Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[CH2:14]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24]O)=[NH:23])=[C:20]([O:28][CH3:29])[CH:19]=1)[CH:15]=[CH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)C>[CH2:14]([O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]2[N:23]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:6]=3)[O:13][N:24]=2)=[C:20]([O:28][CH3:29])[CH:19]=1)[CH:15]=[CH2:16]
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Reactant: C=CCOc1ccc(C(=N)NO)c(OC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.1 %

Procedure:
To a mixture of 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (505 mg, 2.55 mmol), 4-allyloxy-N-hydroxy-2-methoxy-benzamidine (611 mg, 2.75 mmol) and DIPEA (377 mg, 2.92 mmol) in DMF (10 mL) is added TBTU (882 mg, 2.75 mmol). The mixture is stirred at rt for 15 h before it is diluted with diethyl ether (100 mL) and washed with 1 N aq. NaOH (2×30 mL), 1 M aq. KHSO4 (30 mL) and brine (30 mL). The organic extract is dried (Na2SO4), filtered and evaporated. The yellow oily residue is dissolved in dry toluene (10 mL) and heated at 150° C. for 20 min in a microwave oven. The mixture is poured into diethyl ether (100 mL) and washed with brine (75 mL). The organic extract is dried (Na2SO4), filtered and evaporated to give 3-(4-allyloxy-2-methoxy-phenyl)-5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazole (609 mg) as a yellow solid; LC-MS: tR=1.19 min, [M+1]=385.23.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])([CH3:14])[NH:13][C:7]2=[CH:6][CH:5]=1.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[C@@H:24]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:23][C@@H:22]1Br)(=[O:19])[CH3:18]>CC(C)=O>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[C@@H:24]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:23][CH:22]1[N:13]1[C:7]2[C:8](=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:10]([CH3:16])=[CH:11][C:12]1([CH3:15])[CH3:14])(=[O:19])[CH3:18]
Reactant: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2C1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
Ethoxyquin (240 g) and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (228 g) were stirred at 80° for 18 hours. Acetone (200 ml) was added to the hot reaction mixture and stirring continued for an additional 20 minutes. After cooling, the solid ethoxyquin hydrobromide was filtered off, washed thoroughly with acetone and the combined acetone filtrates were evaporated under reduced pressure. The resulted crude product was recrystallised (iso-propanol) to yield 226.5 g of 1-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyl)-6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline. m.p.: 180°-181°.
Reaction SMILES: [CH2:1]=[C:2]([C:4]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:12])=O)C.C=CC(OCCC[Si](OCC)(OCC)OCC)=[O:20].C(CCC[Si](OC)(OC)OC)#N.C(CCC[Si](OCC)(OCC)OCC)#N.N(CCC[Si](OCC)(OCC)OCC)=C=O.N(CCC[Si](OC)(OC)OC)C(N)=O.S(CCC[Si](OC)(OC)OC)C#N.SCCC[Si](OC)(OC)OC.SCCC[Si](OCC)(OCC)OCC.SCCC[Si](C)(OC)OC.SCCCC[Si](OC)(OC)OC.SCCCCCC[Si](OC)(OC)OC.ClCCC[Si](OC)(OC)OC>>[CH2:4]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:12])[CH:2]1[O:20][CH2:1]1
Reactant: C=CC(=O)OCCC[Si](OCC)(OCC)OCC
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Agent: CCO[Si](CCCC#N)(OCC)OCC
Agent: CCO[Si](CCCN=C=O)(OCC)OCC
Agent: CCO[Si](CCCS)(OCC)OCC
Product: CO[Si](CCCOCC1CO1)(OC)OC

Procedure:
CH2═C(CH3)—COO—C3H6—Si(OCH3)3, CH2═CH—COO—C3H6—Si(OC2H5)3, 3-cyanopropyltrimethoxysilane, 3-cyanopropyltriethoxysilane, 3-isocyanatopropyltriethoxysilane, ureidopropyltrimethoxysilane, 3-thiocyanatopropyltrimethoxysilane, 3mercaptopropyltrimethoxysilane, 3-mercaptopropyltriethoxysilane, 3-mercaptopropylmethyldimethoxysilane, 4-mercaptobutyltrimethoxysilane, 6-mercaptohexyltrimethoxysilane, 3-chloropropyltrimethoxysilane and (C2H5O)3Si(CH2)3—S4—(CH2)3Si(OC2H5)3.
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19](=[O:30])[C:20](=[CH:26]OCC)[C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22].Cl.NO>C(#N)C>[Cl:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]([C:20]1[CH:26]=[N:3][O:22][C:21]=1[CH:23]1[CH2:25][CH2:24]1)=[O:30]
Reactant: CCN(CC)CC
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1Cl)C(=O)C1CC1
Agent: Cl
Agent: NO
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
Triethylamine (0.9 g) was added to a mixture of 1-[2-chloro-4-(methylsulphonyl)phenyl]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (3.5 g) and hydroxylamine hydrochloride (1.0 g) in acetonitrile and the mixture was stirred at room temperature for 1 hour and left to stand overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica eluted with ethyl acetate and toluene. The product was recrystallized from ethyl acetate and cyclohexane to give 4-[2-chloro-4-(methylsulphonyl)benzoyl]-5-cyclopropylisoxazole (0.98 g) as a white solid, m.p. 116° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6]Br)[C:3]([OH:5])=[O:4].[C:8]([S-:10])#[N:9].[K+].[OH-].[Na+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH3:1][CH:2]([CH2:6][S:10][C:8]#[N:9])[C:3]([OH:5])=[O:4]
Reactant: CC(CBr)C(=O)O
Reactant: N#C[S-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CSC#N)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
16.7 g of 2-methyl-3-bromopropionic acid are dissolved in 50 ml of toluene, the solution obtained is cooled to 0° C., then 19.42 g of potassium rhodanide and 5 ml of water are added. The pH value of the reaction mixture is adjusted to 6.5 by the dropwise addition of 10 n sodium hydroxide. The pale yellow biphasic solution obtained is stirred at 25° C. for 48 hours while maintaining the pH value between 6.4 and 6.6 by adding further amounts of sodium hydroxide as required. The reaction mixture is cooled to 0° C. and adjusted to a pH value of 2.7 by adding 10 n sulfuric acid, then filtered and the organic phase is separated. The aqueous phase is extracted 5 times with 20 ml of toluene, the organic solutions are combined and extracted with 10 ml of water. The pale yellow toluene solution is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain 11.13 g /76.7%/ of 2-methyl-3-thiocyanatopropionic acid, m.p.: 24°-25° C. Based on determination by gas chromatography, the purity of the product is 98 to 99 per cent.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][NH:26][CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:14][CH:13]=2)[N:10]=1.[CH2:32]=O>>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][N:26]([CH3:32])[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:16][CH:17]=2)[N:10]=1
Reactant: C=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CNCC3)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CN(C)CC3)cc1
Yield: 4 %

Procedure:
4-(2-Fluorobenzyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (3.8 mg, 4%) was synthesised from 4-(2-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 429.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:9]([C:3]1[CH:4]=[C:5]([N:6]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[CH:7]=[CH:8][C:2]=1[F:1])([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: COC1CCC(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(-n2cccc2)ccc1F

Procedure:
To a suspension of 4-fluoro-3-nitroaniline (20g, 0.13mol) in toluene (200mi) is added 2,5-dimethoxytetrahydrofuran (33ml, 0.26mol) and a catalytic amount of pTSA. The mixture is refluxed for 2.5 hours. After cooling the solvent is removed by evaporation and the residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 23.1g (87%). Mp 79-81° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1I)=O.[O:17]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:18]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[Cl-].[Na+].O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(#N)C.C(N(CC)CC)C>[O:17]1[CH:21]=[CH:20][C:19]([C:22]2[NH:5][C:6]3[C:7]([CH:23]=2)=[CH:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=3)=[CH:18]1
Reactant: COc1ccc(I)c(NC(=O)C(F)(F)F)c1
Reactant: C[Si](C)(C)C#Cc1ccoc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3ccoc3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a mixture of 2,2,2-trifluoro-N-(2-iodo-5-methoxyphenyl)acetamide (1.00 g), furan-3-ylethynyltrimethylsilane (714 mg), bis(triphenylphosphine) palladium(II) dichloride (61 mg), copper(I) iodide (33 mg), triethylamine (0.81 mL), and acetonitrile (15 mL) was added tetrabutylammonium fluoride in tetrahydrofuran solution (1 mol/L, 4.4 mL) at 50° C. This mixture was stirred at 50° C. for 1 hour. Then, potassium carbonate (801 mg) was added thereto, followed by stirring at 50° C. overnight. To the reaction mixture was added saturated brine, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (422 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 6.51-6.56 (1H, m), 6.64-6.69 (1H, m), 6.78 (1H, dd, J=2.3, 8.5 Hz), 6.84-6.90 (1H, m), 7.42-7.51 (2H, m), 7.67-7.73 (1H, m), 7.78-8.13 (1H, br).
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.O[C@@H:13]1[CH2:18][C@H:17]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:16]([CH3:31])([CH3:30])[CH2:15][CH2:14]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:30][C:16]1([CH3:31])[CH2:15][CH2:14][C@@H:13]([O:11][C:10]2[C:2]([CH3:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][N:5]=[CH:4]3)[CH2:18][C@@H:17]1[N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]
Reactant: Cc1c(O)ccc2[nH]ncc12
Reactant: CC1(C)CC[C@H](O)C[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(O[C@@H]2CCC(C)(C)[C@@H](N3C(=O)c4ccccc4C3=O)C2)ccc2[nH]ncc12
Temperature: 100 °C
Reaction time: 7 h
Yield: 59.5 %

Procedure:
To a solution of the 4-methyl-1H-indazol-5-ol (500 mg, 1.83 mmol) obtained in Example 402 in toluene (8 ml) were added cis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (400 mg, 1.5 mmol) and cyanomethylenetri-n-butylphosphorane (494 mg, 2.1 mmol) at room temperature, and the resulting mixture was heated to 100° C. After stirring for 7 hours, the reaction solution was concentrated under reduced pressure and the resulting residue was dissolved in chloroform and washed with a 1M-aqueous sodium hydroxide solution. Extraction with chloroform was carried out again and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain trans-2-{2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (360 mg, 61%, containing about 10% of cis isomer).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8].I[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(O)C>[CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:8][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Reactant: COC(=O)CCCI
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NCCCC(=O)OC
Temperature: 45 °C
Yield: 26.3 %

Procedure:
A solution of L-leucyl-L-phenylalanine N-methylamide (1.19 g) in ethanol (24 ml) was treated with methyl 4-iodobutyrate (0.93 g); the resulting colourless solution was heated to 45° C. over 16 h. The crude product was purified by flash silica chromatography, eluting with ethyl acetate/heptane (1:1 to 5:1), to furnish the title compound as an off-white solid (0.42 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([O:12][CH2:13][C:14](N)=[NH:15])[CH3:11]>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:14]([CH2:13][O:12][CH2:10][CH3:11])[N:15]=1
Reactant: CCOCC(=N)N
Reactant: N#Cc1nccnc1N
Solvent: CCO
Product: CCOCc1nc(N)c2nccnc2n1

Procedure:
A mixture of 36.0 g (0.30 mole) of 3-amino-2-pyrazinecarbonitrile [prepared according to A. Albert and K. Ohta, J. Chem. Soc. C, 1970, 1540] and 46.7 g of 2-ethoxyacetamidine in 700 ml of absolute ethanol is refluxed for 2 hours 30 minutes under a nitrogen atmosphere. After cooling, the precipitate obtained is isolated by filtration. It is purified by recrystallization from ethanol. Yld: 52.0 g (84%), m.p. 152°-154° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([CH3:19])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH3:15])C.C1C=CC=CC=1>O>[CH3:19][C:6]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH3:15])=[CH:5][CH2:4][OH:3]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC(C)=C(C)C
Solvent: O
Solvent: c1ccccc1
Product: CC(=CCO)CCC=C(C)CCC(C)=C(C)C
Reaction time: 1 h

Procedure:
To 65 g. of 3,7,10,11-tetramethyl-2,6,10-dodecatrienoic acid ethyl ester in 270 ml. of absolute benzene there was added in a period of one hour under ice cooling, 68 ml. of a 70% by weight benzene solution of sodium dihydro-bis-(2-methoxyethoxy-aluminate). This addition was carried out dropwise. After this addition, the reaction mixture was allowed to stand for one hour at room temperature under constant stirring. The reaction solution is broken up by the addition of water while it is cooled with ice. After the addition of water, the reaction mixture is filtered and poured over a saturated aqueous sodium chloride solution. The resulting reaction mixture is then exhaustively extracted with benzene. The combined benzene extracts are washed several times with water, dried over sodium sulfate and evaporated. Distillation yields pure 3,7,10,11-tetramethyl-2,6,10-dodecatrien-1-ol, b.p. 94°-96°C.10.03 mmHg; nD20 = 1.4946.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2ccnc3ccc(Br)cc23)CC1
Yield: 64.1 %

Procedure:
500 mg 6-bromo-4-chloroquinoline and 340 mg ethyl 4-piperidine carboxylate were reacted by the same method as in Production Example 74, to give 480 mg of the title compound as a yellow oil.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21].O>O1CCCC1>[O:12]=[S:1]1(=[O:11])[C:5]2[CH:6]=[C:7]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)S(=O)(=O)C=C2
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 1-benzothiophen-6-amine 1,1-dioxide (1.00 g, 5.52 mmol) and pyridine (0.525 ml, 6.62 mmol) in tetrahydrofuran (18 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.916 ml, 6.62 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.71 g (87.1%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:11]([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:12][CH:13]=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl.[OH-].[Na+]>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:11]([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:12][CH2:13][OH:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=CC[C@H](Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCC[C@H](Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
Sodium borohydride (0.68 g) was added carefully to an ice-cooled solution of 3(S)-(3,4-dichlorophenyl)-4-(imidazol-1-yl)butan-1-al (4.3 g) (see Preparation 97) in ethanol (40 ml) and the mixture stirred at room temperature for one hour before removing the solvent under reduced pressure to give a residue. The residue was suspended in water (30 ml), cooled in an ice-bath and the mixture first acidified to pH1 with 2N aqueous hydrochloric acid solution and then basified to pH14 by addition of 2N aqueous sodium hydroxide solution. The resulting suspension was filtered and the residue washed with water, dried and then crystallised from acetonitrile to give 3(S)-(3,4-dichlorophenyl)-4-(imidazol-1-yl)butan-1-ol (1.37 g) as a cream solid.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+]>CO>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([C:16]([F:17])([F:19])[F:18])[CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(-n2cncn2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-n2cncn2)cc1C(F)(F)F
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a solution of methyl 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoate (5.07 g) in methanol was added aqueous sodium hydroxide (1.50 g) at 20° C. The mixture was stirred for 4 hours, partially evaporated and extracted with ether. The aqueous layer was acidified (aqueous citric acid) and extracted with ethyl acetate. The organic layer was dried (magnesium sulfate), and evaporated to give 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoic acid (3.32 g), NMR 8.25(1H), 8.34-8.42(3H), 10.00(s,1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.CN(C)CCN(C)C.[Li+].CCC[CH2-].[CH3:22][S:23]SC>>[F:8][C:5]1[CH:4]=[CH:3][C:2]([S:23][CH3:22])=[CH:7][N:6]=1
Reactant: CSSC
Reactant: Fc1ccc(Br)cn1
Agent: CN(C)CCN(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Product: CSc1ccc(F)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (2.05 g, 11.7 mmol) and N1,N1,N2,N2-tetramethylethane-1,2-diamine (2.27 mL, 15.1 mmol) was purged with nitrogen for 45 minutes. Toluene (116 mL) was added and the reaction mixture was cooled to −78° C. N-butyllithium (2.5 M in hexanes, 5.59 mL, 14.0 mmol) was added dropwise over 6 minutes. The reaction mixture was stirred at −78° C. for 1 hour. Dimethyl disulfide (1.26 mL, 14.0 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was warmed to 0° C., then immediately quenched with saturated aqueous ammonium chloride. The layers were separated, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/heptane) to provide the title compound (1.00 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][NH:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Fc1cccc(C(F)(F)F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-fluoro-6-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 166.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH2:12]O)[N:11]=1)=[O:5].O=S(Cl)[Cl:31].CCN(CC)CC.O>C(Cl)Cl>[Cl:31][CH2:12][C:10]1[N:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])[S:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1nc(CO)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nc(CCl)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Into a solution of Compound 39 (123 mg, 0.3 mmol) in 5 mL of CH2Cl2 was added SOCl2 (0.4 mmol) and NEt3 (0.5 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. The solution was treated with 10 mL of water and extracted with CH2Cl2. The combined extracts were washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with 5-50% ethyl acetate in hexane) to give Compound 70 (114 mg, 88%) as a white solid.
Reaction SMILES: [N:1]1([C:6](=[O:24])[CH2:7][C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)C=CN=C1.N>O1CCCC1.O>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[C:8]([CH2:7][C:6]([NH2:1])=[O:24])=[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(-c2nn3cccnc3c2CC(=O)n2ccnc2)cc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nn3cccnc3c2CC(N)=O)cc1
Reaction time: 16 h
Yield: 41.3 %

Procedure:
A stirred slurry of 3.2 g (0.010 mole) of 3-[2-(1H-imidazole-1-yl)-2-oxoethyl]-2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (prepared from 2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 1,1'-carbonyldiimidazol) in 20 ml of dry tetrahydrofuran was treated with 3 ml of ammonia in 10 ml of dry tetrahydrofuran. After stirring for 16 hours, the reaction mixture was diluted with 100 ml of water and the precipitated solid collected by filtration (1.6 g). The crude product was recrystallized from acetonitrile to yield 1.1 g (40.9%) of pale yellow crystals, mp 225°-226° C.