Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](O)=[O:15].CCCCCCCC(O[Sn](OC(CCCCCCC)=O)(CCCC)CCCC)=O>C1(C)C(C)=CC=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCO
Reactant: O=C(O)c1ccco1
Agent: CCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCOCCOC(=O)c1ccco1

Procedure:
2-Butoxyethanol (butyl cellosolve) 121 g (1.02 m), furoic acid 95 g (0.85 m) and 1 g dibutyltin dioctoate were heated with a xylene azeotrope to acid number 3. Xylene removed by distillation to a pot temperature of 200° and reaction product distilled. 2-Butoxyethylfuroate collected in fraction 2, 111°-104°. Yield 162 g, 86%.
Reaction SMILES: C([O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH3:16])[CH:6]=1)(=O)C>CO>[OH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH3:16])[CH:6]=1
Reactant: CC(=O)Oc1cc(-c2ccccc2)n(C)c1
Solvent: CO
Product: Cn1cc(O)cc1-c1ccccc1
Reaction time: 0.25 h

Procedure:
To a mixture of deoxygenated methanol (15.5 ml) and 3-acetoxy-1-methyl-5-phenylpyrrole (11) (1.3 g, 6.2 mmole), under argon, was added deoxygenated NaOH (2N, 12.5 ml). The reaction mixture was stirred in an ice-bath for 15 minutes. Then deoxygenated citric acid (2M, 7 ml) was added and the resulting mixture was stirred in an ice bath for 8 minutes. The reaction mixture was concentrated under reduced pressure, then 20 ml of water was added and was extracted twice with ethylacetate (EtOAc) (50 ml). The EtOAc layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give 3-hydroxy-1-methyl-5-phenylpyrrole (12) as an orange residue. Under argon, a cold solution of anhydrous THF (12.4 ml), pyridine (0.6 ml, 7.4 mmole, 1.2 eq) and trifluoroacetic acid (1.2 ml, 15 mmole, 2.4 eq) was added to the orange residue, followed immediately by the additon of a solution of freshly prepared N-tosyl-L-alaninyl chloride (1.2 g, 7.4 mmole, 1.2 eq) in anhydrous THF (12.4 ml). The resulting mixture was stirred for one hr at 0° C. Then the reaction was quenched by the addition of aqueous citric acid (1M, 5 ml) and EtOAc (30 ml). After a brief mixing, the layers were separated and the organic layer was successively washed with saturated NaCl solution, twice with 5% NaHCO3 solution and again with saturated NaCl solution. The EtOAc extract was then dried over MgSO4, treated with Norit 211, filtered and concentrated under reduced pressure to give the crude product (13) as an orange residue. This was dissolved in hexane:EtOAc (1:1) (5 ml) and chromatographed on a column (SiO2, 100 g) by elution with hexane:EtOAc (7:3) to give 1 g of (13) as a thick light orange oil. A portion of this crude product was further purified by semi-preparative HPLC (column, IBM silica, 1 cm×25 cm; mobile phase, hexane:EtOAc 8:2; flow rate, 4.0 ml/min; pressure, 0.2 psi) to yield a honey color thick oil (13).
Reaction SMILES: N1C=CN=N1.[H-].[Na+].[N:8]1[NH:9][C:10]([SH:13])=[N:11][CH:12]=1.Br[CH2:15][CH:16]([C:39]1[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=1)[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[N:20]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:19]=1>CN(C)C=O>[Cl:30][C:25]1[CH:24]=[C:23]([C:21]2[N:20]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:19]=[C:18]([CH2:17][CH:16]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[CH2:15][S:13][C:10]3[NH:9][N:8]=[CH:12][N:11]=3)[CH:22]=2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: Sc1ncn[nH]1
Reactant: COc1ccc(-n2nc(CC(CBr)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]nn1
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(CC(CSc3ncn[nH]3)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
5-{3-[5-(3.4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-yl]-2-m-tolyl-propylsulfanyl}-1H-1,2,4]-triazole. To a suspension of sodium hydride (4.0 mg, 60% dispersion in oil) in N,N-dimethylformamide (1.0 mL) at 0° C. was added a solution of 2H-[1,2,4]triazole-3-thiol (10.0 mg, 0.1 mmol, 1.1 equiv) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at 0° C. for 30 min then a solution of 3-(3-bromo-2-m-tolyl-propyl)-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole (48 mg, 0.09 mmol, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) was added. The reaction mixture was brought to room temperature then was stirred for 2 h. The reaction was quenched with satd aq ammonium chloride (1.0 mL), and the resulting mixture was diluted with water (10.0 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) then brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by reversed-phase HPLC to yield the title compound (39 mg, 80%). HPLC: Rt=3.26 (Method B). MS (ESI): mass calculated for C28H25Cl2N5OS, 549.12; m/z found, 550.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.32 (br s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.07-7.0 (m, 5H), 6.95 (dd, J=8.4, 21. HZ, 2H), 6.89 (d, J=9.0 Hz, 2H), 6.31 (s, 1H), 3.70 (s, 3H), 3.48 (dd, J=12.9, 6.3 Hz, 1H), 3.36 (dd, J=12.7, 8.2 Hz, 1H), 3.26 (m, 1H), 3.07 (dd, J=14.9, 6.4 Hz, 1H), 2.91 (dd, J=14.9, 8.2 Hz, 1H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:12])=[CH:8][C:9]=2O)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[CH3:24])=[N:3]1.P(Cl)(Cl)([Cl:27])=O>C(#N)C>[Cl:27][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]2[C:4]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][C:14]=3[CH3:24])=[N:3][N:2]([CH3:1])[C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2c(n1)c(-c1ccc(-n3cccn3)cc1C)nn2C
Solvent: CC#N
Product: Cc1cc(Cl)c2c(n1)c(-c1ccc(-n3cccn3)cc1C)nn2C

Procedure:
To a solution of compound 3e (1.0 g) in anhydrous acetonitrile (10 mL) was added phosphorous oxychloride (0.60 mL). The reaction was refluxed under nitrogen for 2 hours. The reaction mixture was cooled and quenched on ice with H20. The mixture was basified to pH 8 with sodium bicarbonate. The product was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over magnesium sulfate and concentrated to afford 7-chloro-1,5-dimethyl-3-(2-methyl-4-pyrazol-1-yl-phenyl)-1H-pyrazolo[4,3-b]pyridine as a yellow oil. The compound was purified by silica gel chromatography, using 30% ethyl acetate/hexanes as eluent to provide 1.0 g (99%) of compound 4a as a white solid; LC/MS: [M+H]=338.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH2:30][CH3:31])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH2:30][CH3:31])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (1.5 g, 3.40 mmole) in THF/water (16 mL, 1:1) was added LiOH (286 mg, 6.80 mmole) followed by 3 mL of methanol at room temperature. The reaction mass was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified with aqueous 1.5 N HCl solutions. The aqueous solution was extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get desired product (1.3 g, 90%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.81-0.93 (m, 6H), 1.12-1.29 (m, 5H), 1.30-1.50 (m, 11H), 1.71-1.80 (m, 2H), 1.91-2.51 (m, 4H), 3.57-3.59 (m, 1H), 4.27-4.35 (m, 3H), 4.92-4.97 (m, 2H), 5.01-5.15 (m, 1H), 5.74-5.79 (m, 1H), 6.30-6.80 (m, 1H), 12.50 (sb, 1H). MS: MS m/z 427.6 (M++1).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:28])([F:29])[F:15])=[CH:22][CH:21]=2)=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.16 min; [M+H]+=402.11.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][OH:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.[H][H]>O1CCOCC1.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:13][OH:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(CO)cc(C(=O)O)c1
Yield: 121.4 %

Procedure:
5-Nitro-3-hydroxymethyl benzoic acid (39.6 g, 0.20 mol) was suspended in a mixture of dioxane (25 ml) and water (50 ml). Palladium on carbon (5%) was added and the mixture was hydrogenated in a Parr apparatus until the stoichiometric amount of hydrogen had been consumed. The catalyst was filtered off and the filtrate passed into concentrated hydrochloric acid (12M, 17 ml). The filtrate was evaporated to dryness to give 40.6 g of a crystalline product. Yield is almost quantitative. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([S:15]([OH:18])(=[O:17])=[O:16])C=CC=1.NC1C=CC(S(O)(=O)=[O:27])=CC=1.NC1C=CC=CC=1S(O)(=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15](=[O:16])(=[O:27])([OH:17])[OH:18]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: Nc1ccccc1S(=O)(=O)O
Solvent: Nc1ccccc1
Product: O=S(=O)(O)O

Procedure:
As a method for the synthesis of a sulfonated polyaniline, there are known, for example, a method for the synthesis of a sulfonated polyaniline by electrochemically polymerizing aniline and m-aminobenzenesulfonic acid (Journal of The Chemical Society of Japan, 1985, 1124 and JA-A-2-166,165), a method for the synthesis of a sulfonated polyaniline by electrochemically polymerizing an o-, m- or p-aminobenzenesulfonic acid alone [Lecture Preprint II in the 64th Autumn Annual Convention of The Chemical Society of Japan, 706 (1992)], a method for the synthesis of a sulfonated polyaniline by chemically polymerizing aniline and an o- or m-aminobenzenesulfonic acid (JP-A-1-301,714), a method for the chemical oxidation polymerization of an aminobenzenesulfonic acid compound or monomers comprising an aminobenzenesulfonic acid compound and an aniline compound (JP-A-6-56,987), a method for the sulfonation with conc. sulfuric acid of an emeraldine type polymer (polyaniline) obtained by chemical or electrochemical polymerization (JP-A-58-210,902), a method for the sulfonation with sulfuric anhydride/triethyl phosphate complex (JP-A-61-197,633), a method for the sulfonation with fuming sulfuric acid [J. Am. Chem. Soc., (1991) 113, 2665-2671, J. Am. Chem. Soc., (1990) 112, 2800 and WO91-06887], a method for the synthesis of a sulfonated polyaniline of the N-substitution type by chemically polymerizing diphenylamine-4-sulfonic acid (sodium salt) [Polymer, (1993) 34, 158-162] and the like.
Reaction SMILES: NC1SC2C=C(OS(C3SC=CC=3)(=O)=O)C=CC=2N=1.[C:20]([N:27]1[CH2:35][CH2:34][CH:30](C(O)=O)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[C:23]([O:22][C:20]([N:27]1[CH2:35][CH2:34][CH2:30][CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Nc1nc2ccc(OS(=O)(=O)c3cccs3)cc2s1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1

Procedure:
1st step: A solution of thiophene-2-sulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 31) (80 mg, 0.256 mmol), Boc-isonipecotic acid (176 mg, 0.768 mmol) HBTU (291 mg, 0.768 mmol) and N,N-diisopropylethylamine (223 μl, 1.28 mmol) in 4 ml of dimethylformamide is stirred for 3 days at room temperature. 30 ml of water are added to the reaction medium, which is extracted with ethyl acetate. The organic phase is washed with water and with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness to give 4-[6-thiophene-2-sulfonyloxy)benzothiazol-2-ylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:41]=[C:40]3[C:36]([CH2:37][N:38]([C@@H:43]([CH:48]([CH3:50])[CH3:49])[C:44]([O:46][CH3:47])=[O:45])[C:39]3=[O:42])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>C1COCC1.CCOC(C)=O>[CH3:49][CH:48]([CH3:50])[C@H:43]([N:38]1[CH2:37][C:36]2[C:40](=[CH:41][C:33]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:8](=[O:10])[CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:32][CH:31]=3)=[CH:34][CH:35]=2)[C:39]1=[O:42])[C:44]([O:46][CH3:47])=[O:45]
Reactant: O=C(O)Cc1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Cc4ccccc4)cc3)cc2C1=O
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 2-phenylacetic acid (150 mg, 1.102 mmol) in THF (5 mL) was added N-methylmorpholine (0.182 mL, 1.653 mmol) and cooled to −20 to −30° C. To this solution was added isobutyl chloroformate (0.145 mL, 1.102 mmol) and the reaction mixture was stirred at −20° C. for 30 min. To the reaction mixture, a solution of compound of example 6 (336 mg, 0.992 mmol) in THF (2.5 mL) was added and stirred at room temperature for 2-3 h. After completion of the reaction, EtOAc was added to the reaction mixture and washed with brine water. The organic extract was dried over anhydrous sodium sulfate and concentrated to obtain a crude material, which was purified by column chromatography (silicagel, 30% ethyl acetate in chloroform).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.O>CN(C)C=O>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][O:1][CH:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
4.66 g (19.23 mmol) of methyl α-hydroxy-α-phenyl-p-toluate was dissolved in 50 ml of N,N-dimethylformamide. 0.77 g (19.23 mmol) of 60% sodium hydride was added thereto and the mixture was stirred at room temperature for 1 hour. 3.10 g (28.85 mmol) of 2-dimethylaminoethyl chloride was added thereto and the mixture was heated at 80° C. for 2.5 hours. After the reaction mixture was cooled and poured into water, the obtained mixture was extracted twice with ethyl acetate and the extract was washed with brine, and dried (MgSO4). The solvent was distilled off and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=40:1 (v/v)) to obtain 0.53 g (1.69 mmol) of methyl α-(2-dimethylaminoethoxy)-α-phenyl-p-toluate as a brown oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH2:30]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)piperazine following a procedure analogous to that described in Example 79. LC (method 10): tR=1.41 min; Mass spectrum (ESI+): m/z=467 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7](/[C:8](=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)/[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.CS(C)=O.O>CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1Cc1cccc(Cl)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Sodium borohydride (3.0 g, 79 mmol) (Aldrich) was added in small portions to a suspension of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (19 g, 66 mmol) (from example 1a supra) in methanol (200 mL) and DMSO (50 mL) at such a rate that gas evolution was not too vigorous. When the addition was complete, mixture was stirred at room temperature for 0.5 hr-1 hr. After adding to water (200 mL), the resulting precipitate was collected and dried to give 18 g of rac-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a light yellow solid. MS: 293 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](F)=[O:7].[CH3:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([NH2:24])[C:20]=1[C:21]([OH:23])=[O:22].C(N(CCCC)CCCC)CCC.ClCC(Cl)C>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:24][C:19]1[C:20](=[C:15]([CH3:14])[CH:16]=[CH:17][CH:18]=1)[C:21]([OH:23])=[O:22])=[O:7]
Reactant: O=C(F)c1cccc(C(F)(F)F)c1
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CC(Cl)CCl
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1C(=O)O
Reaction time: 0.33 h

Procedure:
15.4 parts of 3-trifluoromethylbenzoyl fluoride are added to a stirred mixture of 13.3 parts of 6-methylanthranilic acid and 16.3 parts of tri-n-butylamine in 250 parts of 1,2-dichloropropane at 20°-25° C., and stirring is continued for 20 minutes. The precipitate formed is filtered off and washed with 1 N hydrochloric acid and then with water; the organic filtrate is washed similarly, dried and evaporated down. 27 parts of N-(3'-trifluoromethylbenzoyl)-6-methylanthranilic acid, of melting point 198°-204° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][NH:6][C:7]([C:9]1[NH:10][CH:11]=[C:12]([C:14](=O)[CH2:15][CH3:16])[CH:13]=1)=[O:8].[CH:22](OC(C)(C)C)(N(C)C)N(C)C.[NH2:34][C:35]([NH2:37])=[NH:36]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][NH:6][C:7]([C:9]1[NH:10][CH:11]=[C:12]([C:14]2[C:15]([CH3:22])=[CH:16][N:34]=[C:35]([NH2:37])[N:36]=2)[CH:13]=1)=[O:8]
Reactant: CCC(=O)c1c[nH]c(C(=O)NCc2ccc(F)c(F)c2)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: N=C(N)N
Solvent: C1CCOC1
Product: Cc1cnc(N)nc1-c1c[nH]c(C(=O)NCc2ccc(F)c(F)c2)c1
Reaction time: 24 h

Procedure:
To a solution of compound 6 (1 equivalent) in THF, at ambient temperature, was added (Me2N)2CHOt-Bu (3 equivalents). After 24 hours, the solvent was evaporated and the crude product was utilized without purification. Step 2: To a solution of the compound formed above at Step 1 (1 equivalent) in ethanol, at ambient temperature, was added guanidine (3 equivalents) and the resulting mixture heated at reflux. After 12 hours, the solvent was evaporated and the crude product purified by preparatory HPLC (reverse phase; 10–90% MeCN in water; 15 minutes) to afford the desired compound III-a-74. HPLC using method B provided Rt of 7.9 minutes. 1H NMR was consistent with expected structure. FIA/MS Obs. M+1/M−1.
Reaction SMILES: C(NC(C)C)(C)C.[FH:8].[F:9][C:10]1[C:15]([CH:16]2[O:18][CH2:17]2)=[C:14]([F:19])[C:13]([F:20])=[C:12]([F:21])[C:11]=1[F:22].C(OCC)C>O>[F:8][CH:16]([C:15]1[C:10]([F:9])=[C:11]([F:22])[C:12]([F:21])=[C:13]([F:20])[C:14]=1[F:19])[CH2:17][OH:18]
Reactant: F
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: OCC(F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 30 h
Yield: 29 %

Procedure:
A Teflon vessel containing 2.7 g (22.5 mmol) of diisopropylamine was cooled in a dry-ice methanol bath, and to this was added dropwise 1.8 g (90 mmol) of anhydrous hydrogen fluoride to prepare 4.5 g (22.5 mmol) of (i-Pr)2NH. 4HF. To this was added dropwise 3.15 g (15 mmol) of (+)-pentafluorostyrene oxide at 0° C. and the resulted mixture was stirred for 30 hours under N2 at room temperature. To this was added 30 ml of diethyl ether and 30 ml of water and the aqueous layer was extracted with 20 ml of ether. The combined ether solution was washed with an aqueous solution of sodium carbonate and then water, and was dried over anhydrous sodium sulfate. After ether was distilled off, distillation under reduced pressure was carried out (Kugelrohr, 70-80° C./15 mmHg), thereby obtaining 1.0 g of (+)-2-fluoro-2-(pentafluorophenyl)ethanol. The yield was 29%, the GC purity was 98%, and [α]D25 was +12.0° (c=0.30, CHCl3). The other physical properties were mentioned above.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.CCOC(C)=O>[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: C=CC=CC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)C=CC=Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Reaction time: 96 h
Yield: 26.7 %

Procedure:
A solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (480 mg, 1.2 mmol), 5-(5,5-dimethyl-1,3-hexadiene (200 mg, 1.8 mmol), Pd(OAc)4 (25 mg), tris(o-tolyl)phosphine (125 mg), and triethylamnine (2.5 mL) in acetonitrile (5 mL) was sealed in a tube and headed at 100° C. for 4 days. The solution was then diluted with EtOAc, and the mixture was extracted with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 100:5-100:15 to afford the title compound (135 mg, 43% yield). MS (CI/NH3) m/z 421 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.08 (s, 9H), 1.48 (s, 9H), 1.89 (m, 2H), 2.00 (m, 2H), 3.38 (m, 2H), 3.95 (m, 1H), 4.13 (m, 1H), 4.23 (m, 1H), 5.99 (m, 1H), 6.22 (m, 1H), 6.71 (m, 1H), 6.95 (m, 1H), 7.74 (br s, 1H).