Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4](=[O:18])[C:5]([C:13]([O:15]CC)=[O:14])=[CH:6][NH:7]2.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>CN(C=O)C.O.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4](=[O:18])[C:5]([C:13]([OH:15])=[O:14])=[CH:6][N:7]2[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1c[nH]c2c(F)ccc(F)c2c1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(F)ccc(F)c32)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (5.0 g), potassium iodide (3.3 g) and potassium carbonate (4.1 g) in DMF (100 mL) was added 1-(chloromethyl)-4-methoxybenzene (4.6 g), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in ethanol-THF (1:1, 40 mL), 1 N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with water, neutralized with 1 N hydrochloric acid (20 mL), and the precipitate was collected by filtration, washed with water, and dried to give the title compound (4.4 g).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:13])[CH:10]([CH3:12])[CH3:11].B(F)(F)F>CC([O-])=O.[Na+]>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)C(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: CC(C)C(=O)c1ccc(O)cc1O
Yield: 113.1 %

Procedure:
Resorcinol (10.0 g, 91 mmol) and isobutyric acid (8.00 g, 1 eq.) were treated with BF3-etherate (68 mL, 6 eq.) and heated for 1.5 h to 90° C. After cooling the reaction mixture was carefully poured onto 500 mL of 10% aq. NaOAc solution, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness to leave 18.5 g of the title compound as light brown oil.
Reaction SMILES: [CH2:1]1[O:15][C:14]2[C:3](=[C:4]([CH:11]=[CH:12][CH:13]=2)[CH2:5][C@@H:6]([C:8](O)=[O:9])[NH2:7])[O:2]1.Cl.P(Cl)(Cl)(Cl)(Cl)[Cl:18].Cl.C1(NCC([Cl:34])=O)C=CC=CC=1>>[ClH:18].[CH2:1]1[O:15][C:14]2[C:3](=[C:4]([CH:11]=[CH:12][CH:13]=2)[CH2:5][C@@H:6]([C:8]([Cl:34])=[O:9])[NH2:7])[O:2]1
Reactant: N[C@@H](Cc1cccc2c1OCO2)C(=O)O
Reactant: O=C(Cl)CNc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Product: N[C@@H](Cc1cccc2c1OCO2)C(=O)Cl

Procedure:
The compound 2,3-methylenedioxyphenylalanine, is treated with hydrogen chloride and phosphorous pentachloride in accordance with the procedure described by Hartcastle et al., J. Org. Chem., 31, 897 (1966) for the preparation of phenylglycyl chloride hydrochloride to yield 2,3-methylenedioxyphenylalanyl chloride hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: ClC/C=C/CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])ccc1OC/C=C/CCl
Reaction time: 2 h
Yield: 43.3 %

Procedure:
A solution of 8 g of 5-nitrosalicylaldehyde, 30.8 g of trans-1,4-dichloro-2-butene and 13.2 g of potassium carbonate in 35 ml of dimethylformamide was stirred at room temperature for 19 hours, and further stirred at 80°-87° C. (outside temperature) for 2 hours. The mixture was allowed to cool, poured into 80 ml of water, and extracted with chloroform. The extract (organic layer separated) was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The product was eluted with benzene to give 5.3 g of 2-[(E)-4-chloro-2-butenyloxy]-5-nitrobenzaldehyde. (mp. 65°-66° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][NH2:37])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39](C)C=O.Cl.N(OCCC(C)C)=O>O1CCOCC1>[CH3:38][N:26]1[CH2:24][CH2:12][O:35][CH2:34][CH2:27]1.[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([N:36]=[N+:37]=[N-:39])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCOCC1
Product: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: -20 °C

Procedure:
To a solution of 250 mg. (0.5 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidine hydrazide in 8 ml. of dimethylformamide was added 0.42 ml. of a 4N solution of hydrochloric acid in dioxane, and the mixture was cooled to -60° C. 0.1 ml. of isopentyl nitrite was then added and the reaction temperature was raised to -20° C. After disappearance of the hydrazide had been confirmed, the temperature was lowered to -60° C. The mixture was neutralized with 0.17 g. of N-methylmorpholine to form a solution of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidine azide.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)=[O:13].[C:24](Cl)(=[O:26])[CH3:25]>C(O)C.C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-(3-amino-6-chloroindole-2-carbonyl)benzenesulfonamide (Example 142) and acetyl chloride. m.p.: 250-251° C. (ethanol/toluene)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[N:35]1([C:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[N:3]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)=[O:14])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1
Reactant: C1CCNCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1)N1CCCCC1
Temperature: 0 °C
Yield: 26.2 %

Procedure:
3-Oxo-2-(5-chloro-2-pyridyl)isoindoline-1-acetic acid (1 g) and triethylamine (0.8 g) were dissolved in 20 ml of dry tetrahydrofuran and, under ice-cooling with stirring, 0.39 g of ethoxycarbonyl chloride was added portionwise. The mixture was stirred for 30 minutes, 0.56 g of piperidine was added, and the whole mixture was stirred for an additional 30 minutes. The reaction mixture was poured into 500 ml of ice water, followed by extraction with ethyl acetate. The extract was washed with water and dried. The ethyl acetate was then distilled off and the residue was treated with ether. The resulting crystals thus obtained were collected by filtration and recrystallized from ethyl acetate to give 0.32 g of colorless crystals, melted at 165°-166° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccccc3C(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of methyl 4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylate (248) (0.108 g, 0.24 mmol) in a mixture of EtOH (6 mL) and THF (4 mL) was added an aqueous solution of 1N NaOH (10 mL). The mixture was stirred at 60° C. overnight. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Concentration gave a white residue, which was triturated with hot hexanes containing 1% MeOH to yield the title compound (249) as white solid (92.8 mg, 89%). mp 230-231° C. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (s, 6H), 0.89 (s, 6H), 1.25 (s, 2H), 1.91 (s, 4H), 6.67 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.34-7.44 (m, 2H), 7.50-7.55 (m, 1H), 7.65 (d, J=7.7 Hz, 1H), 9.27 (s, 1H), 12.72 (s, 1H). LCMS (ESI): m/z 441 (M+H)+, 439 (M−H)−.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:5])C.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[O-:22]CC.[Na+].[OH-].[K+]>C(O)C.O>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:6]([C:4]([OH:3])=[O:5])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:12])=[O:22])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: Fc1ccc(CBr)cc1
Reactant: CC[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCC(Cc1ccc(F)cc1)C(=O)O
Yield: 87.6 %

Procedure:
19.2 g of 2-oxocyclohexanecarboxylic acid ethyl ester, 21.4 g of p-fluorobenzyl bromide, 7.7 g of sodium ethoxide and 200 ml of ethanol were mixed together to form a mixture which was refluxed for 2 hours, incorporated with 500 ml of water and subjected to extraction with ethyl ether. The resulting ether layer was freed of the ether to obtain a residue. The thus obtained residue was dissolved in 500 ml of 70% ethanol, incorporated with 16.1 g of potassium hydroxide, refluxed for 3 hours and hydrolyzed to obtain 26.5 g of 1-(4-fluorobenzyl)-1,5-pentane dicarboxylic acid having a melting point of 80°-81° C. in the colorless needle form. 26 g of the thus obtained compound in the needle form and 300 g of polyphosphoric acid were mixed together to form a mixture which was agitated at 100° C. for 3 hours. After the end of the reaction, the resulting reaction mixture was incorporated with iced water and subjected to extraction with ethyl acetate. The organic layer was washed with water, dehydrated and freed of the solvent by distilling it off, thereby to obtain a residue. The thus obtained residue was recrystallized from isopropyl ether to obtain 18.2 g of 6-fluoro-1-oxo-2,3-dihydro-2-indene valeric acid in the colorless platy form.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH2:19])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH:19][C:29]([NH:28][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:30])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1N
Reactant: O=C=NCc1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1NC(=O)NCc1ccccc1
Reaction time: 72 h
Yield: 66 %

Procedure:
5-Methyl-4-amino-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester from Step 2 (0.15 g, 0.5 mmol) was dissolved in hot 1,4-dioxane (6-8 mL) under an inert atmosphere, stirred, and treated with benzyl isocyanate (0.07 g, 0.5 mmol). After 72 hours at room temperature, the mixture was diluted with diethyl ether (50 mL). After another hour the precipitate was filtered off, rinsed with ether, and dried to afford 0.14 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester; mp 216-217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH:10](=O)[CH3:11].[O-:13][C:14]#[N:15].[Na+]>C(O)(C)(C)C.O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:13])[NH:15][C:10]([CH3:11])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: NNc1ccc(Cl)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nn(-c2ccc(Cl)cc2)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A stirring solution of 71.3 grams (0.500 mole) of 4-chlorophenylhydrazine in 175 ml of tert-butanol/water (88/12) is cooled to 0° to 5° C., and a solution of 23.4 grams (0.525 mole) of acetaldehyde in 54 grams of tert-butanol/water (88/12) is added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture is stirred for five minutes, and a slurry of 39.8 grams (91.5% pure--0.560 mole--12% molar excess) of sodium cyanate in 90 grams of water is added in one portion. Additional water is used to wash any of the remaining slurry of sodium cyanate from its container into the reaction mixture. The reaction mixture is cooled to 0° to 5° C., and 39.3 grams (0.655 mole--5% equivalent excess, based on equivalents of sodium cyanate and its sodium carbonate impurity) of acetic acid is added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred for about two hours during which time it is allowed to warm to about 20° C. Upon completion of the two hour stirring time, the reaction mixture is cooled to 10° C., and 321 grams (0.537 mole) of a 12.4% aqueous solution of sodium hypochlorite is added dropwise during a 40 minute period. Upon completion of addition, the reaction mixture is stirred for an additional 40 minutes. The tert-butanol/water medium is then distilled from the reaction mixture by slowly heating the reaction mixture to about 100° C. Upon completion of the distillation, the pot residue is washed with water and dried, yielding 1-(4-chlorophenyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@@H:19]1[CH2:23][CH2:22][N:21](CC2C=CC=CC=2)[CH2:20]1)=[O:17]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:11]([NH:10][CH2:15][CH3:14])[CH3:12].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNCC
Product: O=C(N[C@@H]1CCNC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Reaction time: 56 h
Yield: 4.1 %

Procedure:
20% w/w Palladium hydroxide on carbon (12.5 mg) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3R)-1-benzylpyrrolidin-3-yl]-2-piperidinecarboxamide (62.5 mg) [see Example 1] in ethanol (10 ml). The reaction mixture was hydrogenated at 414 kPa (60 p.s.i.) for 56 hours, after which time the catalyst was filtered off and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 95:5 changing to 90:10, by volume, ethyl acetate:diethylamine to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3R)-pyrrolidin-3-yl]-2-piperidinecarboxamide (1 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[C:11]1[C:12]([S:17]([CH3:20])(=O)=O)=[N:13][CH:14]=[N:15][CH:16]=1.C(S)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+].[H][H]>O1CCCC1.CCCCCC.[OH-].[Na+]>[CH2:20]([S:17][C:12]1[C:11]([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][C:2]2([CH3:21])[CH3:1])=[CH:16][N:15]=[CH:14][N:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: SCc1ccccc1
Reactant: CC1(C)Cc2ccccc2C1c1cncnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2ccccc2C1c1cncnc1SCc1ccccc1
Yield: 82.1 %

Procedure:
A solution of 6.7 g of impure 5-(2,2-dimethyl-1-indanyl)-4-methanesulfonylpyrimidine (approximately 6.1 g (0.20 mol) in 50 mL of dry tetrahydrofuran was prepared and to this was added with stirring 2.5 mL (2.6 g, 0.21 mol) of benzyl mercaptan and then, in several small portions, 0.84 g of 60 percent sodium hydride in mineral oil (0.21 mol). Hydrogen was evolved and the mixture became cloudy. After about 4 hr the mixture was diluted with 200 mL of hexane and 150 mL of 2N aqueous sodium hydroxide. The phases were separated and the organic phase was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain 7.6 g of crude product. This was dissolved in hexane and flash chromatographed on silica gel eluting first with hexane (10×200 mL) and then with a 25:75 by volume mixture of dichloromethane and hexane (14×200 mL) and then with dichloromethane 12×200 mL). There was desired product in fractions 12-36 and these fractions were combined and the resulting mixture was concentrated by evaporation under reduced pressure at 50° C. to obtain 6.3 g of the title compound as a white solid melting at 76°-79° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH:12]3[O:11][CH2:10]2)[C:5]([Cl:28])=[CH:4][N:3]=1.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:5]1[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[N:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1C1COC2C(Nc3nc(Cl)ncc3Cl)COC21
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2ncc(Cl)c(NC3COC4C3OCC4N3C(=O)c4ccccc4C3=O)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 2-(6-((2,5-dichloropyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-yl) isoindoline-1,3-dione (370.0 mg, 0.88 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (354.2 mg, 2.65 mmol) in n-BuOH (10 mL) was added DIPEA (683.1 mg, 5.29 mmol). The mixture was stirred at 150° C. overnight. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (MeOH/CH2C12 (v/v)=1/30) to give the title compound as a red solid (140.0 mg, 33.1%).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:8](Cl)[C:9](Cl)=[O:10]>[Zn].C(O)(=O)C>[CH:2]12[CH2:8][C:9](=[O:10])[CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3]2
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C1=CCCC=C1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC2C=CCCC12

Procedure:
The starting material is prepared by the treatment of 1,3-cyclohexadiene with dichloroacetyl chloride, followed by dechlorination with zinc and acetic acid of the resulting adduct to give bicyclo[4,2,0]-oct-2-en-7-one. This compound is subjected to Baeyer-Villiger oxidation to give 7-oxabicyclo[4,3,0]non-2-en-8-one which is treated with thallium (III) nitrate under carefully controlled conditions to give 6-formyl-2-oxabicyclo[3,3,0]octane-3-one having properties identical with those reported by Corey and Ravindranathan, Tetrahedron Letters, 1971, 4753.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C1COCC1>[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:17])=[O:18])=[CH:20][CH:21]=2)=[CH:38][CH:37]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
In a 100 ml RBF combine 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (2.5 g, 6.62 mmol) and THF (25 ml). Cool the solution in an ice water bath and add 4-methylmorpholine (0.73 ml, 7.29 mmol) follow by the portion wise addition of CDMT (1.16 g, 7.29 mmol). Stir the solution in an ice water bath for one hour. Add dropwise, a solution of 4-fluorobenzylamine (0.83 ml, 7.29 mmol) in THF (8 μl) to the reaction at 0° C. Stir the solution at 0° C. for five hours, and quench with 1N HCl (50 ml). Extract the reaction MTBE (2×50 ml), filter and wash with saturated aqueous sodium chloride (50 ml). Dry the organics over magnesium sulfate, filter and concentrate to give N-(4-fluoro-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide (2.43 g) as a white solid. HPLC=95.5%, MS (ESI) m/z observed 485.1334 calculated 485.1335 (M+H).
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][OH:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])O.[Na+]>C1COCC1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([O:6][CH2:5][CH:3]2[CH2:4][C:2]2([F:7])[F:1])(=[O:26])=[O:25])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CC1(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC2(F)F)cc1
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of (2,2-difluorocyclopropyl)methanol (20.0 g) and triethylamine (32.2 mL) in THF (300 mL) was added 4-nitrobenzenesulfonyl chloride (41.0 g) at 0° C., and the mixture was stirred for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (47.2 g) as a white solid.