Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:41]1[C:49]3[C:44](=[C:45]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=1)([CH2:37][CH2:38][CH2:39]O)[CH2:32][CH2:31]2>O1CCCC1.CCOCC>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:41]1[C:49]3[C:44](=[C:45]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=1)([CH2:37][CH2:38][CH2:39][I:25])[CH2:32][CH2:31]2
Reactant: II
Reactant: CS(=O)(=O)Nc1cccc2c(C3(CCCO)CCc4cc(F)ccc43)c[nH]c12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc2c(C3(CCCI)CCc4cc(F)ccc43)c[nH]c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of triphenylphosphine (422 mg, 1.61 min ol, 1.30 equivalents) and imidazole (219 mg, 3.22 mmol, 2.60 equivalents) in anhydrous tetrahydrofuran (10 ml) add iodine (410 mg, 1.61 mmol, 1.30 equivalents). After stirring for 20 minutes at room temperature under nitrogen, add N-{3-[5-Fluoro-1-(3-hydroxy-propyl)-indan-1-yl]-1H-indol-7-yl}-methanesulfonamide (500 mg, 1.24 mmol) and stir for 48 hours. Dilute with ether, wash with water (2×), wash with 1N aqueous hydrochloric acid (2×), dry over anhydrous sodium sulfate, filter, and concentrate the solution. Purify the residue on silica eluting with 50 to 100% ethyl acetate/hexanes over 25 minutes to obtain the title compound as a white solid (254 mg, 40%). LC-MS m/z 385.0 (M+−I).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:12]#[N:13])=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+]([CH3:18])([O-])=O.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1([C:12]#[N:13])[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:18]1)=[O:14])[CH3:2]
Reactant: CCOC(=O)C(C#N)=C1CCCCC1
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C1(C#N)CC12CCCCC2
Reaction time: 2.5 h
Yield: 74.9 %

Procedure:
To a solution of cyano-cyclohexylidene-acetic acid ethyl ester (1.37 g, 7.09 mmol) in 30 mL acetonitrile was added nitromethane (1.92 mL, 35.5 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.06 mL, 7.09 mmol) resulting in an orange solution. The reaction was stirred for 2.5 hours, then partitioned between ethyl ether (Et2O) and 1N hydrochloric acid (HCl) (aq). The phases were separated, and the organic phase washed with brine, dried over magnesium sulfate (MgSO4), and concentrated. Flash chromatography of the residue (5% ethyl acetate (EtOAc)/hexanes) afforded 1.1 g (75%) of 1-cyano-spiro[2.5]octane-1-carboxylic acid ethyl ester as a colorless oil. 1H NMR (CDCl3) δ 4.22 (m, 2H), 1.77 (d, J=5.1 Hz, 1H), 1.42–1.72 (m, 10H), 1.40 (d, J=5.1 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H). 13C NMR δ 166.40, 118.60, 62.72, 40.20, 34.67, 29.01, 28.75, 25.69, 25.54, 25.28, 24.66, 14.38. LRMS: m/z 208.0 (M+1). IR: 2239, 1732 cm−1. Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.41; H, 8.33; N, 6.75.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=2)[CH:7]=1.[O:31]([CH2:33][CH2:34][NH2:35])[CH3:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:35][CH2:34][CH2:33][O:31][CH3:32])=[O:18])[N:15]=2)[CH:7]=1
Reactant: COCCN
Reactant: COc1ccccc1C(=O)c1ccc(F)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Product: COCCNC(=O)Cc1csc(NC(=O)Nc2cc(F)ccc2C(=O)c2ccccc2OC)n1
Yield: 65 %

Procedure:
2-(2-{3-[5-Fluoro-2-(2-methoxy-benzoyl)-phenyl]-ureido}-thiazol-4-yl)-N-(2-methoxy-ethyl)-acetamide (158 mg, 65%) was prepared from (2-{3-[5-fluoro-2-(2-methoxy-benzoyl)-phenyl]-ureido}-thiazol-4-yl)-acetic acid (215 mg, 0.5 mmol) and 2-methoxylethylamine (38 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O)=[O:6])[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].[NH2:25][NH:26][C:27]([NH2:29])=[O:28]>CO>[CH2:1]([O:4][C:5]([NH:7][CH:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC(C=O)CCC(=O)OC(C)(C)C
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)NC(C=O)CCC(=NNC(N)=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 207a (2.39 g, 8.8 mmol), in MeOH (20 ml) was added sodium acetate (0.72 g, 8.8 mmol) and semicarbazide (0.98 g, 8.8 mmol) stirred overnight, concentrated and diluted with CH2Cl2 (100 ml), washed with water, dried and concentrated. Flash chromatography (2% MeOH in CH2Cl2) afforded 208a (2.10 g, 73%) as an oil: [α]D20 −21 (c 2.55°, CH2Cl2); 1H NMR (CDCl3) δ9.98 (1H, s), 7.27 (1H, d), 5.8 (1H, m), 5.5 (1H, d), 5.35-5.19 (2H, m), 4.58 (2H, m), 4.14 (1H, m), 2.37 (2H, t), 2.09 (1H, m), 2.0-1.75 (2H, m); Anal. Calcd for C14H24N4O5: C, 51.21; H, 7.37; N, 17.06. Found: C, 50.2; H, 7.3; N, 16.1.
Reaction SMILES: CS(C)=O.[Br:5][C:6]1[C:7]([Cl:25])=[C:8]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[C:9]([Cl:16])=[N:10][C:11]=1S(C)(=O)=O.[K].[C:27](#[N:29])C>>[Br:5][C:6]1[C:7]([Cl:25])=[C:8]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[C:9]([Cl:16])=[N:10][C:11]=1[C:27]#[N:29]
Reactant: CS(=O)(=O)c1nc(Cl)c(-c2c(F)cccc2Cl)c(Cl)c1Br
Reactant: CC#N
Agent: [K]
Solvent: CS(C)=O
Product: N#Cc1nc(Cl)c(-c2c(F)cccc2Cl)c(Cl)c1Br
Temperature: 60 °C
Reaction time: 6 h

Procedure:
At room temperature, a spatula tip (about 10 mg) of crown ether (18-crown-6) and 1 ml of dimethyl sulfoxide were added to 1.65 g (3.8 mmol) of 5-bromo-3-(2-chloro-6-fluorophenyl)-2,4-dichloro-6-methylsulfonylpyridine (Example F) dissolved in 50 ml of acetonitrile, and the mixture was heated to 60° C. Over a period of 6 h, 500 mg (7.6 mmol) of potassium cyamide were then added a little at a time at this temperature. The mixture was stirred at room temperature overnight and chromatographed directly on silica gel using cyclohexane/ethyl acetate. Yield 0.57 g of a solid, m.p. 90° C. 1H-NMR (CDCl3) δ=7.18 (m); 7.40 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH2:18][CH2:19]O)[C:16](=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[BrH:22]>O>[BrH:22].[Br:22][CH2:19][CH2:18][N:17]1[C:16](=[O:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=c1c2ccccc2nc(-c2ccc(Cl)cc2)n1CCO
Agent: Br
Solvent: O
Product: O=c1c2ccccc2nc(-c2ccc(Cl)cc2)n1CCBr
Yield: 78 %

Procedure:
A mixture of 2-(4-chlorophenyl)-3-(2-hydroxyethyl)-4(3H)-quinazolinone (0.068 mol) and HBr in water 46% (200 ml) was stirred and refluxed for 90 minutes. 300 ml of water was added. The crystallized product was filtered off and dried (fraction 1). The filtrate (oil) was solidified (fraction 2). Both fractions were combined, yielding 23.5 g (78%) of 3-(2-bromoethyl)-2-(4-chlorophenyl)-4(3H)-quinazolinone monohydrobromide; mp. 214.0° C. (interm. 19).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3SC=CN=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: Brc1ccncc1
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ccncc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 4-bromo pyridine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.23, 7.50, 7.35, 7.28, 6.50, 5.30, 4.90, 4.29, 3.95, 3.76, 3.65–3.58, 3.42, 2.73, 2.49, 1.35–1.27, 1.16; IR (diffuse reflectance) 2971 (s), 2497 (w), 2388 (w), 2350 (w), 2338 (w), 2328 (w), 1596 (s), 1569, 1550 (s), 1516, 1508, 1499 (s), 1467 (s), 1397 (s), 1393 (s) cm−1 HRMS (ESI) calcd for C25H29N5OCl2+H1 486.1827. found 486.1810.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.N1(CO)C=[CH:26]N=N1.[BH4-].[Na+]>CO>[CH3:26][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:3][CH2:2]1
Reactant: OCn1ccnn1
Reactant: C1CCCn2c(nnc2C2(C3CCNCC3)CCCC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C2(c3nnc4n3CCCCCC4)CCCC2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
3-(1-Piperidin-4-ylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (263 mg) and 1H-triazole-1-methanol (86 mg) were diluted with methanol (4 ml), followed by stirring at 60° C. for 1 hour. After 1H-triazole-1-methanol (93 mg) was added thereto and the whole was stirred for 1 hour, 1H-triazole-1-methanol (107 mg) was further added and the whole was stirred for 1 hour. The reaction solution was cooled to room temperature and then sodium borohydride (91 mg) was added thereto, followed by stirring at room temperature for 16 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting residue was diluted with a 1M aqueous sodium hydroxide solution (30 ml), followed by extraction with chloroform (15 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:6) and then the resulting solid washed with hexane to obtain 105 mg of 3-[1-(1-methyl-4-piperidinyl)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (white solid).
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:37])([CH3:36])[C:25](=[O:35])[N:26]2[CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:22][CH:21]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)([CH3:3])[CH3:2].C1C(=O)N([Cl:45])C(=O)C1.CN(C=O)C>O>[Cl:45][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:20]=1[C:18]([N:4]([CH:1]([CH3:3])[CH3:2])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:19])[N:26]([CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25](=[O:35])[C:24]2([CH3:36])[CH3:37]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCCCN1C(=O)C(C)(C)c2ccc(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCN1C(=O)C(C)(C)c2cc(Cl)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 65 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To tert-butyl (3R)-3-(isopropyl{[1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}amino)piperidine-1-carboxylate (220 mg) were added NCS (86 mg) and DMF (5 ml), and the mixture was stirred at 65° C. for one hour. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (200 mg) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][C:26](O)=[O:27])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:26](=[O:27])[CH2:25][C:21]3[CH:22]=[N:23][O:24][C:20]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)Cc1cnoc1-c1ccccc1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cnoc1-c1ccccc1)Nc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 2-amino-4-(4-chlorophenyl)thiazole (0.65 g), 5-phenyl-4-isoxazolylacetic acid (0.60 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.51 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.59 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(4-chlorophenyl)-2-thiazolyl]-5-phenyl-4-isoxazolylacetamide (0.92 g, yield 79%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 210–211° C.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C([O-])([O-])=O.[Ca+2].[CH3:25][NH:26][N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>C(O)C>[CH3:25][N:26]([N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1)[C:5]1[N:6]=[CH:1][N:2]=[C:3]2[C:4]=1[N:8]=[CH:9][N:10]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: CNn1cccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)n1cccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To 100 ml absolute ethanol was added 6-chloropurine riboside (5.0 g, 0.017 mole), CaCO3 (3.5 g, 0.035 mole), and N-methyl-N-(1H-pyrrol-1-yl)amine (3.3 g, 0.035 mole). After stirring at 80° C. for three hours, the mixture was filtered, then evaporated to a solid which was eluted on a silica gel column with 5% methanol/dichloromethane via high pressure liquid chromatography to give a solid after evaporation, 4.0 g, m.p. 195°-197° C. This material was recrystallized from acetonitrile to give 2.4 g (41%) of N-methyl-N-(1H-pyrrol-1-yl)-9-β-D-ribofuranosyl-9H-purin-6-amine, m.p. 198°-199° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:31]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C(F)(F)F)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3-trifluoromethylphenylboronic acid (105 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate. (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 7-trifluoromethyl-4-(3-trifluoromethyl-phenyl)-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:13][OH:14]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(C=NO)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
52.9 g (0.35 mol) of p-nitrobenzaldehyde was dissolved in 100 ml of methanol and a solution of 27.8 g (0.38 mol) of hydroxylamine hydrochloride in 35 ml of water was added dropwise over 30 minutes while maintaining the temperature at 30° C. and then, stirred at the same temperature for two hours followed by dilution with 300 ml of water. White crystals deposited were filtered and dried to obtain 55 g of p-nitrobenzaldoxime. Yield 94.7%; M.P. 128°-131° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:44][NH2:45])=[O:43])[CH:38]=[CH:39][CH:40]=1>>[OH:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:44][NH:45][C:11](=[O:12])[C:10]2[C:14]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:43])[CH:38]=[CH:39][CH:40]=1
Reactant: NNC(=O)Cc1cccc(O)c1
Reactant: O=C(O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1OCc1ccccc1
Product: O=C(Cc1cccc(O)c1)NNC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 40 %

Procedure:
The coupling of 2,4,6-tribenzyloxybenzoic acid to (3-hydroxyphenyl)acetohydrazide is carried out analogously to Example 2.5, giving N′-[2-(3-hydroxyphenyl)acetyl]-2,4,6-tribenzyloxybenzohydrazide, yield 40%; m.p. 154-155°.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH:25]=O)[CH:2]=[CH2:3].C(OC(=O)[NH:34][C@H:35]([C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH2:36][SH:37])(C)(C)C.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:23])([CH3:24])[C:17]([CH3:21])([CH3:22])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH2:25][S:37][CH2:36][C@H:35]([NH2:34])[C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH:2]=[CH2:3]
Reactant: Cc1noc([C@H](CS)NC(=O)OC(C)(C)C)n1
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Reaction time: 18 h
Yield: 74.9 %

Procedure:
To a solution of 13.8 g of 2-formyl-5-methoxy-6-methyl-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid allyl ester in 38 ml of trifluoroacetic acid, cooled to 0° C., were added within 15 min a solution of 13.7 g of (R)-2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethylcarbamic acid tert-butyl ester and 6.2 g of triethylsilane in 38 ml of dichloromethane. The solution was kept at 0° C. for 18 h and then evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was successively washed with water; saturated sodium carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue Was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield 14.1 g of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl-methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methylbenzoic acid allyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][NH2:14].[CH3:15][CH2:16][O:17][C:18]([CH:20]([C:24]([CH3:26])=O)[C:21]([CH3:23])=O)=[O:19].C(Cl)Cl>C(Cl)Cl.CO>[CH2:16]([O:17][C:18]([C:20]1[C:21]([CH3:23])=[N:14][N:13]([C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:24]=1[CH3:26])=[O:19])[CH3:15]
Reactant: COc1ccc(C(F)(F)F)cc1NN
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nn(-c2cc(C(F)(F)F)ccc2OC)c1C
Yield: 58 %

Procedure:
In analogy to the procedure described in Example 38A], (2-methoxy-5-trifluoromethyl-phenyl)-hydrazine and ethyl diacetoacetate gave, after flash column chromatography (CH2Cl2 to CH2Cl2:MeOH 99:1), the title compound in 58% yield as a light green solid. MS: 343.1 (MH+).
Reaction SMILES: C(O)C.[O:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[C:20](Cl)[N:19]=1>O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:18]([NH2:17])=[N:19][C:20]([N:14]3[CH2:13][CH2:12][N:11]([C:9]([CH:5]4[O:4][CH2:8][CH2:7][CH2:6]4)=[O:10])[CH2:16][CH2:15]3)=[N:21][C:22]2=[CH:23][C:24]=1[O:30][CH3:31]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: CCO
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a solution of absolute ethanol (272 ml), water (68 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 32 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 48 hours. The crystals were collected by filtration, washed with absolute ethanol and dried in vacuo at 40° C. to yield 36.44 g (85.5%) of Terazosin.HCl dihydrate. See Trial M in Table I. Trial N was performed using a 10% volume of water.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:20][C:19]3[C:18]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O>C(O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:20][C:19]3[C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc2c1CC(NS(=O)(=O)c1ccccc1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cccc2c1CC(NS(=O)(=O)c1ccccc1)CC2

Procedure:
3.89 g (10 mmol) of ethyl 7-benzenesulphonylamino-5,6,7,8-tetrahydronaphth-1-yl-oxyacetate and 840 mg (15 mmol) of KOH are stirred in 50 ml of C2H5OH and 20 ml of H2O at room temperature for 20 hours. The solvent is stripped off, the residue is partitioned between H2O and CH2Cl2, the mixture is brought to pH 4.5 with 10% strength HCl and extracted twice with CH2Cl2, the organic phases are dried over MgSO4 and concentrated in vacuo, the residue is triturated with ether and the crystals are filtered off with suction and dried.