Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(N(CC)CC)C.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[O:11][CH3:12])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 41.1 %

Procedure:
To a stirred solution of 0.406 g of 4-chloro-2-methoxybenzoyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. An additional 0.406 g of 4-chloro-2-methoxybenzoyl chloride and 0.346 g of triethylamine is added and stirring is continued for 2 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2SO4 filtered and evaporated in vacuo to give a residue which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.320 g of the desired product as a white crystals, m.p. 222°-224 ° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([C:11]1[S:10][C:9]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:24]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Product: COc1cccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)c1
Yield: 82 %

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and 3-methoxybenzoyl chloride were converted to the title compound by the procedure of Example 1 in 82% yield, after crystallization from methanol.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][N:22]([S:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH2:21][CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4cccs4)CC3)c[nH]c12

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.12 mmol), 2-thiophenesulfonyl chloride (23 mg, 0.13 mmol) and triethylamine (0.07 mL, 0.5 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (30 mg, 52%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)(O)[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)C>CO>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:13]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[O:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(C2(O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3OCC2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCO
Product: COc1ccc(C2C(c3ccc(O)cc3)=COc3cc(O)ccc32)cc1
Reaction time: 8 h

Procedure:
7-(tert-Butyldimethylsilyloxy)-3-(4 (tert-butyldimethylsilyloxy)phenyl)-4-(4-methoxyphenyl)chroman-4-ol (42 g), pTsOH (435 g), boiling chips and 2.5 L of ethanol win, combined in a 2-neck SL round bottom flask with condenser attached. The reaction was heated at reflux for 3 hours. The solvent was concentrated in vacuo to ˜1000 ml before being poured into chilled, stirred water (700 ml). The mixture was then extracted with ethyl acetate, the combined organic layers washed with water (3×2 L) brine (1×500 ml), dried over anhydrous magnesium sulphate and filtered and solvent removed in vacuo to give red/brown oil. The oil was dissolved in methanol (˜100 ml) ad put in freezer overnight.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C#N)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2C#N)CC1
Reaction time: 15 h

Procedure:
To a solution of 2-[1-tert-butoxycarbonyl-(1,2,3,6-tetrahydropyridin-4-yl)]benzonitrile (5.3 g, 0.019 mol) and acetic acid (0.28 ml, 4.9 mmol) in ethanol (200 ml), degassed with argon was added palladium on carbon. The reaction was hydrogenated on a Parr apparatus at 50 psi for 15 hours. The mixture was recharged twice with acetic acid (0.14 ml, 0.28 ml) and palladium on carbon (900 mg, 1.8 g), hydrogenated as above and filtered through celite. Solvent evaporation gave 2-(1-tert-butoxycarbonylpiperidin-4-yl)benzonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH:7]([CH3:19])[C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])OCC[O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:19][CH:7]([C:2](=[O:3])[CH3:1])[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9]
Reactant: CC(C(=O)NCCc1ccccc1)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
2-(2-Methyl-[1,3]dioxolan-2-yl)-N-phenethyl-propionamide of Example 1c (0.40 g, 1.5 mmol) was added to p-toluenesulfonic acid monohydrate (0.48 g, 2.5 mmol) in water (20 mmol) under a nitrogen atmosphere at room temperature. Acetone (20 mL) was added, and the reaction mixture was stirred overnight at room temperature and then heated at 95° C. for 3 h. After cooling to room temperature, the solution was made basic with sodium carbonate (0.5 g). The acetone was removed at room temperature under vacuum and the remaining aqueous material was extracted with dichloromethane (50 mL). The organic layer was washed with water (50 mL), brine (50 mL) and then dried with sodium sulfate. After concentration, the product was purified by crystallization from hexanes-ethyl acetate (1:1) to give 2-methyl-3-oxo-N-phenethyl-butyramide (0.17 g, 52%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH3:36][NH2:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Reactant: CN
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CCC1

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268g) and methylamine using a similar method to that described for example 167f.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>O1CCCC1>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1cccc(O)c1
Reaction time: 3 h

Procedure:
3′-Hydroxyacetophenone (5.0 g) was dissolved in tetrahydrofuran (100 ml), and the solution was added dropwise with a 1 M solution of phenylmagnesium bromide in tetrahydrofuran (100 ml) at −30° C. Then mixture was further added with tetrahydrofuran (100 ml), and the mixture was stirred for 3 hours with gradually warming it. The mixture was added with saturated aqueous ammonium chloride under ice cooling, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain the title compound (7.55 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH3:57])=[CH:51][CH:50]=2)=[CH:4][C:5]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.CCN(CC)CC.[Br:65]Br.[NH4+].[Cl-]>CC(O)=O>[Br:65][C:7]1[C:2]([Cl:1])=[C:3]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:56][CH3:57])=[CH:53][CH:54]=2)[CH:4]=[C:5]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)[C:6]=1[OH:8]
Reactant: BrBr
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of phenol 27 (0.98 g, 1.24 mmol) in AcOH (12 mL) were added Et3N (0.37 mL, 1.86 mmol) and bromine (77 μL, 1.50 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min and at room temperature for 12 hours. The reaction mixture was cooled to 0° C. and aqueous saturated NH4Cl solution (30 mL) was added to the mixture. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with H2O (50 mL×2), aqueous saturated NaHCO3 solution (100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude 2-bromo-3-chloro-4-(4-ethoxybenzyl)-6-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenol (28, 1.08 g) was carried on to the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[N:3]1[CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.[N:30]1([O:39][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON.Cl.CN1CCOCC1>CN(C=O)C>[O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[N:3]1[CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH:30][OH:39])=[O:18]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(CCc2ccccc2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)NO)N1C(=O)NC(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of the compound obtained in step e above (109 mg, 0.36 mmol) in DMF (1.8 mL) was added BOP (190 mg, 0.43 mmol) at 0° C. After stirring for 30 min, HONH2×HCl (50 mg, 11.38 mmol) and N-methylmorpholine (0.16 mL, 1.44 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The solvent was removed and the residue was partitioned between EtOAc and a saturated solution of NH4Cl. The aqueous layer was extracted with EtOAc, dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (63 mg, 55% yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:10]2[S:11][C:12]([CH2:14][OH:15])=[CH:13][C:9]=2[CH:8]=1)C>C(O)C.Cl.O>[Cl:18][C:17]1[C:7]([O:6][CH2:5][C:4]([OH:20])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][OH:15])[S:11][C:10]=2[C:16]=1[Cl:19]
Reactant: CCOC(=O)COc1cc2cc(CO)sc2c(Cl)c1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cc2cc(CO)sc2c(Cl)c1Cl
Yield: 9 %

Procedure:
A suspension of 6.05 g of ethyl[(6,7-dichloro-2-hydroxymethylbenzo[b]thien-5-yl)oxy]acetate in 40 ml of 95% ethanol and 56 ml of 3N hydrochloric acid is stirred under reflux for 1 hr. The cooled mixture is diluted with 200 ml of water and made acidic with concentrated hydrochloric acid until pH=2. The precipitate is extracted into ethyl acetate (3×200 ml) and the combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Recrystallization of the residue from acetone-hexane gives 0.5 g of [(6,7-dichloro-2-hydroxymethylbenzo[b]thien-5-yl)oxy]acetic acid, mp 187.5°-118.5°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:21])[CH:15]=[C:16]([NH2:20])[O:17][CH2:18][CH3:19]>C(O)(C)C>[CH3:12][O:13][C:14]([C:15]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:15]([C:14]([O:13][CH3:12])=[O:21])[C:16]([O:17][CH2:18][CH3:19])=[N:20][C:16]=1[NH2:20])=[O:21]
Reactant: CCOC(N)=CC(=O)OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: CCOC1=NC(N)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C1C(=O)OC
Yield: 71 %

Procedure:
Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde and 14.5 g of 3-amino-3-ethoxyacrylic acid methyl ester in 40 ml of alcohol for 6 hours, 2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid dimethyl ester of melting point 163° C (isopropanol) is obtained. Yield: 71% of theory.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1(C)C=CC=CC=1>[S:14]([O:5][CH2:4][C@H:2]1[O:3][CH2:1]1)([CH3:13])(=[O:16])=[O:15]
Reactant: OC[C@@H]1CO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC[C@@H]1CO1
Temperature: 0 °C
Yield: 80 %

Procedure:
To an ice-cooled solution of (R)-glycidol (5.0 g, 0.068 m) and triethylamine (8.1 g, 0.080 m) in toluene (100 ml) was added, over 15 minutes, methanesulfonyl chloride (8.0 g, 0.070 ml) in toluene (25 ml). Stirring was continued with cooling for 1 hour. The solution was filtered and concentrated to give an 80-85% yield of the crude (S)-3-mesyloxy-1,2-epoxypropane; this material could be used without further purification. Distillation gave 7 (61%); bp 92°-95° C./0.1 mm; [α]D22 =23.7° (c=5.16, CH3OH); 1H NMR (CDCl3) 4.5 (1H, d of d, J=12, J=3), 4.1 (1H, d of d, J=12, J=6), 3.3 (1H, m), 3.1 (3H, s), 2.8 (2H, m).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N)=[O:17])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[CH3:30][OH:31]>>[ClH:1].[OH:2][C@H:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:31][CH3:30])=[O:17])=[CH:11][CH:10]=1
Reactant: NC(=O)Cc1ccc(OCCNC[C@H](O)c2ccccc2)cc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OCCNC[C@H](O)c2ccccc2)cc1

Procedure:
(R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (0.45 g) was heated under reflux in methanol (20 ml) containing concentrated sulphuric acid (0.5 ml) for 18 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was dissolved in dichloromethane (30 ml) and washed successively with water (20 ml), 5% NaHCO3 solution (50 ml) and water (20 ml), dried over MgSO4 and then the solvent was removed under reduced pressure. The residue was dissolved in methyl acetate (20 ml) and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallized from a mixture of methanol and methyl acetate to give (R)-methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetate hydrochloride (0.25 g), m.p. 181°-183° C.; microanalysis: found, C, 62.6; H, 6.6; N, 3.8; Cl, 9.9%; required for C19H24ClNO4 : C, 62.4; H, 6.6; N, 3.8; Cl, 9.7%; [α]25D =-25.3° (c=0.99 in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:32])([F:34])[F:33]
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(C(=O)c2ccccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 4-chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (260 mg, 0.49 mmol) in 4M HCl in dioxane (5 mL) and water (1 mL) was refluxed for 3 h. Reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by flash chromatography (SiO2, 70% EtOAc-hexanes) to afford 4-chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (106 mg) as a white solid (after lyophilization) in 45% yield. ESMS m/z (relative intensity): 489 (M+H)+ (100).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:15]=2)=[CH:7][C:6]=1[N+:29]([O-])=[O:30].O.O.Cl[Sn]Cl.O>CCOC(C)=O>[OH:30][N:29]1[C:6]2[C:5](=[N:10][CH:9]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]4)[CH:15]=3)[CH:7]=2)[CH:4]=[CH:3]1
Reactant: CN(C)/C=C/c1ncc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Yield: 54 %

Procedure:
tert-butyl 4-(4-{6-[(E)-2-(dimethylamino)ethenyl]-5-nitropyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (366 mg, 0.81 mmol) and SnCl2.2H2O (966 mg, 4.26 mmol, 5.0 eq) in 3 ml of EtOAc were stirred at r.t. for 2 hours. EtOAc and water were added and layers were separated. The aqueous layer was extracted with EtOAc, washed with sat. NH4Cl and brine. After evaporation, the crude product was chromatographed (Mesh/DCM 1:20) to give a yellow solid, 170 mg, in 54% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: COc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Yield: 95 %

Procedure:
The title compound was prepared from 4-methoxy-benzene sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 95%; mp 124-126° C.; 1H NMR (CDCl3) δ 7.90-7.93 (dd, J=8 Hz, 1H), 7.74 (d, J=9 Hz, 2H), 7.43-7.49 (m, 2H), 7.14-7.27 (m, 2H), 6.79 (d, J=9 Hz, 2H), 6.56-6.58 (dd, J=4 Hz, 1H), 3.41 (s, 3H); 13C NMR (CDCl3) δ 164.1, 135.2, 131.2, 130.1, 129.5, 126.7, 124.9, 123.6, 121.8, 114.8, 113.9, 109.3, 56.0; MS (AP+) m/z288.05 (M++1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(CCO)CC3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A suspension of 2.81 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 5.2 g of N-(2-hydroxyethyl)-piperazine in 25 ml of dimethylsulphoxide is heated at 135°-140° C. for 2 hours. The solvent is distilled off under a fine vacuum, the residue is boiled up with 20 ml of water, the mixture is left to stand overnight at room temperature and the precipitate is filtered off with suction, while cooling with ice, washed with water and dried over calcium chloride in vacuo at 80° C. 2.1 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2-hydroxyethyl)-1-piperazinyl]-3-quinolinecarboxylic acid of decomposition point 237°-239° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26](Br)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ncc2cc(Br)sc2c1O
Product: CCOC(=O)c1ncc2cc(-c3ccc(C(F)(F)F)cc3)sc2c1O

Procedure:
The title compound was prepared from 4-(trifluoromethyl)phenyl boronic acid and 2-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester, example 21.d, under conditions analogous to experimental example 21.e; MS: (+) m/z 367.9 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:10]([NH2:13])[NH:11][N:12]=1.[Na].C([O:24][C:25](=O)[C:26]([CH3:29])=[CH:27]O)C.C(OCC)C>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:12][N:11]3[C:25]([OH:24])=[C:26]([CH3:29])[CH:27]=[N:13][C:10]=23)=[CH:19][CH:18]=1
Reactant: Nc1[nH]nc(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)=CO
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1O
Temperature: 100 °C
Yield: 29.5 %

Procedure:
To a mixture of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-1b; 393 mg, 1.29 mmol) in acetic acid (4.3 ml) was added 3-hydroxy-2-methylacrylic acid ethyl ester sodium salt (590 mg, 3.88 mmol), portionwise. The reaction was heated at 100° C. for 2 hours (precipitate formed after 35 minutes). After cooling to room temperature, the precipitated solid was isolated by vacuum filtration and then repulped from diethyl ether to afford I-3A-1c as a colorless solid (141 mg, 30%): +ESI MS (M+1) 370.0; 1H NMR (400 MHz, DMSO-d6) δ 12.14 (br s, 1H), 7.75 (s, 1H), 7.50–7.38 (m, 4H), 7.32 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 2.01 (s, 3H).