Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][C:6]([CH3:9])(O)[CH3:7])[CH3:3].[ClH:11].O.C(Cl)[Cl:14]>>[Cl:11][C:2]([CH3:3])([CH2:4][CH2:5][C:6]([Cl:14])([CH3:9])[CH3:7])[CH3:1]
Reactant: CC(C)(O)CCC(C)(C)O
Reactant: Cl
Reactant: ClCCl
Solvent: O
Product: CC(C)(Cl)CCC(C)(C)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To 2,5-dimethyl-2,5-hexanediol (10 g, 68.5 mmol) in a 500 mL flask was added reagent grade concentrated HCl (150 mL) and the solution was stirred at ambient temperature for 1 h. Water (100 mL) and CH2Cl2 (100 mL) were then added slowly and the layers were separated. The aqueous layer was washed with additional CH2Cl2 (100 mL). The combined organic layers were dried over MgSO4 and filtered thru silica gel pad. The solvent was removed to yield 10.9 g (87%) of 2,5-dichloro-2,5-dimethylhexane. The dichloride was dissolved in 150 mL of CH2Cl2 and 9.6 mL of toluene (90 mmol) was added. AlCl3 (390 mg, 2.9 mol) was added in portions over 5 min at ambient temperature. HCl is evolved and the solution tums dark red. The reaction was placed in an ice-bath and quenched with deionized water (120 mL). Hexane (150 mL) was added and the organic layer was removed. The aqueous layer was washed with additional hexane (150 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL) and dried over MgSO4. The solvent was removed in vacuo to give 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene as a colorless oil that crystallized after storage at −20° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@H:29]1[CH2:32][C@@H:31]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:35]([O:34][CH2:33][C@H:31]1[CH2:32][C@H:29]([N:16]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]3[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)=[N:15]2)[CH2:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](COCc2ccccc2)C1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](COCc2ccccc2)C1

Procedure:
A solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.452 g, 0.00149 mol) in N,N-dimethylformamide (10 mL) was reacted with cis 3-[(benzyloxy)methyl]cyclobutyl methanesulfonate (0.483 g, 0.00179 mol) and cesium carbonate (0.582 g, 0.00179 mol) at 70° C. for two days. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.325 g, 0.000681 mol) as a tan solid.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH2:34][O:35][CH3:36])(=[O:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>ClCCl.O1CCOCC1>[CH3:36][O:35][CH2:34][CH2:33][S:30]([N:27]1[CH2:26][CH2:25][N:24]([C:21]2[CH:20]=[CH:19][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[CH:23][CH:22]=2)[CH2:29][CH2:28]1)(=[O:32])=[O:31]
Reactant: COCCS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCS(=O)(=O)N1CCN(c2ccc(N3CCNc4ccccc43)cc2)CC1
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
0.35 g of 4-{4-[4-(2-methoxyethanesulphonyl)piperazin-1-yl]phenyl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in 7 ml of dichloromethane. 2.5 ml of a 4N solution of HCl in dioxane are slowly added at 0° C. The mixture is stirred for 5 minutes under cold conditions and then the mixture is allowed to return to ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h and is then diluted with dichloromethane. A saturated aqueous sodium hydrogencarbonate solution is added until a pH=7-8 is reached. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulphate, filtered through a sintered glass filter and concentrated under reduced pressure. 0.246 g of 1-{4-[4-(2-methoxyethanesulphonyl)piperazin-1-yl]phenyl}-1,2,3,4-tetrahydro-quinoxaline is obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH2:15]3)=[O:10])[NH2:8])=[CH:4][CH:3]=1.O=[CH:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([NH:8][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])[CH2:15]3)=[O:10])=[CH:33][CH:34]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@H](N)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
0.24 g of the N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea endo compound, obtained in step 1.5, is dissolved in 5 ml of dichloromethane under N2 in the presence of 0.10 g of tert-butyl N-(2-oxoethyl)carbamate and of 0.22 g of sodium triacetoxyborohydride. The reaction medium is stirred at ambient temperature for 16 h. After evaporation to dryness, 0.05 g of tert-butyl N-(2-oxoethyl)carbamate and 0.1 g of sodium triacetoxyborohydride are added, and stirring is maintained for 3 days. After the addition of 1 ml of methanol and 4 g of Dowex® 50X2 resin, the mixture is stirred for 1 h 30 min. After filtration and washing of the resin with tetrahydrofuran and methanol, the expected compound is released by adding a 1N solution of aqueous ammonia in methanol. The methanol is evaporated off, to give 0.14 g of tert-butyl (2-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}ethyl)carbamate.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:24])[N:4]([CH2:20][CH2:21][CH2:22][CH3:23])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[C:25](Cl)(=O)[O:26]C1C=CC=CC=1.O.[CH:36]([C:39]1[CH:45]=[C:44]([O:46]C(=O)C2C=CC=C(Cl)C=2)[CH:43]=[C:42]([CH:56]([CH3:58])[CH3:57])[C:40]=1[NH2:41])([CH3:38])[CH3:37]>O1CCCC1.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:20]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:2]([NH:1][C:25]([NH:41][C:40]2[C:42]([CH:56]([CH3:57])[CH3:58])=[CH:43][C:44]([OH:46])=[CH:45][C:39]=2[CH:36]([CH3:37])[CH3:38])=[O:26])[C:3]1=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCn1c(=O)c(N)c(-c2cccc(OC)c2)c2cccnc21
Reactant: CC(C)c1cc(OC(=O)c2cccc(Cl)c2)cc(C(C)C)c1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(O)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 45 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of 3-amino-1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine (2.14 g, 6.63 mmol) in tetrahydrofuran (20 ml) is added phenyl chlorocarbonate (1.66 ml, 13.2 mmol), and the mixture is stirred at 40-50° C. for 3 hours. After allowed to cool, water is added to the mixture, and the mixture is extracted with ethyl acetate. The extract is washed with a 5% aqueous brine, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in dimethylformamide (30 ml), and thereto are added dropwise successively a solution of 2,6-diisopropyl-4-(3-chlorobenzoyloxy)aniline (2.0 g, 6.03 mmol) in dimethylformamide (5 ml), and a solution of 4-dimethylaminopyridine (0.74 g, 12 mmol) in dimethylformamide (5 ml) at room temperature. The mixture is stirred at room temperature for 8 hours, and to the reaction solution is added water. The mixture is extracted with ethyl acetate. The extract is washed successively with an aqueous ammonium chloride solution, an aqueous sodium hydrogen carbonate solution, and a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (ethyl acetate:hexane=1:5→ethyl acetate:hexane=1:2) to give the title compound (2.1 g, 3.35 mmol) as amorphous.
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7]C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C.Br>C(O)(=O)C>[CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:7]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N[C@H]1CCC[C@]1(C)Nc1cnc(C(F)(F)F)cn1
Agent: Br
Solvent: CC(=O)O
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Temperature: 90 °C

Procedure:
To a solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (1.03 g, 2.33 mmol) in acetic acid (8 ml) was added HBr (6M, 1.94 ml, 11.64 mmol). The reaction was sealed and heated to 90° C. for 20 hours. To this was added further HBr (6M, 1.00 ml, 6.00 mmol) and the reaction was heated at 90° C. for 36 hours and was then concentrated in vacuo. The crude product was purified by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11]([Cu])#[N:12].CN1C(=O)CCC1>O>[NH2:6][C:5]1[C:7]([F:9])=[CH:8][C:2]([C:11]#[N:12])=[CH:3][C:4]=1[F:10]
Reactant: N#C[Cu]
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(N)c(F)c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline, 223 g (2.5 mol) of CuCN and 800 cm3 of NMP were refluxed for 1.5 hours on a mantle heater. The reaction solution was cooled to room temperature, and after adding 300 cm3 of EDA, it was poured into 2,000 cm3 of water, extracted with hexane, and washed with an aqueous EDA solution and ice. The hexane was removed, and the residue was distilled under reduced pressure (b. p. 143° C./6mmHg) to obtain 108 g (0.7 mol) of 4-amino-3,5-difluorobenzonitrile.
Reaction SMILES: N1C=CN=[CH:2]1.[C:6]([SiH:10](Cl)[CH3:11])([CH3:9])([CH3:8])[CH3:7].[CH:13]1([NH:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH:13]1([NH:18][O:19][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:11])[CH3:2])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: c1c[nH]cn1
Reactant: ONC1CCCC1
Reactant: C[SiH](Cl)C(C)(C)C
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)ONC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
Imidazole (882 mg) and tert-butylmethylsilyl chloride (903 mg) were added to N-cyclopentylhydroxylamine (650 mg, 6.43 mmol) in dimethylformamide (10 ml). The mixture was stirred at room temperature for 3 hours. After diluting the mixture with ethyl acetate and hexane, the organic layer was washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane-ethyl acetate, 20:1 to 10:1) to give the title compound (722 mg) as a colorless oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:30])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]1)[CH:14]=2.CCN(C(C)C)C(C)C.[S:40](Cl)([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:30])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:29][S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH2:22][CH2:21]1)[CH:14]=2
Reactant: O=c1oc2cc(N3CCN(CCCO)CC3)ccc2cc1-c1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2CCN(c3ccc4cc(-c5nc6ccccc6s5)c(=O)oc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
70 mg (0.16 mmol) 3-Benzothiazol-2-yl-7-[4-(3-hydroxy-propyl)-piperazin-1-yl]-chromen-2-one are dissolved in 15 mL dichloromethane under argon. 0.083 mL Hünig base and 10 mg DMAP are added to the stirred solution, followed by 46 mg (1.5 eq.) tosyl chloride. The reaction mixture is stirred for 20 h at room temperature, poured onto ice, treated with 2 mL aqueous sodium bicarbonate solution and extracted (dichloromethane, saline). The organic phase is evaporated and the residue column chromatographed (silica gel, dichloromethane/EtOH 98:2) to yield after evaporation and drying under high vacuum 73 mg (78%) desired product as a light brownish powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8])[CH:3]1[C:11]([OH:13])=[O:12].[CH3:15][O:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(N(CC)CC)C.CCOCC>CC(C)=O>[CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8])[CH:3]1[C:11]([O:13][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH2:17][O:16][CH3:15])=[CH:19][CH:20]=1)=[O:12]
Reactant: COC(=O)C=CC1C(C(=O)O)C1(C)C
Reactant: COCc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCOCC
Product: COCc1ccc(COC(=O)C2C(C=CC(=O)OC)C2(C)C)cc1
Yield: 94.8 %

Procedure:
4.1 g of 2,2-dimethyl-3-(3-methoxy-3-oxo-1-propenyl) cyclopropanecarboxylic acid was dissolved in 50 ml of acetone, and 4.3 g of 4-methoxymethylbezylbromide was added to the solution. Next 2.4 g of triethylamine was added to the solution and underwent reaction at 60-80° C. for 3 hours while agitated, after which ether was added. After the ether solution was fully washed with diluted hydrochloric acid, sodium hydrogencarbonate aqueous solution and brine, it was dried with mirabilite. Ether was distilled under reduced pressure, and 6.3 g of 4-methoxymethylbezyl 2,2-dimethyl-3-(3-methoxy-3-oxo-1-propenyl)cyclopropanecarboxylate was obtained.
Reaction SMILES: [CH2:1]1[CH2:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][S:7][C:3]=2[CH2:2]1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:6]1[S:7][C:3]2[CH2:2][CH2:1][CH2:10][C:8](=[O:9])[C:4]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCc2sccc21
Agent: O=S(=O)(O)O
Product: O=C1CCCc2sc([N+](=O)[O-])cc21
Temperature: -5 °C
Reaction time: 0.83 h
Yield: 75 %

Procedure:
was prepared using a literature procedure (Asprou et al., J. Heterocyclic Chem., 17:87-92 (1980) (“Asprou”), which is hereby incorporated by reference). To a 50 mL round bottom flask charged with a stir bar was added 4-keto-4,5,6,7-tetrahydrothianaphthene (0.61 g, 4 mmole) and concentrated sulfuric acid (6 mL). The solution was then cooled in an ice/salt bath to −5° C. and stirred while a solution of concentrated nitric acid (0.3 mL) in concentrated sulfuric acid (3 mL) was added dropwise over 30 minutes. Solution was stirred for another 50 minutes and allowed to gradually warm to 5° C. The reaction mixture was then poured onto crushed ice and the yellow precipitate filter and washed with several portions of ice-cold water to give product as a yellow solid (0.594 g, 75% yield). Spectral data were consistent with the literature values (Asprou, which is hereby incorporated by reference).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[C:8]([C:12](=[O:17])[CH2:13][S:14]([CH3:16])=O)[NH:9]2)=[CH:5][C:4]=1[Cl:24].[OH2:25].[CH3:26]O>O1CCCC1>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[C:8]([C:12](=[O:17])[CH:13]([S:14][CH3:16])[O:25][CH3:26])[NH:9]2)=[CH:5][C:4]=1[Cl:24]
Reactant: O
Reactant: CO
Reactant: CS(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: COC(SC)C(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccn1

Procedure:
Add 2 ml of concentrated hydrochloric acid to 6-bromo-5-chloro-2[(methylsulfinyl)acetyl]-3-(2-pyridyl)indole (5.0 g) in 50 ml of methanol and 50 ml of tetrahydrofuran, warm the mixture to 60° for 2 hours. Cool, add water and the resulting solid is collected and dried to obtain 6-bromo-5-chloro-2[(methylthio) (methoxy)acetyl]-3-(2-pyridyl)indole.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)#[N:5].O>N1C=CC=CC=1.C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[N:2][OH:3])#[N:5]
Reactant: N#Cc1cccc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.8 %

Procedure:
Hydroxylamine hydrochloride (13.5 g, 194 mmol) was added to a solution of 3-cyanobenzaldehyde (25 g, 191 mmol) in 75 mL of pyridine and 75 mL of ethanol under N2. This was allowed to stir at room temperature for 14 hours. Water (50 mL) was added with vigorous stirring and an off-white solid precipitated. The solid was filtered through a glass frit and washed with another 50 mL of water. Evaporation of residual water under high vacuum gave 19.2 g (69%) of title compound. 1H NMR (CDCl3) δ: 11.61 (s, 1H); 8.21 (s, 1H); 8.00 (s, 1H); 7.96 (d, 1H), 7.85 (d, 1H), 7.61 (t, 1H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][CH:11]2[C:16]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[OH-].[Na+]>C(COC)OC.CO>[CH2:26]([N:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([CH:11]1[C:12]2[C:7](=[C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])[CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)COc1cccc2c1CCCC2C(=O)N(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: O=C(O)COc1cccc2c1CCCC2C(=O)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of the compound prepared in example 1 (204 mg) in dimethoxyethane (3 ml) and methanol (2 ml) was added 1N aqueous solution of sodium hydroxide. After stirred for 2 h, the mixture was quenched by addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium salfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→ethyl acetate) to give the title compound (171 mg) having the following physical data.
Reaction SMILES: CC(C)CCCC([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])OC1CCCCO1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26](S([O-])(=O)=O)=[CH:25][CH:24]=1.[NH+]1C=CC=CC=1.C([OH:42])C>>[OH:42][CH2:25][CH2:26][CH2:27][CH2:28][C:23]([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])([CH3:24])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCOP(=O)(OCC)C(CCCC(C)C)OC1CCCCO1
Reactant: CCO
Agent: c1cc[nH+]cc1
Product: CCOP(=O)(OCC)C(C)(C)CCCCO

Procedure:
19.9 g (0.052 mol) of diethyl 1,1-dimethyl-5-(tetrahydropyran-2-yloxy)-5-pentylphosphonate were stirred at 55° C. for 8 hours with 1.5 g (0.006 mol) of pyridinium toluene-4-sulfonate in 200 ml of aqueous ethanol. The solvent was evaporated, the residue was taken up in ethyl acetate, the solution was filtered through a silica gel column and, after evaporating the solvent, the residue was distilled in a bulb tube.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[I:10]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[I:10]
Reactant: OCc1ccc(F)c(I)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(F)c(I)c1
Reaction time: 8 h
Yield: 29.2 %

Procedure:
The product from Example 12B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol), stirred overnight, treated with an additional portion of manganese dioxide (2.25 g), stirred overnight, filtered and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4) to provide 1.9 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 7.23 (t, 1H), 7.89 (m, 1H), 8.32 (dd, 1H), 9.91 (s, 1H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl.Cl[CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:3]=1
Reactant: Cc1ccc2c(I)n[nH]c2c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(I)nn(CCCN(C)C)c2c1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A mixture of 3-iodo-6-methyl-1H-indazole (2.58 g, 10 mmol), 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (2.37 g, 15 mmol) and potassium carbonate (4.14 g, 30 mmol) in 50 ml, of DMF was heated to 85° C. for 3 hours. After cooling to room temperature, 100 mL of water was added and the mixture was extracted with ethyl acetate (4×100 mL). Then the combined organic phases were added with 20 mL of 6N HCl, and the solution was extracted with dichloromethane (4×50 mL). The combined organic phases were dried with sodium sulfate, concentrated to give 3-(3-iodo-6-methyl-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (1.74 g, 50.6%). LCMS: (M+H)+=344; 1H NMR (300 MHz, CDCl3): δ 7.33 (d, 1H, J=8.4 Hz), 7.21 (s, 1H), 7.03 (d, 1H, J=8.4 Hz), 4.43 (t, 2H, J=6.6 Hz), 2.51 (s, 3H), 2.27-2.23 (m, 8H), 2.09-2.07 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)\[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.C(O)C.[OH-].[Na+].Cl>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)\[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(CO/N=C(\CCC(=O)O)c2ccccc2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of methyl E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyrate (1.55 g, ethanol (10 ml) and 1N aqueous sodium hydroxide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and acidified with 1N hydrochloric acid to give E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyric acid as crystals (1.40 g, yield 93%). Recrystallization from ethanol-isopropyl ether gave colorless prisms. m.p. 131-132° C.