Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([CH2:17][CH2:18][CH3:19])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([CH2:17][CH2:18][CH3:19])=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCCc1nn2ccccc2c1-c1ccnc(F)c1
Reactant: NC1CCCC1
Product: CCCc1nn2ccccc2c1-c1ccnc(NC2CCCC2)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (126 mg, 0.49 mmol) in cyclopentylamine (5 mL) was heated in a sealed vessel at 150° C. for 18 h. The mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by flash chromatography on silica gel (2:1 hexane-ethyl acetate) to give N-cyclopentyl-4-(2-propylpyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine (155 mg, 98%) as a yellow solid. 1H NMR (CDCl3) δ 8.41 (d, 1H), 8.07 (d, 1H), 7.58 (d, 1H), 7.14 (t, 1H), 6.74 (td, 1H), 6.66 (dd, 1H), 6.45 (s, 1H), 5.01 (broad, 1H), 3.95 (m, 1H), 2.91 (t, 2H), 2.04 (m, 2H), 1.80–1.50 (m, 8H), 0.98 (t, 3H); MS m/z 321 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][C:3]=1[NH2:4].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][C:3]=1[N:4]1[C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=2[C:15]1=[O:20]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(OC2CCCC2)ccc1F
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)ccc1F
Temperature: 25 °C
Yield: 34 %

Procedure:
2-Fluoro-5-cyclopentyloxyaniline (330 mg, 1.69 mmol), 3,4,5,6-tetrahydrophthalic anhydride (258 mg, 1.70 mmol) and acetic acid (10 ml) as a solvent were placed in a round bottom flask (50 cc) followed by heating under refluxing for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate (20 ml×3 portions). The organic layers were combined, and, after washing with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. After removing the drying agent, the solvent was distilled off under reduced pressure. The resulting dark red oily substance (345 mg) was isolated and purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to obtain the desired N-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a light yellow oily substance (171 mg, 0.575 mmol, 34% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)(O)O.[NH2:16][C:17](N)=N>O>[NH2:16][C:17]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: N=C(N)N
Reactant: Nc1cccnc1S(N)(=O)=O
Agent: O=C(O)O
Solvent: O
Product: NC1=NS(=O)(=O)c2ncccc2N1

Procedure:
An intimate mixture of 1 g of 3-aminopyridine-2- sulfonamide (Preparation 1) and 2.1 g of guanidine carbonate is progressively brought to the molten state (200° C.) and then heated for 24 hours at this temperature. After cooling, the residue is taken up in water. The possible insoluble material is filtered and the filtrate, treated with animal charcoal, is acidified to a pH of 7. The white precipitate is collected on a filter, washed with water and recrystallized from hot water.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@:10]1([N:30]=[N+:31]=[N-:32])[C@@H:15](OS(C(F)(F)F)(=O)=O)[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6].C(OCC)C>CN(C)C=O>[CH2:5]([O:7][C:8]([C@:10]1([N:30]=[N+:31]=[N-:32])[C@H:15]([N:1]=[N+:2]=[N-:3])[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N=[N+]=[N-])[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
56 mg of sodium azide was added to 250 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 5 mL of N,N-dimethylformamide, and the mixture was stirred for 30 minutes at room temperature. After 100 mL of diethyl ether was added to the reaction solution, this ether solution was washed four times with water and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=10:1), thereby yielding 175 mg of (1R,2R,3R,5R,6R)-2,3-diazido-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[C:3]=1[NH:20][CH2:21][CH:22]([OH:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl.C(N=C=NCCCN(C)C)C.O1CCCC1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][CH:22]([OH:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(O)CNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(O)Cn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N)c21
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
Under nitrogen atmosphere, a mixture of methyl 4-{[2-amino-6-({[(2,4-dichlorophenyl)amino]carbonothioyl}amino)phenyl]amino}-3-hydroxybutanoate (Reference Example 81; 1.42 g, 3.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.84 g, 9.60 mmol) and tetrahydrofuran (30 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient to give the title compound as an oil (790 mg, 1.93 mmol, 60%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[S:33])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)OC(C)(C)C)ncn2-c2ccccc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1Cc2c(C(=O)OC(C)(C)C)ncn2-c2ccccc2C1=S

Procedure:
1 g of t-butyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 50 ml of toluene is treated with 0.82 g of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide and the mixture obtained is heated to boiling under reflux for 6 hours. The mixture is poured into water and the toluene phase is separated. After drying the organic phase over magnesium sulphate and evaporation, the crude product is chromatographed on silica gel. There is obtained t-butyl 5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate on melting point 207°-208°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][O:13][C:7]=2[N:6]=[CH:5]1.[Br:16]Br>CN(C=O)C>[Br:16][C:12]1[O:13][C:7]2[N:6]=[CH:5][N:4]([CH2:3][C:2]([F:1])([F:14])[F:15])[C:9](=[O:10])[C:8]=2[CH:11]=1
Reactant: O=c1c2ccoc2ncn1CC(F)(F)F
Reactant: BrBr
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)oc2ncn1CC(F)(F)F
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a stirred solution of 3-(2,2,2-trifluoroethyl)furo[2,3-d]pyrimidin-4(3H)-one (0.64 g, 2.93 mmol) in anhydrous DMF (11 ml) at 0° C. was added bromine (0.333 ml, 6.45 mmol) and the mixture stirred for 30 min. The mixture was partitioned between ethyl acetate (30 ml) and an aqueous mixture (3:1:4, water, saturated sodium hydrogen carbonate solution and 20% w/w sodium thiosulfate solution, 110 ml). The aqueous phase was separated and extracted with ethyl acetate (3×30 ml). The combined ethyl acetate fractions were washed with brine/water (1:1, 4×30 ml), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-30% ethyl acetate in cyclohexane) to afford the title compound (673 mg, 77%). LCMS RT=1.04 min, [M+H+(79Br)]=297.0, [M+H+(81Br)]=298.9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16](=O)([O:22]C(C)(C)C)[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:14]([O:13][C:11]([CH2:10][C:2]1[N:1]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)Cc1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cc2ccccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of ethyl 2-(1H-indol-2-yl)acetate (14.7 g, 72.2 mmol) in dichloromethane (150 mL) was added 4-dimethylaminopyridine (8.83 g, 72.2 mmol) and di-tert-butyl carbonate (23.7 g, 108 mmol) in portions. After stirring for 2 h at room temperature, the mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and purified by silica gel chromatography (0 to 20% EtOAc in hexane) to give tert-butyl 2-((ethoxycarbonyl)methyl)-1H-indole-1-carboxylate (20.0 g, 91%).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH:7][CH3:6])=[CH:11][CH:12]=2)=[CH:18][C:19]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 8 h

Procedure:
{2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.08 g, 2.51 mmol, 1 eq) was dissolved in dry DCM (10 ml) under argon atmosphere and TFA (961 μl, 5 eq) was added. Reaction mixture was stirred for overnight. In the reaction mixture was added more DCM (15 ml) and was extracted with saturated NaHCO3 (3×15 ml) and brine. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a crude product. Crude product was purified via Biotage SP-1 Snap Si 25 g; 25 ml/min; UV Wavelength (Collection: 254 nm; Monitor: 290 nm) in the gradient of MeOH in DCM: 2% for 1.5 CV, 2-10% for 20 CV. The appropriate fractions were combined and product 2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (501 mg, yield=58.1%, purity 96%). [M+H]+=330.75 1H NMR (300 MHz; CDCl3) δ/ppm 2.47 (s, 3H), 2.78-2.92 (m, 4H), 6.91-7.10 (m, 3H), 7.19-7.33 (m, 3H), 7.41 (d, J=8.99 Hz, 1H)
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH:10]=O)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30]>CCOCC.C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][N:29]([CH3:30])[CH3:28])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: CNC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CN(C)C)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and dimethylamine hydrochloride, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): δ 7.09 (m, 4 H), 3.49 (septet, J=6.6 Hz, 1 H), 3.21 (septet, J=6.6 Hz, 1 H), 3.05 (s, 2 H), 2.22 (t, J=5.2 Hz, 2 H), 1.99 (s, 6 H), 1.18 (m, 18 H), 0.790 (t, J =6.3 Hz, 3 H). FAB-MS: calcd for (C25H37FN2) 384, found 385 (M+H). Anal. Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.95; H, 9.66; N, 7.12; F, 5.25. mp 69-71° C. Rf=0.4 (20% ether/CH2Cl2).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24](=[S:26])[NH2:25])[CH2:7]1)(=[O:4])=[O:3].CO[CH:29](OC)[N:30](C)C>>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([C:24]2[S:26][N:30]=[CH:29][N:25]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2ncns2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To (2S, 4R) -4-methanesulfonyloxy-1-(4-nitrobenzyloxy-carbonyl)-2-thiocarbamoylpyrrolidine (1.5 g) was added N,N-dimethylformamide dimethylacetal (1.5 ml) and the mixture was stirred at room temperature for 1.5 hours. After the solvent was removed, the residue was dissolved in dichloromethane (30 ml). To the solution was added dropwise O-(mesitylenesulfonyl)hydroxylamine (1.5 g) in dichloromethane (20 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was washed with saturated aqueous sodium bicarbonate and brine successively. The dried organic layer was evaporated and the residue was subjected to a column chromatography on silica gel (30 g) eluting with a mixture of n-hexane and ethyl acetate (1:2 V/V) to give (2S, 4R) -4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) -2- (1,2,4-thiadiazol-5-yl) pyrrolidine (850 mg) .
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH2:8][S:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=2)[CH:17]=1)[CH2:13]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH2:8][S:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=2)[CH:17]=1)[CH2:13][Br:42])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CSc2cc(CO)cc(SCc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CSc2cc(CBr)cc(SCc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reaction time: 8 h
Yield: 64.1 %

Procedure:
3,5-Bis(3,5-di-tertiary-butylbenzylthio)benzyl alcohol (49.0 g, 84.9 mmol) and carbon tetrabromide (28.2 g, 85.0 mmol) were dissolved in 300 ml of tetrahydrofuran. To this solution was added with stirring triphenylphosphin (23.5 g, 89.6 mmol), at the temperatures of 10° C. or below. The reaction mixture became clear once, and then colorless crystals separated gradually. After stirring overnight at 25–30° C., the crystals were removed by filtration and the filtrate was concentrated. The residue obtained was purified by means of chromatography with n-hexane:dichloromethane=1:1, giving 34.8 g of 3,5-bis(3,5-di-tertiary-butylbenzylthio)benzyl bromide.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]([F:17])([F:16])[F:15])[C:8]([C:18]([O:20]CC)=[O:19])=[CH:7]2.[OH-].[Na+]>CO.O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]([F:15])([F:16])[F:17])[C:8]([C:18]([OH:20])=[O:19])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)ccc2NC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)ccc2NC1C(F)(F)F
Temperature: 25 °C
Yield: 88.9 %

Procedure:
The ethyl 1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylate from Step 4 (880 mg, 2.5 mmol) and 2.5 N aqueous sodium hydroxide (2 mL) were mixed in methanol (15 mL) and water (15 mL). The solution was heated on a steam bath for 2 hours. The reaction was allowed to cool to room temperature and was extracted with diethyl ether (50 mL). The aqueous layer was acidified (pH=1) with 3 N HCl and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo leaving an oil. The oil was crystallized from cold dichloromethane-hexanes to afford the 1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylic acid as yellow needles (0.727 g, 89%): mp 127.7-128.9° C. 1H NMR (CDCl3, 300 MHz) 7.80 (s, 1H), 7.05 (m, 2H), 6.62 (d, 1H, J=8.0 Hz), 5.13 (m, 1H), 4.62 (brs, 1H). ESHRMS m/z 326.0252 (M−H, Calc'd 326.0252). Anal. Calc'd for C12H7NO3F6: C, 44.05; H, 2.16; N, 4.28. Found: C, 43.89; H, 2.04; N, 4.24.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[OH:5][C:6]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)([CH3:8])[CH3:7]>C1COCC1>[CH3:3][O:5][C:6]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)([CH3:8])[CH3:7]
Reactant: CI
Reactant: CC(C)(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a suspension of sodium hydride, 60% dispersion in mineral oil (0.322 g) and methyl iodide (1.00 mL) in 10 mL THF at room temp was carefully added portionwise benzyl 4-(2-hydroxypropan-2-yl)piperidine-1-carboxylate (1.49 g, 0.00537 mol) in 15 mL THF. The reaction was heated at 50° C. for 18 hours and then it was cooled down to 0° C. and carefully quenched by addition of sat NH4Cl solution, then extracted with EtOAc twice. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chrom to get 1.2 g benzyl 4-(2-methoxypropan-2-yl)piperidine-1-carboxylate as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([CH2:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][N:8]=1)=[O:6])=O.C(OCC)(=O)C.Cl.C([Br:28])(=O)C>ClCCl>[CH3:1][S:2][CH:4]([Br:28])[C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][N:8]=1)=[O:6]
Reactant: CS(=O)CC(=O)c1cc(-c2ccccc2)on1
Reactant: CC(=O)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSC(Br)C(=O)c1cc(-c2ccccc2)on1
Yield: 103.5 %

Procedure:
A reaction identical with that of Example 3 is performed on the 3-methylsulfinylacetyl-5-phenylisoxazole (1.25 g) prepared in a manner similar to that described in Example 1 or 2 with the exception that the ethyl acetate solution of hydrogen chloride is replaced by a solution of acetyl bromide (741 mg, 6.025 milimoles) in dichloromethane (10 ml) to give 3-(2-methylthio-2-bromoacetyl)-5-phenylisoxazole (1.62 g, 103.5 %) as a crude crystalline residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([Cl:49])[C:35]=1[OH:50]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=2)=[CH:3][C:2]([C:38]2[CH:39]=[C:34]([Cl:33])[C:35]([OH:50])=[C:36]([Cl:49])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 99 %

Procedure:
Following general procedure F, tert-butyl 4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]benzylcarbamate (58 mg, 0.117 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.176 mmol) to afford the crude product (67 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@@H:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][C@H:20]([C:31](OC)=[O:32])[CH2:19]2)=[O:16])[N:10]=[N:9]1.[CH3:39][OH:40]>C1COCC1.O.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:18]2[CH2:19][C@@H:20]([C:31]([N:8]3[CH2:3][CH2:2][O:40][CH2:39][CH2:12]3)=[O:32])[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23]2)=[O:16])[N:10]=[N:9]1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3F)c2CO)CN(C(=O)OC(C)(C)C)C1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.05 g) was dissolved in THF (10 ml)-methanol (8 ml)-water (8 ml), 8M aqueous sodium hydroxide solution (600 μl) was added and the mixture was stirred at 70° C. for 1.5 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue, morpholine, 1-hydroxybenzotriazole (150 mg) and triethylamine (700 μl) were dissolved in acetonitrile (20 ml), WSC.HCL (555 mg) was added and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with water. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (764 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1
Reactant: C1=COCCC1
Reactant: OCc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1cccc(COC2CCCCO2)c1

Procedure:
A solution of 3-bromobenzyl alcohol (84.9 g; Aldrich), 3,4-dihydro-2H-pyran (44 g) and anhydrous p-toluene sulfonic acid (1 g) in CH2Cl2 (800 mL) was stirred at 5° C. for 1 hr. then at r.t. overnight. The mixture was concentrated and the residue chromatographed (5% EtOAc/hexane) to afford the title compound as an oil.