Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1C2C=CC=CC=2OC(C=O)C1)=O)C1C=CC=CC=1.C[Si](C(P(OCC)(OCC)=O)C([O-])=O)(C)C.[H-].[Na+].[CH2:41]([O:48][C:49]([N:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]([CH:61]=[CH:62][C:63]([OH:65])=O)[CH2:52]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([O:48][C:49]([N:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]([CH:61]=[CH:62][C:63](=[O:65])[NH2:11])[CH2:52]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=CC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Reactant: O=C(O)C=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Agent: CCOP(=O)(OCC)C(C(=O)[O-])[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Product: NC(=O)C=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1

Procedure:
The reaction of 1.48 g of N-benzyloxycarbonyl-2(R,S)-formyl-3,4-dihydro-2H-1,4-benzoxazine (Example 107) with 2.15 ml of trimethylsilyl-diethylphosphonoacetate and 0.3 g of sodium hydride (80% dispersion in oil) gives, after customary working up, 1.7 g of N-benzyloxycarbonyl-3(R,S)-[(2-carboxy)ethen-1-yl]-1,2,3,4-tetrahydroquinoline. The title compound is obtained therefrom in a manner analogous to that described in Example 1a): Rf (X)=0.47.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:16]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:16]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccs2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1csc(-c2cccc3c2OCCNC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of tert-butyl 9-(2-thienyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (160 mg, 0.483 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (111 mg, 86.0%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][C:32](OCC)=[O:33]>CN(C)C=O>[CH3:23][N:21]([CH3:22])[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]1[CH2:31][C:32](=[O:33])[N:1]=[C:2]1[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:10]2
Reactant: COc1ccc(CN2Cc3cc(N(C)C)ccc3N=C2N)cc1
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3cc(N(C)C)ccc3N3CC(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 19.5 g of 2-amino-6-dimethylamino-3,4-dihydro-3-(p-methoxybenzyl)-quinazoline in 300 ml of dimethylformamide was treated with 90 g of potassium carbonate and 12.9 g of ethyl iodoacetate and the mixture was stirred at room temperature for 20 hours and then at 85° for 5 hours. The mixture was then cooled, poured into ice/water and the crude product was filtered. Pure 7-dimethylamino-4,5-dihydro-4-(p-methoxybenzyl)-imidazo[1,2-a]quinazolin-2(1H)-one of melting point 196°-200° was obtained by recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([CH3:11])[CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:11])\[C:7]#[N:8])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(Cl)ccc1CC#N
Reactant: O=Cc1cccc(Cl)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Yield: 62.2 %

Procedure:
Step C In a manner similar to the method described in Example 1b, 4-chloro-2-methylbenzyl cyanide (3.5 g, 21 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (100 mL) at 50° C. for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)-acrylonitrile as a white powder (4 g, 62%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:7]([O:17][CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:6][CH:5]=1.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[C:7]([O:17][CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:25])=[O:2])=[CH:11][CH:12]=1
Reactant: COC(=O)c1cnc(OCc2nccn2C)c(-c2ccc(Cl)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1COc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5-(4-Chloro-phenyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)-nicotinic acid methyl ester (0.28 g, 0.8 mmol) was dissolved in tetrahydrofuran (4.5 mL). Water (1.5 mL) and lithium hydroxide (99 mg, 2.3 mmol) was added and the mixture was stirred for 1 h at 80° C. The mixture was cooled to room temperature; citric acid (4 mL, 10%) was added and the mixture was extracted with ethyl acetate. Organic phases were pooled dried with Na2SO4 and the solvent evaporated to give a quantitative yield of the title compound as beige solid, MS (ISP) 342.0 (M−H)−.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[O:22][N:21]=1.C(=O)(O)[O-].[Na+].[I-].[K+]>CN(C)C=O>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]2[C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[O:22][N:21]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CCN(CCCc2noc3cc(F)ccc23)CC1)c1ccccc1
Yield: 17.4 %

Procedure:
A mixture of 3.7 g of 4-benzamidopiperidine, 4.3 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 8 g of sodium bicarbonate and a few crystals potassium iodide in 30 ml of dimethylformamide was stirred at 55° C. for 2.5 hrs. The reaction mixture was cooled and concentrated to an oil. The oil was stirred with water and extracted with ether/ethyl acetate. The organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. Crystallization of the residue with isopropyl ether gave 1.2 g (17%) of product, mp 150°-151° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C(OCC)(=O)C.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>[F:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: OB(O)c1cccc(F)c1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cc2cccc(F)c2)c(F)c1
Temperature: 130 °C
Yield: 66 %

Procedure:
Methyl 4-(bromomethyl)-3-fluorobenzoate (0.285 g; 1.15 mmol) was suspended in a mixture of water (1 mL) and 1,2-dimethoxyethane (3 mL) and 3-fluorophenylboronic acid (0.183 g; 1.27 mmol), tetrakis(triphenylphosphine)palladium(0) (0.067 g; 0.0058 mmol) and sodium carbonate (0.246 g; 2.31 mmol) were successively added. The resulting suspension was heated at 130° C. in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 1 to 12% of ethyl acetate in heptane) to give 0.199 g (66%) of methyl 3-fluoro-4-(3-fluorobenzyl)benzoate as an oily residue which was directly used in the next step.
Reaction SMILES: C([O:3][C:4](=[O:37])[C@H:5]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[C:22]3[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=3[S:20][N:19]=2)[C:7]1=[O:29])C.[Li+].[OH-]>O1CCOCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@H:5]([N:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[C:22]4[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[S:20][N:19]=3)[C:7]2=[O:29])[C:4]([OH:37])=[O:3])=[CH:31][CH:32]=1
Reactant: CCOC(=O)[C@H](c1ccc(Cl)cc1)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c2c(Cn3c(=O)n([C@H](C(=O)O)c4ccc(Cl)cc4)c(=O)c4ccccc43)nsc2c1
Reaction time: 4 h

Procedure:
To a solution of (S)-(4-Chloro-phenyl)-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid ethyl ester (50 mg, 0.094 mmol) in 1,4-dioxane (10 mL) and water (1 mL) is added LiOH (6.7 mg, 0.28 mmol) at room temperature. The solution is stirred at the same temperature for 4 hours. The solution is concentrated and water is added to the residue. The solution is acidified by 12N HCl in an ice-bath. The precipitated solid is collected by filtration to afford the title compound.: LCMS (ESMS): m/z 506.10 (M+H+)
Reaction SMILES: [NH3:1].[C:2]1([S:12](Cl)(=[O:14])=[O:13])[C:3]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1>C(O)C.C1(C)C=CC=CC=1>[S:12]1(=[O:14])(=[O:13])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:1]1
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S1(=O)NS(=O)(=O)c2ccccc21
Yield: 91 %

Procedure:
A solution of 0.65 mol of ammonia in 1,050 ml of absolute ethanol is added dropwise, with stirring, to 0.13 mol of 1,2-benzenedisulphonyl chloride in 720 ml of absolute toluene at 25° C. The mixture is stirred a further hour, slight cloudiness is removed by filtration through a layer of kieselguhr, and the filtrate is evaporated to dryness. The ammonium salt of 1,3,2-benzodithiazole 1,1,3,3-tetroxide is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=O)=[C:13]([CH2:24][O:25][CH3:26])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].[OH-].[K+]>CN(C)C=O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=[N:28][OH:29])=[C:13]([CH2:24][O:25][CH3:26])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1c(C=O)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COCc1c(C=NO)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13.5 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde is dissolved in 150 ml of dry dimethyl formamide (DMF) and there are added thereto 6 g of hydroxylamine hydrochloride and a solution of 6 g of potassium hydroxide in 30 ml of ethanol. The reaction mixture is stirred for one hour at room temperature, filtered, and the residue washed with 2×20 ml of DMF. The DMF fraction is combined with 200 ml of ice water, the precipitate is filtered off, washed with water, and dried. Yield: 9.6 g.
Reaction SMILES: C([C:4]1[CH:31]=[C:8]2[C:9]([N:11]([CH:14]([CH2:29][CH3:30])[C:15]([N:17]3[CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:19][NH:18]3)=[O:16])[C:12](=[O:13])[C:7]2=[CH:6][CH:5]=1)=[O:10])(O)=O.C(N1CC[O:37][CH2:36]C1)C.P(Cl)(Cl)(Cl)(Cl)Cl>O1CCCC1>[O:37]=[C:36]1[CH2:30][CH2:29][C@H:14]([N:11]2[C:12](=[O:13])[C:7]3=[CH:6][CH:5]=[CH:4][CH:31]=[C:8]3[C:9]2=[O:10])[C:15](=[O:16])[N:17]2[C@H:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:19][N:18]12
Reactant: CCN1CCOCC1
Reactant: CCC(C(=O)N1NCCC1C(=O)OC(C)(C)C)N1C(=O)c2ccc(C(=O)O)cc2C1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Reaction time: 1 h
Yield: 33.3 %

Procedure:
A stirred solution of 3.45 g of the tert.butyl 2-(5-carboxy-2-phthalimidobutyryl)-3-pyrazolidinecarboxylate and 0.92 g of N-ethylmorpholine in 50 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 1.66 g of phosphorus pentachloride. After 1 hour, a further 0.92 g of N-ethylmorpholine and 1.66 g of phosphorus pentachloride were added and, after a further 1 hour, another 0.92 g of N-ethylmorpholine was added. The solvent was removed by evaporation and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The oil obtained was chromatographed on silica gel. Elution with diethyl ether yielded firstly 1.1 g (33%) of tert.butyl 2,3,6,7,8,9-hexahydro-5,9-dioxo-8(S)-phthalimido-1H,5H-pyrazolo[1,2-α][1,2]diazepine-1(S)-carboxylate in the form of a white foam and then 0.52 g (15%) of tert.butyl 2,3,6,7,8,9-hexahydro-5,9-dioxo-8(S)-phthalimido-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(R)-carboxylate in the form of a white solid of melting point 180°-181° C. (from ethyl acetate/n-hexane).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([C:6]([O:15][CH3:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1>[Pd].CCO>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([O:15][CH3:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccnc2c([N+](=O)[O-])c(Cl)ccc12
Agent: [Pd]
Solvent: CCO
Product: COc1ccnc2c(N)c(Cl)ccc12
Reaction time: 8 h
Yield: 107.2 %

Procedure:
7-Chloro-4-methoxy-8-nitro-quinoline (Intermediate 69) (261 mg, 1.1 mmol) was treated with 10% palladium on carbon (11.6 mg, cat) in EtOH (20 ml) in a Parr pressure reaction system and placed under a hydrogen atmosphere at 5 Barr pressure whilst stirring overnight. The pressure was released and the catalyst removed by filtration through celite. The solvent was removed in vacuo to give the title compound (246 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=3)[C:21]([OH:23])=O)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:36][NH:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=3)[C:21]([N:37]([CH3:38])[CH3:36])=[O:23])[C:14]([F:17])([CH3:15])[CH3:16])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(F)C(c1cc(F)cc(C(=O)O)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: CNC
Product: CN(C)C(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
Prepared from 3-(1-{1-[(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzoic acid and dimethylamine according to the procedure described in Preparation 22; Mass Spectrum: m/e=522 (M+1, 35Cl), 524 (M+1, 37Cl).
Reaction SMILES: [OH:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]([C:7]1[C:8]([O:25][CH3:26])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:6].C(N(CC)CC)C>ClCCl.CS(C)=O.O>[O:1]=[C:2]([CH3:27])[CH2:3][NH:4][C:5]([C:7]1[C:8]([O:25][CH3:26])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:6]
Reactant: COc1c(C(=O)NCC(C)O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(=O)NCC(C)=O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 40 °C
Yield: 80.4 %

Procedure:
100 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid (2-hydroxylpropyl) amide obtained by Example 825 and 300 μl of triethylamine were dissolved in a mixed solvent of 4 mL dichloromethane/1 mL dimethyl sulfoxide, added with 1 mL of a solution of 260 mg of pyridine sulfur trioxide complex in dimethyl sulfoxide under ice cooling, and the reaction solution was heated at 40° C. for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3), and then crystallized from ethyl acetate and diisopropyl ether, to afford 80 mg of the title compound as a colorless powder.
Reaction SMILES: [N+]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[Cl:15]Cl>>[Cl:15][C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: ClCl
Product: O=C(O)c1cc(F)c(F)cc1Cl

Procedure:
2-chloro-4,5-difluorobenzoic acid may be prepared by decarboxylating 4,5-difluorophthalic anhydride or 4,5-difluorophthalic acid to form 3,4-difluorobenzoic acid in N-methyl-2-pyrrolidone, quinoline, or dimethyl acetamide optionally using copper, copper oxide, copper salts, or halides and salts of Zn, Cd, Ag and Ni as a catalyst, treating said 3,4-difluorobenzoic acid with a mixture of nitric and sulfuric acids, to produce 2-nitro-4,5-difluorobenzoic acid, and treating said 2-nitro-4,5-difluorobenzoic acid with elemental chlorine to form 2-chloro-4,5-difluorobenzoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.CO.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nccs2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-(1,3-thiazol-2-yl)benzoate (560 mg, 2.6 mmol) in a mixture of 2:1:1 tetrahydrofuran/methanol/water (20 mL) is added lithium hydroxide (322 mg, 3 mmol). The reaction mixture is stirred at room temperature for 2 h. The solvent is removed under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is acidified to pH 1 with 1 N hydrochloric acid and a precipitate is observed. The solid is collected by filtration to afford the title compound. 1H NMR (300 MHz, CD3OD) δ 8.14-8.05 (m, 4H), 7.95-7.93 (m, 1H), 7.71-7.69 (m, 1H).
Reaction SMILES: CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[Si]([O:34][CH2:35][CH2:36][N:37]([CH3:102])[CH2:38][CH2:39][C@@H:40]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([S:56]([NH:59][C:60](=[O:94])[C:61]2[CH:66]=[CH:65][C:64]([N:67]3[CH2:72][CH2:71][CH:70]([C@H:73]([C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=4[C:87]4[CH:92]=[CH:91][C:90]([Cl:93])=[CH:89][CH:88]=4)[NH:74][S@:75]([C:77]([CH3:80])([CH3:79])[CH3:78])=[O:76])[CH2:69][CH2:68]3)=[CH:63][CH:62]=2)(=[O:58])=[O:57])=[CH:52][C:51]=1[S:95]([C:98]([F:101])([F:100])[F:99])(=[O:97])=[O:96])[CH2:41][S:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[Cl:93][C:90]1[CH:91]=[CH:92][C:87]([C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][C:81]=2[C@H:73]([NH:74][S@:75]([C:77]([CH3:80])([CH3:79])[CH3:78])=[O:76])[CH:70]2[CH2:71][CH2:72][N:67]([C:64]3[CH:65]=[CH:66][C:61]([C:60]([NH:59][S:56]([C:53]4[CH:54]=[CH:55][C:50]([NH:49][C@H:40]([CH2:39][CH2:38][N:37]([CH2:36][CH2:35][OH:34])[CH3:102])[CH2:41][S:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[C:51]([S:95]([C:98]([F:101])([F:100])[F:99])(=[O:96])=[O:97])[CH:52]=4)(=[O:58])=[O:57])=[O:94])=[CH:62][CH:63]=3)[CH2:68][CH2:69]2)=[CH:88][CH:89]=1
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](N[S@@](=O)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: CN(C)C=O
Product: CN(CCO)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](N[S@@](=O)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 119.2 %

Procedure:
A solution of TASF (0.40 ml. 0.40 mmol, 1.0M in DMF) was added to a solution of N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzamide (EXAMPLE 11, STEP 1, 0.26 g, 0.20 mmol) in DMF (1.6 ml) and the reaction mixture was stirred at r.t for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with DCM and washed with H2O. The organic layer was dried (Na2SO4), concentrated under reduced pressure and dried under vacuum to give 4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)-N-(4-((R)-4-((2-hydroxyethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 11, STEP 2, 0.25 g) which was used in the preparation of EXAMPLE 11, STEP 3, without further purification.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][CH2:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[N:16]=[CH:15]3)=[CH:6]1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[C:17]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[N:16]=[CH:15]3)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1C=C(c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)CC1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)N1CCC(c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)C1
Reaction time: 48 h

Procedure:
To the solution of trans-4-({8-[1-(methylsulfonyl)-4,5-dihydro-1H-pyrrol-3-yl]quinazolin-2-yl}amino)cyclohexanol (88 mg, 0.23 mmol) in methanol (8 mL) was added 20 mg of Pd/C (dry, 10%). The mixture was hydrogenated with a H2 balloon at RT for 48 h. The catalyst was filtered off and washed with methanol (15 mL). The filtrate was concentrated in vacuo, and the residue was purified by chromatography (eluting with DCM, then DCM/EA=2/1) to give the title compound as off white solid (52 mg, 62%). 1H-NMR (CDCl3, 400 MHz): δ 8.97 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.21 (dd, J=7.6, 7.6 Hz, 1H), 5.17 (d, J=6.8 Hz, 1H), 4.30-4.25 (m, 1H), 4.01 (dd, J=9.2, 7.6 Hz, 1H), 4.01-3.98 (m, 1H), 3.71-3.67 (m, 2H), 3.54-3.50 (m, 1H), 2.92 (s, 3H), 2.49-2.29 (m, 2H), 2.28-2.24 (m, 2H), 2.12-2.06 (m, 2H), 1.57-1.50 (m, 2H), 1.45-1.30 (m, 2H). MS (m/e) 391.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>COCCO>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)c1cc(OCc2ccccc2)ccc1O

Procedure:
To a stirred solution of t-butyl hydroquinone (1.0 Kg) in 2-methoxy ethanol (2.0 L), was charged K2CO3 (2.0 Kg) portionwise under nitrogen atmosphere and the mixture refluxed. Benzyl chloride (0.762 L) was added dropwise at reflux temperature and heated further for 1.5 hr. The progress of the reaction was monitored on TLC. The reaction mixture was cooled and added DM Water (6.0 L). The uppermost oily layer was separated, dissolved in ethyl acetate (3.4 L), and washed with DM water (3.4 L×3). The uppermost oily layer was separated, dried over sodium sulfate and evaporated to dryness to give the crude title compound (1.5 Kg). The crude product was employed in the next step without further purification,