Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].I[CH2:14][CH2:15][CH2:16][CH3:17]>CO>[CH2:14]([S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)c1cccnc1S
Reactant: CCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCSc1ncccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
After MeOH (20 mL) was added to 2-mercapto-nicotinic acid (1 g, 6 mmol), the mixture was cooled to 0° C., and 6 M NaOH aqueous solution (3.2 mL) was added slowly thereto. The reactant was stirred at 0° C. for 30 minutes. 1-Iodobutane (0.74 mL, 6 mmol) was added to the reactant, and the mixture was stirred under reflux at 80° C. for 16 hours. The reactant was concentrated under reduced pressure, and 6 M HCl aqueous solution was added thereto to adjust the pH of the solution to 7. The resulting precipitate was filtered and dried to obtain the title compound (1.27 g, 93%).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: CC(C)CN
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCC(C)C)ncnc32)[C@]1(C)F
Yield: 41.9 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added isobutyl amine (about 1.03 ml, 10.38 mmol) and refluxed for about 20 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.18 g) as a colorless gummy mass. Yield: 41.6%; 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 8.06-7.79 (m, 3H), 7.58-7.55 (m, 3H), 6.54 (d, 1H, J=23.4 Hz), 5.90 (bs, 1H), 4.83-4.78 (m, 2H), 4.49-4.44 (m, 1H), 3.49 (m, 2H), 2.14 (s, 3H), 2.09-1.90 (m, 1H), 1.89 (d, 3H, J=2.4 Hz), 1.45 (d, 3H, J=22.8 Hz), 1.02 (d, 6H, J=6.6 Hz); Mass: [M+1]+ 500 (100%), 501 (35%); IR cm−: 3372, 3141, 2927, 1752, 1622, 1274, 1063, 1026, 952, 713; HPLC: 94.7%.
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[NH:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[NH2:20][C:18](=[N:19][S:43]([CH3:42])(=[O:45])=[O:44])[CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:21])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=N)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(N)=NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamimidoyl-7fluoro-2-hydroxy-7-methyl-octyl)-amide in methylene chloride is added 1.0 equivalents of triethylamine followed by 10 equivalents of methanesulfonyl chloride. The reaction is stirred at ambient temperature for approximately 5 hours. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[CH:13][CH:14]=4)=[C:4]2[CH:3]=1.[C:24]([NH2:28])(=[O:27])[CH:25]=[CH2:26]>>[CH3:23][N:16]1[C:15]2[C:10]3[C:11](=[C:4]4[C:5](=[N:8][C:9]=3[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1=3)[CH:6]=[CH:7][C:2](/[CH:26]=[CH:25]/[C:24]([NH2:28])=[O:27])=[CH:3]4)[CH:12]=[CH:13][CH:14]=2
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cccc1c23
Reactant: C=CC(N)=O
Product: CN1c2ccccc2-c2nc3ccc(/C=C/C(N)=O)cc3c3cccc1c23
Yield: 91 %

Procedure:
The general procedure (Method M) applied to 3-chloro-8-methyl-8H-quino[4,3,2-kl]acridine, 28 (100 mg, 0.32 mmol) and acrylamide (46 mg, 2 eq) gave the title compound (102 mg, 0.29 mmol, 91%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:21])[CH2:9][CH2:8][N:7]1[C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)=[O:5])C.CCO.[OH-].[Na+]>CO>[CH3:19][C:14]1[CH:13]=[C:12]([CH2:11][C:10]([N:7]2[CH2:8][CH2:9][C:6]2([CH3:21])[C:4]([OH:5])=[O:3])=[O:20])[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: CCOC(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)O)c1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid ethyl ester, Intermediate 94 (1 eq.) in either EtOH or MeOH was added aqueous NaOH (2N) (2 eq.). The reaction was stirred at 20° C. for 6 h. The solvent was removed under reduced pressure and the crude was partitioned between water and EtOAc. The organic layer was discarded and the aqueous layer was neutralized by addition of aqueous HCl (2N) and thoroughly extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:3]=1)#[N:20]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethyl)benzene (86 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (20 ml), washed successively with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from 2-butanone/n-hexane to give the title compound (165 mg, 70%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[C:39]([O:40][CH3:41])=[CH:38][C:28]([C:29]([C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[NH2:33])=[O:30])=[C:27]([CH3:42])[CH:26]=1>>[CH3:23][O:24][C:25]1[C:39]([O:40][CH3:41])=[CH:38][C:28]([C:29]([C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[NH:33][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[O:30])=[C:27]([CH3:42])[CH:26]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1cc(C)c(C(=O)c2ccccc2N)cc1OC
Product: COc1cc(C)c(C(=O)c2ccccc2NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1OC

Procedure:
N-[2-(4,5-Dimethoxy-2-methylbenzoyl)phenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-(4,5-dimethoxy-2-methylbenzoyl)aniline using method I. LCMS; retention time 3.82 min, MH+ 548.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27]CCCCC.CI>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: CCCCCC
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2coc3ccccc23)C1
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(C2=CCN(CCc3coc4ccccc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (342 mg, 1 mmol) (obtained from example 1, step 6) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Light green semi-solid. Yield: 280 mg (78%); 357 (M+H); 1H NMR: δ□7.94 (d, 1H), 7.6 9 (d, 1H), 7.5–7.0 (m, 8H), 6.2 (bs, 1H), 3.8 (s, 3H), 3.49 (bs, 2H), 3.0 (m, 2H), 2.85 (m, 4H), 2.6 (bs, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[CH3:8]>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CO)cnc1C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc(C=O)cnc1C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of (5,6-dimethyl-3-pyridinyl)methanol (105 mg, 0.765 mmol) in DCM (4 ml), MnO2 (532 mg, 6.12 mmol) was added. After stirring overnight, an excess of MnO2 (333 mg, 3.83 mmol) was added and then the mixture was stirred for 3 h more. The reaction mixture was filtrated and evaporated to afford 51 mg of title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.C[Si](C)(C)[O:10][C:11]([CH:13]=[CH2:14])=[CH2:12].C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[O:10]=[C:11]([CH3:12])[CH2:13][CH2:14][N:5]1[C:4](=[O:7])[CH:3]=[C:2]([Cl:1])[S:6]1
Reactant: Oc1cc(Cl)sn1
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CCn1sc(Cl)cc1=O

Procedure:
A solution of 5-chloro-3-hydroxyisothiazole (1.5 g, 0.011 mole), 2-trimethylsiloxy-1,3-butadiene (5.6 g, 0.04 mole) and 0.5 g of hydroquinone in 20 ml of toluene was heated at 80° C. for 96 hours. After cooling, the mixture was concentrated in vacuo. The residual oil was dissolved in diethyl ether and washed with saturated NaHCO3 solution and then with water. After drying (MgSO4) and concentrating the solution, the residual oil was purified by column chromatography on silica gel, using diethyl ether/methanol (9/1) as eluant. Compound 1 was obtained as an oil, 0.3 g; IR (neat) 1625,1650 cm-1 ; NMR (CDCl3) δ6.25 (s,1H); 4.0 (t, 2H); 2.9 (t,2H); 2.2 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=C=O.[CH3:14][S:15]([CH3:17])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[S:15]([CH3:17])[CH3:14]
Reactant: CS(C)=O
Reactant: O=C=Nc1ccccc1C(F)(F)F
Product: CS(C)=Nc1ccccc1C(F)(F)F

Procedure:
The process of claim 15 in which 2-trifluoromethylphenyl isocyanate is reacted with dimethylsulfoxide to produce N-(2-trifluoromethylphenyl)-S,S-dimethylsulfilimine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[CH:6][C:7]1[S:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C:14]=2[N:15]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[CH:6][C:7]1[S:8][C:9]2[N:10]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:12][CH2:13][C:14]=2[N:15]=1
Reactant: COc1cccc(C=Cc2nc3c(s2)NCCC3)c1OC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cccc(C=Cc2nc3c(s2)N(S(C)(=O)=O)CCC3)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 2-(2,3-dimethoxystyryl)-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridine (1.0 g, 3.3 mmole) in pyridine (10 ml) was added dropwise methanesulfonyl chloride (0.45 g, 3.97 mmole) with ice-cooling. The reaction mixture was heated with stirring at room temperature for 3 hours and then a sodium bicarbonate solution was added to the mixture which was extracted with a chloroform-methanol mixed solvent. The extract was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography and recrystallized from hexane-ethyl acetate to obtain the title compound (1.09 g, yield: 92.7%).
Reaction SMILES: Cl.[CH2:2]([N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[O:20][C:21]([CH2:23][CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>>[CH2:2]([N:9]1[C:25]2[CH:24]([CH2:23][C:21]([OH:22])=[O:20])[CH2:29][CH2:28][CH2:27][C:26]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NN(Cc1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: O=C(O)CC1CCCc2c1n(Cc1ccccc1)c1ccc(F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(benzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([OH:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:4]=1[OH:5])[CH3:2].S(=O)(=O)(O)O.[CH3:17][C:18](O)([CH2:20][CH:21](O)[CH3:22])[CH3:19]>C(OC(C)C)(C)C>[CH2:1]([C:3]1[C:4]([OH:5])=[CH:6][C:7]([CH3:11])=[C:8]2[C:9]=1[O:10][C:18]([CH3:19])([CH3:17])[CH2:20][CH:21]2[CH3:22])[CH3:2]
Reactant: CCc1c(O)cc(C)cc1O
Reactant: CC(O)CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Product: CCc1c(O)cc(C)c2c1OC(C)(C)CC2C
Yield: 64.1 %

Procedure:
A mixed solution was prepared from 6.1 g. of 2-ethyl-5-methyl resorcinol, 40 ml of isopropyl ether and 2 ml of concentrated sulfuric acid. To this solution, 5.7 g. of 2-methylpentane-2,4-diol were added dropwise at about 60° C. for about 30 minutes. After cooling, this solution was successively washed with water, with aqueous 1 N sodium hydroxide solution and again with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by subjecting to column chromatography filled with silica gel. There were obtained 6.0 g. (yield: 64.1%) of the subject compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:32])[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]>>[CH3:12][N:13]([CH3:32])[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:30])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:16]
Reactant: CN(C)S(=O)(=O)c1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: Nc1ccc2cccnc2c1
Product: CN(C)S(=O)(=O)c1cccc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (18 mg, 0.13 mmol) and 3′-dimethylsulfamoyl-1,1′-biphenyl-4-carboxylic acid (D68) (45 mg, 0.15 mmol) as a yellow oil. MS(ES): MH+ 432, M-H+ 430
Reaction SMILES: [C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]2[C:19]([CH2:20][CH:21](O)[CH3:22])=[CH:18][CH:17]=[C:11]3[C:12]([NH:14][C:15](=[O:16])[C:10]=23)=[O:13])[CH2:5][CH2:4]1)#[N:2].C(N(S(F)(F)[F:36])CC)C>C1C=CC=CC=1>[C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]2[C:19]([CH2:20][CH:21]([F:36])[CH3:22])=[CH:18][CH:17]=[C:11]3[C:12]([NH:14][C:15](=[O:16])[C:10]=23)=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)Cc1ccc2c(c1N1CCC(C#N)(c3ccccc3)CC1)C(=O)NC2=O
Solvent: c1ccccc1
Product: CC(F)Cc1ccc2c(c1N1CCC(C#N)(c3ccccc3)CC1)C(=O)NC2=O
Temperature: 70 °C
Yield: 54.4 %

Procedure:
A mixture of 3-(4-cyano-4-phenylpiperidin-1-yl)-(2-hydroxypropyl)phthalimide (2.60 g, 6.1 mmol) and diethylaminosulfur trifluoride (DAST, 1.96 g, 12.2 mmol) in benzene (100 mL) was stirred and heated at 70° C. under argon atmosphere for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (1.30 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]([CH3:26])([CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:19]#[N:20]>>[C:19]([C:18]([NH:17][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])#[N:20]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Reactant: CC(N)(C#N)CS(C)(=O)=O
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)c1cc(OCC(F)(F)F)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a) as starting materials and isolated (583 mg, 56%) as a white solid; MS (ESI, m/z): 400.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7].CN1CCOCC1.[C:35]([O:39][C:40]([NH:42][CH2:43][CH2:44][C:45](O)=[O:46])=[O:41])([CH3:38])([CH3:37])[CH3:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:35]([O:39][C:40](=[O:41])[NH:42][CH2:43][CH2:44][C:45](=[O:46])[NH:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 119.1 %

Procedure:
To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone (0.066 g, 0.17 mmol) in methylene chloride (2 mL) at ambient temperature was added N-methylmorpholine (0.025 mL, 0.23 mmol), 3-tert-butoxycarbonylamino-propionic acid (0.044 g, 0.23 mmol) and O-benzotriazole-1-yl-N,N,N′, N′-tetramethyluronium hexafluorophosphate (0.076 g, 0.20 mmol). The resulting solution was stirred at ambient temperature for 60 hours, then concentrated. Radial chromatography (2 mm plate) gave the title compound (0.114 g)
Reaction SMILES: [C:1](=O)([O-])[O-:2].[Na+].[Na+].[F:7][CH2:8][CH2:9][NH:10][C:11](=[O:14])[O:12][CH3:13]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.C([N+](CC)(CC)CC)C.CO>[F:7][CH2:8][CH:9]([NH:10][C:11](=[O:14])[O:12][CH3:13])[O:2][CH3:1]
Reactant: COC(=O)NCCF
Reactant: O=C([O-])[O-]
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)NC(CF)OC
Reaction time: 1 h
Yield: 251.4 %

Procedure:
An undivided electrochemical flow cell was constructed from two 150 cm2 graphite block electrodes separated with a 6 mm Viton® gasket and plumbed to a 500 ml jar reservoir, a Teflon® lined pump and a refrigerated cooling system so that the contents of the reservoir could be continuously recirculated thorugh the cell and cooling system. The electrodes were connected to a power source and a voltage meter. The system was flushed with chromatography grade methanol to remove any contaminants. The reservoir was charged with 10-20 g of molecular sieves to keep the system dry, 290 g of chromatography grade methanol, 12 g (0.039 mol) of tetraethylammonium p-toluenesulfonate, 2 g (0.02 mol) of sodium carbonate, and 27.5 g of 91 percent purity (0.227 mol) of methyl 2-fluoroethylcarbamate and the resulting solution was circulated through the electrochemical cell while maintaining the current at 10 amperes and the temperature at 12°-16° C. After 1 hour gas chromatographic analysis indicated about 2 percent conversion. The current was increased to 12 amperes and the conversion went up to about 8 percent during the next hour and 39 percent after 6 hours. The process was continued overnight to increase the conversion to about 95 percent based on starting material and 81 percent based on product. The volatiles were removed under reduced pressure and the residue was dissolved in 200 ml of methylene chloride. The resulting solution was extracted with 100 ml of water, 100 ml of saturated aqueous sodium bicarbonate, and 100 ml of saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the volatiles under reduced pressure left 22.0 g of an oily residue which was found to be the title compound of about 81 percent purity by gas chromatography. The aqueous extracts were combined and extracted with methylene chloride to obtain another 7.6 g of the title compound of about 85 percent purity. The total yield recovered was about 85 percent of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1>C(O)C.[Pd].[C]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-nitro(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.29 mmol) in ethanol (30 mL) was added a scoup of Pd/carbon. The reaction was stirred overnight at room temperature under an atmosphere of hydrogen. It was filtered over celite and the solution concentrated to an oil. The oil was taken up in methanol (20 mL) and 6N HCl (20 mL) and the solution was heated to 75° C. for 3 hours. The solution was concentrated under vacuo, added to saturated bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried (Na2SO4), concentrated to an oil and chromatographed on silica gel, eluting with 50% ethyl acetate/hexane to give the title compound (35 mg, 53% yield). 1H NMR (CDCl3) δ 10.1 (br s, 1H), 7.89 (dd, 1H), 7.23-7.16 (m, 4H), 6.91 (dd, 1H), 3.6 (br s, 1H); ES-MS (m/z) 228 [M+1 ]+.