Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:9]=3)[N:14]=[C:13]([CH3:18])[C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:24][CH:25]=1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(F)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 408.2 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (79 mg, 0.076 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (73 mg, 0.152 mmol) and cesium carbonate (1.86 g, 5.7 mmol). 6-Bromo-4-(4-fluoro-phenyl)-3-methanesulfonyl-2-methyl-quinoline (compound of example 14) (200 mg, 0.52 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.40 g, 4.56 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient from 100:0 to 40:60 to give a yellow solid (850 mg, 56%). MS: m/z=401 (M+H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][N:6]([CH3:23])[C:7]1[CH:12]=[CH:11][C:10]([CH:13](O)[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:9][CH:8]=1>C(O)(=O)C>[CH3:23][N:6]([CH3:5])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:1][C:2](=[O:3])[NH:4][C:14]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: CN(C)c1ccc(C(O)C(=O)c2ccccc2)cc1
Reactant: NC(N)=O
Solvent: CC(=O)O
Product: CN(C)c1ccc(-c2[nH]c(=O)[nH]c2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To acetic acid (2 mL) was added urea (0.6 g, 10 mmol) and 2-(4-dimethylaminophenyl)-2-hydroxy-l-phenylethanone (2.6 g, 10 mmol). After stirring for 2 hours at 120° C., the reaction was cooled to ambient temperature. The resulting solid was filtered, washed with ether, and dried in vacuo to give 4-(4-dimethylaminophenyl)-2,3dihydro-5-phenyl-1H-imidazol-2-one; NMR (CDCl3) 10.98 (s,2), 7.5 (m,4), 7.4 (m,5), 3.18 (s,6) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:5]([CH:3]=[O:2])[N:6]=1
Reactant: COC(=O)c1cc2ccccc2cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2cn1
Yield: 85.7 %

Procedure:
3-Isoquinolinecarboxaldehyde (7 g, 84%) was prepared by reduction of 3-isoquinolinecarboxylic acid methyl ester (10 g, 52 mmol) with 1M LAH (27 ml in THF, 27 mmol) in 300 ml of dry THF at -78° C. for 30 minutes. The mixture was quenched with 7 ml of acetic acid, concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 2:1) to afford 7 g (84%) of 3-iso-quinolinecarboxaldehyde.
Reaction SMILES: [OH-].[K+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].[O:9]([C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[S:24])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C=O)C.O>[C:3]([CH:5]([C:23](=[S:24])[NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=1)[C:6]([NH2:8])=[O:7])#[N:4]
Reactant: N#CCC(N)=O
Reactant: S=C=Nc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C(N)=O)C(=S)Nc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
To a suspension of 85% powdered KOH in 20 ml DMF was added 1.74 g of cyanoacetamide at room temperature. The solution was stirred at room temperature for 15 minutes and then cooled in a water bath at room temperature. To this solution 4.7 g of 3-phenoxy-phenyl isothiocyanate was added dropwise. The solution exothermed slightly with the internal temperature rising to 28° C. during the addition. The solution was stirred at room temperature for 16 h, then diluted with 150 ml water and extracted with ethyl acetate to remove small amounts of starting material and by-products. The aqueous layer was isolated and acidified with 1N HCl to pH 1 with vigorous stirring. The resulting tan precipitate was filtered, washed with water, and dried for 16 hours in a vacuum oven to afford 4.66 g of 2-cyano-2-(3-phenoxy-phenylthiocarbamoyl)-acetamide.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8])(=O)C.[OH-].[Na+].Cl>O1CCCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[N:14]=1)=[O:8]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(NC(=O)c2cc(Br)ccc2O)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide (100.1 mg, 0.25 mmol) was dissolved in tetrahydrofuran (3 mL). 2 N sodium hydroxide (0.2 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was crystallized (isopropyl ether/n-hexane) to give the title compound (70.1 mg, 78.9%) as a light gray solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CO
Reactant: CSc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(SC)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 4-(methylthio)phenylacetic acid (6.91 g, 37.9 mmol) in methanol (100 mL) was treated slowly with concentrated sulfuric acid (1 mL). The resulting reaction mixture was heated under reflux for 19 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3×300 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 98%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[O:8][C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:1][C:2]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[O:8][C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OC(=O)c2cccc(O)c2O1
Product: CC1(C)OC(=O)c2cccc(OCc3ccccc3)c2O1

Procedure:
The title compound was prepared from 8-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and benzylbromide under conditions analogous to experimental example 38-b, to give the desired product as an off-white solid. MS: (+) m/z 285.10 (M+1).
Reaction SMILES: [C:1]1(=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:28].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[C:1]1(=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([Cl:28])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic acid (11) (0.3 g, 0.861 mmol) and dry CH2Cl2 (5 mL) was added oxalyl chloride (0.15 mL, 1.72 mmol) slowly, followed by DMF (2 drops). The reaction mixture became a clear solution immediately after the addition of DMF. The reaction mixture was stirred at room temperature for 2 h under nitrogen. The reaction mixture was concentrated to give 39 as an oily residue that was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (s, 8H), 2.21-2.25 (m, 4H), 6.48 (d, J=16 Hz, 1H), 7.19 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.54 (d, J=16 Hz, 1H), 7.62 (d, J=8.1 Hz, 2H), 9.35 (s, 1H).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26].O>CC(C)=O>[CH:1](=[N:8]/[O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: COC(=O)C(O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(O)c1ccccc1CO/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.8 %

Procedure:
Then, benzaldehyde oxime (0.28 g, 2.3 mmol) and potassium carbonate (0.43 g, 3.1 mmol) were added to a solution of methyl 2-bromomethyl-α-hydroxyphenylacetate (0.40 g, 1.5 mmol) in acetone (6 ml), and the mixture was stirred at room temperature for 18 hours. Water was added, and the mixture was extracted with ether, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/1) to give the desired compound methyl (E)-2-benzylideneaminooxymethyl-α-hydroxy-phenylacetate (0.08 g, 17%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:38]1([CH2:44][S:45](Cl)(=[O:47])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:45]([CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)(=[O:47])=[O:46])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1c(C2=NS(=O)(=O)c3c(CNS(=O)(=O)Cc4ccccc4)csc3N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of the product of Example 353E (16.5 mg, 0.037 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and α-toluene sulfonyl chloride was added (0.008 g, 0.041 mmol). The reaction mixture was warmed to 23° C. and stirred for 0.5 hours. The reaction mixture was then heated to 50° C. and stirred for 1.75 hours. Additional triethylamine (0.010 mL, 0.074 mmol) and α-toluene sulfonyl chloride (0.007 g, 0.037 mmol) were added and the reaction mixture was stirred at 23° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (7.7 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.04 Hz, 2 H) 0.42 (d, J=7.72 Hz, 2 H) 1.00 (m, 1 H) 2.84 (d, J=7.35 Hz, 2 H) 4.23 (d, J=5.52 Hz, 2 H) 4.44 (s, 2 H) 6.37 (bs, 1 H) 7.32 (s, 1 H) 7.42 (m, 6 H) 7.86 (m, 2 H) 8.07 (d, J=8.46 Hz, 1 H) 8.16 (dd, 1 H) 14.50 (bs, 1 H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([Cl:12])[C:6]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)(=O)C.[OH-].[K+].O>O1CCOCC1>[Br:11][C:9]1[CH:8]=[C:7]([Cl:12])[C:6]2[O:13][CH2:14][CH:15]([CH2:17][OH:16])[O:4][C:5]=2[CH:10]=1
Reactant: CC(=O)Oc1cc(Br)cc(Cl)c1OCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OCC1COc2c(Cl)cc(Br)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
To a solution of 5-bromo-3-chloro-2-(oxiran-2-ylmethoxy)phenyl acetate (4.4 g, 13.7 mmol) in dioxane (20 ml) was added KOH (10%, 40 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the solution was extracted with EtOAc: The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. Purification on flash column chromatography (isooctane/EtOAc) gave the title compound (0.34 g). MS m/z (rel. intensity, 70 eV) 280 (M+, bp), 278 (78), 224 (68), 222 (54), 57 (37).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5](CC1C=CC=CC=1)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.C.[H][H]>C(O)C>[NH2:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][C:3]=1[CH2:4][NH:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(N)c(CN(Cc2ccccc2)C(C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(CNC(C)(C)C)c1

Procedure:
3.4 gm of 2-amino-N-benzyl-N-tert.butyl-5-carbethoxy-benzylamine were dissolved in 50 ml of ethanol. Ethanolic hydrochloric acid was added to the solution until a pH of about 2 was reached. The solution was then hydrogenated in the presence of palladized (10%) charcoal. After absorption of 1 mol of hydrogen, the hydrogenation was terminated, the catalyst was filtered off, the filtrate was evaporated to dryness in vacuo, and the residue was distributed between a mixture of dilute ammonia and chloroform. The chloroform phase was dried and evaporated to dryness, and the residue was recrystallized from ethanol, yielding 2-amino-N-tert.butyl-5-carbethoxy-benzylamine, m.p. 77°-79°C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:13](=[O:14])[CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(N)=O)cc1
Yield: 63 %

Procedure:
A mixture of p-hydroxybenzamide (3.43 g), methyl bromoacetate (2.37 ml) and K2CO3 (3.45 g) was stirred for 12 hr in 25 ml of DMF. The reaction mixture was diluted with water (150 ml); the solid was filtered, washed with water, and air dried. Crystallization from ethanol gave 3.3 g (63%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([NH:24]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[N:10]=[CH:9]2.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([NH2:24])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:16])=[O:17])[N:10]=[CH:9]2
Reactant: COC(=O)[C@@H](Cc1ccc2c(cnn2S(=O)(=O)CC[Si](C)(C)C)c1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](N)Cc1ccc2c(cnn2S(=O)(=O)CC[Si](C)(C)C)c1
Yield: 95.5 %

Procedure:
A mixture of (R)-2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester (1.24 g, 2.40 mmol) and 10% palladium on carbon (124 mg) in methanol (50 mL) was agitated for 2 h under 50 psi hydrogen using a Parr hydrogenator. The reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give 879 mg (96%) of the title compound as a sticky gum. 1H-NMR (CDCl3, 300 MHz) δ 8.21 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.59 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 3.72 (s, 3H), 3.38-3.32 (m, 2H), 3.21 (dd, J=13.9, 5.1 Hz, 1H), 2.98 (dd, J=13.9, 7.9 Hz, 1H), 0.91-0.85 (m, 2H), −0.02 (s, 9H). Mass spec.: 384 (MH)+
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[NH:6][CH:7]=[C:8]([C:12]([O-:14])=O)[C:9]([O-:11])=[O:10].[CH:20]1C=CC(C2C=CC=CC=2)=C[CH:21]=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[OH:14][C:12]1[C:15]2[C:5](=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:17][CH:16]=2)[N:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:20][CH3:21])=[O:10]
Reactant: O=C([O-])C(=CNc1cccc(C(F)(F)F)c1)C(=O)[O-]
Reactant: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 240 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2-{[3-(trifluoromethyl)anilino]methylene}malonate (80 g, 0.24 mol) and Dowtherm A was heated to 240° C. and then stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature and then stirred for 16 hours. The solids were isolated by filtration then washed with hexane to provide 47.5 g of ethyl 4-hydroxy-7-(trifluoromethyl)-3-quinolinecarboxylate as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=O)[C:4]=2[CH:3]=1.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>S(Cl)(Cl)=O>[Br:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:11])[C:4]=2[CH:3]=1
Reactant: COc1cc2scc(C(=O)O)c2cc1Br
Reactant: Nc1cccnc1
Solvent: O=S(Cl)Cl
Product: COc1cc2scc(C(=O)Nc3cccnc3)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
5-Bromo-6-methoxybenzo[b]thiophene-3-carboxylic acid (D5) (0.36 g, 0.0013 mole) and thionyl chloride (20 ml) were heated under reflux for 1 hour, after which the reaction mixture was cooled to ambient temperature and evaporated in vacuo. The resulting acid chloride was dissolved in dry dichloromethane (30 ml) and acetonitrile (10 ml) under argon. 3-Aminopyridine (0.12 g, 0.0013 mole) was added and the reaction mixture stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the resulting solid basified with 10% sodium hydroxide solution, extracted into dichloromethane, dried (Na2SO4) and evaporated in vacuo. The resulting solid was recrystallised from ethyl acetate/methanol to afford the title compound (0.11 g, 23%) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH:8]=[CH:7][C:6]1=[O:11].S(C)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH:8]([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3])[CH2:7][C:6]1=[O:11]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Solvent: C1CCOC1
Solvent: CSC
Product: C=CCCCCC1CCC(CC)(CC(=O)OC)C(=O)C1
Yield: 165.2 %

Procedure:
A solution of 1-ethyl-2-oxocyclohex-3-eneacetic acid methyl ester (25 g, 127.6 mmol), CuBr.Me2S (2.62 g, 12.8 mmol) and Me2S (25.5 mL) in 375 mL of tetrahydrofuran was cooled to -40° C. under nitrogen and treated dropwise with H2C=CHCH2CH2CH2CH2MgBr (166.6 mmol, 303 mL of a 0.55M solution in tetrahydrofuran). Fifteen minutes after the addition, the reaction mixture was quenched with 300 mL of 1M HCl and extracted with 4×120 mL of ether. Drying (MgSO4), concentration in vacuo and flash chromatography (114 mm diameter column, 10% ethyl acetate in petroleum ether eluent) afforded the oily product (29.51 g, 105.4 mmol, 83%) as a mixture of diastereomers. A portion of the diastereomers was separated by preparative HPLC affording 2.25 g of isomer A, the higher Rf material, as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([O:11][CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:3]([OH:22])=[O:2])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)C(OC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)OC(C(=O)O)c1ccccc1
Yield: 88.8 %

Procedure:
Methyl((((4-chlorophenyl)amino)carbonyl)oxy)(phenyl)acetate (0.73 g) obtained in Example 3a) and 1 N sodium hydroxide (3.0 ml) were dissolved in methanol (10 ml) and THF (10 ml), and then mixed at room temperature for 15 hours. The reaction solution was then concentrated under reduced pressure, acidified by adding 1 N hydrochloric acid to the concentrated solution, and then the precipitate was collected by filtration and washed with water to obtain the title compound as pale brown powder (0.62 g, 89%).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CC(C)=O>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CC(C)=O
Product: O=S1(=O)N=C(Nc2ccc(Br)cc2)c2ccccc21
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of 3-chloro-1H-1λ6-benzo[d]isothiazole-1,1-dione (1.0 g, 0.00496 mol) in acetone (20 mL), 4-bromoaniline (1.71 g, 0.00992 mol) was added at once and the mixture was stirred for 15 min. The mixture was concentrated under reduced pressure and the residue was suspended in water (100 mL). The precipitate was collected by filtration, thoroughly washed with water and dried to yield 3-(4-bromoanilino)-1H-1λ6-benzo[d]isothiazole-1,1-dione (1.57 g, 0.00467 mol) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[ClH:17].[CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=3)[CH2:28][CH2:29]2)=[O:14])=[CH:15][CH:16]=1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)nc1C
Yield: 79.5 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (422 mg) described in Preparation Example 37 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (483 mg) described in Preparation Example 52, the title compound (675 mg) was obtained.