Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](Cl)([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])C.O=S(Cl)Cl.S(O)(O)(=O)=O.[NH2:32][NH2:33].CC[O-].[Na+]>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:33][NH:32]3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: CCOC(=O)CC(C)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 32.1 g of 3-chloro-3-(4'-fluoro-4-biphenylyl)-butyric acid ethyl ester (obtainable from the hydroxy ester and SOCl2), 15 g of hydrazine sulfate and 20.5 g of sodium ethylate in 500 ml of absolute ethanol is boiled for 2 hours and the solvent is evaporated. Working up gives 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].Br[CH2:8][C:9](=O)[C:10]([OH:12])=[O:11]>C1COCC1>[C:1]([CH2:3][C:4]1[S:5][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[N:6]=1)#[N:2]
Reactant: N#CCC(N)=S
Reactant: O=C(O)C(=O)CBr
Solvent: C1CCOC1
Product: N#CCc1nc(C(=O)O)cs1
Temperature: 0 °C
Yield: 48.1 %

Procedure:
(Cyano)thioacetamide (2 g, 19.97 mmol) was stirred in excess THF (40 mL) under nitrogen atmosphere. The solution was cooled to 0° C. and the solution of 3-bromopyruvic acid (3.33 g, 19.97 mmol) dissolved in 5 mL THF was added dropwise. The mixture was refluxed for 3 h. Solvent was evaporated and the crude product was purified by flash chromatography (silica, eluent: 0-40% DCM-10% MeOH/DCM mixture) to yield 1.615 g of the title compound. 1H NMR (400 MHz; CDCl3): δ 4.20 (s, 2H), 8.33 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:31]([C:30]1[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 44.3 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (128 mg, 0.373 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (77.2 mg, 0.485 mmol), triethylamine (113 mg, 1.12 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (77 mg, 44%) was obtained as a white powder. melting point 255° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[CH2:17]Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:20]=[C:21]2[C:26]([Br:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]2[CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Cc1cnc(N)c(Br)c1
Product: Cc1cc(Br)c2nc([C@@H]3CCCN3C(=O)OCc3ccccc3)cn2c1
Yield: 44.4 %

Procedure:
Following the procedures of example 14, (S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (0.295 g, 0.90 mmol) and 2-amino-3-bromo-5-methylpyridine (0.1765 g, 0.94 mmol), produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (12 g SiO2, 0-50% ethyl acetate in hexanes) to give (S)-benzyl-2-(8-bromo-6-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.165 g, 0.40 mmol, 44%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[C:17]3([CH2:24][CH2:23][N:22](C(OCC4C=CC=CC=4)=O)[CH2:21][CH2:20]3)[N:16]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:15]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.CO>[O:19]=[C:18]1[C:17]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:16]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:15][N:14]1[C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Yield: 99 %

Procedure:
Benzyl 3-(4-(tert-butoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.62 g, 1.14 mmol) and palladium on carbon (10 wt. %, wet, Degussa type E101 NE/W,) (0.12 g) in ethyl acetate (5 mL) and methanol (5 mL) was stirred at room temperature under hydrogen (balloon) for 3 hours. The catalyst was removed by filtration and the filtrate evaporated and dried under vacuum to give product as foam (0.46 g, quant.); MS for C24H29N3O3 m/z 408 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O)#[N:2].Cl.[NH2:14][OH:15]>C(O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[N:14][OH:15])#[N:2]
Reactant: NO
Reactant: N#Cc1cccc2c1CCC2=O
Agent: Cl
Solvent: CCO
Product: N#Cc1cccc2c1CCC2=NO
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 157 mg (1.0 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one [Coll. Czechoslov. Chem. Commun. 43, 3227 (1978)] and 139 mg (2.0 mmol) of hydroxylamine hydrochloride in 4 ml of ethanol is stirred at 80° C. for 1.5 hours and cooled in an ice-water bath. The product that has crystallized out is filtered off with suction, washed with cold ethanol and diethyl ether and dried. In that manner there is obtained the intermediate 4-cyano-2,3-dihydro-1H-inden-1-one oxime, which melts at 200°-202° C. with decomposition; 1H-NMR (DMSO): δ=11.22 (s, 1H); 7.84 (d, 1H); 7.81 (d, 1H); 7.45 (t, 1H); 3.15 (t, 2H); 2.84 (t, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:15]I>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:15])=[C:9]([CH:12]=1)[C:10]#[N:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1ccc(O)c(C#N)c1
Agent: [Na]
Solvent: CCO
Product: COc1ccc(C(C)(C)C)cc1C#N

Procedure:
5-tert-Butyl-2-hydroxybenzonitrile (50 g; prepared as described by F. B. Dains and I. R. Rothrock, J. Amer. Chem., 1894 16, 635) was added to a solution of sodium (7.43 g.) in anhydrous ethanol (150 ml.), followed by methyl iodide (50 ml.). The mixture was refluxed for 3 hours, during which time a further quantity of methyl iodide (20 ml.) was added in portions. The mixture was evaporated in vacuo, and the residue treated with water (500 ml.). The oil obtained was extracted with diethyl ether, and the aqueous layer further extracted twice with diethyl ether. The combined extracts were dried and evaporated, and the residual oil was distilled in vacuo to give 5-tert-butyl-2-methoxybenzonitrile (50.3 g.), b.p. 138°-140° C./0.2 mm.Hg.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]3[N:14]=[N:15][N:16]=[C:8]3[C:7]=2[N:17]=1>CO>[ClH:2].[Cl:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]3[N:14]=[N:15][N:16]=[C:8]3[C:7]=2[N:17]=1
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNC(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: CO
Product: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCN)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 171.8 %

Procedure:
Concentrated hydrochloric acid (10 mL) was added to a suspension of tert-butyl 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butylcarbamate (prepared in Parts A-D of Example 87, 1.00 g, 2.30 mmol) in methanol (23 mL). The reaction mixture was stirred at room temperature for 2 hours, then was concentrated under reduced pressure to yield a residue. The residue was concentrated twice from toluene to remove residual water, then was triturated with methanol. A solid was isolated by filtration and was dried under vacuum to provide 0.68 g of 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butan-1-amine hydrochloride.
Reaction SMILES: [OH:1][C:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4]1.[BH4-].[Na+]>CO>[OH:1][C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
A solution of 13.5 g of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α, α-dimethylphenylacetate, prepared in accordance with Example 6, in 250 mL of CH3OH is cooled in an ice CH3OH bath, and 1.8 g of NaBH4 is added in portions. After 1 hr, the mixture is concentrated to a solid. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous portion is extracted with EtOAc. The combined organics are washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α, α-dimethylphenylacetate as a foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[C:5]([CH3:14])=[C:4]([Cl:15])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[OH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>O1CCOCC1.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>[Cl:15][C:4]1[C:5]([CH3:14])=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:7]=[C:2]([C:27]2[CH:28]=[C:23]([OH:22])[CH:24]=[CH:25][CH:26]=2)[N:3]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Cc1c(Cl)nc(Cl)nc1N[C@@H]1CCOC1
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: C1COCCO1
Product: Cc1c(Cl)nc(-c2cccc(O)c2)nc1N[C@@H]1CCOC1
Temperature: 100 °C
Reaction time: 14 h
Yield: 107.5 %

Procedure:
To a solution of (R)-2,6-dichloro-5-methyl-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine (1.8 g, 7.3 mmol) in degassed dioxane and H2O (4/1, 21 mL) was added Na2CO3 (1.5 g, 14.5 mmol); Pd(PPh3)4 (296 mg, 0.36 mmol) and 3-hydroxy-phenylboronic acid (1.21 g, 8.8 mmol). The system was purged with nitrogen stream and then stirred at 100° C. for 14 h., cooled down to room temperature, diluted with water (30 mL) and the resulting mixture extracted with EtOAc (30 mL×2). The combined organic layer were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (EtOAc/petroleum ether, gradient elution, from 1/10 to 2:1) to give (R)-3-(4-chloro-5-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenol (2.4 g, 33%) as a white solid. ESI-LCMS (m/z): 306.1 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][OH:13])[C@@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][O:13][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][O:21]3)[C@@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOC(=O)[C@@H]1C[C@@]2(CO)C[C@H]2N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@@]2(COC3CCCCO3)C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (1R,3S,5S)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester (500 mg, 1.75 mmol), 3,4-dihydro-2H-pyran (176 μL, 1.93 mmol) and TsOH.H2O (33 mg, 0.17 mmol) in CH2Cl2 (6 mL) was stirred 3 h at RT. Then poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). Colorless oil. TLC, Rf (EtOAc)=0.85; MS (UPLC/MS): 370.4 [M+H]+, 387.4 [M+H2O]+; tR (HPLC conditions f): 2.28 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([Cl:19])[CH:13]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Br:20])=[C:14]([Cl:19])[CH:13]=1
Reactant: COc1ccc(C=Cc2ccc(C)c(Cl)c2)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C=Cc2ccc(CBr)c(Cl)c2)c(Cl)c1

Procedure:
4-(2-Chloro-4-methoxystyryl)-2-chlorobenzyl bromide was prepared from 27.8 g. of 2,3'-dichloro-4-methoxy-4'-methylstilbene, 17.8 g. of N-bromosuccinimide and 0.5 g. of benzoyl peroxide in carbon tetrachloride according to the procedure of Example 10(b); yield 23.0 g., m.p. 106°-108° C.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCN(c3ccc(O)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 15.5 parts of 4-(1-piperazinyl)phenol dihydrobromide, 40 parts of ethanol and 75 parts of water are added 15.2 parts of 4-methylbenzenesulfonyl chloride and stirring is continued for 30 minutes at room temperature. Then there are added portionwise 12.6 parts of sodium hydrogen carbonate at 0° C. Upon completion, stirring is continued overnight at room temperature. The precipitated product is filtered off and taken up in alkaline water. The mixture is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and taken up in water. The free base is liberated in the conventional manner with a sodium hydroxide solution. The whole is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and dried, yielding 4.8 parts of 1-(4-hydroxyphenyl)-4-(4-methylphenylsulfonyl)piperazine; mp. 193.1° C.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH3:32].O>CN(C=O)C>[CH2:31]([O:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:32]
Reactant: CCBr
Reactant: CN1CC(C(Oc2ccccc2O)c2ccccc2)OCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1OC(c1ccccc1)C1CN(C)C(=O)CO1
Temperature: 60 °C
Yield: 78 %

Procedure:
To a solution of 10 g of 2-[α-(2-hydroxy-phenoxy)-benzyl]-4-methylmorpholin -5-one in 150 ml of anhydrous DMF addition was made of 4.8 g of potassium carbonate, and then dropwise addition was made under stirring of 2.6 ml of bromoethane in 20 ml of DMF. The mixture was heated for 4 hours at 60° C. under stirring. The mixture was poured into 1.5 liters of water and extracted with ethyl acetate. The organic extracts were washed with H2O, dehydrated over Na2SO4 and concentrated under reduced pressure. There was obtained 8.49 g (Yield 78%) of 2-[α-(2-ethoxy-phenoxy)-benzyl]-4-methyl-morpholin -5-one.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:24][C:23]=1[CH2:22][S:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1NS(=O)(=O)c1ccc(S)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CSc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the title B compound, 2-(4-mercaptobenzene-sulfonylamino)-benzoic acid (200 mg, 0.65 mmol), 4-chloromethyl-5-methyl-2-phenyl-oxazole (134 mg, 0.65 mmol) and cesium carbonate (1.05 g, 3.24 mmol) in DMF is stirred at RT for 3 h. The mixture is then partitioned between EtOAc and 1 N aqueous HCl. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue is chromatographed on silica gel using 15% EtOAc in hexane (containing 0.5% formic acid) as the eluent to afford 2-[4-(5-methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl-amino]-benzoic acid as a white foam: m.p. 182-184° C.; ESI-MS 481 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.O1CCCCC1[O:33][N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[O:40]>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:37]3/[C:38](=[O:39])[N:34]([OH:33])[C:35](=[O:40])[S:36]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1CSC(=O)N1OC1CCCCO1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1O

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-hydroxy-1,3-thiazolidine-2,4-dione was prepared from [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) and 3-(tetrahydropyran-2-yl)oxy-1,3-thiazolidine-2,4-dione (from Example 288) following General Procedure F.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[NH2:19][C:20]([NH2:22])=[S:21].O>C(O)C>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:19]=1
Reactant: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: NC(N)=S
Solvent: CCO
Solvent: O
Product: Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 65.7 %

Procedure:
A solution of 31.1 g (0.096 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide in 130 ml of absolute ethanol was carefully mixed with 8.4 g (0.11 mole) of thiourea. As the thiourea dissolved, the temperature of the solution increased from 23° to 38°. After the exothermic reaction had subsided, the solution was refluxed for four hours and poured into 130 ml of water. A small quantity of insoluble material was removed by filtration and the filtrate was made basic (pH 9) with ammonium hydroxide. Stirring and cooling yielded a crystalline solid which was collected. There was obtained 19 g (65.7%) of dry product, m.p. 116°-18°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 3.4 (CH2), 6.3 hetero-aromatic), 6.8 (NH2), 7.3-8.0 (aromatic), 10.3 (HNC=O).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Mg]Br>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:7]1([OH:14])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: Clc1ccccc1[Mg]Br
Reactant: CCOc1ccc2c(c1)C(=O)C(=O)N2
Product: CCOc1ccc2c(c1)C(O)(c1ccccc1Cl)C(=O)N2

Procedure:
This compound is prepared according to the procedure described in Preparation 6 from 5-ethoxyisatin and 2-chlorophenylmagnesium bromide (prepared according to P. G. Gassman in J. Am. Chem. Soc., 1974, 9, 5512).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:16]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:16])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2nccnc2c1
Product: O=C(Cl)c1ccc2nccnc2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of quinoxaline-6-carboxylic acid (1.8 g, 10.3 mmole) (Chem. Ber. 1953, 86, 1295) in SOCl2 (30 ml) was stirred at 80° C. for 3 h. The resulting yellow solution was concentrated by distillation, and the residue treated with toluene and concentrated to dryness in vacuo giving a pale beige solid (2.0 g, quant.). m/z [ESMS]: 203 [M+EtOH−Cl]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([O:14][CH3:15])[CH2:9]2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([O:14][CH3:15])[CH2:9]2
Reactant: CON1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CCO
Product: CON1Cc2cccc(N)c2C1=O
Yield: 84.2 %

Procedure:
A solution of 7-nitro-2-methoxy-2,3-dihydro-1H-isoindol-1-one (Compound 187B, 0.25 g, 1.2 mmol) in ethanol (5 mL) was hydrogenated over 5% Pd/C (30 mg) overnight at room temperature. The catalyst was filtered off by a glass filter paper and the filtrate was concentrated to give 0.18 g of the pure product (yield: 85%). 1H NMR (CDCl3, 600 MHz): δ=3.93 (s, 3H), 4.48 (s, 2H), 6.56 (d, J=8.5 Hz, 1H) 6.63 (d, J=7.0 Hz, 1H), 7.24 (dd, J=7.5, 8.5 Hz, 1H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>>[F:8][C:9]([F:17])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:2]2[CH2:7][CH2:6][O:5][C:3]2=[O:4])=[CH:12][CH:11]=1
Reactant: O=C1OCCC1Br
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: O=C1OCCC1Oc1ccc(C(F)(F)F)cc1
Yield: 46 %

Procedure:
The compound is prepared according to the experimental procedure described in Preparation 1, starting with α-bromo-γ-butyrolactone (6.7 g, 0.040 mol) and 4-trifluoromethylphenol (5.0 g, 0.031 mol) to give 3.51 g of the expected compound in the form of a white powder.