[NH:23][N:24]=[CH:25][C:26]1[N:27]=[C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:29][C:30]=1[CH2:31][CH3:32]>>[CH2:31]([C:30]1[N:29]=[C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[C:26]=1[CH:25]=[N:24][NH:23][C:22]2=[S:21])[CH3:32]
Reactant: CCc1[nH]c(-c2ccccc2)nc1C=NNC(=S)SC
Agent: CSC(=S)NN=Cc1nc(-c2ccccc2)[nH]c1C
Product: CCc1nc(-c2ccccc2)n2c(=S)[nH]ncc12

Procedure:
The general procedure of Example 62 is repeated but replacing the 3-[(5-methyl-2-phenyl-4-imidazolyl)methylene]-dithiocarbazic acid methyl ester employed in that example with 3-[(5-ethyl-2-phenyl-4-imidazolyl)methylene]dithiocarbazic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[CH2:32]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:11][C:12]1=[O:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CN(c2ccc([N+](=O)[O-])cn2)CCN1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc([N+](=O)[O-])cn2)CCN1Cc1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 4-(5-nitropyridin-2-yl)piperazin-2-one (B-13) (365 mg, 1.64 mmol) in DMF (6 mL) was added, dropwise, 1.0 M sodium bis(trimethylsilyl)amide solution in THF (1.8 mL, 1.8 mmol), followed 1 min later by benzyl bromide (215 μL, 1.8 mmol), also dropwise. After 1 h, the reaction mixture was poured into water and extracted with EtOAc. The extract was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluant: gradient of EtOAc in hexanes) to give 1-benzyl-4-(5-nitropyridin-2-yl)piperazin-2-one (B-14) (329 mg, 64% yield). MS (M+1): 313.2
Reaction SMILES: C([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:24][Si:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][CH2:16]4)[CH2:13][CH:12]=[C:11]1[CH2:10][C@@H:9]([O:44][Si:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:8][CH2:7]2)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[C:58]1([Si:45]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[O:44][C@H:9]2[CH2:8][CH2:7][C@@:6]3([CH2:5][OH:4])[C:11](=[CH:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][CH2:17][C@@H:18]3[O:24][Si:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:10]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CC(=O)OC[C@]12CC[C@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)CC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@]43CO)[C@@H]1CC[C@@H]2O[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To an ether solution of 3β,17β-di(triphenylsiloxy)androst-5-en-19-ol acetate is added a suspension of lithium aluminum hydride in ether. After refluxing for a period of one hour, water is cautiously added, the ether solution is separated, dried over sodium sulfate and evaporated under reduced pressure. The residue when purified from an acetone-hexane mixture results in the preparation of the desired 3β,17β-di(triphenylsiloxy)-androst-5-en-19-ol.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][CH2:9][CH:10]([OH:12])[CH3:11].C(O)(=O)C.C([BH3-])#N>CO>[CH:1]1([NH:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)CN
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)CNC1CCCCC1

Procedure:
Cyclohexanone (0.98 g, 10 mmol) and 1-amino-propan-2-ol (0.75 g, 10 mmol) were mixed and MeOH (20 mL), acetic acid (12 mg, 0.5 mmol), cyanoborohydride resin (7 g, 14 mmol, 2 mmol/g, prepared as described by A. R. Sande et al, Tetrahedron Letters 1984, 3501) were added. The reaction mixture was heated under reflux for 16 h. The resin was filtered off and the filtrate was evaporated in vacuo. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH:11]=[CH:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH:11]=[CH:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Yield: 69.7 %

Procedure:
A suspension of 1.1 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),6-tetraene in 25 ml of methanol and 2.5 ml of water is refluxed at a bath temperature of 100° C. with 1.1 mg of oxalic acid for 1.5 hours. Then, it is added to water, extracted with dichloromethane, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 0.6 g of 17-difluoromethylene-estra-1,3,5(10),6-tetraen-3-ol is obtained as colorless crystals with a melting point of 132-134° C., [α]D22 =-167.9° (c=0.505% in pyridine).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:18]=[N+:19]=[N-:20].[Na+].Cl>C1(C)C=CC=CC=1>[NH:18]1[C:6]([C:5]2[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:7][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2nnn[nH]2)cc1
Yield: 44.1 %

Procedure:
A mixture of p-amino benzonitrile (2 g, 16.9 mmol), triethylamine hydrochloride (3.49 g, 25.38 mmol) and sodium azide (1.65 g, 25.38 mmol) were taken in anhydrous toluene (20 ml) and heated to reflux for 24 hr. The reaction mixture was cooled to room temperature and neutralized with dilute hydrochloric acid. The resultant precipitate was filtered, washed with water then dried to give 4-(1H-tetrazol-5-yl)-phenylamine (1.2 g, 44%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:13]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH3:26])[C:14]=1[CH2:15][C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[CH3:12].N>ClCCl.C(N(CC)CC)C>[CH2:11]([C:13]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH3:26])[C:14]=1[CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: CCc1cccc(CC)c1CC1=NCCN1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1cccc(CC)c1Cc1ncc[nH]1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 73.9 %

Procedure:
To a solution of 1.08 g (14 mmol) dimethylsulfoxide in 100 ml dichloromethane cooled to −78° C. was added a solution of 1.82 g (14 mmol) oxalyl chloride in 7 ml dichloromethane. The mixture was stirred for 50 minutes at −78° C. and then a solution of 0.620 g (3 mmol) 2-(2,6-diethyl-benzyl)-4,5-dihydro-1H-imidazole in 80 ml dichloromethane was added and stirring continued at −78° C. for 90 minutes. Then 2.90 g triethylamine were added and the reaction mixture warmed to ambient temperature and stirring continued for 2 hours. Concentrated ammonia was added and the reaction mixture extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. Purification on silica gel by flash-chromatography with a heptane/ethyl acetate gradient followed by trituration of residue of the collected and evaporated fractions in tert.-butyl methyl ether provided 0.475 g 2-(2,6-diethyl-benzyl)-1H-imidazole as colourless solid: MS (ISP): 215.2 ((M+H)+.).
Reaction SMILES: [C:1]1([CH2:7]N2C3C=CC=CC=3N=N2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=NC2C=CC=CC=2)=[CH:21][CH:20]=1>CO>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C=Nc2ccccc2)cc1
Reactant: c1ccc(Cn2nnc3ccccc32)cc1
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)cc1
Yield: 67 %

Procedure:
Procedure similar to that of Example 16 using [phenylmethyl]-1H-benzotriazole (10 mmol) and N-[(4-methoxyphenyl)methylene]benzenamine (10 mmol): 67% yield: mp 57°-58° C. (MeOH) (lit.1 58°-60° C.); 1H NMR (300 MHz, CDCl3) δ3.84 (s, 3H, OCH3), 6.89 (d, 1.9H, 2H, C(3 and 5)H), 7.30-7.38 (m, 3H), 7.45-7.54 (m, 4H).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[C:26]([OH:34])(=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[C:26]([O-:34])(=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCC(=O)O
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Solvent: O
Product: CCCCCCC(=O)[O-]

Procedure:
According to the preceding example, 8.3 g of the salt are obtained starting from 6.73 g of apovincamine and 2.61 g of enanthic acid. The substance is insoluble in water and alcohol and the apovincamine content is 73%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH:15]=[CH:14][CH:13]=1
Reactant: Brc1cccc2cc[nH]c12
Reactant: OB(O)c1cccc(Cl)c1
Product: Clc1cccc(-c2cccc3cc[nH]c23)c1

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 3-chlorophenylboronic acid: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: C([O:8][N:9]([C:16](=[O:54])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([O:46]CC1C=CC=CC=1)[C:25](=[O:45])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([O:37]CC1C=CC=CC=1)[C:34](=[O:36])[CH3:35])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])C1C=CC=CC=1.[ClH:55]>CO>[ClH:55].[OH:8][N:9]([C:16](=[O:54])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([OH:46])[C:25](=[O:45])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([OH:37])[C:34](=[O:36])[CH3:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(=O)N(CCCCCCCC(=O)N(CCCCCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CC(=O)N(O)CCCCCCCC(=O)N(O)CCCCCCCC(=O)N(O)CCCCCN

Procedure:
Compound [VIII] (1.20 g, 1.62 mmol) was hydrogenated in CH3OH and 0.1N HCl with 10% PdC. by the procedure used for [A]. Purification by Sephadex LH-20 column chromatography with 15% EtOH/toluene as the eluant produced 0.386 g (47%) of [A] as a colorless solid: NMR (CD3OD) δ 1.17-1.87 (m, 26 H), 2.07 (s, 3 H), 2.30-2.55 (m, 4 H), 2.90 (t, 2 H, J=6), 3.43-3.70 (m, 6 H). Anal. (C23H47ClN4O6) C, H, N.