Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[C:7]([F:18])[C:8](=[O:17])[N:9]3[CH2:13][C:12]([OH:16])([CH2:14][OH:15])[C:11]=1[C:10]=23.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.O1CCCC1.C([Sn](=O)CCCC)CCC>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:15][CH2:14][C:12]2([OH:16])[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[C:7]([F:18])[C:8](=[O:17])[N:9]([C:10]=43)[CH2:13]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1c(F)cc2ncc(F)c3c2n1CC3(O)CO
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)c(F)cc4ncc(F)c2c43)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.3 %

Procedure:
A solution of 3,8-difluoro-4-hydroxy-4-(hydroxymethyl)-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (710 mg, 2.79 mmol) in dichloromethane (35 ml) and tetrahydrofuran (35 ml) was treated with triethylamine (0.58 ml, 4.19 mmol), para-toluenesulphonyl chloride (586 mg, 3.07 mmol) and dibutyltin oxide (35 mg, 0.14 mmol). After 6 hours stirring at room temperature under argon, the mixture was evaporated and water (200 ml) was added. The aqueous phase was extracted with dichloromethane (3×200 ml) and the combined organic extracts dried over magnesium sulphate and evaporated to give the desired compound (1.2 g, 100%) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11](N)[CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1.C=O.[BH3-][C:19]#[N:20].[Na+].[C:22](O)(=O)C>C(#N)C.C(OCC)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([N:20]([CH3:19])[CH3:22])[CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1
Reactant: [BH3-]C#N
Reactant: CN1CC(=O)Nc2ccc(N)cc2C1=O
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CN1CC(=O)Nc2ccc(N(C)C)cc2C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of intermediate 3 (3.0 g, 13 mmol) and 37% aq formaldehyde (21 mL, 0.26 mol) in acetonitrile at 0° C., NaBH3CN (4.8 g, 77 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 2 h and then at room temperature for 1 h. Acetic acid (1.4 mL) was then added and the reaction mixture was stirred for another 2 h. The reaction mixture was poured into ethyl ether, washed with 2N KOH and the basic layer was extracted several times with ethyl acetate. The organic phases were collected and dried and solvents removed in vacuum to give an amorphous yellowish solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=1.[Li]CCCC.[F:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[C:27]([F:30])([F:29])[F:28].C[Si](Cl)(C)C.[CH2:36]([Mg]Cl)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1COCC1.Cl>CCOCC>[F:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=2)([NH2:24])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:21][C:20]=1[C:27]([F:28])([F:29])[F:30]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
An ether solution (40 mL) of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.0 g, 8.23 mmol) was stirred in an oven-dried round bottom flask at −78° C. under Ar. n-BuLi (2.5 M in hexanes, 3.6 ml, 9.05 mmol, 1.1 eq) was added dropwise. The resulting solution was stirred at −78° C. for 30 min. A solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (1.55 g, 8.23 mmol, 1.0 eq) in Et2O (5 mL) was added dropwise. The resulting reddish mixture was stirred at −78° C. for 2 h. TMSCl (pretreated with Et3N (TMSCl:Et3N=10:1, v:v), 1.14 mL, 1.2 eq) was added dropwise. The dry ice bath was removed, and the resulting slurry was stirred at room temperature for 2 h. The reaction was cooled to −78° C. and a solution of benzyl magnesium chloride in THF (2.0 M, 8.4 mL, 2 eq) was added dropwise. The resulting mixture was slowly warmed up to room temperature and stirred at room temperature overnight. 1N HCl (100 mL) was added. The mixture was stirred at room temperature for 30 min, extracted with Et2O (2×), washed with 1N NaOH, H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, hexanes:ethyl acetate) to give 1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (1.6 g, yield: 44%). LC-MS ESI 3.42 min 429.2 (M-NH3+H); 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.66 (dd, J=6.7, 2.3 Hz, 1H), 7.49-7.59 (m, 1H), 7.45 (s, 1H), 7.18-7.30 (m, 6H), 6.74 (d, J=6.9 Hz, 2H), 3.57 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14]1[NH:15][CH2:16][CH2:17][C:18]=1[N+:19]([O-:21])=[O:20]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]1[NH:15][CH2:16][CH2:17][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSC1=C([N+](=O)[O-])CCN1
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC1=C([N+](=O)[O-])CCN1
Yield: 65.9 %

Procedure:
A solution of 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine (1.3 g, 0.0076 mol) and 2-methylthio-3-nitro4,5-dihydropyrrole (1.2 g, 0.0075 mol) in ethanol (50 ml) was refluxed for 11/2 hours. The mixture was cooled, and the solid was filtered off and recrystallised from methanol/water to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-4,5-dihydropyrrole (1.4 g, 66%) m.p. 207.5°-208°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23]N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:9])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:20]3[CH2:21][C:22]([CH3:25])([CH3:23])[N:26]=[C:18]23)=[CH:6][CH:7]=1
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Reactant: CC(C)(N)CN
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CN2C(=O)c3ccccc3C(O)(c3ccc(F)cc3)C2=N1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (25 g) (Step 1 of Example 2), 2-methyl-1,2-diaminopropane (40 mL), and toluene (125 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was slurried with ethanol. The solid was collected by filtration and dried to give the title compound (26 g) as a white solid, m.p. 168-170° C. Anal. for C19H17N2O2F: Calculated: C, 70.35; H, 5.28; N, 8.64. Found: C, 70.16; H, 5.35; N, 8.55.
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2>C(O)C.[Pd]>[CH3:1][CH:2]1[CH:7]([OH:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2
Reactant: C=C1C(=O)C2CCN1CC2
Agent: [Pd]
Solvent: CCO
Product: CC1C(O)C2CCN1CC2
Yield: 77.7 %

Procedure:
The 2-methylenequinuclidin-3-one (3.50 g) in ethanol (30 mL) was reduced over 10% Pd/C (50 wt %) under a H2 atmosphere. When judged complete by TLC (˜3 days), the catalyst was filtered off and the filter cake washed with ethyl acetate. The solvent was removed in vacuo to afford the desired product (2.80 g, 80%) was obtained and used without further purification. 1H NMR (400 MHz, CDCl3) 3.37-3.31 (m, 1H), 3.21-3.13 (m, 2H), 3.09-3.00 (m, 1H), 2.97-2.89 (m, 1H), 2.46-2.43 (m, 1H), 2.05-1.91 (m, 4H), 1.34 (d, J=7.6 Hz, 3H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[S:40][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[O:34][C@H:35]4[CH2:39][CH2:38][O:37][CH2:36]4)[C:20]=3[C:19]=2[CH3:41])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[S:40][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[O:34][C@H:35]4[CH2:39][CH2:38][O:37][CH2:36]4)[C:20]=3[C:19]=2[CH3:41])=[O:17])[CH2:10][CH2:9]1
Reactant: Cc1c(C(=O)NC2CCCN(C(=O)OC(C)(C)C)CC2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)NC2CCCNCC2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12
Temperature: 25 °C

Procedure:
A mixture of 380 mg (0.65 mmol) 4-[(4-{4-fluoro-2-[(S)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester and 0.15 ml trifluoroacetic acid and 10 ml dichloromethane was stirred at room temperature over night. The reaction mixture was concentrated in vacuo.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:17]1[N:22]=[C:21](Cl)[C:20]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)(=[O:15])=[O:14].CCOCC>C1COCC1>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:17]1[N:22]=[C:21]([NH:4][CH2:1][CH2:2][CH3:3])[C:20]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)(=[O:14])=[O:15]
Reactant: CCCN
Reactant: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(Cl)n1)c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCNc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
n-Propylamine (25 mg, 0.42 mmol) was added to a solution of 11 (50 mg, 0.08 mmol) in THF (5 mL) and the mixture was stirred at 50° C. for 2 hours. The solution was cooled to room temperature, filtered and the precipitate was washed with THF. The filtrate was concentrated under reduced pressure to afford a yellow oil. Trituration with ether gave a solid which was purified by flash column chromatography (2% MeOH in DCM) to afford 12 as a white solid (28 mg). 1H NMR (DMSO): δ 0.54 (t, 3H), 1.22 (q, 2H), 1.33-1.34 (m, 2H), 1.51 (quin, 4H), 2.80-2.84 (m, 6H), 7.32 (d, 2H), 7.56 (d, 1H), 7.58 (d, 2H), 7.70 (s, 1H), 7.97 (br s, 1H), 8.07 (d, 1H), 8.15, (s, 1H) ppm. Mass Spectrum m/e=618.0 (M+1)
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[CH:11][C:10]2[N:9]3[CH:13]=[N:14][N:15]=[C:8]3[C@@H:7]([CH2:16][CH3:17])[N:6]([C@@H:18]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]3)[C:5]=2[N:4]=1.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]=1[O:37][CH3:38]>C(O)C.O>[F:23][C:20]1([F:24])[CH2:21][CH2:22][C@@H:18]([N:6]2[C:5]3[N:4]=[C:3]([NH:25][C:26]4[CH:36]=[CH:35][C:29]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]=4[O:37][CH3:38])[N:12]=[CH:11][C:10]=3[N:9]3[CH:13]=[N:14][N:15]=[C:8]3[C@H:7]2[CH2:16][CH3:17])[CH2:19]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Reactant: CCNC(=O)c1ccc(N)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(Nc2ncc3c(n2)N([C@@H]2CCC(F)(F)C2)[C@H](CC)c2nncn2-3)c(OC)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
Concentrated hydrochloric acid (36 □l) was added to a mixture of (R)-7-chloro-5-((R)-3,3-difluorocyclopentyl)-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (70 mg, 0.21 mmol) and 4-amino-N-ethyl-3-methoxybenzamide (59.84 mg, 0.31 mmol) in ethanol (0.9 mL) and water (3.6 mL). The reaction mixture was heated to 95° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (82 mg, 80% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([NH2:15])=[N:20][OH:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: NC(=NO)C1CN(Cc2ccccc2)CCO1

Procedure:
To a stirred solution of 4-benzylmorpholine-2-carbonitrile (intermediate 25, 5.0 g, 24.7 mmol) in the mixture of ethanol and water (2/1, 75 ml) was added hydroxylamine hydrochloride (5.2 g, 74.2 mmol) and sodium bicarbonate (13.1 g, 123.5 mmol), and the reaction mixture was stirred under reflux for 12 hours. The reaction was diluted with chloroform, and the reaction mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The resulting 4-benzyl-N′-hydroxymorpholine-2-carboxamidine (intermediate 26) was used for next reaction without further purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][CH:6]1[CH:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21](F)=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[CH:14][C:13]=2[F:30])[CH2:7]1>CO>[NH2:5][CH:6]1[CH:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21]([O:2][CH3:1])=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:24][CH2:25]3)=[CH:14][C:13]=2[F:30])[CH2:7]1
Reactant: C[O-]
Reactant: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1N
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(N2CC(C)C(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 86 h

Procedure:
To a solution of sodium methoxide prepare from sodium (50 mg) and absolute methanol (3 ml) was added 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (80 mg) and the mixture in sealed tube was stirred for 86 hours at 140° to 150° C. and then concentrated. Small amount of water was added to the residue, and the solution was adjusted pH 7 with acetic acid and concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from a solution of dichloromethanemethanol (1:1) to give the title compound (9 mg) as pale yellow prisms, mp 191.5°-193.5° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[C@H:4]([NH2:7])[CH2:5][OH:6].N1C=CC=CC=1.[S:20]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]([F:12])([F:13])[CH:3]([C:8]([F:9])([F:10])[F:11])[C@H:4]([NH:7][S:25]([C:22]1[CH:23]=[CH:24][S:20][CH:21]=1)(=[O:27])=[O:26])[CH2:5][OH:6]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: N[C@H](CO)C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(N[C@H](CO)C(C(F)(F)F)C(F)(F)F)c1ccsc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of (1S)-3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine (prepared according to the method of Example 13, 0.100 g, 0.4 mmol) in CH2Cl2 (1 mL) was stirred under nitrogen at 25° C. Pyridine (0.097 mL, 1.2 mmol) was added followed by 3-thiophenesulfonyl chloride (0.072 g, 0.4 mmol) in CH2Cl2 (0.5 mL), and the resulting solution stirred for 18 h at 25° C. The crude reaction mixture was loaded onto the TsOH Syntage™ samplet and after concentration was purified by the Biotage Flash™ 12 chromatography system, eluent: 30:70 EtOAc:hexanes, to obtain N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide as a white solid (0.053 g, 35% yield).
Reaction SMILES: Cl.[C:2]1([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([Cl:17])(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[ClH:17].[C:8]12([C:2]3[CH:3]=[CH:4][C:5]([C:14](=[O:16])[CH3:15])=[CH:6][CH:7]=3)[CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(C23CNCC2C3)cc1
Reaction time: 8 h

Procedure:
A 3 g. portion of 1-phenyl-3-azabicyclo[3.1.0]hexane hydrochloride is added to a cold (0° C.) mixture of 2.8 g. of acetyl chloride and 6.9 g. of aluminum chloride in 30 ml. of dichloromethane, and the reaction is stirred for 15 minutes. The mixture is then brought to room temperature, stirred overnight and carefully poured onto ice. This mixture is extracted twice with dichloromethane, and the extracts are combined, dried, filtered and concentrated to an oil. This oil is dissolved in a minimum of dichloromethane and treated with an excess of ether to give a solid which is collected, washed with ether and dried. Recrystallization from acetonitrile gives 500 mg. of the desired product, m.p. 195°-197° C.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]1([CH2:20][CH2:21][C:22](=[CH2:26])[C:23]([OH:25])=[O:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[S:27]1C=CC=C1CC(O)=O.[CH3:36][CH2:37][O:38]CC>>[C:37]([S:27][CH2:26][CH:22]([CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:23]([OH:25])=[O:24])(=[O:38])[CH3:36]
Reactant: C=C(CCc1ccccc1)C(=O)O
Reactant: CCOCC
Reactant: O=C(O)Cc1cccs1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)SCC(CCc1ccccc1)C(=O)O
Temperature: 5 °C
Yield: 81 %

Procedure:
A 250 mL round bottomed flask, fitted with a Teflon magnetic stirring bar and a reflux condenser, was filled with 150 mL of toluene, 0.5 mL piperidine and 8.6 g (49 mmol) of 4-phenyl-2-methylenebutyric acid. Then 4.1 g (54 mmole) of thiolacetic acid was added to the solution and the mixture heated to reflux for 8 h under nitrogen. 1H-NMR analysis of the reaction mixture indicated some starting material remained. Another 1 g of thiolacetic acid was added and the mixture stirred at reflux for an additional 4 hours. By 1H-NMR, all of the starting material was seen to have reacted. The solution was cooled to 5° C. and 100 mL of ether added to the mixture. The excess thiolacetic acid was removed by extraction (3×50 mL 2% sodium bicarbonate). Then 50 ml of 1N HCl was added to the organic layer and the solution shaken vigorously. The organic layer was separated and dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. Recovered 10.0 g of product (81% yield).
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]1(=[N:30]O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.[OH-:32].[Na+]>>[NH:30]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:29]=2[CH2:28][CH2:27][CH2:26][C:25]1=[O:32]
Reactant: [OH-]
Reactant: ON=C1CCCc2ccccc21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: O=C1CCCc2ccccc2N1
Temperature: 90 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To 10 L of methanesulfonic acid in a 22 L 3-neck flask equipped with an overhead stirrer, a temperature probe, nitrogen inlet and reflux condenser, was added 2.6 Kg (18.61 mol) of phosphorus pentoxide. An additional 1.6 L of methanesulfonic acid was used to wash all the phosphorus pentoxide into the vessel. The mixture was heated at 90° C. for 2.5 hours then cooled to 50° C. using an ice bath and treated with 2.00 Kg (12.41 mol) of 1-tetralone oxime in several portions over 15 minutes. The mixture was heated at 63° C. for 10 minutes then slowly heated to 80° C. and kept at 80° C. for 3 hours. The reaction mixture was pumped into 70 L of ice then treated slowly with 11.25 L of 50% aqueous sodium hydroxide over 90 minutes at such a rate so as to maintain the temperature below 28° C. The mixture was filtered and 4 L of the filtrate was used to rinse the vessel. The wet cake (pink) was washed with 8 L of water then suction dried for 45 minutes and transferred to two trays and dried under vacuum at 40° C. for 2 days to give 1.9 Kg (11.79 mol, 95%) of product. 1H MNR (250 MHz,CDCl3): 2.24 (m, 2H), 2.38 (t,6 Hz, 2H), 2.82 (t, 6 Hz, 2H), 7.03 (d, 8 Hz, 1H), 7,13 (m,1H), 7.24 (m, 2H), 8,63 (br s 1H).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:19]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Yield: 70.3 %

Procedure:
Benzenesulfonamide (3.14 g, 20 mmol) was dissolved in DMF (100 mL) and NaH (60% in oil, 40 mmol, 1.60 g) was added. The reaction was stirred until the gas evolution ceased. 2,4-Difluoronitrobenzene (18 mmol, 2.9 g, 2 mL) was added and the reaction mixture was stirred over night at 35° C. The reaction mixture was poured into HCl (1M aq, 100 mL) and extracted with toluene (25 mL×5). The organic phase was dried (MgSO4) and concentrated and re-crystallized from EtOH to give a first crop of 3.75 g of a yellow solid. A second crop of 0.20 g was collected from the EtOH remains. Yield 3.95 g, 13.3 mmol (74%). MS (posES-FIA) m/z=found: 296; Calc: 296,0.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([CH2:36][NH2:37])[CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([CH2:36][NH:37][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:35][CH2:34]1
Reactant: NCC1CC1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopropylmethylamine (29 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 101 mg of the title compound as a colorless solid.