Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])(=O)[CH3:2].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C.C(OCC)(=O)C>[OH:25][N:24]=[C:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(C(C)=O)c2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(C(C)=NO)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
175 mg of Methyl (3′-acetyl-4′-methoxybiphenyl-3-yl)acetate was dissolved in 3 m of ethanol, then 55 mg of hydroxylamine hydrochloride and 65 mg of sodium acetate were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated to give methyl [3′-(1-hydroxyiminoethyl)-4′-methoxybiphenyl-3-yl]acetate. This product was dissolved in 4 ml of ethanol, then 0.5 ml of 5N sodium hydroxide was added thereto, and the mixture was left at room temperature for 6 hours. The reaction mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated to give 166 mg of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19]C2C=CC3C(=CC=CC=3)N=2)=[CH:14][CH:13]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:8]1([CH3:31])[NH:9][C:10](=[O:30])[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:36]3[CH:37]=[CH:38][C:39]4[C:40](=[CH:8][CH:7]=[CH:11][CH:10]=4)[N:35]=3)=[CH:16][CH:17]=2)=[C:7]1[C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: OB(O)c1ccncc1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
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: C1COCCO1
Solvent: O
Product: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1c1ccncc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (2.0 g, 0.004 mol) in 1,4-dioxane (50 mL) were added pyridin-4-yl boronic acid (598 mg, 4.8 mol), Na2CO3 (1.0 g, 0.012 mol) and water (20 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (468 mg, 0.4 mol) was added. The mixture was then heated at 80° C. for 16 h, diluted with water, and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 5,5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (250 mg, 15%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.74-8.68 (m, 1H), 8.66-8.56 (m, 2H), 8.06-7.94 (m, 2H), 7.78 (t, J=7.2 Hz, 1H), 7.66-7.56 (m, 3H), 7.30-7.18 (m, 4H), 6.98-6.88 (m, 3H), 5.36 (s, 2H), 1.36 (s, 6H). MS: M+H m/z=422.1; M+Na: m/z=444.1. HPLC: 89%, (Condition-I).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7](Br)[CH:6]=1)[CH3:2].[CH2:15]([O:23][C:24](=[O:28])[CH2:25][CH2:26][SH:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])C.[CH:29](N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:27][CH2:26][CH2:25][C:24]([O:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:22][CH3:29])=[O:28])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)c(Br)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)CCCCCOC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCCCCCCOC(=O)CCSc1cc(C(=O)OCC)ccc1OC
Temperature: 90 °C

Procedure:
3-Bromo-4-methoxy-benzoic acid ethyl ester (1.61 g, 6.62 mmol) and isooctyl-3-mercaptopropionate (1.73 g, 7.95 mmol) were dissolved in dioxane (26 mL) and the mixture was sparged with N2 (g) for 10 minutes. Diisopropylethyl amine (2.31 mL, 13.25 mmol), Xanthphos (0.1917 g, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.1517 g, 0.166 mmol) were added and the mixture was sparged with N2 (g) for 5 minutes. The reaction was then heated to 90° C. for 2 hours after which time it was filtered to remove solid impurities. The mixture was concentrated and the residue was purified on silica gel (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[C:39]([F:51])[CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[C:39]([F:51])[CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)c(F)c3)c2s1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)c(F)c3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogencarbonate (2.8 g) and dimethyl sulfoxide (40 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (1.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 mL). N,N′-Carbonyldiimidazole (0.31 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.3 g, 39%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2ccccc2c2c1c(C(=O)C(N)=O)c(C)n2CC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3ccccc3c2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 54.2 %

Procedure:
To a solution of 2-[[3-(2-amino-1,2-dioxoethyl)-1-cyclohexylmethyl-2-methyl-1H-benz[g]indol-4-yl]oxy]acetic acid methyl ester (0.042 g, 0.096 mmol) in 60% tetrahydrofuran/40% methanol (5 mL) was added 1 M lithium hydroxide solution (3 mL). The resulting mixture was stirred at room temperature for 28 h. The mixture was warmed briefly, diluted with water, and acidified with concentrated hydrochloric acid. The resulting yellow precipitate was collected via vacuum filtration and air-dried to provide 0.022 g (54%) of the title compound. 1H NMR (DMSO-d6) δ13.00 (bs, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.73 (bs, 1H), 7.48 (t, J=7.0 Hz, 1H), 7.45 (bs, 1H), 7.39 (t, J=7.0 Hz, 1H), 6.91 (s, 1H), 4.76 (s, 2H), 4.45 (bs, 2H), 2.55 (s, 3H), 1.90 (bs, 1H), 1.60 (m, 5H), 1.10 (m, 5H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=O)=O)[CH:6]=[CH:7][CH:8]=1.[S:20]([NH2:24])([NH2:23])(=[O:22])=[O:21]>CO>[F:2][C:3]1[CH:4]=[C:5]([C:9]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:24][S:20](=[O:22])(=[O:21])[N:23]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(C(=O)c1cccc(F)c1)c1cccc(F)c1
Agent: Cl
Solvent: CO
Product: O=S1(=O)N=C(c2cccc(F)c2)C(c2cccc(F)c2)=N1
Temperature: 66 °C
Yield: 72.8 %

Procedure:
Hydrogen chloride is bubbled through a solution of 3,3′-difluorobenzil (20) (3.81 g, 15.7 mmol) and sulfamide (1.53 g, 15.9 mmol) in methanol (15 mL) for 0.5 min followed by heating at 66° C. for 2 h. The reaction mixture is cooled to RT, the solvent rotary evaporated, and the residue triturated from heptane to give 3.50 g of the product 21.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48](O)=O)[CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([CH:39]2[CH2:38][CH2:37][N:36]([CH3:34])[CH2:41][CH2:40]2)[CH:43]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Product: CCN(Cc1cccc(C2CCN(C)CC2)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 38.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (80 mg) and 4-(3-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (39 mg) was obtained.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:20]=[C:21]([CH:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:4]1([CH:3]=[CH:2][C:1]([NH:27][CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH:20]=2)[CH3:26])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(N)c1cccc(Oc2ccccn2)c1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1ccccc1)c1cccc(Oc2ccccn2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of cinnamic acid (0.11 mmol), 1-[3-(pyridine-2-yloxyl)phenyl]-ethylamine (16.3 mg, 0.11 mmol), EDAC.HCl (42 mg, 0.22 mmol), DMAP (13 mg, 0.11 mmol) and Et3N (0.1 mL, 0.44 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[O:31][CH3:32])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2.[CH3:33][O-:34].[Na+].CO>CS(C)=O.CCOC(C)=O>[CH3:33][O:34][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[O:31][CH3:32])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: COc1cc(C(F)(F)F)ccc1-c1nc(Cl)cc2cc(S(=O)(=O)Nc3nccs3)ccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc2cc(S(=O)(=O)Nc3nccs3)ccc2c(-c2ccc(C(F)(F)F)cc2OC)n1
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A vial was charged with 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Example 249) (35.79 mg, 0.072 mmol), sodium methoxide (25.1 mg, 0.465 mmol), and MeOH (477 μl). The vial was sealed and heated in a 100° C. heating bath for 1 h. The mixture was diluted with DMSO (0.5 mL) to solubilize the solids, and an additional portion of sodium methoxide (25.1 mg, 0.465 mmol) was added. The vial was sealed and heated to 120° C. for 1.5 h. The mixture was cooled to room temperature and diluted with EtOAc, then washed with 1N aq. HCl, washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give 3-methoxy-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (23.2 mg, 0.047 mmol, 65.4% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.88 (s, 1H), 8.40 (s, 1H), 7.61-7.56 (m, 3H), 7.55-7.48 (m, 3H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H). m/z (ESI) 496.2 (M+H)+.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)([O-])=O.[H-].[Na+]>CN(C=O)C>[CH3:1][N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([NH2:9])[CH:13]=[CH:14][C:15]1=2
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCOc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Potassium carbonate (800 mg, 6 mmol) and methyl iodide (1.3 g, 9 mmol) were added to a solution of 3,4-dihydro-7-nitro-2H-benzo[b][1,4]oxazine (540 mg, 3 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. Sodium hydride (100 mg, 95%) and methyl iodide (1.0 g) were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was suspended in water. A solid precipitated which was filtered and washed with water. The bright yellow solid was then suspended in MeOH (20 mL) and Pd/C (10%) was added. The suspension was stirred under an atmosphere of hydrogen overnight, then filtered through celite and the filtrate concentrated under vacuum to give the product (470 mg) as a purple oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:16][CH2:17][CH3:18])=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([N:8]([CH3:10])[CH3:9])=[O:7].[S:19](=[O:21])=[O:20].[NH2:22]OS(O)(=O)=O>>[NH2:22][S:19]([C:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[C:4]([CH2:16][CH2:17][CH3:18])[C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])(=[O:21])=[O:20]
Reactant: O=S=O
Reactant: NOS(=O)(=O)O
Reactant: CCCc1c(C(=O)N(C)C)ccc(OC)c1OC
Product: CCCc1c(OC)c(OC)cc(S(N)(=O)=O)c1C(=O)N(C)C
Yield: 63 %

Procedure:
By the method of Example 22A 3,4-dimethoxy-2-propyl-N,N-dimethylbenzamide (9.2 g) was aminosulfonylated with sulfur dioxide and hydroxylamine-O-sulfonic acid (5.6 g) to give 2-aminosulfonyl-4,5-dimethoxy-6-propyl-N,N-dimethylbenzamide (7.4 g, 63% yield), which was cyclized in quantititive yield to 4-propyl-5,6-dimethoxysaccharin, phenylthiomethylation of which with chloromethyl phenyl sulfide (1.42 mL) gave 2-phenylthiomethyl-4-propyl-5,6-dimethoxy-saccharin (4.07 g), reaction of part (3.59 g) of which with sulfuryl chloride (2.12 mL) gave 2-chloromethyl-4-propyl-5,6-dimethoxysaccharin, 2.84 g, 97% yield.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][O:23][CH:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[O:23]1[CH:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:15][CH:16]=2)[N:21]=[CH:22]1
Reactant: O=C(NCCOc1ccc(-c2cocn2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Product: NCCOc1ccc(-c2cocn2)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A stirred mixture of 234.0 g (0.692 mol) of [2-(4-oxazol-4-yl-phenoxy)-ethyl]-carbamic acid benzyl ester l-3, 295.1 ml (3.097 mol) of 1,4-cyclohexadiene, and 93.60 g of 10% Pd/C (50% water wet) in 5.6 l of methanol was stirred at room temperature for about twenty-two hours. The mixture was filtered through a pad of diatomaceous earth (13×3 cm), and the filter cake was then washed with 12 l of 100:1 v/v methanol/triethylamine. The filtrate was evaporated in vacuo, and to the residual solid was added 250 ml of toluene. The mixture was stirred at room temperature for about thirty minutes, 2.5 l of hexanes was then added over a period of about five to ten minutes, and the resulting slurry was then stirred for about one hour. The mixture was filtered, and the filter cake was then washed with a mixture of 1:10 toluene/hexanes (3×100 ml), and the solid was dried under vacuum at about 50° C. for about eighteen hours. The title compound (115 g, 81.5% yield) was obtained as a white powder.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][SH:28])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:9].[ClH:10].[ClH:10].[C:1]1([NH:7][C:8](=[SH:28][CH2:27][CH2:26][CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:24][CH2:23]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: SCCCN1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O
Product: OC(Nc1ccccc1)=[SH]CCCN1CCN(Cc2ccccc2)CC1
Yield: 41.9 %

Procedure:
1.6 g of phenyl isocyanate were added to a solution of 4.0 g of 3-(4-benzylpiperazin-1-yl)propanethiol dihydrochloride and 2.6 g of triethylamine in 50 ml of methylene chloride. The mixture was refluxed for four hours, washed with water and dried (sodium sulfate). Precipitation of the salt with ethereal hydrochloric acid gave 1.2 g (20% of theory) of N-phenyl-S-[3-(4-benzylpiperazin-1-yl)-propyl]thiocarbamate dihydrochloride monohydrate as a white crystalline solid, M.p. 216°-219° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[NH:24])[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH3:23])[CH:16]=1)([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[CH2:31][CH:32]=O.CC(O)C>O.C(OCC)(=O)C>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[N:13]1[CH:32]=[CH:31][N:24]=[C:14]1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH3:23])[CH:16]=1)([CH3:12])[CH3:11]
Reactant: O=CCCl
Reactant: COc1cc(C)cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1

Procedure:
To a 250 mL round bottom flask was mixed N-(2,6-diisopropylphenyl)-3-methoxy-5-methylbenzimidamide (5.83 g, 17.97 mmol), sodium bicarbonate (3.02 g, 35.9 mmol), 2-chloroacetaldehyde (50%, 4.56 ml, 35.9 mmol), and 80 mL of 2-propanol. The reaction mixture was heated to reflux for 3 hours under nitrogen. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with 10% LiCl solution, brine, dried over magnesium sulfate, filtered, evaporated leaving a brown oil. The oil was purified by column chromatography eluting with 20% ethyl acetate/hexane (5.78 g, 92%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=O.P(Cl)(Cl)(OCl)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: O=P(Cl)(Cl)OCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Yield: 99.6 %

Procedure:
To a solution of tert-butyl 4-[4-(aminocarbonyl)phenyl]-1-piperidinecarboxylate (3.34 g) in DMF (18 ml) was dropwise added phosphoryloxychloride (3.07 ml) keeping under 10° C. with stirring and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was poured into a mixture of saturated aqueous sodium carbonate (60 ml) and ice-water (250 ml) with stirring and extracted twice with a mixture of ethyl acetate (200 ml) and hexane (80 ml). The extract was washed twice with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (4:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give tert-butyl 4-(4-cyanophenyl)-1-piperidine carboxylate (3.13 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1)[CH3:2].C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(C2(O)c3ccccc3-c3ccccc32)c1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: CCc1cccc(C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)c1

Procedure:
from 9-(3-ethylphenyl)-9H-fluoren-9-ol (Example 3r) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[S:18])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][O:22][CH3:23].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][S:18][C:10]1[NH:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: S=C1NN=C(c2ccccc2)C1c1ccccc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 4 h
Yield: 73.2 %

Procedure:
To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.5 g, 1.981 mmol) in DMF (5 mL), were added 1-bromo-2-methoxyethane (0.275 g, 1.981 mmol) and K2CO3 (0.274 g, 1.981 mmol) at room temperature. After stirring for 4 h, the reaction was poured into water and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (0.45 g). LCMS m/z=311.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (s, 3H), 3.12-3.54 (m, 4H), 7.22-7.49 (m, 10H), 13.2 (s, 1H).