Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(NCC(C)C)C(C)C.S(Cl)([Cl:26])(=O)=O>C1(C)C=CC=CC=1>[Cl:26][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: Oc1ccc(C2CCOCC2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCOCC2)cc1Cl
Temperature: 70 °C
Yield: 78.9 %

Procedure:
To a 30ml Toluene solution of 4-(4-tetrahydropyranyl) phenol 1 g (5.61 mmol) and diisobutylamine 0.08 ml (0.46 mmol) was added sulfuryl chloride 0.51 ml (6.35 mmol) over 3 hr period upon heating at 70° C. Stirring was continued at that temp. for 2 hr after the addition of sulfuryl chloride was complete. The solvent was removed under reduced pressure, diluted with ethyl acetate and washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, chromatographed on silica gel (hexanes:ethyl acetate) to give 0.941 g of the title compound as while solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C)C=O>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.O>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3cc(O)ccc23)c1
Temperature: 180 °C
Yield: 55.3 %

Procedure:
The mixture of 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (300 mg), 3-methoxy-phenylboronic acid (318 mg), Na2CO3 (400 mg), Tetrakis(triphenylphosphine)palladium(0) (100 mg), N,N-dimethylformamide (DMF) (2 ml) and water (2 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the mixture was sent to preparative LC-MS and 1-(3-methoxy-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (180 mg) was produced as a solid. LC-MS m/e 347(MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([O:11][CH2:12][C:13]([F:26])([F:25])[C:14]([F:24])([F:23])[C:15]([F:22])([F:21])[C:16]([F:20])([F:19])[CH2:17][OH:18])=[C:5]([F:27])[C:4]=1[F:28].Cl[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[N+:40]([O-:42])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[CH3:1][N:2]([CH3:29])[C:3]1[C:4]([F:28])=[C:5]([F:27])[C:6]([O:11][CH2:12][C:13]([F:26])([F:25])[C:14]([F:23])([F:24])[C:15]([F:21])([F:22])[C:16]([F:19])([F:20])[CH2:17][O:18][C:35]2[CH:36]=[CH:31][C:32]([N+:40]([O-:42])=[O:41])=[CH:33][C:34]=2[N+:37]([O-:39])=[O:38])=[C:7]([F:10])[C:8]=1[F:9]
Reactant: CN(C)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(F)c1F
Yield: 73.2 %

Procedure:
N,N-Dimethyl-4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,3,5,6-tetrafluorobenzeneamine (1.05 g) was treated with 1-chloro-2,4-dinitrobenzene (0.51 g) and potassium carbonate (0.35 g) in NMP (5 mL) at 80° C. for 21.5 hrs. The mixture was diluted with water and extracted with ethyl ether. The extracts were washed with water and brine, dried (K2CO3), and concentrated to an orange oil. The oil was purified by chromatography to give N,N-dimethyl-4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]2,3,5,6-tetrafluorobenzeneamine (1.05 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:6][C:7](=[CH:10][N:11]1[CH2:16][CH2:15]OCC1)[C:8]#[N:9].Cl.N[C:32]1[CH:37]=CC=[CH:34][CH:33]=1.O>C(O)(C)C>[NH:11]([CH:10]=[C:7]([CH2:6][C:5]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]#[N:9])[C:16]1[CH:34]=[CH:33][CH:32]=[CH:37][CH:15]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(COc2ccc(CC(C#N)=CN3CCOCC3)cc2OC)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(COc2ccc(CC(C#N)=CNc3ccccc3)cc2OC)cc1
Yield: 71.4 %

Procedure:
To a homogeneous solution of 2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}-3-morpholin-4-ylprop-2-enenitrile (14.5 g, 36.7 mmol) in isopropanol (050 mL) was added aniline hydrochloride (4.9 g, 37.5 mmol), and the mixture was stirred at reflux for 20 minutes, combined with 20 mL of water and cooled in an ice bath for 30 minutes. The resulting precipitate was filtered off, washed with water and air dried to give 13.7 g of crude product. This material was recrystalized from methanol/ethanol to afford pure product as a crystalline tan solid (10.5 g, 26.2 mmol). 1H NMR (300 MHz, d6-DMSO): δ 9.03 (d, J=12.8 Hz, 1H), 7.59 (d, J=12.8 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.4 Hz, 2H), 7.16 (m,2H), 6.93 (d, J=8.2 Hz, 1H), 6.88 (d, J=8.4, 1H), 6.86 (m, 1H), 6.83 (s, 1H), 4.90 (s, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.50 (s, 2H), 3.28 (s, 2H). MS (ES-, m/z)=399 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>O1CCCC1>[F:10][C:4]1[CH:3]=[C:2]([C:17]2([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-methoxybenzene (2 g, 9.7 mmol) in tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium (1.6 M in hexanes, 7.9 mL, 12.7 mmol). The reaction mixture was stirred in the cold for 2 h, and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.94 g, 9.7 mmol) in THF (10 mL) was added dropwise. The mixture was then allowed to warm to rt and stir for 12 h. It was quenched with a saturated NH4Cl solution and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography to provide 2.0 g (63%) of the desired compound; 1H NMR (400 MHz, DMSO-d6) δ 7.29 (dd, J=13.3, 2.3 Hz, 1H), 7.24-7.18 (m, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.09 (s, 1H), 3.85 (br. s., 2H), 3.82 (s, 3H), 1.86-1.68 (m, 2H), 1.56 (d, J=12.0 Hz, 3H), 1.46-1.38 (m, 11H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CN(C)C=O>[N:14]1([CH2:13][CH2:12][O:8][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Nc1cccc(O)c1
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(OCCN2CCOCC2)c1
Reaction time: 1 h

Procedure:
To 36.01 g. of m-aminophenol dissolved in 325 ml. of N,N-dimethylformamide, 16.3 g. of 50% sodium hydride in oil was added. The reaction was stirred for 1 hour, until the effervescence stopped; then 57 g. of N-(2-chloroethyl)morpholine, from above, was added. After stirring overnight, the mixture was heated on a steam bath for 1/2 hr., then concentrated under vacuum. The residue was taken up in 300 ml. of 2N hydrochloric acid and washed twice with ether. After basifying with 10N sodium hydroxide, the product was extracted into ether, dried (magnesium sulfate), filtered through hydrous magnesium silicate and evaporated to a brown oil. Distillation gave 34.0 g. of a golden oil, b.p. 165°-180° C./0.45 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([O:16]CC)=[O:15])=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:23]CCCCC>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2([CH3:23])[C:14]([OH:16])=[O:15])=[N:4][CH:3]=1
Reactant: CCCCCC
Reactant: CCOC(=O)C1CCCCN1c1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
To an ice-cold solution of ethyl 1-(5-bromopyrimidin-2-yl)piperidine-2-carboxylate (0.37 g, 1.18 mmol) in THF (25 mL) was added NaH (60% dispersion in mineral oil, 0.06 g, 1.41 mmol) portion wise. The mixture was stirred at the same temperature for 45 min followed by addition of MeI (0.52 mL, 8.26 mmol) at 0° C. The temperature of the reaction was slowly raised up to rt and left to stir for 16 h. The reaction was then cooled to 0° C., quenched by drop wise addition of ice-cold water then extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 2% EtOAc: hexane to obtain the desired product as off-white solid (0.115 g, 32% yield). MS: 300.09 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Br)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]#[N:33])[CH:28]=[CH:29][CH:30]=1.[H-].[Na+]>C1COCC1.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=1)[C:32]#[N:33])=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)cnc12
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(C#N)c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 3-benzyl-4-bromo-8-(trifluoromethyl)quinoline (10.0 g, 27.31 mmol) and (3-methoxyphenyl)acetonitrile (5.57 mL, 40.96 mmol) in THF (100 mL) is treated with NaH (1.64 g, 41.0 mmol, 60% dispersion in oil). After 0.5 h at ambient temperature, the reaction is heated at 50° C. for 2 h. The cooled reaction is diluted with water, extracted with ethyl acetate, and the combined extracts are dried (MgSO4) and concentrated. The residue is purified via column chromatography using 10:90 ethyl acetate:hexane as the eluent. The purified product is dissolved in a mixture of methylene chloride and hexane and concentrated until precipitation commences. After precipitation is complete, [3-benzyl-8-(trifluoromethyl)quinolin-4-yl](3-methoxyphenyl)acetonitrile is isolated as an off-white crystalline solid (5.18 g, 44%). HRMS: calcd for C26H19F3N2O+H+, 433.15222; found (ESI, [M+H]+), 433.1528.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)[CH3:2].Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][CH2:6][CH:5]([CH2:4][N:3]([CH2:1][CH3:2])[CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=4[CH:30]=3)[O:10][C:9]=2[CH:11]=1
Reactant: CCNCC1COc2ccc(O)cc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)CC1COc2ccc(O)cc2O1
Temperature: 94 °C
Yield: 13.5 %

Procedure:
N-Ethyl-2,3-dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine (2.11 g, 13.1 mmole), 7-(3-chloropropoxy)coumarin (3.44 g, 14.4 mmole), diisopropylethylamine (11 ml, 63.2 mmole) and sodium iodide (1.98 g, 13.2 mmole) were combined in 175 ml of DMF and heated at 94° C. for 2 days under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue column chromatographed on silica gel using first 0.5% methanol/dichloromethane and then 1.5% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue redissolved in dichloromethane and boiled on a hot plate, the dichloromethane gradually being replaced with isopropanol. 4N HCl/isopropanol (4 ml) was added and the title compound was collected by filtration. A second recrystallization from isopropanol yielded 0.73 g of white solid, monohydrochloride, m.p. 208°-215° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][C:13]([OH:15])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][CH:7]=[N:8]3)[S:20][CH:21]=1
Reactant: O=C(O)Cc1c(F)ccc2ncccc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cc1c(F)ccc2ncccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-5-yl)acetamide was prepared from 2-(6-fluoroquinolin-5-yl)acetic acid (42 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=2.499, method [7], MS(ESI) 432.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.99 (dd, J=4.2, 1.1 Hz, 1H), 8.86 (d, J=7.9 Hz, 1H), 8.23 (dd, J=8.9, 4.5 Hz, 1H), 8.08 (s, 1H), 7.85 (dd, J=9.4, 9.2 Hz, 1H), 7.81 (dd, J=9.2, 4.5 Hz, 1H), 7.07 (s, 1H), 4.48 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:9][C:5]([CH:6](O)[CH3:7])=[CH:4][CH:3]=1.C([O-])(=[O:12])C.[Na+]>O>[CH3:7][CH:6]1[C:2]([OH:9])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:12]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(C(C)O)o1
Agent: [Na+]
Solvent: O
Product: CC1C(=O)C=CC1(C)O
Yield: 78 %

Procedure:
In the same apparatus as in Example 1, 5-methyl-α-methyl-furfuryl alcohol (35 parts), water (1050 parts) and sodium acetate (0.07 part) were charged, and the resultant mixture was stirred at 100° C. in a nitrogen stream while maintaining the pH at 5.0 to 5.7 until the starting compound was consumed. The reaction mixture was treated as in Example 1 to give 2-methyl-3-hydroxy-3-methyl-4-cyclopentenone in a yield of 78 %.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH2:9][CH3:10])[CH:4]=1.[NH3:11].O>>[CH2:9]([C:5]1[CH:4]=[C:3]([CH2:2][NH2:11])[N:7]([CH3:8])[N:6]=1)[CH3:10]
Reactant: N
Reactant: CCc1cc(CBr)n(C)n1
Solvent: O
Product: CCc1cc(CN)n(C)n1

Procedure:
A solution of compound 5 (660 mg, 3.27 mmol) in NH3.H2O (5 mL) was stirred at 90° C. for 3 h. The solvent was evaporated to give the crude product as a white solid which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.COC(=O)C1C=CC(N2C=C(C3[C:46]([C:54]4[CH:59]=[CH:58]C=CC=4)=[N:47]OC=3C(F)(F)F)N=C2)=CC=1>>[CH:54]1([CH2:46][NH:47][C:3](=[O:2])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)=[N:17][O:18][C:19]=4[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]3)=[N:6][CH:5]=2)[CH2:59][CH2:58]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NCC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 51 %

Procedure:
As described for Example 10, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (90 mg, 0.22 mmol), instead of 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester was converted, to the title compound (50 mg, 51%) which was obtained as a white solid. MS: m/e=454.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[C:14]([S:18][S:19][CH2:20][C@H:21]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][CH:29]=[CH2:30])[C:22]([OH:24])=[O:23])([CH3:17])([CH3:16])[CH3:15].C(O)(=O)CCC=C.[Cl-].[NH4+]>CN(C)C=O>[C:14]([S:18][S:19][CH2:20][C@H:21]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][CH:29]=[CH2:30])[C:22]([O:24][CH2:2][C:3]#[N:4])=[O:23])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCCC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Reactant: N#CCBr
Agent: C=CCCC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 62 %

Procedure:
2-Bromoacetonitrile (0.957 ml, 13.74 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.76 ml, 10.1 mmol) were added to a solution of the mixed crude product C (1.75 g, 8.70 mmol) of (R)-3-(tert-butyldisulfanyl)-2-(pent-4-enamido)propanoic acid (Compound 2k-C) and pent-4-enoic acid (1:0.9) in N,N-dimethylformamide (11 ml), and the mixture was stirred at room temperature for 50 minutes. A saturated aqueous ammonium chloride solution (6 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→50/50) to afford (R)-cyanomethyl 3-(tert-butyldisulfanyl)-2-(pent-4-enamido)propanoate (Compound 21-C) (940 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)=[CH:11][C:10]([CH:22]=O)=[N:9]1.[CH3:24][NH2:25].CO.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)=[CH:11][C:10]([CH2:22][NH:25][CH3:24])=[N:9]1
Reactant: COc1cccc(Sc2cc(C=O)nn2-c2ccccc2Cl)n1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(Sc2cccc(OC)n2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(6-methoxypyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (404 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.5 mL) and methanol (4 mL) at 0° C. The mixture was stirred at room temperature for 14 hr, and concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), sodium borohydride (76 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 436 mg, yield quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].N12CCCN=C1CCCCC2.Cl.Cl.[CH:34]12[NH:42][CH2:41][CH:38]([NH:39][CH2:40]1)[CH2:37][CH2:36][CH2:35]2>C(#N)C>[Cl:1][C:2]1[C:3]([N:39]2[CH2:40][CH:34]3[NH:42][CH2:41][CH:38]2[CH2:37][CH2:36][CH2:35]3)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: C1CC2CNC(C1)CN2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A suspension of 1.0 g (3.34 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30 ml of acetonitrile, 1.52 g (10.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 0.72 g (3.62 mmol) of 6,8-diazabicyclo [3.2.2]nonane, dihydrochloride was heated under reflux for 3 hr, then stirred at room temperature overnight. The precipitate was removed by filtration and washed with acetonitrile and ether to give 0.82 g of the title compound, mp 217°-220° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([S:29](Cl)(=[O:31])=[O:30])=[CH:24]2.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([S:29]([N:11]1[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]1)(=[O:30])=[O:31])=[CH:24]2
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2c(Cl)cccc2c1)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 69 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (193 mg, 3.888 mmol) with 5-chloronaphthalene-2-sulfonyl chloride (202.1 mg, 0.777 mmol) was carried out according to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.7 mL, 3.887 mmol) as base. 1-[(5-chloro-2-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 69% yield (256 mg) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)[CH3:2].C([BH3-])#N.[Na+].[CH:30](=O)[CH2:31][CH3:32]>C(O)(=O)C.O1CCCC1>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:30][CH2:31][CH3:32])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCC=O
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Yield: 90.1 %

Procedure:
Following general procedure Q and using 4-[(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 79, 0.2 g, 0.64 mmol), sodiumcyanoborohydride (0,121 g, 1.92 mmol) and propionaldehyde (1 mL, 13.7 mmol) in 5 mL of acetic acid and 5 mL of tetrahydrofuran, the title compound (0.22 g, 90%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 2H, J=9.0 Hz), 7.08 (s, 2H), 6.90 (s, 1H), 6.67 (d, 2H, J=8.9 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.66 (t, 2H, J=7.8 Hz), 1.77-1.64 (m, 2H) 1.54 (s, 6H), 1.50 (s, 6H), 1.34 (t, 3H, J=7.1 Hz), 0.94 (t, 3H, J=7.4 Hz).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[N+]=[N-].[ClH:17]>C(O)C.[Pd]>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([NH:15][CH3:16])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNS(=O)(=O)c1cc(F)ccc1CN
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of intermediate 51, 2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide, (560 mg, 2.3 mmol) in ethanol (10 mL) was added 6N HCl (1 mL) and 10% Pd—C (100 mg) and the mixture hydrogenated with 1 atm of H2 for 14 hrs. The catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo to provide 630 mg (Yield>100%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm: 4.36 (2H, d, J=5.2 Hz) 7.63-7.70 (2H, m) 7.77-7.83 (1H, m) 8.11 (1H, d, J=4.9 Hz) 8.41 (3H, s); LC/MS m/z 219 (M+H).