Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.N>ClCCl.CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(S(C)(=O)=O)cn2)CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)nc1

Procedure:
The product of step D (207 mg, 0.488 mmol) was dissolved in dichloromethane (1.63 mL) and trifluoroacetic acid (1.62 mL, 21.0 mmol) was added. At 1.75 h the volatiles were removed to yield an oil, which was dissolved in 1 mL of MeOH and 1.5 mL of 7 M NH3 in MeOH. After 30 min all volatiles were removed. The free base was used without further purification. 1H NMR (500 MHz, CDCl3) δ 9.10 (d, 1H), 8.26 (dd, 1H), 7.68 (d, 1H), 4.78 (d, 1H), 4.71 (d, 1H), 3.89-3.84 (m, 1H), 3.53-3.49 (m, 1H), 3.46-3.41 (m, 1H), 3.15 (s, 3H), 2.93-2.81 (m, 2H), 2.19-2.12 (m, 1H), 2.02-1.94 (m, 1H), 1.80-1.68 (m, 2H), 1.80-1.68 (m, 2H), 1.38-1.30 (m, 1H), 1.19-1.09 (m, 1H), 0.89-0.22 (m, 2H), 0.11-0.06 (m, 1H). MS (ESI) m/z 437 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:23]([O:25][CH3:26])=[O:24])=[CH:11][CH:10]=3)[CH2:22][CH2:21]1)(=[O:39])=[O:38]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCNCC3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(piperazin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.43 mmol, 1.00 equiv), DIEA (3 mL) in DCM (15 mL). This was followed by the addition of methanesulfonyl chloride (0.5 mL) at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was washed by sat. NaCl and concentrated under vacuum. This resulted in 0.17 g (93%) of methyl 3-(4-(methylsulfonyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a brown yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (350.98 mg, 1.43 mmol) was dissolved in anhydrous DCM and triethylamine (434.11 mg, 4.29 mmol, 0.6 mL) was added under argon. The reaction mixture was cooled to 0EC and methanesulfonyl chloride (180.19 mg, 1.57 mmol, 0.12 mL) was added via syringe. The reaction was stirred at 0EC for 30 min and then allowed to warm to room temp and stir for 12 h. The reaction was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (2:1 hexane-ethyl acetate) Yield 406.92 mg. C12H21NO7S MS m/e=323.1 (M+H).
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[Cl:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([C:16](Cl)=[O:17])=[CH:11][N:10]=1.C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[Cl:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([C:16]([NH:2][CH3:1])=[O:17])=[CH:11][N:10]=1
Reactant: CN
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNC(=O)c1cnc(Cl)nc1Cl

Procedure:
To a solution of methyl amine (2M) in THF (2.4 mL, 4.70 mmol) in DCM (50 ml), TEA (963 mg, 9.50 mmol) and 2,4-dichloropyrimidine-5-carbonyl chloride (1 g, 4.70 mmol) were added slowly at −78° C. for 1 h. TLC showed completion of starting material (TLC system: 10% ethyl acetate in hexane (Rf): 0.3). The reaction mixture was diluted with DCM (50 ml), washed with water (2×30 ml) and a saturated solution of NaHCO3. The organic layer was separated, dried over sodium sulphate, and concentrated. Crude compound was purified by column chromatography using silica gel (100-200 mesh) with 5% ethyl acetate in hexane to obtain 2,4-dichloro-N-methylpyrimidine-5-carboxamide as white solid. Yield: (400 mg, 33%). 1HNMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 6.50 (br s, 1H), 3.07 (d, 3H, J=4.8 Hz).
Reaction SMILES: [OH:1][C@H:2]([C@H:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C([Sn](=O)CCCC)CCC.C(Cl)Cl>[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)([O:4][CH2:3][C@H:2]([OH:1])[C@H:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CCc1ccccc1)[C@@H](O)CO
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)[C@H](C)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a 2 L 3-neck round-bottom flask equipped with a mechanical stirrer and nitrogen inlet was added diol 17 (58 g, 0.30 mol), dibutyltin oxide (1.5 g, 0.006 mol, 2 mol %), p-toluenesulfonyl chloride (57.5 g, 0.30 mol), CH2Cl2 (580 mL) and triethylamine (42.0 mL, 0.30 mol). The resulting mixture was stirred at room temperature for 2 h (although the reaction was complete within 1 h), filtered, washed with water and dried over MgSO4. Concentration of the volatiles in vacuo afforded the title compound (104.1 g) as a slightly amber oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:26])[N:8](CC3C=CC(OC)=CC=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1>F>[CH3:1][O:2][CH2:3][C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:26])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1
Reactant: COCc1cc2c3ccccc3n(Cc3ccc(OC)cc3)c(=O)n2n1
Agent: F
Product: COCc1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
2.9 g (0.01 mole) of 2-(methoxymethyl)-6-(p-methoxybenzyl)pyrazolo[1,5-c]quinazolin-5(6H)-one in 100 ml of anhydrous hydrogen fluoride is stirred at 20° C. for one hour. The hydrogen fluoride is then evaporated; the residue is partitioned between methylene chloride and dilute aqueous sodium bicarbonate. The organic phase is washed with water, dried and evaporated. The residue is stirred with ether and the title compound is filtered off and dried.
Reaction SMILES: [CH3:1][N:2]([CH3:22])/[CH:3]=[N:4]/[S:5]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:7])=[O:6].[CH2:23](Br)[CH:24]=[CH2:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:25]([O:14][C:13]1[C:8]([S:5](=[O:7])(=[O:6])/[N:4]=[CH:3]/[N:2]([CH3:1])[CH3:22])=[C:9]([NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH:10]=[CH:11][CH:12]=1)[CH:24]=[CH2:23]
Reactant: CN(C)/C=N/S(=O)(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(NC(=O)C(C)(C)C)c1S(=O)(=O)/N=C/N(C)C

Procedure:
A solution of N-(2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-3-hydroxy-phenyl)-2,2-dimethyl-propionamide (600 mg, 1.84 mmol) in DMF (4 ml) is treated at 70° C. with allyl bromide (217 μl, 2.57 mmol) and K2CO3 (380 mg) for 45 min with stirring. After evaporation of the solvent, the residue is partitioned between water and EtOAc. The organic layer is dried (Na2SO4) and evaporated yielding N-(3-allyloxy-2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-phenyl)-2,2-dimethyl-propionamide. A solution of N-(3-allyloxy-2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-phenyl)-2,2-dimethyl-propionamide (387 mg, 1.05 mmol) in ethanol (12 ml) and 12 drops of conc HCl (aprox. 0.2 ml) is refluxed for 36 h. After evaporation of the solvent, the residue is partitioned between ammonia (pH 10 to 11) and EtOAc. The organic layer is dried (Na2SO4) and evaporated. Chromatography (silica gel, EtOAc/hexanes=2:1) afforded N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide containing some N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide. Treatment of this material with ethanol (20 ml) and conc. HCl (2 ml) for 30 h at reflux temperature and workup as above gives N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[N:8]2)=[C:4]([CH3:21])[CH:3]=1.OS(O)(=O)=O.[CH2:27](O)[CH3:28]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18][CH2:27][CH3:28])=[O:17])=[N:8]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: CCO
Reactant: Cc1cc(Cl)ccc1Cn1nc(C(=O)O)c2ccccc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nn(Cc2ccc(Cl)cc2C)c2ccccc12
Temperature: 25 °C

Procedure:
To a suspension of 1-(4-chloro-2-methylbenzyl)-1H-indazole-3-carboxylic acid, prepared as described in J. Med. Chem. (1976) 19, 778-783, (120 g; 0.4 mol) in absolute ethanol (850 ml), stirred at room temperature, was cautiously added concentrated H2SO4 (15 ml). The mixture was then refluxed for 9 hours. The reaction was then completed by cooling the mixture to room temperature. The solid thus formed was filtered off under cold conditions (10° C.) and washed thoroughly on the filter with water. 126 g of ethyl 1-(4-chloro-2-methylbenzyl)-1H-indazole-3-carboxylate were thus obtained, and were used in the following reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:38][CH:37]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1)([CH3:36])[CH3:35]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)N1CCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCC3)cc2)C(C)C)c1
Yield: 78 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-piperidin-1-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:17][C:18]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)(=O)C.C([BH3-])#N>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH2:15][NH:17][C:18]3([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC1(CO)CCCC1
Reactant: O=Cc1cccc(-c2ccc(F)c(Cl)c2)n1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: OCC1(NCc2cccc(-c3ccc(F)c(Cl)c3)n2)CCCC1
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a solution of Example 266A (0.500 g, 2.12 mmol) in methanol (20 mL) and CH2Cl2 (20 mL) at ambient temperature was added cycloleucinol (0.244 g, 2.12 mmol), acetic acid (0.50 mL, 8.5 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated and the residue partitioned between ether and 1N NaOH. The organic extract was concentrated and purified by chromatography to provide 418 mg (59%) of the title compound. MS (DCI+) m/z 335 (M+H); 1H NMR (500 MHz, CDCl3) δ 8.03 (dd, J=7.1, 2.2 Hz, 1H), 7.86 (ddd, J=8.6, 4.6, 2.3 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.30-7.19 (m, 2H), 3.95 (s, 2H), 3.48 (s, 2H), 1.87-1.52 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH2:32])(=[O:31])=[O:30])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=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>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH2:32])(=[O:30])=[O:31])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Reactant: OB(O)c1cccc(Cl)c1Cl
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: CN(C)C=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(-c2cccc(Cl)c2Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol), was added to a solution of 2,3-dichlorophenylboronic acid (57 mg, 0.30 mmol) and 2-[(3-bromophenyl)-sulfonylamino]benzenesulfonamide (97 mg, 0.25 mmol) in DMF (1 mL). The reaction mixture was stirred at RT under argon for 15 minutes before addition of 2M Na2CO3 (0.5 mL). The reaction was stirred overnight at 90° C., filtered and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (61 mg, 53%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[NH2:32][S:33]([C:36]1[CH:46]=[CH:45][C:39]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:32][S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])=[CH:45][CH:46]=3)(=[O:34])=[O:35])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: CC(=O)NCc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: CC(=O)NCc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and N-[4-(aminosulfonyl)benzyl]acetamide: 1H-NMR [CDCl3/CD3OD(4:1)]δ 7.90-7.87 (2H, m), 7.48-7.26 (11H, m), 4.44 (2H, s), 3.45-3.41 (2H, m), 2.87-2.82 (2H, m), 2.32 (3H, s), 2.27 (3H, s), 2.03 (3H, s).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[OH:14]>>[Cl:1][S:2]([C:11]1[CH:12]=[C:7]([F:6])[C:8]([OH:14])=[C:9]([F:13])[CH:10]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1c(F)cccc1F
Product: O=S(=O)(Cl)c1cc(F)c(O)c(F)c1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
Chlorosulfonic acid (112.6 g) was added dropwise with ice cooling to 2,6-difluorophenol (25 g). The reaction mixture was stirred at room temperature for an hour and poured into ice-water (600 ml), and the separated oily substance was extracted with methylene chloride. The methylene chloride layer was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-chlorosulfonyl-2,6-difluorophenol (31.5 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10]CC)=O.C(O)(=O)C.[CH:17](N)=[NH:18]>CCO>[N:2]1[C:3]2[CH:7]=[CH:6][NH:5][C:4]=2[C:8](=[O:10])[NH:18][CH:17]=1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: N=CN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc[nH]c12
Temperature: 83 °C
Yield: 80.1 %

Procedure:
Ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (3.00 g, 15.7 mmol) was dissolved in EtOH (40 mL). Formamidine acetic acid salt (2.44 g, 23.5 mmol) was added and the reaction mixture was heated under reflux at 83° C. for 18 h. The reaction mixture was cooled to r.t. and the precipitate was collected by filtration, washed with EtOH and dried in vacuo to give the title compound as a beige solid (1.70 g, 80%). LCMS (ES+): 135.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][CH2:14][NH:15][C:16]([O:18]C(C)(C)C)=O)=[C:6]([CH:11]=1)C(OC)=O.C(O)(C(F)(F)F)=O.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][CH2:13][CH2:14][NH:15][C:16](=[O:18])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(Br)ccc1OCCNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCOc2ccc(Br)cc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 58.9 %

Procedure:
A solution of methyl 5-bromo-2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]oxy}benzoate (Preparation 70) (8.92 g, 23.8 mmmol) in DCM (18 ml) was treated with TFA (7 ml) and stirred for 5 hrs. Additional (2 ml) TFA was added and the reaction left overnight. The solvent was evaporated, re-evaporated with toluene (5×) and dissolved in toluene (50 ml). The resulting residue was treated with triethylamine (4 equiv) and heated at 100° C. overnight then evaporated. The residue was purified by flash chromatography twice eluting with 50% EtOAc/hexane then 40-45% EtOAc/hexane. The fractions were evaporated to give the title compound (3.4 g) as a white solid. MS (ES): C9H881BrNO2 requires 243; found 244 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:3]=1[NH:4][C:5](=[O:8])[CH2:6][Cl:7].C1[CH2:19][O:18][CH2:17][CH2:16]1.COCCCl>C(OCC)C>[CH3:19][O:18][CH:17]([N:4]([C:5](=[O:8])[CH2:6][Cl:7])[C:3]1[C:9]([CH2:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:2]=1[CH3:1])[CH3:16]
Reactant: C1CCOC1
Reactant: CCc1cccc(C)c1NC(=O)CCl
Agent: COCCCl
Solvent: CCOCC
Product: CCc1cccc(C)c1N(C(=O)CCl)C(C)OC
Yield: 86 %

Procedure:
The same general procedure of Example 32 was followed, except here the sec-amide, 2'-methyl-6'-ethyl-2-chloroacetanilide, 21.1 g (0.1 mol), was solubilized with a small amount of THF in 400-500 ml diethyl ether. Reaction went well, but gas evolved when chloroethyl methyl ether was added. However, at final addition (about 2.5×theory) the added ether didn't react although some KH was still present. Upon workup, the product, N-(1-methoxy-1-ethyl)-2'-methyl-6'-ethyl-2-chloroacetanilide, was obtained in 86% yield, b.p. 130° at 0.05 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[C:1]([O:5][C:6]([NH:7][C:8]1[N:9]=[C:10]([CH2:14][O:15][C:33](=[O:35])[CH3:34])[CH:11]=[CH:12][CH:13]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
(6-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.85 g, 3.79 mmol) was dissolved in dichloromethane (30.00 ml) and triethylamine (1.32 ml) and treated with dimethylaminopyridine (0.09 g, 0.76 mmol) and acetic anhydride (0.43 g, 4.17 mmol). The mixture was stirred at room temperature for 10 min, then partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate) to yield acetic acid 6-tert-butoxycarbonylamino-pyridin-2-ylmethyl ester (0.85 g, 84%) as a white solid, MS (ISP): m/e=267.1 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccnn1Cc1ccccc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(Cn2nccc2NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of 1-benzyl-1H-pyrazol-5-amine (2.09 g) in acetic acid (20 mL) was added tetrahydro-4H-pyran-4-one (1.25 g), and the mixture was stirred at room temperature for 30 min. After stirring, sodium triacetoxyborohydride (3.90 g) was added at room temperature, and the mixture was stirred overnight. Acetic acid was evaporated under reduced pressure and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (3.00 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[C:3]=1[C:4]([O-:6])=O.[Li+].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:55]1([N:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[NH:61][CH2:60][CH2:59]2)[CH2:57][CH2:56]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:4]([N:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:58]([CH:55]3[CH2:57][CH2:56]3)[CH2:59][CH2:60]2)=[O:6])=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])c(Cl)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution of 120 mg (0.355 mmol) lithium 2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate in 3 mL dry N,N-dimethylformamide was added 0.30 mL (1.773 mmol) N-ethyldiisopropylamine and 163 mg (0.425 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 74 mg (0.425 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermediate a). The reaction mixture was stirred for 18 hours at room temperature and evaporated. The residue was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 100:0) to provide 45 mg (26%) of the title compound as a light yellow foam (30%). MS (ESI): m/z=488.07 [M+H]+.