Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccc(F)cc2)cc1

Procedure:
Compound (118) was prepared from compound (26) and (4-fluoro-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt=1.79 mins, m/z (ES−)=325 (M−H for C19H15FO4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: CC(C)I
Reactant: Cc1ccc2cc(F)c(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2cc(F)c(OC(C)C)cc2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
To 6-fluoro-2-methylquinolin-7-ol (800 mg, 3.16 mmol) in acetone (5 mL) were added 2-iodopropane (1075 mg, 6.32 mmol) and potassium carbonate (1310 mg, 9.48 mmol). The reaction was stirred at 70° C. in a sealed tube for 18 hours then cooled and diluted with water. The aqueous phase was extracted with DCM, dried over MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-7-isopropoxy-2-methylquinoline (270 mg, 39.0% yield) as an oil.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])(=O)=O>CCOC(C)=O>[Si:42]([O:27][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)[nH]c2c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C)(C)C(C)(C)C)[nH]c2c1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A solution (0.039 M) of methyl 3-cyclohexyl-2-[2-(hydroxymethyl)phenyl]-1H-indole-6-carboxylate was treated with 2,6-lutidine (2 eq) and then with tert-butyl(dimethyl)silyl trifluoromethanesulfonate (1.2 eq). The solution was stirred for 15 min. Removal of the volatiles in vacuo gave a residue that was diluted with EtOAc, washed with 1N HCl, saturated aqueous NaHCO3, brine, dried and concentrated in vacuo to afford the title compound (90%) as a solid. MS (ES+) m/z 478 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[C:12]1([N:18]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21](=O)[C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:21]3[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:19]3=[O:20])=[CH:11][C:6]=2[N:7]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Product: Cc1nc2cc(N=C3C(=O)N(c4ccccc4)c4ccccc43)ccc2s1
Temperature: 140 °C
Yield: 32.3 %

Procedure:
5-amino-2-methylbenzothiazole (52.2 mg, 0.31 mmol) was mixed with 1-phenylisatin (69.7 mg, 0.31 mmol) and heated at 140° C. for 3 h. The resulting crude product was purified by preparative TLC using ethyl acetate/hexane (6:4) as the eluent to give the desired product as a yellow solid (36.9 ma, 32.3%). 1H NMR Data: δ 7.9-6.7 (m, 12H), 2.9 (s, 3H). ESI-MS m/z found 370 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:21])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N+:6]([O-:21])=[CH:5][CH:4]=1
Reactant: COc1ccnc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc[n+]([O-])c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 25 mL of a chloroform solution containing 1.72 g of 4-methoxyquinoline, 3.16 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with 20 mL of an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a light brown oily substance, 4-methoxyquinoline N-oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)[C:15](F)=[N:16][CH:17]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[N:20]=2)[C:15]([NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:16][CH:17]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.67 h
Yield: 88 %

Procedure:
A stirred mixture of 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 0.834 g, 5.87 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.8776 g, 3.91 mmol) in THF (50.0 mL, 610 mmol) was treated dropwise with LiHMDS (1.0 M in THF, 16.74 mL, 16.74 mmol) at −15° C. (ice-salt bath) and stirred for 40 min. The reaction was then quenched with water and saturated NH4Cl (aq) (25 mL each) and diluted with EtOAc (25 mL). Organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Chromatographic purification of the residue (silica gel, 0% to 1% MeOH/DCM) followed by washing of the purified product with isopropanol gave 4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.07 g, 3.44 mmol, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J=2.54 Hz, 1H); 8.23 (d, J=2.54 Hz, 1H); 7.95 (d, J=1.96 Hz, 1H); 7.90 (d, J=12.13 Hz, 1H); 7.18 (dd, J=17.41, 8.41 Hz, 4H); 6.86 (t, J=8.12 Hz, 4H); 4.86 (s, 2H); 4.82 (s, 2H); 4.01 (s, 3H); 3.81 (s, 3H); 3.79 (s, 3H); 2.60 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([Cl:10])=[C:6]([Cl:8])[N:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc(Cl)c1Cl
Yield: 115.7 %

Procedure:
1 g (6.1 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 5 ml of DMF. To this solution was added 0.98 g (7.32 mmol) of N-chlorosuccinimide. The solution was poured onto 100 ml of cool water. The formed precipitate was filtered, washed with water and dried to yield 1.4 g (80%) of a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:29][Mg]Br.Cl>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH:16]([OH:17])[CH3:29])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C=O)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoyl)amino]pyrrolidine (250 mg, 0.63 mmol) prepared in Step A of Example C3 in THF was slowly added dropwise methylmagnesium bromide (in diethylether, 3.0M, 0.25 ml, 0.76 mmol) at 0° C., and the solution was stirred at rt for 2 h. After the reaction finished, to the solution was added 1N-HCl at 0° C., and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/2) to give the title compound (238 mg, 92%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 67 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.090 g, 0.187 mmol) obtained in step 2 and methanesulfonamide (0.039 mg, 0.412 mmol), the title compound (0.070 g, 67%) was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[NH:12][N:11]=1.[CH3:25]I>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH3:25])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])[N:14]=1
Reactant: CI
Reactant: Fc1ccccc1-c1n[nH]c(-c2ccccc2C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2C(F)(F)F)nc1-c1ccccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
0.19 g of sodium hydride is placed in 10 ml of N,N-dimethylformamide. A solution of 2.3 g of 3-(o-fluorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole in 15 ml of N,N-dimethylformamide is allowed to drop in while stirring during 10 minutes. After stirring for a further 45 minutes the solution, which has meanwhile become brown, is treated dropwise with 1.17 g of methyl iodide while cooling with ice. The reaction mixture is stirred for a further one hour and thereafter poured on to ice-water, and the aqueous mixture is extracted three times with ethyl acetate. The combined extracts are washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. In this manner there is obtained a mixture of isomeric N-methyltriazoles which can be separated by chromatography on silica gel. By elution with n-hexane/ethyl acetate (19:1) there is obtained pure 5-(o-fluorophenyl)-1-methyl-3-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole as a resinous product, 1H-NMR(CDCl3): 3.93 (d, CH3, coupling with F).
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][N:11]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2([CH3:29])[CH2:28][O:27]2)[CH2:21][CH2:20]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].C([O-])(=O)C.[Na+]>C(O)CC>[CH3:10][N:11]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2([CH3:29])[O:27][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:28]2)[CH2:21][CH2:20]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(CC2(C)CO2)CC1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCO
Product: CN(C(=O)OC(C)(C)C)C1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Yield: 12 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1.08 g, 7.31 mmol), tert-butyl N-methyl-[1-(2-methyloxiran-2-yl-methyl)piperidin-4-yl]carbamate (2.08 g, 7.31 mmol) and sodium acetate (660 mg, 8.04 mmol) in 1-propanol (15 ml) were stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was added water, and the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1), crystallized from methylene chloride-isopropyl ether to afford tert-butyl N-methyl-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]carbamate (348 mg, yield 12%) as a white powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:8]=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:3][OH:2])[CH:10]=2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: COC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(Cl)c(Cl)c2)ccn1

Procedure:
The title compound, MS: m/e=252.0 ([M-H]-) was obtained as a light brown oil (94% yield) by the reaction of 4-(3,4-dichloro-phenyl)-pyridine-2-carboxylic acid methyl ester with 1M lithium aluminum hydride/THF solution in THF at 20° C. for 1 h followed by chromatographic purification.
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:10]1[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OC)(C)(C)C>[CH3:1][C@H:2]([N:9]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCCCN1[C@@H](C)c1ccccc1
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H]1CCCCN1[C@@H](C)c1ccccc1
Reaction time: 24 h
Yield: 44.5 %

Procedure:
Methyl N-[(S)-α-methylbenzyl]-(RS)-pipecolate (159 mg) was dissolved in methyl tert-butyl ether (2 ml) at room temperature. To this solution was added a mixture of (2S)-L-(−)-malic acid (120 mg) and methyl tert-butyl ether (2 ml) at room temperature and stirred. The resultant solution was allowed to stand at −20° C. for one day to form crystals. The crystals were separated by filtration and dried to yield a (2S)-L-(−)-malic acid salt of methyl N-[(S)-α-methylbenzyl]-(S)-pipecolate (70.8 mg) in an optical purity of 41% de and a yield of 29%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28].Cl.ClCCl>N1C=CC=CC=1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a stirred solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (3 g, 12.00 mmol) in pyridine (12 ml), 2,4-difluorobenzenesulfonyl chloride (1.774 ml, 13.19 mmol) was added and the reaction mixture stirred at RT for 2 h. 2 N hydrogen chloride (aq) (20 ml) and dichloromethane (20 ml) were added and the layers separated. The aqueous layer was washed with additional dichloromethane (2×15 ml) and the organic layers combined, dried (hydrophobic frit) and evaporated in vacuo to give a brown oil. There was still some pyridine in the reaction mixture so 2M hydrogen chloride (aq) and dichloromethane (15 ml) were added to extract one more time. The solvent was removed in vacuo to give the title compound as an orange solid (4.3 g).
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:26])[CH2:4][C:5]([S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:6]#[N:7].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)([CH2:4][CH:3]([CH3:26])[CH2:2][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[C:6]#[N:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CC(C)CCl)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(C(C#N)(CC(C)CN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 17563.4 %

Procedure:
The procedure of Example 2 is repeated using 4.0 g of α-(3-chloro-2-methylpropyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 3.5 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 0,985 g of the desired product as a yellow foam.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.CON(C)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.O>O1CCCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:30])=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccncc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
To a solution of 4-pivaloylaminopyridine (7.0 g, 39 mmol) in tetrahydrofuran (100 ml) was added n-butyllithium (39.3 ml, 98 mmol, 2.5 M solution in tetrahydrofuran) at −78° C. under a N2 atmosphere. The reaction mixture was stirred at 0° C. for 5 h, re-cooled to −78° C. and quenched with a solution of N-methoxy-N-methyl-4-fluorobenzamide (7.9 g, 43 mmol) in 100 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and poured into water. The product was extracted into ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (10% ethyl acetate/hexanes gradient) to afford N-[3-(4-fluorobenzoyl)pyridin-4-yl]-2,2-dimethylpropanamide (10 g).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].COCO[C:12]1[CH:13]=C(C=[CH:18][CH:19]=1)CCl>CN(C=O)C>[CH2:1]([S:5][CH2:13][CH2:12][CH2:19][CH3:18])[CH2:2][CH2:3][CH3:4]
Reactant: COCOc1cccc(CCl)c1
Reactant: CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
n-Butanethiol (0.69 mL, 6.4 mmol) was added dropwise to a cold suspension of NaH (60% oil dispersion, 307 mg, 7.7 mmol) in DMF (10 mL). After 30 min, the resulting solution was treated with 3-methoxymethoxybenzyl chloride (40) (595 mg, 3.2 mmol) and stirred for an additional hour at room temperature. The reaction mixture was quenched with saturated NH4Cl and extracted with ether. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude residue was purified by flash chromatography eluting with 1% AcOEt-Hexanes to yield n-butylsulfide 42 (248 mg, 32%). 1H NMR (400 MHz, CDCl3) δ: 0.90 (t, J=7.3 Hz, 3H, —CH3), 1.40 (m, 2H, —CH2—CH2), 1.56 (m, 2H, —CH2—CH2), 2.44 (t, J=7.5 Hz, 2H, —CH2—S), 3.50 (s, 3H, OMe) 3.69 (s, 2H, —CH2—S), 5.20 (s, 2H, —CH2—O), 6.96 (d, J=7.2 Hz, 1H, Ar), 6.98 (d, J=7.3 Hz, 1H, Ar), 7.01 (s, 1H, Ar), 7.24 (t, J=7.8 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:30][C:25]1[CH:24]=[C:23]([NH:22][C:11](=[O:13])[CH2:10][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:14])[CH:28]=[CH:27][C:26]=1[OH:29]
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
3-(4-Fluorophenylamino)-3-oxopropanoic acid (197 mg, 1.00 mmol) was dissolved in 4 mL of dimethylformamide. Triethylamine (140 μL, 1.00 mmol) was added and the solution was cooled to 0° C. 4-Amino-2-fluorophenol (127 mg, 1.00 mmol, Aldrich) was added followed BOP reagent (442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and was then stirred at room temperature for 3 h. The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water gave the title compound (211 mg, 69%) as a white solid. 1H NMR (CD3OD) δ 7.61 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08 (m, 3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS(ESI+) m/z 307.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=O)[CH:3]=1.[OH-:13].[K+].[O-]Cl.[Na+]>C(O)C.O>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]2=[N+:6]([O-:13])[O:12][N:10]=[C:4]2[CH:3]=1
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCO
Solvent: O
Product: [O-][n+]1onc2cc(Br)c(F)cc21
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 41.7 %

Procedure:
4-Bromo-5-fluoro-2-nitroaniline (8.5 g, 36 mmol) was stirred in 200 mL ethanol and treated with 45% KOH solution (4.5 g, 36 mmol) to produce a dark solution. This solution was cooled to 0-5° C. and treated dropwise with 6% NaOCl solution (84 g, 68 mmol) over 20 min while maintaining the temperature below 10° C. After 90 min, the mixture was diluted with 300 mL water and extracted twice with 200 mL portions of ethyl acetate. The combined extracts were washed with 30 mL saturated NaCl, dried (Na2SO4) and evaporated. The crude material was chromatographed on silica gel with a 0-30% ethyl acetate-hexane gradient to give the title compound as pale yellow solid (3.5 g, 42%): mp 87-89° C.; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.23 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −96.03; EIMS m/z 232.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[OH:5])[CH2:3][CH2:2]1.O[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([CH:4]([C:6]2[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[O:5][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[O:23][CH3:24])[CH2:2][CH2:3]1
Reactant: COc1ccc(C(O)C2CC2)cn1
Reactant: COc1cc(C#N)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(Oc2ccc(C#N)cc2OC)C2CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a stirred 0° C. solution of cyclopropyl(6-methoxypyridin-3-yl)methanol (3.80 g, 21.20 mmol), 4-hydroxy-3-methoxybenzonitrile (1.60 g, 10.73 mmol), and triphenylphosphine (5.60 g, 21.35 mmol) in tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (3.70 g, 21.25 mmol) dropwise. The resulting mixture was allowed to warm to room temperature. After 2 h, the mixture was concentrated. Chromatographic purification of the residue (silica gel, 10% ethyl acetate in petroleum ether elute) afforded 2.70 g (80%) of 4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzonitrile as a light yellow oil.