Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[F:19][C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:27]=1)[CH2:25]Br.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([CH:14]([CH2:25][C:24]3[CH:27]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=3[N+:28]([O-:30])=[O:29])[C:15]([O:17][CH3:18])=[O:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1CBr
Reactant: CCc1cc(-c2nc(CC(=O)OC)cs2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCc1cc(-c2nc(C(Cc3cc(F)ccc3[N+](=O)[O-])C(=O)OC)cs2)ccn1
Temperature: -78 °C

Procedure:
Methyl 2-[2-(2-ethyl-4-pyridyl)-1,3-thiazole-4-yl]acetate (520 mg, 2.0 mmol) (Example 12(a)) was dissolved in toluene and the solution was concentrated by rotary evaporation. This procedure was repeated, and the dry residue was dissolved in 18 mL anhydrous THF (18 mL). The solution was cooled to −78° C., and LHMDS (2.1 mL, 1.0 M in THF, Aldrich) was added slowly via a syringe. To the resulting red solution, 5-fluoro-2-nitrobenzyl bromide (400 mg, 1.7 mmol) was added as a solid in one portion. The reaction was warmed slowly to RT over 4 h. Saturated aqueous NH4Cl (50 mL) was added, and the mixture was extracted with 100 mL of EtOAc. The organic layer was separated, washed with H2O (100 mL), dried (Na2SO4), and concentrated. Flash chromatography (gradient elution: 10-40% EtOAc in hexanes) of the crude material afforded the title compound as a clear oil. MS m/z: 416 (M+1). Calc'd for C20H18FN3O4S: 415.10.
Reaction SMILES: N1([C:7]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:8])CCCCC1.Cl.[OH-:22].[K+]>>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]([OH:8])=[O:22])=[N:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: [OH-]
Reactant: O=C(c1ccc(N2CCOCC2)cn1)N1CCCCC1
Agent: Cl
Agent: [K+]
Product: O=C(O)c1ccc(N2CCOCC2)cn1
Yield: 71 %

Procedure:
25% KOH (100 mL) was added to 4-[6-(piperidin-1-ylcarbonyl)pyridin-3-yl]morpholine (18.3 g), and the mixture was refluxed and then neutralized with HCl. The solution was evaporated in vacuum, and the product was extracted with hot isopropanol to give the title compound (yield 71%, 11.5 g). +ESI MS (M+H) 209.7; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (br. s., 1H), 8.03 (d, 1H), 7.65 (dd, 1H), 3.75 (br. s., 4H), 3.40 (br. s., 4H).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C:2]1=2.C(O)(=O)C>[Pd].CO>[NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C@@H:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C@H:2]12
Reactant: O=C1CCC2=C(Cc3ccccc32)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CC[C@@H]2c3ccccc3C[C@@H]2N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (1.10 g), 10% palladium on carbon (0.15 g), acetic acid (0.75 mL), and methanol (20 mL) is shaken under hydrogen atmosphere (3 bar) at room temperature for 6 h. The catalyst is then separated by filtration and the filtrate is concentrated. The residue is triturated with tert-butyl methyl ether and dried to give the title compound as a colorless solid. Yield: 0.99 g (89% of theory); LC (method 1): tR=2.53 min; Mass spectrum (ESI+): m/z=188 [M+H]+.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>C(O)C>[OH:33][N:32]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)[CH2:22][CH2:23]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: NO
Reactant: Cc1cccc(N2CCN(CCCCc3ccc(C(=O)CCC(=O)O)cc3)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(N2CCN(CCCCc3ccc(C(CCC(=O)O)=NO)cc3)CC2)c1
Yield: 66.8 %

Procedure:
To 14 g of 4-oxo-4-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid, 200 ml of ethanol is added. To this mixture, 3.1 g of hydroxylamine hydrochloride and 4.0 g of sodium hydrogencarbonate are further added, and this is followed by reflux with heating for 6 hours under stirring the mixture. After the completion of the reaction, the solvent is distilled off under reduced pressure. To this residue, water is added, and the crystals precipitated are collected by filtration to give 9.7 g of 4-hydroxyimino-4-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl ]butyric acid having a melting point of 175° to 177° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[C:9]2=[O:12])=[CH:4][CH:3]=1.CI.[CH3:21]C(C)([O-])C.[K+]>[Cl-].[Na+].O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:21])[CH2:14][CH2:13]3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1c2cc(Br)ccc2CCC12CCC(O)CC2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC1CCC2(CCc3ccc(Br)cc3C2=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
7′-Bromo-4-hydroxy-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-naphthalen]-1′-one (Intermediate 8, 1.78 g, 5.76 mmol) was dissolved in 2-methyl THF (15 mL) under an inert atmosphere and the solution was cooled to 0° C. Methyl iodide (0.720 mL, 11.5 mmol) was added followed by portion wise addition of potassium tert-butoxide (1.29 g, 11.5 mmol). The resulting mixture was stirred at r.t. overnight. Potassium tert-butoxide (0.323 g, 2.88 mmol) and methyl iodide (0.717 mL, 11.5 mmol) were added. The mixture was stirred for 1.5 h. Potassium tert-butoxide (0.194 g, 1.73 mmol) was added and the mixture was stirred for an additional 2 h. Brine was added and the phases were separated. The aqueous phase was extracted with EtOAc and to the combined organics were added activated charcoal. The mixture was filtered through a pad of diatomaceous earth and rinsed with EtOAc. The organic phase was concentrated in vacuo to give the title compound (1.41 g, 76% yield): MS (ES+) m/z 323 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].Cl[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:22])([CH3:21])[C:19]#[CH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:22][C:18]([CH3:21])([C:19]#[CH:20])[CH2:17][CH2:16][CH2:15][CH2:14][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: C#CC(C)(O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CC(C)(O)CCCCn1cnc2c1c(=O)[nH]c(=O)n2C

Procedure:
33.2 g (0.2 mol) of 3-methylxanthine in 350 ml of dimethylformamide were stirred with 32.1 g (0.2 mol) of 1-chloro-5-hydroxy-5-methyl-6-heptyne from Example 1B1) in the presence of 13.8 g (0.1 mol) of potassium carbonate at 120° C. for 6 hours. The hot mixture was then filtered, evaporated to dryness under reduced pressure and taken up in ethanol and, at the boiling point, diisopropyl ether was added to cloudiness, and the mixture was left to crystallize with cooling.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12]C(=O)[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:30](=[O:32])[CH3:31])[C:27](=[O:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][NH:10][CH:14]([CH3:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]3[O:22][C:26]([C:30](=[O:32])[CH3:31])([C:27](=[O:29])[CH3:28])[O:23][C:18]=3[CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(Br)(Br)C(C)=O
Reactant: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)C1(C(C)=O)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
One equivalent of 5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727, Example 1, is combined with 1.1 equivalents of 3,3-dibromo-2,4-pentanedione and 2.2 equivalents of powdered potassium carbonate in acetonitrile. The reaction mixture is stirred at room temperature for 48 hours, evaporated in vacuo and partitioned between methylene chloride and water. The organic layer is dried, filtered and evaporated in vacuo to give 5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,2-diacetyl-1,3-benzodioxole.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:15]=[N:14][C:13]=1[O:24]C)[CH3:2].C(#N)C.O.C(O)=O>C(O)C.[OH-].[Na+]>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[C:13](=[O:24])[NH:14][N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:17]=1)[CH3:2]
Reactant: CCc1c(-c2cc(-c3ccncc3)nnc2OC)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CCO
Product: CCc1c(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]c2ccccc12
Temperature: 150 °C

Procedure:
60 mg 3-Ethyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole is dissolved in 0.5 ml ethanol and 0.5 ml 1N aqueous NaOH solution. The reaction mixture is stirred at 150° C. in microwave apparatus (200 W). The reaction mixture is directly applied to HPLC chromatography to isolate the product (RP18 column, acetonitrile/water, 0.05% HCOOH)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH3:16]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCO
Reactant: O=C(O)Cc1n[nH]c2ccc(F)cc12
Product: CCOC(=O)Cc1n[nH]c2ccc(F)cc12
Yield: 37.4 %

Procedure:
2-(5-Fluoro-1H-indazol-3-yl)acetic acid (1.12 g, 5.77 mmol) was dissolved in anhydrous ethanol (50 mL) concentrated sulfuric acid (1.5 mL), and heated under reflux for 16 hours. After concentrated under reduce pressure to remove most of ethanol, water (20 mL) was added, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the product 0.48 g, at a yield of 37.4%.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([S:13][C:14]2[CH:15]=[C:16]3[C:24]([NH:25][C:26](=[O:47])[C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)=[CH:29][C:28]=4[NH:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[N:23][NH:22][C:17]3=[N:18][C:19]=2[O:20]C)[CH:9]=[C:10]([F:12])[CH:11]=1.CO>ClCCl.ClCCCl>[F:5][C:6]1[CH:7]=[C:8]([S:13][C:14]2[CH:15]=[C:16]3[C:24]([NH:25][C:26](=[O:47])[C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)=[CH:29][C:28]=4[NH:40][CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)=[N:23][NH:22][C:17]3=[N:18][C:19]=2[OH:20])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: COc1nc2[nH]nc(NC(=O)c3ccc(N4CCN(C)CC4)cc3NC3CCOCC3)c2cc1Sc1cc(F)cc(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: ClCCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4nc(O)c(Sc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
443 μl (3 eq) of a solution of 1 M boron tribromide in dichloromethane is added to a solution of 90 mg (0.148 mmol) of N-(5-(3,5-difluorophenylthio)-6-methoxy-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (example 18) in 4 ml of 1,2-dichloroethane at 0° C. The reaction medium is stirred at 60° C. for 3 hours and then cooled in an ice bath before adding methanol. The solvents are evaporated and the residue is redissolved in a mixture of methanol and ethyl acetate. The solid formed is filtered, redissolved in 3 ml of tetrahydrofuran and is added to 1 N soda solution. The reaction medium is stirred for 18 hours at room temperature. The pH of the solution is adjusted to 8-9 and the aqueous phase is extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and the crude product is purified on a silica gel column (dichloromethane/methanol as eluent) to yield 21 mg (24%) of N-(5-(3,5-difluorophenylthio)-6-hydroxy-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[CH2:20]([O:22][CH:23]([O:31][CH2:32][CH3:33])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1)[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:32]([O:31][CH:23]([O:22][CH2:20][CH3:21])[C:24]1[S:28][C:27]([CH2:29][N:8]2[S:7](=[O:13])(=[O:12])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:10](=[O:11])[CH2:9]2)=[CH:26][CH:25]=1)[CH3:33]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: CCOC(OCC)c1ccc(CO)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(CN2CC(=O)N(Cc3ccc(OC)cc3OC)S2(=O)=O)s1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (13.9 g, 48.5 mmol), (5-diethoxymethyl-thiophen-2-yl)-methanol (10.5 g, 48.5 mmol) and triphenylphosphine (19.1 g, 72.2 mmol) are dissolved in dry THF (300 mL) and the mixture is cooled to 0° C. Diethyl azodicarboxylate (12. g, 72.7 mmol) is added dropwise over 3 min and the mixture is stirred at RT for 16 h. The solvent is evaporated and the residue is taken up in Et2O (100 mL). The solution is cooled to 0° C. and the precipitate is filtered and discarded. The filtrate is concentrated to dryness and the residue is chromatographed on silica gel using 0→100% EtOAc in hexane as the eluent to afford 5-(5-diethoxymethyl-thiophen-2-ylmethyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as an orange oil.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[Br:17][C:18]1[C:26]([CH3:27])=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[CH3:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:22](=[O:23])[C:21]1[CH:25]=[C:26]([CH3:27])[C:18]([Br:17])=[C:19]([CH3:28])[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)cc(C)c1Br
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C(=O)OC(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 25 h
Yield: 69.5 %

Procedure:
Dehydrated tert-butanol (0.19 ml, 2.0 mmol), 4-dimethylaminopyridine (81 mg, 0.67 mmol) and EDCI (255 mg, 1.33 mmol) were added to a solution of 4-bromo-3,5-dimethyl-benzoic acid (123 mg, 0.535 mmol) in dichloromethane (1.0 ml) at 0° C., and the mixture was stirred at room temperature for 25 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/1→50/1) to give 4-bromo-3,5-dimethyl-benzoic acid tert-butyl ester (106 mg, 70%).
Reaction SMILES: [OH:1][CH:2]([CH2:12][OH:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:14][S:15][CH2:16][C:17](Cl)=O>[OH-].[Na+].CO>[CH3:14][S:15][CH2:16][CH2:17][O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: OCC(O)COc1ccc(O)cc1
Reactant: CSCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCCOc1ccc(OCC(O)CO)cc1
Yield: 87.2 %

Procedure:
A 1.84 g quantity of 4-(2,3-dihydroxypropoxy)phenol was dissolved in 0.40 g of sodium hydroxide and 10 ml of 90% methanol. To the solution was added 1.11 g of 2-methylmercaptoacetyl chloride, and the mixture was refluxed for 6 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The chloroform layer was washed with water, dewatered with Glauber's salt and concentrated. The residue was recrystallized from benzene-petroleum ether, giving 2.25 g of 2-{4-(2,3-dihydroxypropoxy)phenoxy}ethyl methyl sulfide in 87.2% yield, M.P. 59° to 61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=CC=CC=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.[CH:45]([NH2:48])([CH3:47])[CH3:46]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][NH:48][CH:45]([CH3:47])[CH3:46])=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:3][CH:2]=[CH:44][CH:43]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:30])=[O:31])=[N:7]1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Solvent: C1CCOC1
Product: CC(C)NCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 200.1 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.339 g, 0.524 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 2 hours. Isopropylamine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80° C. in a sealed tube for 2 hours. Isopropylamine (1.0 mL, 12 mmol) was added to the reaction mixture, and it was stirred at 80° C. in a sealed tube for 30 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. It was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo for 20 minutes at 80° C. to give {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-isopropyl-amine as a yellow solid (0.280 g, 100%). It was dissolved in chloroform, and ethereal hydrochloride was added. The resulting solid was filtered and dried at 82° C. in vacuo for 14 hours. The result was the hydrochloride as a pale yellow solid (0.236 g): MP: 206-8° C.; Mass Spectrum (+EI, [M+H]+) m/z 534. 1HNMR (500 MHz, DMSO-d6): δ8.65-8.76 (m, 3H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.17 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.27 Hz), 7.72 (dd, 1H, J=8.07 Hz and 7.57 Hz), 7.57-7.63 (m, 2H), 7.24-7.28 (m, 2H), 7.16-7.21 (m, 3H), 7.05 (d, 1H, J=7.81 Hz), 5.73 (s, 2H), 4.27 (t, 2H, J=5.00 Hz), 3.31-3.37 (m, 3H), 1.23 ppm (d, 6H, J=6.69 Hz). Elemental Analysis for C29H28ClN3O3S.1.00 HCl: Calcd: C, 61.05; H, 5.12; N, 7.36; Found: C, 60.68; H, 5.26; N, 7.14.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: COc1cc2c(c(-c3c(C)cccc3C)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.076 g, 57%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.175 g, 0.40 mmol) and methylamine (0.12 g, 4.0 mmol). mp 170-172° C.
Reaction SMILES: [CH2:1]1[O:12][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=2)[O:3][CH2:2]1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(OCC)(=O)C>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]3[O:3][CH2:2][CH2:1][O:12]3)[CH:6]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Nc1cccc(C2OCCO2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
A solution of 3-aminobenzaldehyde ethylene acetal (10 g, 60.5 mmol) and TEA (7.35 g, 72.6 mmol) in ethyl acetate (100 mL) at 0° C. is treated dropwise with 4-chlorobenzoyl chloride (9.44 mL, 72.6 mmol) during 30 min. The reaction mixture is stirred at RT for 3 h before dilution with EtOAc. The medium is washed twice with sat. aq. NaHCO3 (100 mL) and once with brine (100 mL). The organic layer is dried over MgSO4, filtered and evaporated. The residual oil is triturated with ethyl acetate and the resulting crystalline material is filtered to give the title compound (14.33 g, 78%) as a slightly pink solid; LC-MS B: tR=0.86 min; [M+H]+=304.03.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19](O)=[O:20])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:47][C:48]([NH:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:44]([O:43][CH:39]([O:40][CH2:41][CH3:42])[C@@H:38]([N:26]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:20])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH2:47][C:48](=[O:49])[NH:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[CH3:46])[CH3:45]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 67 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][CH:8]2[CH2:12][O:11][S:10](=[O:13])[N:9]2[CH:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1.O.C([O-])(O)=[O:29].[Na+].C(Cl)Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:12][O:11][S:10](=[O:29])(=[O:13])[N:9]2[CH:14]([CH:22]([CH3:23])[CH3:24])[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[CH:25][CH:26]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(CC2COS(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(CC2COS(=O)(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
t-Butyl 2-(4-(4-methoxybenzyl)-2-oxo-(1,2,3) oxathiazolidin-3-yl)-3-methylbutyrate (2.2 g; 5.7 mmol) was dissolved in acetonitrile (15 ml) and the reaction solution was cooled to 0° C. Then NaIO4 (1.47 g; 6.8 mmol), RuCl3.H2O (128.5 mg; 0.57 mmol) and water (15 ml) were added. The reaction solution was stirred at 0° C. for 5 minutes and then at RT for 30 minutes. This was followed by addition of NaHCO3 solution, extraction with CH2Cl2 (3×) and drying of the organic phase over NaSO4 and concentration in a rotary evaporator. The crude product was filtered through an SiO2 cartridge (10 g). t-Butyl 2-(4-(4-methoxybenzyl)-2,2-dioxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbutyrate (2.02 g; 5.0 mmol) was obtained as a yellow oil. MS: 417.45 (M+NH4+); Rt: 1.86 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)