Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:21])([CH2:11][C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=O>C(N(CC)CC)C>[CH:1]1([CH2:7][C:8]([OH:21])([CH2:11][C:12]([CH3:13])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:20])[CH:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(CC(O)(CO)CC1CCCCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(CC(O)(C=O)CC1CCCCC1)c1ccccc1

Procedure:
Analogously to Example 1, 160 mg of 2-cyclohexylmethyl-4-methyl-4-phenyl-1,2-pentanediol is reacted with 342 mg of pyridine-sulfur trioxide complex, 1.95 ml of DMSO and 0.39 ml of triethylamine to form 2-cyclohexylmethyl-2-hydroxy-4-methyl-4-phenylpentanal ('H-NMR (CDCl3); δ=0.90-1.60 (m, 10H), 1.30 (s, 3H), 1.41 (s, 3H), 1.76 (m, 2H), 1.95 (m, 1H), 2.20 (d, 1H), 2.35 (d, 1H), 2.97 (s, 1H), 7.20 (m, 1H), 7.30 (m, 4H), 8.76 (s, 1H)). The crude product is reacted with 137 mg of 5-aminoquinoline and 524 mg of sodium triacetoxy borohydride to form imine (180 mg; 'H-NMR (CDCl3); δ=0.90-1.90 (m, 18H), 2.25 (m, 1H), 2.80 (d, 1H), 3.00 (d, 1 H), 3.76 (t, 1H), 5.06 (d, 1H), 6.25 (d, 1H), 7.10-7.55 (m, 8H), 8.25 (d, 1H), 8.87 (dd, 1H); MS (ESI), 415). Reductive amination with 49 mg of sodium borohydride yields 130 mg of end product after column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C@H:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C@@H:20]([NH:19][C:15]([C@H:9]2[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH3:21])=[CH:23][CH:24]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(=O)CCN2C(=O)OC(C)(C)C)cc1

Procedure:
The title compound (D60) (300 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (R)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (200 mg; available from Aldrich#701130) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (195 mg). Reaction time: 1 h
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH2:17]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:37])=[CH:39][CH:40]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 4(4-tetradecenylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated and the residue is crystallized from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]([CH3:16])[O:13][C:12]1=[O:17].[H][H]>[Pd].O1CCCC1>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:15][CH:14]([CH3:16])[O:13][C:12]2=[O:17])=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1CN(c2ccc([N+](=O)[O-])cc2Cl)C(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1CN(c2ccc(N)cc2Cl)C(=O)O1

Procedure:
A solution of 16.5 g of 2B and 0.5 g of 10% palladium-on-carbon catalyst in 200 ml of tetrahydrofuran was treated with hydrogen in a Parr shaker, giving 3-(4-amino-2-chlorophenyl)-5-methyl-2-oxazolidinone (2C), as a white solid, mp: 140°-141° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[O:19]1CC[CH2:21][CH2:20]1.C(Cl)(=O)C>O.C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:20](=[O:19])[CH3:21])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A mixture of commercially available 4-phenylpiperidine (10 g, 62 mmol), pyridine (5.7 mL, 70.5 mmol), and tetrahydrofuran (80 mL) was stirred at 0° C. and a mixture of acetyl chloride (5 mL, 70.3 mmol) and tetrahydrofuran (20 mL) was dripped over 10 minutes. The mixture was stirred under nitrogen atmosphere at 25° C. for 14 hours. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction liquid for separation. The aqueous layer was extracted with ethyl acetate (100 mL), then the organic layers were combined, and the resultant was washed with a saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL), and then a saturated saline solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated to obtain the title compound (12.3 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[F:24][C@@H:25]([CH3:28])[CH2:26]O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:24][C@@H:25]([CH3:28])[CH2:26][O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccncc1
Reactant: C[C@H](F)CO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](F)COc1ccncc1
Yield: 89.9 %

Procedure:
A solution of 1.5 g of 4-hydroxypyridine, 7.6 g of cyanomethylenetributylphosphorane, and 1.4 g of (2S)-2-fluoro-1-propanol in 20 mL of toluene was stirred at 105° C. overnight. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate, and the organic layer was separated. The aqueous layer was adjusted to pH 11 by the addition of a 1 M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 2.2 g of 4-{[(2S)-2-fluoropropyl]oxy}pyridine.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][NH:13]2)=[CH:8][C:7]=1[F:23])(=[O:5])[CH3:4].Br[CH2:25][CH2:26][F:27]>CN(C)C=O>[C:3]([C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:13]2[CH2:25][CH2:26][F:27])=[CH:8][C:7]=1[F:23])(=[O:5])[CH3:4]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(C(C)=O)c(F)cc2c1=O
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)c2c(F)c(C(C)=O)c(F)cc2c1=O
Reaction time: 2 h
Yield: 32.3 %

Procedure:
To 1.62 g (34.0 mmol) of sodium hydride (50% dispersion in oil, pentane washed) in 250 ml of dimethylformamide was added 10.0 g (34 mmol) of the ethyl 7-acetyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate dissolved in 100 ml of dimethylformamide at room temperature. The mixture was stirred for two hours, and 13.0 g (2.4 eq) of 1-bromo-2-fluoroethane was added. The mixture was stirred overnight at 50° C. It was concentrated, and partitioned between water and dichloromethane. The dichloromethane was then concentrated and the residue purified by column chromatography to give 3.75 g of ethyl 7-acetyl-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3quinoline carboxylate, mp 155°-156° C. This material was hydrolyzed with 2 N hydrochloric acid and 2-propanol as co-solvent to give 2.95 g of the 7-acetyl-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, mp 215°-216° C.
Reaction SMILES: O[C:2]1([CH:14]=[CH2:15])[C:11]2([CH3:12])[C:6](=[CH:7][C:8](=[O:13])[CH2:9][CH2:10]2)[CH:5]=[CH:4][CH2:3]1.S(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+].[Cl-]>C(Cl)Cl.O.N1C=CC=CC=1>[Cl:18][CH2:15][CH:14]=[C:2]1[C:11]2([CH3:12])[C:6](=[CH:7][C:8](=[O:13])[CH2:9][CH2:10]2)[CH:5]=[CH:4][CH2:3]1
Reactant: C=CC1(O)CC=CC2=CC(=O)CCC21C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC12CCC(=O)C=C1C=CCC2=CCCl
Reaction time: 0.08 h

Procedure:
To a solution of 1hydroxy-8a-methyl-1-vinyl-1,2,6,7,8,8a-hexahydro-6-naphthalenone (0.204 g.) in anhydrous methylene chloride (20 ml.) was added 0.5 ml. of pyridine. The reaction mixture was cooled in an ice-bath and thionyl chloride (150 mg.) was added. After 5 minutes, the reaction mixture was diluted with methylene chloride (20 ml.) and water (10 ml.) and neutralized with saturated sodium bicarbonate solution (5 ml.). The aqueous layer was extracted with methylene chloride (3×25 ml.) and the combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent gave 217 mg. of the oily chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([NH2:25])=O)=[O:20])[C@@H:10]([CH3:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][CH:22]1[C:23]#[N:25])=[O:20])[CH:10]([CH3:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccc(F)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1ccc(F)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the product from Step A (91.7 mg, 0.233 mmol) in anhydrous DMF (1 mL) was added cyanuric chloride (86 mg, 0.466 mmol). After stirring at room temperature for 16 h, the reaction was diluted with ethyl acetate. The organic phase was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine, dried (magnesium sulfate), and concentrated under reduced pressure. Purification by preparative thin layer chromatography (silica, ethyl acetate eluant) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(S(C)(=O)=O)C4)CC2)no1
Reaction time: 0.75 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50 mg, 0.13 mmol) and triethylamine (0.036 ml, 0.26 mmol) in dichloromethane (1.3 ml) was added methanesulfonyl chloride (0.020 ml, 0.26 mmol) at room temperature. Stirring for 45 minutes was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (37 mg, 62%) as white solid. MS m/e: 462 ([M+H]+).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][NH:24]3)[C:11]1=[O:30])[CH2:7][CH2:8][CH3:9])C>CO>[Cl:29][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:31])=[O:3])[C:11]2=[O:30])[CH:28]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Solvent: CO
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Reaction time: 18 h
Yield: 52.8 %

Procedure:
3-[3-(6-Chloro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (100 mg, 0.23 mmol), prepared as described in example 72 using the appropriate reagents, was dissolved in methanol (1 mL) and treated with Amberlyst® A26 (OH— form) (1.2 g, 1.6 mmol). The resulting mixture was agitated 18 h. The mixture was filtered and the resin was washed with several portions of methanol. The product was eluted from the resin with 20% formic acid in methanol (2×2 mL). The solution was concentrated and purified by preparative HPLC using an acetonitrile/water/formic acid gradient to provide 50 mg (53%) of the title compound. LCMS (ESMS): m/z 412 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14]Cl)[C:6]=2[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:26]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][N:33]3[CH2:34][CH2:35][CH:30]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32]3)[C:6]=2[CH:16]=1
Reactant: CCCCC1CCNCC1
Reactant: O=C1COc2c(F)cc(Br)cc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CCCCC1CCN(CCCN2C(=O)COc3c(F)cc(Br)cc32)CC1
Yield: 34.7 %

Procedure:
6-Bromo-4-(3-chloropropyl)-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF50(2084)) (0.086 g, 0.27 mmol), K2CO3 (0.074 g, 0.53 mmol), NaI (0.080 g, 0.53 mmol) and 4-butylpiperidine (0.039 g, 0.28 mmol) were mixed according to GP13. CC (SiO2; CH2Cl2/MeOH 10:0.2-4) gave the title compound (95MF58) (0.040 g, 35%). 1H NMR (CDCl3) δ 6.92-6.84 (m, 2H), 6.79-6.74 (m, 1H), 4.59 (s, 2H), 3.93 (t, J=7.4 Hz, 2H), 2.81 (d, J=10.8 Hz, 2H), 2.31 (t, J=7.0 Hz, 2H), 1.87-1.75 (m, 4H), 1.62 (d, J=9.2 Hz, 2H), 1.27-1.12 (m, 9H), 0.84 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3) δ 163.7, 151.8 (d, J=246.0 Hz), 133.8 (d, J=14.6 Hz), 130.7 (d, J=3.5 Hz), 122.1 (d, J=8.0 Hz), 111.2 (d, J=18.4 Hz), 110.4 (d, J=3.4 Hz), 67.6, 55.8, 54.2, 40.0, 36.4, 35.8, 32.6, 29.0, 24.8, 22.9, 14.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[C:16]([C:17]#[N:18])=[C:11]3[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:36]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:21][CH:20]=4)[C:16]([C:17]([NH2:18])=[O:36])=[C:11]3[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1cccc(O)c1)C2
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1cccc(O)c1)C2

Procedure:
The desired product was prepared from 6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. MS (ESI) m/e [M+1]+ 426.9.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:23]=1[CH2:24][O:25][NH2:26].CC([O-])=O.[Na+].CC(O)=O>CO.O>[F:20][C:21]([F:35])([F:36])[C:22]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][C:23]=1[CH2:24][O:25][N:26]=[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH3:2]
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(=NOCc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 18.6 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (300 mg, 0.99 mmol), O-(2,5-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (296 mg, 1.0 mmol) and anhydrous NaOAc (53 mg, 0.65 mmol) in MeOH (5 mL) and H2O (15 mL) was adjusted to pH 4.5 with AcOH and heated for 15 h at reflux. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19 to 1:9) afforded N-{2-[1-(2,5-bistrifluoromethylbenzyloxyimino)ethyl]-4-chlorophenyl}trifluoromethanesulfonamide 120 (100 mg, 19%), as a pale yellow solid. M.p. 73-75° C. 1H n.m.r. (200 MHz, CDCl3) δ 10.94, br s, 1H; 7.88-7.71, m, 3H, 7.60, d, J=8.8 Hz, 1H, 7.50, d, J=2.4 Hz, 1H, 7.33, dd, J=2.4 and 8.8 Hz, 1H, 5.46, s, 2H, 2.41, s, 3H.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].[OH-].[K+].O>ClCCl>[CH3:12][O:13][CH:14]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: COCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(COCCOCCO)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
200 g of p-toluenesulfonyl chloride and 172.4 g of triethylene glycol monomethyl ether are dissolved in 1 liter of dichloromethane and cooled to 0° C. With vigorous stirring, 236.3 g of freshly powdered potassium hydroxide are metered in at a rate such that the temperature does not exceed 5° C. The mixture is maintained at 0° C. for 3 hours. 1 liter of dichloromethane and 1.2 liters of iced water are added. If more solids form, a further 0.5 liter of iced water are added. The organic phase is separated off and washed with 0.3 liter of saturated sodium chloride solution. It is dried over Na2SO4 and evaporated to dryness under reduced pressure.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.OCC1[CH:21]=[CH:20][C:19]([SiH:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1.CO>C(OCC)(=O)C>[C:5]([O:4][CH2:1][C:2]1[CH:17]=[CH:18][C:19]([SiH:22]([CH:23]([CH3:25])[CH3:24])[CH:26]([CH3:27])[CH3:28])=[CH:20][CH:21]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[SiH](c1ccc(CO)cc1)C(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OCc1ccc([SiH](C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Acetic anhydride (3.1 mL, 33 mmol) and 4-N,N-dimethylaminoprydine (7.3 mg, 6 mmol) were added under argon atmosphere to pyridine (100 mL) dissolving 4-(hydroxymethyl)phenyl-diisopropylsilane (3) (4.9 g, 22 mmol). The resulting mixture was then stirred for 2 hours at a room temperature and methanol (20 mL) was added to it. The reaction mixture was diluted with ethyl acetate (400 mL), and then extracted three times with saturated saline solution (300 mL). An organic layer was collected and dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure to give a desired product (5.4 g, 93%). Its NMR data are as follows:
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][S:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:6].C1C=C(Cl)C=C(C(OO)=[O:19])C=1>>[Br:1][CH2:2][CH2:3][NH:4][S:5]([C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:19])=[O:6]
Reactant: CC(C)(C)S(=O)NCCBr
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(C)S(=O)(=O)NCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid (2-bromo-ethyl)-amide (0.8 g, 3.5 mmol) was added mCPBA (77%, 0.95 g, 4.2 mmol) and stirred at a temperature of about 25° C. for 2 hrs. The reaction mixture was condensed and purified to provide 2-methyl-propane-2-sulfonic acid (2-bromo-ethyl)-amide as a white solid (0.4 g, 46% yield).
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:8]=2)[C:5](=[O:30])[NH:4][C:3]1=[O:31].[CH3:32]I>>[CH3:32][N:4]1[C:3](=[O:31])[CH:2]([CH3:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[C:23]([CH3:29])[N:22]=4)[CH2:19][CH2:20]3)=[O:14])=[CH:9][CH:8]=2)[C:5]1=[O:30]
Reactant: CI
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)cc3)CC2)nc1C

Procedure:
Using 5-methyl-1-{4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidine-2,4-dione (50 mg) described in Example 550 and methyl iodide (8.1 μL) and by the reaction and treatment in the same manner as in Example 551, the title compound (27 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[CH:12]([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:11]([CH:12]([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C(CC(=O)C(F)F)c1nc2ccc(F)cc2s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3ccc(F)cc3s2)cc1
Yield: 65 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-fluoro-2-[1-(4-methylsulfonylphenyl)-3-difluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 65%). NMR(DMSO-d6) δ: 3.30 (3H, s), 7.23 (1H, t, J=54.1 Hz), 7.38-7.46 (1H, m), 7.56 (1H, s), 7.83-7.88 (2H, m), 7.94-7.99 (1H, m), 8.05-8.13 (3H, m); mp 204-206° C. (ethanol)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:18]([N:21]1[CH2:26][CH2:25][CH:24](OS(C)(=O)=O)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:18]([N:21]1[CH2:26][CH2:25][CH:24]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCC(OS(C)(=O)=O)CC1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCC(Oc2ccc(C3(C#N)CCOCC3)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (459 mg, 2.26 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-isopropyl-piperidin-4-yl ester (400 mg, 1.81 mmol) in DMF (1.3 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by successive column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a pale yellow solid (116 mg, 19%). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.93 (d, 2H), 4.30 (m, 1H), 4.12-4.02 (m, 2H), 3.89 (td, 2H), 2.84-2.68 (m, 3H), 2.45-2.34 (m, 2H), 2.15-1.96 (m, 6H), 1.88-1.75 (m, 2H), 1.06 (d, 6H).