Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:23])[O:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:14]([CH2:21]O)[O:13]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:34])[NH2:33].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.O>[CH3:31][N:32]([CH3:34])[N:33]=[CH:21][C@H:14]1[O:13][C:12]([CH3:23])([CH3:11])[O:16][C@H:15]1[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C[C@@H]1OC(C)(C)O[C@@H]1CO
Reactant: CN(C)N
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H]1OC(C)(C)O[C@@H]1C=NN(C)C
Temperature: -40 °C
Reaction time: 0.05 h

Procedure:
Oxalyl chloride (0.51 mL, 5.8 mmol) in 14 mL methylene chloride was cooled to -60° C. in a dry ice/chloroform bath. Dimethyl sulfoxide (0.9 mL, 11.7 mmol) in 1.0 mL methylene chloride was added and the reaction mixture was stirred for 3 minutes. The alcohol resulting from Example 8A (1.0 g, 5.31 mmol) in 2.0 mL of methylene chloride was added in one portion maintaining the temperature at -40° C. After 15 minutes, triethylamine (3.7 mL, 26.6 mmol) was added dropwise and the mixture was stirred for 5 minutes, warmed to ambient temperature, and N,N-dimethylhydrazine (1.61 mL, 1.28 g, 21.2 mmol) and magnesium sulfate (1.3 g) were added. The mixture was stirred for 1 hour at ambient temperature. Water (100 mL) was added and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Evaporation of the filtrate gave the hydrazone as a yellow oil. The crude hydrazone was purified by silica gel chromatography using (7:93) ethyl acetate:hexane to afford 808 mg (62%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 0.90 (d, J=6 Hz, 3H), 0.95 (d, J=6 Hz, 3H), 1.29-1.19 (m, 1H), 1.38 (s, 3H), 1.53-1.42 (m, s, 4H), 1.85-1.67 (bm, 1H), 2.82 (s, 6H), 4.33-4.25 (m, 1H), 4.6 (dd, J=7,8 Hz, 1H), 6.41 (d, J=6 Hz, 1H). MS (DCI/NH3) m/e 229 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([O-:9])=O)[CH3:2].[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH3:29][O:30][CH2:31]C(Cl)=O.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)C>[CH2:16]([O:15][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH:6]([C:7](=[O:9])[CH2:29][O:30][CH3:31])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOC(=O)C(CC(OCC)OCC)C(=O)[O-]
Reactant: COCC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(OCC)OCC)C(=O)COC
Temperature: 75 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To 11 L of dehydrated ethyl acetate solution containing 2.45 Kg (8.54 mol) of potassium 4,4-diethoxy-2-ethoxycarbonylbutanoate obtained in Reference example 15-(a) were added 1.63 Kg (17.1 mol) of anhydrous magnesium chloride and 3.12 L (22.2 mol) of triethylamine under argon atmosphere, and the mixture was stirred at 75° C. for 1 hour. Then, 974 g (8.97 mol) of methoxyacetyl chloride was added dropwise to the mixture at 15° C. or lower under cooling in ice-bath, and the mixture was further stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 10 L of ice-water, neutralized with 20% aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.68 kg (purity: 66.4%) of the title compound as a yellowish oil. (Yield: 47.3%)
Reaction SMILES: [CH3:1][C@H:2]1[C@H:28]([CH3:29])[C@@H:27]2[C@@:5]([C:31]([OH:33])=[O:32])([CH2:6][CH2:7][C@@:8]3([CH3:30])[C@:13]4([CH3:26])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[CH2:19][CH2:18][C@:17]5([CH3:25])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:41](Cl)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH3:1][C@H:2]1[C@H:28]([CH3:29])[C@@H:27]2[C@@:5]([C:31]([O:33][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:32])([CH2:6][CH2:7][C@@:8]3([CH3:30])[C@:13]4([CH3:26])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[CH2:19][CH2:18][C@:17]5([CH3:25])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: ClCc1ccccc1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
5 g of ursolic acid was dissolved in 300 ml of dimethylformamide, and 63 ml of triethylamine was added thereto. Then, 20 g of benzyl chloride was added thereto, and the whole was stirred at 50° C. for 1 hour and concentrated under reduced pressure, followed by purification by silica gel chromatography (elution solvent; chloroform:methanol=100:0 to 80:20), to thereby obtain benzyl ursolate.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)C1N2N=C(N3CCN([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([CH:44]([F:46])[F:45])=[CH:40][CH:39]=4)CC3)C=CC2=NN=1>>[F:45][CH:44]([F:46])[C:41]1[CH:42]=[CH:43][C:38]([CH2:37][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:39][CH:40]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: FC(F)c1ccc(CN2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)cc1
Product: FC(F)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 23 %

Procedure:
Obtained in 23% yield by General Synthetic Method 5, starting from 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 4-difluoromethylbenzaldehyde (obtained as described in Example 826, preparation of starting materials).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[CH2:1]([O:3][C:4]1[C:5]([OH:11])=[CH:6][C:7]([F:10])=[C:8]([CH:9]=1)[CH:24]=[O:25])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1ccc(F)cc1O
Agent: C1N2CN3CN1CN(C2)C3
Product: CCOc1cc(C=O)c(F)cc1O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The 2-ethoxy-5-fluoro-phenol (14.3 g) described in example 1.2 was dissolved in trifluoroacetic acid (90 ml). This solution was slowly added to a solution of hexamethylene tetramine (25.7 g) in trifluoroacetic acid (90 ml) at 80° C. The mixture was stirred for 1 h at 80° C. and concentrated. Water (250 ml) was added and stirred for 10 min. The mixture was neutralized with Na2CO3 and extracted with ether. The crude product was purified by column chromatography (n-hexane/ethyl acetate) to yield 9.43 g of 5-ethoxy-2-fluoro-4-hydroxy-benzaldehyde as a yellow solid. MS: 184 ([M]+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4](N)=[O:5].C12C(=CC=CC=1)NC(=O)[O:20][C:18]2=[O:19].[N+]([O-])(O)=O.OS(O)(=O)=O.O=S(=O)=O.S(=O)(=O)=O>>[N+:11]([C:10]1[CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=[C:3]2[C:4]([O:20][C:18](=[O:19])[NH:1][C:2]=12)=[O:5])([O-:13])=[O:12]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O=[N+]([O-])O
Product: O=c1[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2c(=O)o1

Procedure:
A process for the manufacture of 2-amino-3,5-dinitrobenzamide which comprises nitrating at -20° C. to 80° C. isatoic anhydride dissolved in an inert organic solvent with an acid mixture consisting of 85-100% strength nitric acid and oleum, said acid mixture containing 0.5 to 20 moles of sulfur trioxide per mole of nitric acid, to produce 3,5-dinitroisatoic anhydride, allowing the reaction mixture to separate into an organic phase and an acid phase containing the 3,5-dinitroisatoic anhydride, adding 20-30% strength aqueous ammonia to the resultant acid phase in an amount of 9 to 25 moles of ammonia per mol of isatoic anhydride, and reacting the ammonia and the acid phase to produce a high yield of 2-amino-3,5-dinitrobenzamide.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1.CO.Cl>C1COCC1>[CH:1]1([NH:7][S:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([CH2:14][OH:15])[CH:12]=2)(=[O:9])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)NC2CCCCC2)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(NC1CCCCC1)c1cccc(CO)c1
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of 3-[(cyclohexylamino)sulfonyl]benzoic acid (2.25 g) in THF (100 ml) under nitrogen at 0° was treated dropwise with 1M borane-THF solution (23.82 ml). The mixture was stirred at 0° for 0.5 h and then at 20° for 72 h. The mixture was cooled to 0° and MeOH (20 ml) was added dropwise. The mixture was stirred for 15 min and then 2N hydrochloric acid (50 ml) was added and the mixture was allowed to warm to 20°. The bulk of the organic solvents were removed by evaporation in vacuo and the residual aqueous phase was extracted with EtOAc (2×40 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by SPE on alumina (10 g, activated, neutral, Brockmann 1). Elution with MeOH-dichloromethane (1:20) gave the title compound (1.944 g). LCMS RT=2.95 min, ES+ve 270 (MH)+.
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][CH2:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O>[CH2:19]([O:9][CH2:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OC[C@H](CCO)O1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CCOCc2ccccc2)O1
Yield: 88.4 %

Procedure:
Sodium hydride (1.33 g, 33.3 mmol, 60% in oil) was loaded under argon circumstance in three-necked flask and hexane (20 ml) was added thereto. After stirring for a while, it was allowed to stand and the supernatant was removed by syringe. By repeating this procedure three times, the oil of sodium hydride was removed. After drying in vacuo, anhydrous N,N-dimethylformamide (DMF) (5 ml) was added and the mixture was cooled at 0° C. (S)-4-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (4.42 g, 30.25 mmol) in DMF (8 ml) was dropped to the mixture over a one hour period by taking care of the temperature and then the mixture was stirred for 1 hour. Benzyl chloride (3.83 ml, 33.3 mmol) in DMF (3 ml) was dropped to the solution over a one hour period in the range of 0° C. and 5° C. and then the solution was stirred for 4 hours. After stirring water (20 ml) was added to the solution and the solution was extracted with ethyl acetate. The extract was washed with water (40 ml) twice and with saturated brine once, dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-(2-benzyloxyethyl)-2,2-dimethyl-1,3-dioxolane (6.32 g, yield 88%).
Reaction SMILES: C[Si](C)(C(C)(C)C)[O:3][C@@H:4]([C@@H:6]1[C@@H:9]([S:10][CH2:11][CH3:12])[N:8]([C:13](=[C:27]([O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:43][Si](C3C=CC=CC=3)(C3C=CC=CC=3)C(C)(C)C)=[O:42])=[CH:37][CH:36]=2)[C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[S:15])[C:7]1=[O:61])[CH3:5].Cl>O1CCCC1>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([O:34][C:27]([C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[C:13]([N:8]2[C@H:9]([S:10][CH2:11][CH3:12])[C@@H:6]([C@H:4]([OH:3])[CH3:5])[C:7]2=[O:61])[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[S:15])=[CH:40][CH:39]=1)([OH:43])=[O:42]
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1)C(=O)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)O)cc1)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.1 %

Procedure:
A mixture of 50 g of 4-nitrobenzyl 2-(3(S)-[1(R)-[dimethyl-(2-methylprop-2-yl)silyl]oxyethyl]-4(R)-ethylthioazetidin-2-on-1-yl)-3-(4-{diphenyl[2-methylprop-2-yl]silyloxycarbonyl}phenoxy)-3-trimethylacetylthiopropenoate, 500 ml of tetrahydrofuran and 100 ml of 5.5M hydrochloric acid was stirred at room temperature for 24 hours, and then partitioned between diethyl ether and water. The organic layer was washed with water, and with brine, was dried over anhydrous magnesium sulphate, and evaporated in vacuo. Chromatography of the residue over silica gel, and elution with hexane-ethyl acetate-formic acid mixtures afforded 10.2 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cnccc1Br
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cnccc1Br
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-pyridine-3-carbaldehyde (400 mg, 2.15 mmol) in THF (10 mL) at −78° C. was added dropwise 3.0 M phenylmagnesium bromide solution in THF (1.08 mL). After 15 min, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, then purification by flash chromatography eluted with 50% ethyl acetate in hexane to yield (4-bromo-pyridin-3-yl)-phenyl-methanol as slight yellow crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[N:14][N:15]([CH2:17][C:18](O)=[O:19])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:28][CH3:29])[C:4]1=[O:30])[CH3:2].C(N1C=CN=C1)([N:33]1[CH:37]=[CH:36]N=C1)=O.C(N)C>ClCCl>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[N:14][N:15]([CH2:17][C:18]([NH:33][CH2:37][CH3:36])=[O:19])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:28][CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCn1c(=O)n(CC)c2cc(-c3cn(CC(=O)O)nc3-c3cccc(C)c3)ccc21
Agent: CCN
Solvent: ClCCl
Product: CCNC(=O)Cn1cc(-c2ccc3c(c2)n(CC)c(=O)n3CC)c(-c2cccc(C)c2)n1
Temperature: 23 °C
Yield: 66.3 %

Procedure:
To a dichloromethane (2 mL) solution of [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetic acid (0.106 g) was added carbonyldiimidazole (0.055 g). After stirring at 23° C. for 0.5 hours ethyl amine (0.2 mL, 2M in tetrahydrofuran) was added. The reaction was stirred at 23° C. for an additional hour then was concentrated. Preparative thin layer chromatography gave 2-[4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-N-ethyl-acetamide (0.075 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.C(=O)(O)[O-].[K+].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:22]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [K+]
Agent: c1ccc2c(c1)CCNC2
Solvent: c1ccccc1
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2Cl)C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (9.2 g) prepared as in Example 4 was dissolved in dry benzene (100 ml) and 0.5 g of dry potassium bicarbonate was added. A 0.1 mole excess of 2-chlorobenzoyl chloride was dissolved in dry benzene (100 ml) and this solution was added to the solution of the tetrahydroisoquinoline. A white precipitate formed immediately and the mixture was then refluxed for 1 hour. The precipitate was collected by filtration and was washed with 10% sodium carbonate solution followed by water. The washings were discarded and the remaining residue was recrystallized from ethanol to yield 12.6 g of the desired product as fluffly, crystalline plates, m.p., 189.5°-191.5° C.
Reaction SMILES: Cl.C([O:9][C:10](=[O:39])[C@@H:11]([NH:31]C(OC(C)(C)C)=O)[CH2:12][C:13]1[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[N:14]=1)C1C=CC=CC=1.CN1CCOCC1.[C:47]1([S:53](Cl)(=[O:55])=[O:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C.C(O)C.ClCCl>[C:47]1([S:53]([NH:31][C@@H:11]([CH2:12][C:13]2[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[N:14]=2)[C:10]([OH:9])=[O:39])(=[O:55])=[O:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1nc(CCCc2ccc3cccnc3n2)no1)C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: O=C(O)[C@H](Cc1nc(CCCc2ccc3cccnc3n2)no1)NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4M HCl in dioxane (20 mL) was added to 8-5 (0.7 g, 1.4 mmol). After 30 minutes, the solvent was evaporated to give a white solid. To this solid (0.3 g, 0.64 mmol) was added dichloromethane (10 mL), and NMM (0.7 mL, 6.4 mmol), and the mixture was cooled to 0° C. Phenylsulfonyl chloride (0.081 mL, 0.64 mmol) was added. After 30 minutes, the mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Evaporation gave the crude ester 8-6, which was dissolved in ethanol (5 mL); sodium hydroxide (0.7 mL, 1 N in water) was added. After 1 hr, the solvent was evaporated, and the residue was chromatographed (silica gel, 25:10:1:1 followed by 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 8-7 as a white solid.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].C[Al](C)C.CO[C:13]([C:15]1[CH:16]=[N:17][C:18]([C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1)=[O:14]>ClCCCl.C(Cl)Cl>[CH2:2]([N:4]([CH2:5][CH3:6])[C:13]([C:15]1[CH:16]=[N:17][C:18]([C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[N:19][CH:20]=1)=[O:14])[CH3:3]
Reactant: COC(=O)c1cnc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)nc1
Reactant: CCNCC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1cnc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirring suspension of diethyl amine hydrochloride (986 mg, 9.01 mmol) in 1,2-dicloroethane (25 mL) at 0° C. was added a 2.0 M solution of AlMe3 (4.5 mL, 9.01 mmol) dropwise. The resulting mixture stirred at room temperature for 1 hour. (2-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid methyl ester (750 mg, 1.80 mmol) was added in one portion and the mixture was heated to 85° C. for 16 hours. The reaction was slowly poured into a saturated solution of Rochelle salts (50 mL) and diluted with CH2Cl2 (50 mL). The layers were separated, the aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were dried and concentrated. The crude material was filtered through a plug of silica gel with 5% MeOH/CHCl3, and the resulting solution was concentrated to yield 815 mg (99% yield) of the desired amide. 1HNMR (400 MHz, CDCl3) δ 8.72 (s, 2H), 7.29-7.14 (comp, 6H), 6.97-6.95 (comp, 2H), 6.68-6.66 (comp, 1H), 3.73 (s, 3H), 3.54-3.52 (comp, 2H), 3.39 (s, 2H), 3.27-3.25 (comp, 2H), 2.98-2.95 (comp, 2H), 2.77-2.74 (comp, 2H), 2.34-2.31 (comp, 2H), 2.16-2.02 (comp, 2H), 1.26-1.17 (comp, 6H); MS (M+1) 459.2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[N:8]/[S:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10].[CH2:15]1COCC1.C[Mg]Br.CCOCC>[NH4+].[Cl-]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([NH:8][S:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH3:15]
Reactant: Cn1ccnc1/C=N/S(=O)C(C)(C)C
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(NS(=O)C(C)(C)C)c1nccn1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
In a 250 mL round-bottomed flask, 2-methyl-propane-2-sulfinic acid 1-(1-methyl-1H-imidazol-2-yl)-meth-(E)-ylideneamide (670 mg, 3.14 mmol) was combined with THF to give a colorless solution. Methylmagnesium bromide in ether (3.0 M, 5.24 ml, 15.7 mmol) was added at 0° C. The reaction was stirred at 0° C. for 2 h. The reaction mixture was diluted with sat aq. NH4Cl. The aqueous layer was back-extracted with dichloromethane (2×100 mL). The aqueous layer was back-extracted with EtOAc (1×125 mL). The crude reaction mixture was concentrated in vacuo to provide 700 mg (92%) of 2-methyl-propane-2-sulfinic acid [1-(1-methyl-1H-imidazol-2-yl)-ethyl]-amide as a single diastereomer. 1H NMR (300 MHz, DMSO-d6): δ 6.98 (bs, 1H), 6.82 (bs, 1H), 4.61 (q, 1H, J=6 Hz), 4.10 (bs, 1H), 1.61 (d, 1H, J=6 Hz), 1.29 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN(P(N(C)C)(N(C)C)=O)C.C(#N)C>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:7])=[CH:14][CH:15]=1)(=[O:21])=[O:20])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Reactant: O=C(O)CCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccccc1NS(=O)(=O)c1ccc(N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 474 mg (2.84 mmol) of 4-bromo-butanoic acid in 6 mL of 5:1 HMPA/acetonitrile was cooled to 0 deg and thionyl chloride (0.207 mL, 2.84 mmol) was added. The reaction mixture was warmed to room temperature, and transferred to a flask containing 250 mg (0.709 mmol) of neat 4-amino-N-(2-benzoylphenyl)benzenesulfonamide. The solution was allowed to stir overnight. The reaction was quenched w/saturated sodium bicarbonate and diluted with EtOAc (˜100 mL), washed with water (3×20 mL) and brine (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (15% to 75% EtOAc/hexanes)to provide the title compound. LC/MS (ES MS, M+H+ found: 457).
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([NH2:40])=[O:39]>C1COCC1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:37][C:38]([NH2:40])=[O:39])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(OCC(N)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 8 h
Yield: 50.8 %

Procedure:
0.5 g (1.3 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 1) were dissolved, under nitrogen atmosphere and magnetic stirring, in 5 ml of THF; 0.5 g (3.6 mmol) of K2CO3, 0.27 g (1.9 mmol) of 2-bromoacetamide and a small amount of KI were added. The reaction mixture was left overnight under magnetical stirring; the precipitate was filtered off and the residue dissolved in H2O and extracted with EtOAc; the organic layer was washed with sat. sol. NaCl, dried over Na2SO4 and evaporated in-vacuo to dryness. The crude product was triturated with hexane and then recrystallized form EtOH to yield 0.29 g of the title compound as a white solid.