Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:37])=[C:19]([CH:36]=2)[O:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30]C(=O)OCC)=S)=[N:25][CH:26]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(O)C.Cl.NO.C([N:47](CC)C(C)C)(C)C>CO>[NH2:47][C:28]1[N:27]=[C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:36]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:16]=[CH:17][C:18]=3[CH3:37])=[CH:26][N:25]2[N:30]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Temperature: 60 °C
Yield: 35 %

Procedure:
To a solution of the above-mentioned crude product, ethyl ({5-[5-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)-2-methylphenoxy]pyridin-2-yl}carbamothioyl)carbamate, in methanol (100 mL)/ethanol (100 mL) were added hydroxylamine hydrochloride (5.08 g, 73.1 mmol) and N,N-diisopropylethylamine (15.3 mL, 87.8 mmol), and the mixture was stirred with heating at 60° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL, 50 mL). The combined organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (NH silica gel, hexane/ethyl acetate=30/70→0/100), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (1.81 g, 35%) as a colorless solid.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]=[CH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:2]=12.S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:12]=[C:11]1[C:2]2[NH:1][C:6](=[O:19])[CH:5]=[CH:4][C:3]=2[CH:7]=[CH:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1c2ccccc2ccc2ccc[n+]([O-])c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2ccc3ccccc3c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 0.75 gram (0.0034 mole) of the N-oxide thus obtained and 0.77 gram (0.0043 mole) of tosyl chloride in 37.5 milliliters of chloroform was added a solution of 0.58 gram (0.0042.mole) of potassium carbonate in 5.8 milliliters of water and the resulting mixture was stirred vigorously at room temperature for about 60 hours. At the end of this time the reaction mixture was washed with 10 percent aqueous sodium hydroxide whereupon a solid precipitated in the chloroform phase. The solid was recovered by filtration and recrystallized from isopropyl alcohol/methanol to obtain purified 1-oxo-benzo[5,6]cyclohepta[1,2-b]pyrid-2(1H)one product, m.p. 195°-196° C. The elemental analyses were as follows:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28]>[N+](C1C=CC=CC=1)([O-])=O>[N+:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([C:8]2[CH:7]=[CH:6][C:5]([C:11]3([C:21]4[CH:22]=[CH:23][C:24]([C:34](=[O:35])[C:33]5[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:10][CH:9]=2)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCC1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCC1CCC(c2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)(c2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)CC1
Temperature: 67 °C
Yield: 74.9 %

Procedure:
Aluminum chloride 101.22 g and nitrobenzene 200 ml were mixed, the mixture was poured and dissolved in para-nitrobenzoyl chloride 57.10 g on ice cooling. Then, a solution of 1,1-diphenyl-4-butylcyclohexane 30.0 g in nitrobenzene 50 ml was added dropwise for 30 minutes. 30 minutes after adding, the ice bath was removed and the mixture was slowly heated to 67° C. for four hours in a mantle heater. The finish of the reaction was confirmed by liquid chromatography, and then the reaction solution was poured into ice 1.5 liters to extract with chloroform 1.0 liter. The solution was washed with a 6N-HCl solution, an aqueous solution of sodium bicarbonate, an aqueous solution of sodium chloride and water. After chloroform was removed with a rotary evaporator, nitrobenzene was removed by steam distillation. The residue was dissolved in toluene, and the solution was purified with a silica gel column to obtain 1,1-bis[4-(4-nitrobenzoyl)phenyl]-4-butylcyclohexane 45.40 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)[OH:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(OC)cc(C(O)c2ccc([N+](=O)[O-])c(OC)c2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)c1
Reaction time: 72 h
Yield: 94.8 %

Procedure:
A suspension of (3-methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.9 g, 12.3 mmol) and MnO2 (8.5 g, 98.4 mmol) in CH2Cl2 (100 mL) was stirred for 3 days. The mixture was filtered through Celite and the Celite was washed with CH2Cl2. The filtrate was concentrated to afford (3-methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanone (3.7 g, 94%): 1H NMR (CDCl3) δ 7.85 (d, J=8 Hz, 1H), 7.52 (d, J=0.9 Hz, 1H), 7.39-7.35 (dd, J=2, 9.6 Hz, 1H), 6.89 (d, J=2 Hz, 2H), 6.71 (d, J=2 Hz, 1H), 4.01 (s, 3H), 3.83 (s, 6H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].Cl>C(OCC)(=O)C.O>[CH3:1][CH2:2][O:3][C:4]([C@@:6]1([CH3:14])[N:10]([C:22](=[O:24])[CH3:23])[C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1(C)NC(C(=O)O)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@]1(C)SC[C@@H](C(=O)O)N1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
L-cysteine hydrochloride monohydrate (50 g, 285 mmol) was dissolved in water (100 ml), and the pH of the solution was adjusted to 5.15 with 6N aqueous sodium hydroxide. The reaction mixture was heated to 40° C., ethyl pyruvate (38 ml, 342 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 4 hr. Water was added, and the mixture was cooled to room temperature to precipitate the crystals and the crystals were collected by filtration. The obtained crystals were washed with water, and dried under reduced pressure at 50° C. to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (trans form:cis form=88:12, 12.1 g, yield 19%). The synthesized 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (5 g, 22.8 mmol) was dissolved in ethyl acetate (40 ml), and triethylamine (6.4 ml, 45.9 mmol) was added under argon. Acetyl chloride (2.4 ml, 33.8 mmol) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After completion of the reaction, water (15 ml) was added thereto, and the pH of the mixture was adjusted to 1.0 with HCl. The aqueous layer was separated, and the organic layer was washed with water (10 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated to precipitate crystals. The crystals were collected by filtration, washed with heptane/ethyl acetate=1/1 (10 ml), and dried under reduced pressure at 50° C. to give (2S,4R)-N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester as crystals (3.3 g, yield 55%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH2:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:5][CH2:4][CH2:3][CH2:2][N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: ClCCCBr
Reactant: CCCCCCCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCCN(CC)CCCCl
Yield: 44 %

Procedure:
A mixture of 30 g 0.19 mole) of 1-bromo-3-chloropropane, 25 g (0.17 mole) of ethylheptylamine, 28 g (0.20 mole) of potassium carbonate and 250 ml of toluene was refluxed for 8 hours. After cooling, the solid was collected by filtration, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give 17 g of the desired compound (yield 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]2[C:6]([CH:7]=[N:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[N:8]=[CH:7][C:6]2[C:11](=[C:12]([CH:13]([CH3:15])[CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc2cnc(=O)[nH]c2c1C(C)C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2cnc(Cl)nc2c1C(C)C
Temperature: 110 °C

Procedure:
7-Methoxy-8-(2-propyl)quinazol-2(1H)-one (1.2 g) was dissolved in 25 mL of phosphorus oxychloride, and the resulting reaction mixture was heated at 110° C. for 2 hours. Excess POCl3 was removed under reduced pressure. To the residue ice-cold water was added, and the product was extracted with ethyl acetate (3×50 mL). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound. This was purified on a column of silica gel (Hexane:Ethyl acetate), off-white solid, (780 mg, 60%), mp 135–137° C.; 1H NMR (CDCl3): δ 1.41 (d, 6H, 2×CH3), 4.02 (s, 3H, OCH3), 4.33 (m, 1H, CH), 7.38 (d, 1H, Ar-H, J=9 Hz), 7.8 (d, 1H, Ar-H, J=9 Hz), 9.1 (s, 1H, Ar-H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][O:48][C:49](=[O:53])[CH2:50][CH2:51][NH2:52].Br[C:55]1[CH:60]=[C:59]([N+:61]([O-:63])=[O:62])[CH:58]=[CH:57][C:56]=1[CH3:64].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:47][O:48][C:49](=[O:53])[CH2:50][CH2:51][NH:52][C:55]1[CH:60]=[C:59]([N+:61]([O-:63])=[O:62])[CH:58]=[CH:57][C:56]=1[CH3:64]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: COC(=O)CCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)CCNc1cc([N+](=O)[O-])ccc1C

Procedure:
A mixture of 2,2′-Bis(diphenylphosphino)1,1′-binaphthyl [BINAP] (54.35 mg, 0.085 mmol) and Palladium(II)acetate [Pd(OAc)2] (6.95 mg, 0.028 mmol) in dry toluene (3 ml) was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. To this, 3-Amino-propionic acid methyl ester (72.00 mg, 0.699 mmol), 2-Bromo-1-methyl-4-nitrobenzene (181.29 mg, 0.839 mmol) and dry Cesium Carbonate (683.5 mg, 2.097 mmol) were added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to reflux overnight. The mixture was cooled, diluted with ethylacetate, water was added and the layers separated. The aqueous layer was extracted with ethyl acetate and the two organic extracts were combined. The organics were washed with brine, then dried (sodium sulfate), filtered and concentrated. Further purification by silica gel chromatography using 5-10% ethyl acetate/hexane as eluent provided 3-(2-Methyl-5-nitro-phenylamino)propionic acid methyl ester [5] as a yellow solid [Yield: 149.00 mg, 74.7%]
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1.[H-].[Na+].I[CH3:29]>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]([CH3:29])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:6]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A solution of tert-butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate (Compound C of Example 6, 44 mg, 0.13 mmol) in anhydrous DMF (1 mL) was cooled in an ice bath and treated with 60% NaH (44 mg, 0.16 mmol) and stirred at the same temperature for 30 minutes. The reaction mixture was treated with iodomethane (10 μL, 0.15 mmol) and stirred at 0-5° C. for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the product (35 mg, 74%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 8.57 (d, 1H, J=1.1 Hz), 8.37 (dd, 1H, J=9.8, 3.0 Hz), 8.19 (ddd, 1H, J=9.1, 2.5, 1.0 Hz), 7.71 (dd, 1H, J=8.8, 8.8 Hz), 7.66 (s, 1H), 3.38 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([S:16](=[O:19])(=[O:18])[NH2:17])[O:13][C:12]=2[CH:20]=1)=[O:5])C>[OH-].[Na+]>[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([S:16](=[O:19])(=[O:18])[NH2:17])[O:13][C:12]=2[CH:20]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1ccc2cc(S(N)(=O)=O)oc2c1
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc2ccc(OCC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Solid 6-[(ethoxycarbonyl)methoxy]-2-sulfamoylbenzo[b]furan (5 mmol) is added to 10% NaOH (40 ml) and stirred at room temperature 4-6 hours. The solution is acidified and extracted with ethyl acetate, dried (Na2SO4) and evaporated. The residue is dissolved in hot ethyl acetate, filtered, and evaporated until crystallization begins to give product.
Reaction SMILES: C[CH:2]([CH:6]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][OH:4])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)C(c2ccccc2)C(C)C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C(CCO)c2ccccc2)cc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Part C: To a solution of 5.0 g (15 mmol) of methyl 3-[(4-methoxyphenyl)sulfonyl]-3-phenylpropanoic acid, from Part B in 60 mL of anhydrous THF at zero° C. under nitrogen, was added 16.4 mL (0.6 g, 15 mmol) of a 1.0 M solution of lithium aluminum hydride in THF. After 2 hours, the reaction mixture was cooled to zero° C. and 1.2 mL of water was added, followed by 1.2 mL of 2.5 N sodium hydroxide solution and 3.6 mL of water, the reaction was filtered, the filtrate concentrated in vacuo, ethyl acetate and 5% citric acid solution were added, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 3.9 grams of pure 3-[(4-methoxyphenyl)sulfonyl]-3-phenylpropan-1-ol, m/z=313 (M+Li).
Reaction SMILES: Cl.[N:2]([C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])=C=O>C(O)(=O)C>[CH3:7][C:5]([NH2:2])([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:6]
Reactant: CC(C)(N=C=O)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(N)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.1 %

Procedure:
Concentrated hydrochloric acid (18 ml) was added to an acetic acid solution (24 ml) of 1-(2-isocyanatopropan-2-yl)-4-[4-(trifluoromethyl)benzyloxy]benzene (4.35 g, 13.0 mmol) and stirred at room temperature. After 2.5 hours, the mixture was heated to 80° C. and stirred for 1 hour. The solvent was then distilled off. Ice and a 5 N sodium hydroxide aqueous solution were sequentially added to the residue and stirred, followed by extraction with ethyl acetate. The resultant was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off to afford the title compound as a brown solid (3.3 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Clc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1Cl

Procedure:
Using methyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzoate and 4-bromochlorobenzene, 2-chloro-4-(4′-chlorophenyl)benzoic acid was obtained in the same method as in Production Example 292b).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7]OS(C)(=O)=O)(=[O:4])=[O:3].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OC(=O)C)C>[CH2:13]([NH:20][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)NCCOS(C)(=O)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Methanesulphonamido 2-methanesulphonyloxyethane (23.3 g) was added in small portions to benzylamine (24 ml) at such a rate that the temperature did not rise above 30° C. When the addition was complete the mixture was stirred at room temperature for one hour. Ethylacetate (150 ml) was then added to the mixture and the precipitated solid was filtered off. The filtrate was evaporated and the product isolated by column chromatography of the residue using gradient elution (Kieselgel, ethylacetate going to 30% methanol in ethylacetate as eluent). The product was recrystallised from ethylacetate-petroleum ether to give 10.9 g of pale yellow crystals, mpt 71°-73° C.
Reaction SMILES: CN1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19](O)[CH:20]=1.BrCCC=C>O.CC(C)=O>[CH:6]([O:7][C:20]1[CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=[CH:16][C:15]=1[F:14])=[CH:5][CH2:4][CH3:3]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCC=COc1cc([N+](=O)[O-])ccc1F
Reaction time: 0.25 h

Procedure:
To a suspension of NMP (20 ml), acetone (20 ml) and potassium carbonate (8.85 ) was added 5-fluoro-2-nitro phenol (5.0 g, 30 mmol) in one portion. After 15 minutes, the suspension began to turn yellow. After stirring 30 minutes under nitrogen, 4-bromobutene (4.25 ml) was added and the suspension was refluxed for 18 hours. The suspension was poured into water and extracted with 3×200 ml of diethyl ether. The aqueous layer was acidified with 2N HCl and extracted with ether. The ether layers were combined, washed with 2N HCl and water and dried over anhydrous magnesium sulfate. Filtration and in vacuo concentration yielded 6.0 g of 2-(3-butenyloxy-4-fluoronitrobenzene, as an oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8].[OH-].[K+].Br[CH2:38][CH2:39][O:40][CH3:41]>CS(C)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:38][CH2:39][O:40][CH3:41])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8]
Reactant: COCCBr
Reactant: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCOc1ccc2c(C(N)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-hydroxy-1H-indole-3-carboxylic acid amide Example 578 (50 mg, 0.102 mmol) in DMSO (1 mL) was treated with KOH (26.0 mg, 0.458 mmol). The mixture was stirred at RT for 5 min, followed by addition of (2-bromoethyl)methyl ether (0.015 mL, 0.158 mmol) and stirring at RT for 2 h. The mixture was partitioned between water and CH2Cl2, and the aqueous phase was extracted twice with CH2Cl2. The combined organics were washed with brine (3×), dried (phase separator) and concentrated under reduced pressure. Purification by preparative HPLC (SunFire C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) afforded after lyophilization of the purified fractions the title compound as a white solid. MS: 549 [M+H]+; tR (HPLC conditions c): 4.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1>CCOC(C)=O>[CH2:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:41][C@@H:32]([C:30]([NH:29][C@@H:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:14][CH2:13]2)=[O:11])=[O:31])[NH:33]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
((3S) (3-1,2,3,4-Tetrahydroisoquinolyl))-N-[(1S)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carboxamide (600 mg, 0.86 mmol) was prepared from the compound of Step 3 according to the procedure for Preparation XVI. The resulting crude material was diluted with EtOAc and washed with satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude was purified by preparative HPLC (AcOH buffer) to afford the title compound (240 mg) as the acetate salt. MS (ESI, pos. ion) m/z: 596 (M+H), (ESI, neg. ion) m/z: 594 (M−H). Calc'd for C30H34ClN5O4S: 595.20 Anal. Calc'd for C30H34ClN5O4S—C2H4O2—H2O: C, 57.01; H, 5.98; N, 10.39; Cl, 5.26. Found C, 57.69; H, 5.82; N, 10.54; Cl, 5.20.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][S:6]([C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][O:15][C:11]=2[C:10]=1[Cl:25])(=[O:8])=[O:7])C.[OH-].[Na+]>CO>[Cl:25][C:10]1[C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:12]=2[CH:23]=[CH:24][C:9]=1[S:6]([CH2:5][C:4]([OH:26])=[O:3])(=[O:8])=[O:7]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CS(=O)(=O)c1ccc2c(-c3ccccc3F)noc2c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
4.9 g (12.3 mmol) of ethyl[[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfonyl]acetate was added to 500 ml of methanol and 40 ml of 15% aqueous NaOH was added to the suspension. A yellow solution resulted and within 15 minutes a creamy precipitate formed. After stirring four hours at room temperature the reaction mixture was poured into an ice/dilute HCl mixture and the precipitate was filtered, dried, and recrystallized from toluene to afford a white solid, 2.5 g of [[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfonyl]acetic acid , m.p. 204° C.