Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1[N:8]([CH2:9][CH2:10][C@@H:11](O)[CH2:12][C@@H:13](O)[CH2:14][C:15](O)=O)[C:7](C2C=CC(F)=CC=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)C=1C(NC1C=CC=CC=1)=O)C>C(#N)C>[CH2:9]([NH:8][CH2:7][CH2:6][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Solvent: CC#N
Product: c1ccc(CCNCc2ccccc2)cc1

Procedure:
The benethamine salt of atorvastatin (Form A) was synthesized by preparing a stock solution of the free acid of atorvastatin (U.S. Pat. No. 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N-benzyl-2-phenylethylamine (benethamine) was prepared by dissolving 378.59 mg (1.0 equivalents) in acetonitrile (10 mL). The stock solution of atorvastatin free acid was added to the counterion solution with stirring. Over time, an additional 40 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at ambient temperature, the solids were isolated by vacuum filtration using a Buchner funnel fitted with a paper filter (#2 Whatman). The solids were rinsed with acetonitrile (75 mL), and placed in a 25° C. oven under nitrogen to dry overnight to afford atorvastatin benethamine Form A.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:20])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:20])=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2ccc[n+]([O-])c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1c2cc(Br)ccc2oc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide in 100 mL of toluene at 0° C. was added dropwise phosphorus oxychloride (35.8 mL, 391 mmol) followed by 2 mL of DMF and the mixture was stirred at RT overnight. The solvent was evaporated under vacuum and the residue which crashed out of water, was filtered and washed with water, methanol and acetone in sequence. The solid was air dried to give 8-bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one as a tan solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([NH:10][CH3:11])=[N:8][N:9]=1)(=[O:4])=[O:3].[C:12]([Cl:15])(Cl)=[O:13]>C1C=CC=CC=1>[CH3:1][S:2]([C:5]1[S:6][C:7]([N:10]([CH3:11])[C:12]([Cl:15])=[O:13])=[N:8][N:9]=1)(=[O:4])=[O:3]
Reactant: CNc1nnc(S(C)(=O)=O)s1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CN(C(=O)Cl)c1nnc(S(C)(=O)=O)s1

Procedure:
2-methylsulfonyl-5-methylamino-1,3,4-thiadiazole (0.1 mole) and a solution of phosgene (0.11 mole) in benzene (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 4 hours. After this time the mixture is stripped of benzene and unreacted phosgene to yield the desired product N-(2-methylsulfonyl-1,3,4-thiadiazol-5-yl)-N-methylcarbamoyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1)#[N:2].[NH3:13]>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:13])=[O:11])[CH:4]=1
Reactant: COC(=O)c1cc(C#N)ccn1
Reactant: N
Agent: [Ni]
Solvent: CCO
Product: NCc1ccnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
830 mg of methyl 4-cyanopyridine-2-carboxylate was dissolved in 20.0 mL of ethanol and 20.0 mL of aqueous ammonia, and 160 mg of Raney nickel was added thereto, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere. The reaction liquid was filtered through Celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 410 mg of 4-(aminomethyl)pyridine-2-carboxamide.
Reaction SMILES: C(N[C:5](=[CH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH3:26])[CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.Cl.[O:28]1CCOCC1>>[CH2:19]([O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][C:5](=[O:28])[C:6]([OH:8])=[O:7])=[CH:12][C:13]=1[CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C(=Cc1cc(C)c(OCc2ccccc2)c(C)c1)NC(C)=O
Reactant: C1COCCO1
Agent: Cl
Product: Cc1cc(CC(=O)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31.1 g (88.1 mmol) methyl 2-acetylamino-3-(4-benzyloxy-3,5-dimethyl-phenyl)-acrylate in 150 mL 1,4-dioxane were combined with 125 mL 4 M HCl, refluxed for 7 h and stirred overnight at RT. The precipitate was suction filtered, washed with water and dried at 45° C. in the vacuum drying cupboard.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.Br[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:31]1([CH2:30][CH2:29][CH2:28][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)(=[O:12])=[O:11])[CH2:5][CH2:4]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCCc1ccccc1
Reactant: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)CC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)CC1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.402 g (0.925 mM) of (E)-4-[2-(piperidin-4-ylmethanesulfonyl)vinyl]-5-thia-1,8b-diazaacenaphthylene dihydrochloride, 0.28 g (1.39 mM) of 1-bromo-3-phenylpropane, and 0.45 ml (3.24 mM) of triethylamine in 20 ml of ethanol was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol : 9/1-1/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:40][C:41]([Si:44]([CH3:55])([CH3:54])[O:45][C:46]1[CH:47]=[C:48]([CH2:52][NH2:53])[CH:49]=[CH:50][CH:51]=1)([CH3:43])[CH3:42]>ClCCl>[CH3:12][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([CH3:1])[C:10]=1[OH:11])[C:5]([NH:53][CH2:52][C:48]1[CH:49]=[CH:50][CH:51]=[C:46]([O:45][Si:44]([C:41]([CH3:43])([CH3:42])[CH3:40])([CH3:54])[CH3:55])[CH:47]=1)=[O:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxybenzoic acid (1.53 g, 9.2 mmol) in dichloromethane (30 mL) at 0° C. was added benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (4.45 g, 10 mmol), 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanamine (Example 70; 3.28 g, 13.8 mmol), followed by diisopropylethylamnine (4.9 mL, 27.6 mmol) slowly dropwise. After stirring 1 h, the reaction was warmed to 25° C. and stirred for 1 h. The solvent was removed under reduced pressure and the residual oil was diluted with ethyl acetate (100 mL) and washed with 1N hydrochloric acid solution (2×25 mL), saturated aqueous sodium bicarbonate solution (2×25 mL), water (25 mL) and brine (25 mL). The organic layer was dried (MgSO4), filtered, evaporated and flash chromatographed (silica gel, 20-30% ethyl acetate in petroleum ether) to give 3,5-dimethyl-N-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]-4-hydroxybenzamide (3.1 g, 87% yield) as an off-white foam.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH3:44])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH3:44])[CH:42]=[N:41][N:40]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4C)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4C)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85416.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.70 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.41 g) in dichloromethane (5 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., and to the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (ethanol:ethyl acetate ˜1:9), and was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 133) (613.2 mg) as yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][CH2:14][C:15](=[O:17])[CH3:16].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:13][CH2:14][C:15](=[O:17])[CH3:16])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)CO
Reactant: CCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(=O)OCC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Monohydroxyacetone was distilled prior to use. Chloroform was distilled from phosphorus pentoxide prior to use. Decanoyl chloride (65 cm3, 0.3146 mole) was added dropwise to stirred solution of monohydroxyacetone (21.8 cm3, 0.3146 mole) and anydrous pyridine (25.4 cm3, 0.3146 mole) in anhydrous chloroform (500 cm3). During the addition the solution was maintained in an ice bath. The mixture was then stirred at room temperature overnight. The solution was washed with water (4×200 cm3) and saturated sodium chloride solution (200 cm3). The organic phase was dried over sodium sulphate and evaporated in vacuo. The resulting oil was distilled to yield 1-decanoyloxypropan-2-one as a mobile liquid, bp 154°-60° (1 mm) (52.4 g, 0.230 mole, 73%),ir (neat) 2860, 1700, 1400, 1340, 1150, 1110 and 1050 cm-1 ; pmr (CDCI3) δ 4.6 (s, 2 H), 2.4 (t, 2 H), 2.1 (s, 3 H), 1.8-1.0 (bm, 14 H) and 0.9 (t, 3 H) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH:18]([OH:19])[CH:12]12)=O)C1C=CC=CC=1>CO>[CH:22]([NH:21][C:20]([N:16]1[CH2:17][CH:18]([OH:19])[CH:12]2[NH:11][CH2:15][CH2:14][CH:13]12)=[O:25])([CH3:24])[CH3:23]
Reactant: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)NC(=O)N1CC(O)C2NCCC21
Reaction time: 3 h
Yield: 117.9 %

Procedure:
A mixture containing crude 53 (˜6.2 g, 17.9 mmol) and 10% Pd-on-carbon (wet, 1.9 g, 1.8 mmol) in MeOH (200 mL) was stirred vigorously under an atmosphere of H2. After 3 h, the catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford 4.5 g of 54 as a colorless oil which was used without further purification.
Reaction SMILES: [H-].[K+].[CH3:3]CCCCC.[OH:9][CH2:10][CH:11]1[C:20]23[CH2:21][CH2:22][CH:13]([CH:14]4[O:29][C:28]5[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:27]=5[C:15]42[CH2:16][CH2:17][N:18]([CH2:24][CH2:25][CH3:26])[C:19]3=[O:23])[CH2:12]1.CI>O1CCCC1>[CH3:35][O:34][C:30]1[C:28]2[O:29][CH:14]3[CH:13]4[CH2:22][CH2:21][C:20]5([CH:11]([CH2:10][O:9][CH3:3])[CH2:12]4)[C:15]3([CH2:16][CH2:17][N:18]([CH2:24][CH2:25][CH3:26])[C:19]5=[O:23])[C:27]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CCCCCC
Reactant: CCCN1CCC23c4cccc(OC)c4OC2C2CCC3(C1=O)C(CO)C2
Agent: [H-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCN1CCC23c4cccc(OC)c4OC2C2CCC3(C1=O)C(COC)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 9 g of 35% potassium hydride in oil, prewashed with hexane, and 40 mL of tetrahydrofuran was added 4.05 g of 5-hydroxymethyl-9-methoxy-3-n-propyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one. The mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 30 minutes. Methyl iodide (8 mL) was added to the cooled mixture which was then heated under reflux for one hour. Excess hydride was destroyed by addition of 10 mL of methanol, and the solvent was removed. The product was taken up in methylene chloride/water, and the aqueous layer was extracted with methylene chloride. Removal of the solvent gave 4.45 g of 9-methoxy-5-methoxymethyl-3-n-propyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one. NMR spectrum (δ in CDCl3); 6.8 (m, 2H); 6.5 (m, 1H); 4.5 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H) and 1.0 (t, 3H), among others.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C)C=O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:13][C:4]=1[Cl:3]
Reactant: Fc1ccccn1
Reactant: OCCOc1ccc(Cn2cccn2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Cn2cccn2)ccc1OCCOc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 24 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous N,N-dimethylformamide (5 ml) solution of 500 mg of 2-[2-chloro-4-(l-pyrazolyl)methylphenoxy]-ethanol (produced in Reference Production Example 3 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 250 mg of 2-fluoropyridine was added dropwise over 30 minutes. The mixture was then stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. After completion of the reaction, the reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 595 mg of 2-chloro-4-(1-pyrazolyl)methylphenyl 2-(2-pyridyloxy)ethyl ether (compound 8). Yield, 91%.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[CH:32]1([C:35]([CH:43]2[CH2:45][CH2:44]2)=[N:36][S@@:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])[CH2:34][CH2:33]1.C(O)(=O)C>O1CCCC1>[CH:43]1([C:35]([CH:32]2[CH2:34][CH2:33]2)([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)[NH:36][S@@:37]([C:39]([CH3:41])([CH3:42])[CH3:40])=[O:38])[CH2:45][CH2:44]1
Reactant: CC(C)(C)[S@@](=O)N=C(C1CC1)C1CC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(N[S@](=O)C(C)(C)C)(C3CC3)C3CC3)s2)c1
Reaction time: 0.67 h
Yield: 76.3 %

Procedure:
To a solution of lithium diisopropylamide (1.8 M, 2.12 mL, 3.81 mmol) in tetrahydrofuran (5 mL) at −78° C. was added a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 24, 564 mg, 1.68 mmol) in tetrahydrofuran (5 mL) over 8 minutes. After 40 minutes, a solution of (R)—N-(dicyclopropylmethylidene)-2-methylpropane-2-sulfinamide (0.325 g, 1.52 mmol) in tetrahydrofuran (4 mL) was added all at once. After 90 minutes, acetic acid (0.275 mL) was added and the reaction mixture was partitioned between ethyl acetate (45 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated and the organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the crude material using silica gel flash chromatography (ethyl acetate/hexanes) yielded (R)—N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-methylpropane-2-sulfinamide (638.6 mg, 1.16 mmol, 76% yield) as a yellow film. MS ESI: [M H] m/z 550.1.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[OH:24].[OH-].[K+].CS(C)=O>CC(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH:21]=[C:22]([Cl:25])[C:23](=[O:24])[C:18]([Cl:17])=[CH:19]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: Oc1c(Cl)cncc1Cl
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: O=c1c(Cl)cn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1Cl
Reaction time: 8 h
Yield: 79.6 %

Procedure:
First, 1.129 g of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 1.648 g of 3,5-dichloro-4-hydroxypyridine, and 672 mg of powdered potassium hydroxide were added to 10 ml of dry dimethylsulfoxide. The mixture was allowed to react at 130° C. for 3 hours in a nitrogen atmosphere. The subsequent processes were conducted in the same way as in Example 2. The resultant precipitate was dissolved by heating in dimethylformaldehyde and the solution was decolorized with activated carbon and filtered. Water in an equal amount was added thereto and the solution was allowed to stand overnight to give 1.473 g of crystals of 6-nitro-7-(3,5-dichloro-4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]F)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][C:9]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: CN(C=O)c1ccc2c(c1)[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc3c(c2)[nH]c2cc(N(C)C=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.7 %

Procedure:
To N-(7-hydroxy-9H-carbazol-2-yl)-N-methylformamide (45 mg, 0.187 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (172 mg, 0.38 mmol) in 0.5 mL NMP was added Cs2CO3 (65 mg, 0.2 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with water (2×50 mL), 0.5 M HCl (50 mL) and brine (50 mL), and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified with silica chromatography (hexane/EtOAc) to afford 2-(2-(2-(7-(N-methylformamido)-9H-carbazol-2-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (AD-CB-004 Pa-WZ01179) as a light-brown oil (48 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.45 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.80-7.77 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.17 (d, J=2.4 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H), 6.89 (dd, J=8.8, 2.4 Hz, 1H), 4.23 (m, 1H), 4.17 (m, 2H), 3.88 (m, 2H), 3.72-3.68 (m, 4H), 3.66-3.61 (m, 2H), 3.39 (s, 3H), 2.41 (s, 3H); MS (ESI) m/z 527 (M+H+).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].O=[CH:10][CH2:11][CH2:12][C:13]([O:15]CC(C)C)=O>>[O:8]=[C:5]1[CH2:6][N:7]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[N:4]1[CH2:2][CH3:3]
Reactant: CC(C)COC(=O)CCC=O
Reactant: CCNC(=O)CN
Agent: Cl
Product: CCN1C(=O)CN2C(=O)CCC12

Procedure:
Glycine ethylamide hydrochloride (2.1 g, 15.1 mmol) and isobutyl 4-oxobutanoate (2 g, 12.6 mmol) were reacted together according the procedure of Example 2 to give the title compound, 0.5 g (23.5%) as a viscous oil. Rf=0.51 (silica gel plates, eluent dichloromethane-methanol 9:1). NMR (CDCl3): deltaH =5.27 (t, J=6 Hz, 1H, N--CH--N); 4.20 and 3.45 (ABq, J=17 Hz, 2H, N--CH2 --CO); 3.25 (q, J=7 Hz, 2H, NCH2CH3); 2.70-1.75 (c.a., 4H, COCH2CH2CH); 1.12 (t, J=7 Hz, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=168 (M+), 112 (M-C3H4O)+, 97 (M-C4H7O)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.F[C:21](F)(F)[S:22](O[Si](C(C)(C)C)(C)C)(=[O:24])=[O:23].CS(Cl)(=O)=O>O1CCCC1>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
A solution of 4-amino-7-chloro-3-phenyl-2(1H)-quinolone (0.55 g, 2 mmol) (Example 2) and potassium (bistrimethylsilyl) amide (4 ml, 0.5M solution in toluene) in 50 ml tetrahydrofuran were stirred for 10 mins prior to the addition of tert-butyldimethylsilyl trifluoromethanesulfonate (6.1 ml). After a further 10 mins a further portion of potassium(bistrimethylsilyl)amide (6.1 ml) was added followed after 10 mins by methanesulfonyl chloride (0.48 ml). The solvent was removed in vacuo after one hour and the residue was suspended in 5N HCl (30 ml), and treated with ultrasound for 5 mins before being filtered. The solid was suspended in 1N NaOH and re-exposed to ultrasound then filtered to give the title compound (0.077 g); mp 222°-224° C. (DMF-water-diethyl ether); δ (360 MHz, DMSO-d6) 2.17 (3H, s, CH3), 7.34-7.67 (8H, m, aromatics), 9.60 (1H, br s, NHSO2), 12.16 (1H, br s, NHCO); m/z (EI) 348 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC(C)([O-])C.[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
4-Amino-3-nitrophenol (25 g, 162.2 mmol) was dissolved in DMF and cooled to 0° C. 1M potassium tert-butoxide (162.2 mL) was added dropwise over 20 min. After stirring 30 min at 0° C., benzyl bromide (19.8 mL, 162.2 mmol) in DMF was added dropwise. After 30 min at 0° C., the reaction was quenched with NH4Cl solution. 4-benzyloxy-2-nitroaniline (32 g, 131 mmol) was isolated by filtration. MS(CI, NH3) m/e 245 (M+1)+.