Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1

Procedure:
A suspension of 23.02 g (0.1 mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 1 L of dichloromethane, and 42.0 ml (0.303 mol) of triethylamine is stirred at 0°-5° and 42.17 ml (0.33 mol) of chlorotrimethylsilane is added. The ice bath is removed and the mixture is stirred at room temperature for 1 hr. The hazy solution is cooled to 10° and 23.8 ml (0.31 mol) of methanesulfonyl chloride is added. The resulting solution is stirred at room temperature for 24 hours and the dichloromethane is evaporated under reduced pressure and 500 ml of water is added to the residue. The mixture is cooled to 10° and the solid is filtered, washed with water, acetonitrile, and ether, and dried to give 29.9 of 6-[4-(methylsulfonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>320°.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:31]=[C:30](S(C4C=CC(C)=CC=4)(=O)=O)[S:29][N:28]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(#N)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:31]=[C:30]([O:9][C:7]4[C:6]([CH3:10])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=4)[S:29][N:28]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Cc1ccc(S(=O)(=O)c2nc(C3(c4ccc(Cl)cc4)CC3)ns2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Oc2nc(C3(c4ccc(Cl)cc4)CC3)ns2)c(C)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
0.70 g (5.12 mmol) of 2,5-dimethyl-4-hydroxyaniline is placed in 18 ml of acetonitrile, 0.85 g (6.14 mmol) of potassium carbonate is added at ambient temperature and the mixture is stirred at ambient temperature for 30 min. Subsequently, 2.0 g (5.12 mmol) of 3-[1-(4-chloro-phenyl)cyclopropyl]-5-[(4-methylphenyl)sulphonyl]-1,2,4-thiadiazole are added and the reaction mixture is stirred at 50° C. for 12 h. After cooling, the reaction mixture is concentrated using a rotary evaporator and the residue is taken up in dichloromethane, extracted twice with water, dried over Na2SO4 and freed from the solvent under vacuum. 1.46 g of clean product are obtained (76.9% yield, log P (pH 2.3)=4.44).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([NH:12][CH:11]=[CH:10]3)=[C:5]2[CH2:4]1.O>O1CCOCC1>[CH3:2][N:3]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([NH:12][CH2:11][CH2:10]3)=[C:5]2[CH2:4]1
Reactant: CN1Cc2c(ccc3cc[nH]c23)C(c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN1Cc2c(ccc3c2NCC3)C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
12.5 ml (0.131 mol) of 10.5N hydrochloric acid are added dropwise to a mixture of 26 g (0.1 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole and 29.2 g (0.4 mol) of trimethylaminoborane in 150 ml of absolute dioxane at a temperature of 16° C., with stirring and in the absence of moisture. The mixture is then heated under reflux for 30 minutes and cooled to room temperature, 50 ml (0.3 mol) of 6N HCl are added and the mixture is heated under reflux once more for 15 minutes. After cooling to room temperature, 600 ml of H2O are added to the reaction mixture, the mixture is filtered over kieselguhr and, after addition of a further 600 ml of H2O, the filtrate is brought to pH 9 with 20% strength NaOH. The aqueous phase is now extracted several times with CH2Cl2 and, after drying over Na 2 SO4, the solvent is distilled off on a rotary evaporator. The oily residue is chromatographed on silica gel (silica gel 60 from E. Merck, Darmstadt) using ethyl acetate and MeOH (20:7) as the eluent.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23]/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:19][CH2:18]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:43][CH2:44][C:45]([NH2:47])=[O:46]>>[C:8]1([C:6]2[N:7]=[C:2]([NH:43][CH2:44][C:45]([NH2:47])=[O:46])[CH:3]=[C:4]([NH:14][C:15](=[O:32])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:23]/[CH:24]=[CH:25]/[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19][CH2:18]3)[N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCC(N)=O
Reactant: O=C(CN1CCN(C/C=C/c2ccccc2)CC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CNc1cc(NC(=O)CN2CCN(C/C=C/c3ccccc3)CC2)nc(-c2ccccc2)n1
Temperature: 100 °C
Yield: 3.9 %

Procedure:
To a crude sample of N-(6-chloro-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide (22.54) (0.75 g in 60 ml DMSO) were added glycinamide hydrochloride (1.85 g in 10 ml DMSO) and N,N-diisopropylethylamine (2.96 ml) and the mixture heated to 100° C. for 16 hrs. The solvent was then removed in vacuo and the residue purified twice by flash chromatography on silica gel using mixtures of dichloromethane and methanol (97:3, 95:5 then 93:7 v/v/v). Further purification by recrystallization from methanol furnished the title compound (32 mg over 2 steps).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2-:10].[Na+].Cl>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1)[CH2:2][CH3:3]
Reactant: [NH2-]
Reactant: CCCc1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1ccnc(N)c1
Temperature: 140 °C
Reaction time: 48 h
Yield: 50.7 %

Procedure:
To a solution of 4-propylpyridine (10.0 g, 82.5 mmol) in toluene (170 mL), sodium amide (6.4 g, 165 mmol) was added at room temperature, and the mixture was stirred at 140° C. for 2 days. Under ice-cold conditions, the reaction solution was added 6N aqueous solution of hydrochloric acid (30 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate/1% triethylamine), and the title compound (5.70 g (yield 51%)) was obtained as a red-brown solid.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[N:25]1([C:23](=[O:24])[CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:32][CH:31]=3)[CH2:13][CH2:14]2)=[O:19])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCCC(=O)N3CCOCC3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1)N1CCOCC1

Procedure:
4-[4-(2-aminoethyl)anilino]-N-[3-(4-morpholinyl)-3-oxopropyl]-1-piperidinecarboxamide formate (0.90 g, 2.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to yield the title compound (0.39 g, 0.5 mmol).
Reaction SMILES: [F:1][C:2]([F:17])([S:13](F)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].CCN(CC)CC.[CH2:25]([CH:32]1[C:40]2[C:35](=[CH:36][C:37]([F:42])=[C:38]([OH:41])[CH:39]=2)[CH2:34][CH:33]1[NH:43][C:44](=[O:48])[O:45][CH2:46][CH3:47])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:1][C:2]([F:17])([S:13]([O:41][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][C:37]=1[F:42])[CH2:34][CH:33]([NH:43][C:44]([O:45][CH2:46][CH3:47])=[O:48])[CH:32]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: CCOC(=O)NC1Cc2cc(F)c(O)cc2C1Cc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1Cc2cc(F)c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
Perfluorobutanesulfonyl fluoride (0.392 ml, 2.004 mmol) and Et3N (0.419 ml, 3.01 mmol) in abs. dichloromethane (10 ml) was added dropwise to the intermediate ethyl 1-benzyl-5-fluoro-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate (330 mg, 1.002 mmol), dissolved in dichloromethane and stirred at room temperature over night. Evaporated and purified by flash silica gel chromatography on 12 g SiO2-cartridge using dichloromethane to afford 3-benzyl-2-(ethoxycarbonylamino)-6-fluoro-2,3-dihydro-1H-inden-5-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate as a yellow product. M=389 mg (63%)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][CH2:7][C:8]1[S:9][C:10]([CH2:13][N:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=1)C.[NH3:18]>C(O)C>[CH3:15][N:14]([CH2:13][C:10]1[S:9][C:8]([CH2:7][O:6][CH2:5][C:4]([NH2:18])=[O:3])=[CH:12][CH:11]=1)[CH3:16]
Reactant: CCOC(=O)COCc1ccc(CN(C)C)s1
Reactant: N
Solvent: CCO
Product: CN(C)Cc1ccc(COCC(N)=O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [[5-(N,N-dimethylaminomethyl)2-thienyl]methoxy] acetic acid ethyl ester (4.0 g) in a mixture of 0.88 ammonia solution (75 ml) and ethanol (75 ml) was stirred for 1 hr at room temperature. The solvent was removed and the residue recrystallised from a 1:1 mixture of benzene and petroleum spirit (b.p. 60°-80°) to afford a white crystalline solid (3.2 g) m.p. 86.5°-95°. NMR (CDCl3) 7.71, s, (6H); 6.38, s, (2H); 6.00, s, (2H); 5.30, s, (2H); 3.5, br, (2H); 3.12, q, (2H).
Reaction SMILES: [OH:1][C@@H:2]([CH3:15])[CH2:3][NH:4][C:5]1[C:10]([CH:11]=O)=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1.C[O:17][C:18](=O)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[O:20][C:19]1[C:18](=[O:17])[N:4]([CH2:3][C@@H:2]([OH:1])[CH3:15])[C:5]2[N:6]=[C:7]([S:13][CH3:14])[N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: CSc1ncc(C=O)c(NC[C@H](C)O)n1
Reactant: COC(=O)COc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Oc3ccc(F)cc3F)c(=O)n(C[C@H](C)O)c2n1
Temperature: 60 °C
Yield: 108.3 %

Procedure:
To a mixture of 4-((S)-2-hydroxy-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (16.5 g, 73 mmol) and (2,4-difluorophenoxy)acetic acid methyl ester (29.4 g, 145 mmol) in anhydrous dimethyl formamide (300 mL) was added potassium carbonate (30 g, 218 mmol). The reaction mixture was heated to 60° C. and after 18 hours, the reaction mixture was cooled and the dimethylformamide was distilled off under vacuum. Crude residue suspended in water (300 mL) and extracted with dichloromethane, washed with brine and dried over magnesium sulfate. Filtered and concentrated under vacuum to give 41 g crude material which was chromatographed on silica gel column eluding with 1% methanol in dichloromethane to give 30 g 6-(2,4-difluorophenoxy)-8-((S)-2-hydroxypropyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec M+1=274).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[C:27]([O-])(=[O:31])[C@H:28]([CH3:30])[OH:29].[Na+]>CN(C=O)C>[OH:29][C@@H:28]([CH3:30])[C:27]([N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1)=[O:31]
Reactant: C[C@H](O)C(=O)[O-]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(C(=O)[C@H](C)O)C3)cc1-2

Procedure:
Following the procedure for 318, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and sodium L-lactate were reacted in DMF to give 359. LCMS: RT=10.69 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.36 (1H, s), 7.90 (1H, s), 7.20-7.11 (1H, m), 7.09-7.01 (1H, m), 5.84-5.75 (1H, m), 4.62-4.30 (4H, m), 4.26-4.07 (3H, m), 3.98-3.87 (1H, m), 3.43-3.35 (2H, m), 1.61 (6H, d, J=6.65 Hz), 1.32 (3H, dd, J=10.70, 6.64 Hz). 1 Exchangeable not observed
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=3)=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[NH:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:40])([F:1])[F:39])[CH:4]=3)=[O:11])=[CH:14][CH:15]=2)=[CH:21]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cc2c[nH]c3ncccc23)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
1-(3-Trifluoromethyl-phenyl)-3-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-urea (114, 85.0 mg, 0.150 mmol) was dissolved in tetrahydrofuran (10.0 mL) and tetra-n-butylammonium fluoride (52.2 mg, 0.200 mmol) was added. After 10 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with by silica gel chromatography to give the compound (P-0262, 23 mg, 38% over steps 6 & 7). MS (ESI) [M+H+]+=411.2
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[N+:35]([O-])=O)[C:12]([N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17](=[O:31])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCOCC1>[NH2:35][C:34]1[CH:33]=[CH:32][C:11]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17](=[O:31])[CH2:16][CH2:15]2)=[O:13])=[CH:10][C:9]=1[OH:8]
Reactant: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc(N)c(O)c2)c2ccccc21
Yield: 89.5 %

Procedure:
A solution of 5-(3-benzyloxy-4-nitrobenzoyl)-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (2.2 g), 10% palladium on carbon (220 mg) in ethanol (30 ml) and 1,4-dioxane (15 ml) was stirred under 4 atmospheric pressure of hydrogen at ambient temperature for 7 hours. The reaction mixture was filtered through a bed of celite, concentrated and purified by silica gel column chromatography (SiO2 60 g, ethyl acetate:n-hexane =2:1) to give 5-(4-amino-3-hydroxybenzoyl)-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.5 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:23]3[N:22]=[CH:21][S:20][CH:24]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cscn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cscn1
Yield: 68 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 4-thiazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 68% yield.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][CH:7]([N:15]=[N+]=[N-])[C@@H:6]1[Cl:18])(=[O:3])[CH3:2].[H][H]>O1CCOCC1.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][CH:7]([NH2:15])[C@@H:6]1[Cl:18])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC[C@H]1OC(N=[N+]=[N-])[C@H](Cl)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1OC(N)[C@H](Cl)[C@@H]1OC(C)=O
Yield: 99 %

Procedure:
Compound (30) obtained in step (2) above (300 mg) was dissolved in dioxane (6 ml). The solution obtained was subjected to a catalytic reduction by blowing hydrogen therein at room temperature in the presence of palladium black as catalyst for 1 hour. The resulting reaction solution was filtered and the filtrate was concentrated to about a half volume and then diluted with dichloroethane (50 ml). The solution as diluted was dried over calcium chloride and concentrated to afford compound (31) as a colorless syrup (270 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[O:8][C:7]([CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:25][CH:24]=1)([CH3:20])[CH2:6][C:5]2=O.Cl.[NH2:39][OH:40].N1C=CC=CC=1>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([CH3:16])([CH3:17])[CH3:15])[O:8][C:7]([CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:35][CH:36]=1)([CH3:20])[CH2:6]/[C:5]/2=[N:39]\[OH:40]
Reactant: CC(C)(C)CC(C)(C)c1cc2c(cc1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)CC(C)(C)c1cc2c(cc1O)/C(=N/O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
The procedure described in Example 13 was repeated, but using 1.0 g of 5-{4-[6-hydroxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman -2-ylmethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 7), 0.26 g of hydroxylamine hydrochloride, 0.3 g of pyridine and 10 ml of methanol, to give the title compound as a white powder, softening at 115°-120° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1>>[O:15]=[C:9]1[CH2:14][CH:13]([P:4]([O:5][CH2:6][CH3:7])(=[O:8])[O:3][CH2:1][CH3:2])[CH2:12][CH2:11][CH2:10]1
Reactant: O=C1C=CCCC1
Reactant: CCOP([O-])OCC
Product: CCOP(=O)(OCC)C1CCCC(=O)C1

Procedure:
Diethyl 5-oxocyclohexanephosphonate (B.Pt. 142°-3° C./0.2 mm) was prepared by the base catalysed addition of diethylphosphite to 2-cyclohexen-1-one.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([CH2:18][CH2:19][CH:20]([OH:36])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H-].[Na+].I[CH3:40]>>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([CH2:18][CH2:19][CH:20]([O:36][CH3:40])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:11])([CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCC(O)c2ccc(-c3cccc(C(F)(F)F)c3)s2)c(Cl)c1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(CCC(OC)c2ccc(-c3cccc(C(F)(F)F)c3)s2)c(Cl)c1Cl

Procedure:
Ethyl 2-(2,3-dichloro-4-(3-methoxy-3-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoate is prepared from ethyl 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate using 1.1 equivalents of sodium hydride and 1.1 equivalents of iodomethane according to general procedure H.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH3:16])=[O:7].C(=O)([O-])O.[Na+]>O>[Br:1][C:12]1[C:11]([O:14][CH3:15])=[CH:10][C:9]([CH3:16])=[C:8]([C:6](=[O:7])[C:5]2[C:4]([Cl:3])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[CH:13]=1
Reactant: COc1ccc(C(=O)c2c(Cl)cccc2Cl)c(C)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1Br
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of bromine (0.25 ml in 3 ml of trichloromethane) is added dropwise to a stirred solution of 2,6-Dichloro-4'-methoxy-2'-methyl-benzophenone (1.5 g; 5 mmol in 5 ml of trichloromethane), followed by 15 minutes of stirring at 20° C. The mixture is shaken with water, sodium hydrogencarbonate solution and water. The organic phase is dried and evaporated. The residue is purified by chromatography (flash column filled with 30 g of silicagel, elution with petrolether/ethylacetate changing from 20:1 to 9:1, 8:2, 7:3 (v/v). After evaporation, the residue crystallises when treated with petrolether/toluene to give white crystalls (0.45 g; 24% y); mp. 159° C.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH2:12])=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[CH2:1]([NH:9][C:10]1[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)NCCc1ccccc1
Solvent: CO
Product: O=C(O)c1csc(NCCc2ccccc2)n1
Yield: 94.8 %

Procedure:
2-Phenethylamino-thiazole-4-carboxylic acid (235 mg) was prepared according to General Procedure B using phenethyl-thiourea (180 mg) and 3-bromo-2-oxo-propionic acid (167 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5])[OH:2].[CH2:10](O)[CH3:11]>>[CH2:1]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH2:10][CH3:11])=[O:5])[OH:2]
Reactant: CCO
Reactant: CC(CO)(CO)C(=O)O
Product: CCOC(=O)C(C)(CO)CO

Procedure:
2,2-Bis(methylol)propionic acid (bisMPA; 22.1 g, 0.165 mol) was added in ethanol (150 mL) with Amberlyst-15 (6.8 g) and refluxed overnight. The resins were then filtered out and the filtrate was evaporated. Methylene chloride (200 mL) was added to the resulting viscous liquid to filtrate the unreacted reagent and byproduct. After the solution was dried over MgSO4 and evaporated, ethyl 2,2-bis(methylol)propionate (EtMPA) was obtained as a clear and colorless liquid (21.1 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:21].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[O:21])=[CH:4][N:3]=1
Reactant: Fc1ccccc1Sc1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(c1ccc(Cl)nc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)thio]pyridine (Example 1 Step 1, 1.0 g, 4.17 mmol) was taken up in dichloromethane (20 mL) and 3-chloroperoxybenzoic acid (50%; 1.44 g, 4.17 mmol). The reaction was stirred at room temperature under nitrogen for 1 hour. 4N sodium hydroxide solution was added and the products extracted into dichloromethane (×2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using toluene followed by 10% ethyl acetate/toluene gave 2-chloro-5-[(2-fluorophenyl)sulfinyl]pyridine (0.65 g, 61%). δH (500 MHz, d6 DMSO) 8.71 (1H, s), 8.07 (1H, d, J 8.2), 7.83 (1H, t, J 6.7), 7.68 (1H, d, J 8.2), 7.63-7.59 (1H, m), 7.46 (1H, t, J 7.3), 7.33 (1H, t, J 9.1); m/z (ES+) 256, 258 [MH+].