Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH:8]3[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]3[CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CCN(C)C(S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(C(=O)O)CC1S(=O)(=O)c1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
[4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 75 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.9 g (50%); off white solid; MS: 426.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:25][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-methoxyphenyl)(p-tolyl)methanone, 32-b. (3 g, 13.3 mmol) in CCL4 (30 ml) was added NBS (2.8 g, 16 mmol) and AIBN (50 mg), the reaction mixture was then stirred for 3 h under refluxed. The resulting mixture was cooled to ambient temperature, filtered, and filtrate was concentrated under reduce pressure. Purified by column chromatography on silica gel (petroleum ether/ethyl acetate=6:1), the pure product, 32-c, was obtained as a colorless oil (3 g, 74% yield). 1H NMR (300 MHz, DMSO-d6) δ 3.84 (s, 3H), 4.49 (s, 2H), 6.90-6.94 (m, 2H), 7.43-7.61 (m, 2H), 7.67-7.79 (m, 4H). LC-MS 305 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:32].[CH3:33][N:34]1[CH2:39]C[O:37][CH2:36][CH2:35]1.CN(C)CC(O)=O>CN(C=O)C.CCOC(C)=O>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([NH:1][C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])=[C:3]([F:32])[CH:4]=3)[CH2:8][S:9](=[O:28])(=[O:29])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:26])([CH3:27])[CH3:25]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(N)c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Agent: CN(C)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1ccc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1F

Procedure:
A mixture of (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1oxa-5lambda*6*-thia-3-aza-inden-2-one (example 1j), 1.06 g, 2.3 mmol), N-methylmorpholine (0.507 mL, 4.6 mmol), N,N-dimethylglycine (0.356 g, 3.45 mmol) and propylphosphoric acid anhydride (50% in DMF, 2.68 mL, 4.6 mmol) was stirred in DMF (9.2 mL) at 25° C. for 19 h. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to leave the title compound as a colorless, amorphous powder: TLC (toluene-ETA 85:15) Rf=0.36; HPLC RtA=1.84 min; ESIMS [M+H]+=546; 1H NMR (600 MHz, DMSO-d6): δ 9.46 (s, 1H), 7.85 (t, 1H), 7.39 (s, 1H), 7.32 (d, 1H), 7.28 (t, 1H), 7.17-7.11 (m, 2H), 7.0 (d, 1H), 4.42 (d, 1H), 4.23 (d, 1H), 4.16 (t, 1H), 3.74-3.65 (m, 2H), 3.45 (t, 1H), 3.08 (m, 3H), 3.01 (m, 1H), 2.93 (m, 1H), 2.58 (m, 1H), 2.52 (m, 1H), 2.30 (s, 6H), 1.25 (s, 9H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:19]([C:20](O)=[O:21])=[CH:18][N:17]=[C:16]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:15]=1.[CH2:29]([NH:36][CH:37]1[CH2:40][CH2:39][CH2:38]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:29]([N:36]([CH:37]1[CH2:38][CH2:39][CH2:40]1)[C:20]([C:19]1[C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[F:7])=[N:15][C:16]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[N:17][CH:18]=1)=[O:21])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Reactant: c1ccc(CNC2CCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(N2CCOCC2)nc1-c1ccccc1F)N(Cc1ccccc1)C1CCC1
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
A solution of 2M oxalyl chloride in CH2Cl2 (0.062 mL, 0.125 mmol) was added to a stirred solution of 4-(2-fluorophenyl)-2-morpholinopyrimidine-5-carboxylic acid (Example 1; 0.03 g, 0.1 mmol) in CH2Cl2(2 mL) and DMF (0.030 mL) at room temperature, and stirring continued for 15 min. A solution of N-benzylcyclobutanamine (0.016 g, 0.1 mmol) in CH2Cl2 (1 mL) and diisopropylethylamine (0.044 mL,0.25 mmol) were added and stirred for 3 h. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give N-benzyl-N-cyclobutyl-4-(2-fluorophenyl)-2-morpholinopyrimidine-5-carboxamide (0.032 g,72%). Mass Spec. FIA MS 447 (M+1), 1H NMR(DMSO-d6, 500 MHz) δ 8.43(brs,1H), 7.52-7.55(m,2H), 6.99-7.31(m,7H), 4.62(brm,2H), 3.78(brm,4H0, 3.68(brn,4H), 2.15(brm,2H), 1.85(brm,2H), 1.17(brm,2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[O:14])=[C:3]([CH2:4][OH:5])[CH:6]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: OCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)COc2ccc(Br)cc2CO)cc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixed solution of 2-hydroxy-5-bromobenzyl alcohol (3.00 g) and 2-bromo-4′-methylacetophenone (3.50 g) and potassium carbonate (2.45 g) in acetone (50 ml) was stirred at 80° C. for 4 hours. After cooling to room temperature, a solid material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 2:3→1:1) to obtain 2-[4-bromo-2-(hydroxymethyl)phenoxy]-1-(4-methylphenyl)-1-ethanone (3.60 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:25])([C@H:16]([C:18]1[C:23]([F:24])=[CH:22][N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(C(C)C)[P:30]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(C)C.ClC1C=C(C=CC=1)C(OO)=[O:55]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[P:30]([O:25][C@@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([C@H:16]([C:18]1[C:23]([F:24])=[CH:22][N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:55]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](c1ncncc1F)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H](c1ncncc1F)[C@@](Cn1cncn1)(OP(=O)(OCc1ccccc1)OCc1ccccc1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (the compound of Example 7, EP 0440372, also known as voriconazole, 17.0 g, 48.7 mmol), 4-dimethylaminopyridine (10.2 g, 83.5 mmol) 10.2 g, 146 mmol) and dibenzyl diisopropylphosphoramidite (33.6 g, 97.4 mmol) in methylene chloride (100 ml) was stirred at reflux for 2 hours and a further 16 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then washed with hydrochloric acid and then sodium bicarbonate, dried (MgSO4) and concentrated. The crude product phosphite was purified by column chromatography (silica gel, 300 g, eluting with 3:1 to 1:1 hexane:ethyl acetate gradient) to give a pale yellow oil. This was dissolved in methylene chloride (100 ml) and cooled to −10° C., whereupon a solution of 3-chloroperoxybenzoic acid (14.8 g, 57% w/w, 48.9 mmol) in methylene chloride (100 ml) was added maintaining the temperature below 0° C. The resulting mixture was allowed to warm to room temperature for 10 minutes before washing with aqueous sodium metabisulphite and sodium bicarbonate. After drying (MgSO4) and concentrating the crude product was purified by column chromatography (silica gel, 300 g, eluting with ethyl acetate) to give the subtitle compound as a viscous syrup (17.86 g, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([CH3:16])[CH:8]=[CH:7]2.[CH3:17][O-:18].[Na+].N1C=CC=CC=1.Cl>CO.O.[Cu](I)I>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([CH3:16])[CH:8]=[CH:7]2
Reactant: C[O-]
Reactant: COC(=O)c1c(C)ccc2cccc(Br)c12
Agent: I[Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1c(C)ccc2cccc(OC)c12
Yield: 40 %

Procedure:
A mixture of methyl 8-bromo-2-methylnaphthalene-1-carboxylate (Intermediate 191, 1.0 g), sodium methoxide (25% wt/solution in methanol, 5 g), copper iodide (0.37 g), and pyridine (13 ml) in methanol (13 ml) was stirred and heated at reflux for 3 days. After cooling, the mixture was diluted with water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with 1M HCl and brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give methyl 8-methoxy-2-methylnaphthalene-1-carboxylate (0.33 g) as a lilac oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33].[H-].[Na+].[CH3:38]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]([CH3:38])[S:32]([CH3:35])(=[O:33])=[O:34]
Reactant: CI
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2N(C)S(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
To a solution of 1.4 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of DMF was added 229 mg of sodium hydride under ice-cooling, followed by stirring at the same temperature for 10 minutes, and then 0.17 ml of methyl iodide was added thereto, followed by stirring under ice-cooling for 30 minutes. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 545 mg of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[methyl(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C([O-])(=O)C.[Na+]>O.Cl.C(O)C>[CH2:19]([O:18][C:12](=[O:17])[C:13](=[N:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14](=[O:15])[CH3:16])[CH3:20]
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NNc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 80255.7 %

Procedure:
A solution of aniline (37.2 g, 0.4 mmol) in water (32 ml) and concentrated hydrochloric acid (100 ml) was poured into ice (400 g). The 0° C. solution was treated with a solution of sodium nitrite (27.6 g, 0.4 mmol) in water (50 ml). The diazonium salt solution was poured rapidly into a stirred solution of ethyl acetoacetate (52 g, 0.4 mmol) in ethanol (300 ml) and ice water (1.0 L) containing sodium acetate (100 g, 1.2 mmol). Th mixture was stirred at 0° C. for 2.5 hours, filtered, and the filter cake was crystallized from ethanol to yield the title compound (75.2 g), m.p. 75°-76° C. (lit 61°-64° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[OH-].[Li+]>CO.Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc2ccnc(OC)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1nccc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To a solution of methyl 1-methoxyisoquinoline-7-carboxylate (443 mg, 2.04 mmol) in methanol (10 mL) was added 2 N aqueous lithium hydroxide (20 mL). The reaction was stirred at room temperature for 24 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid and ethyl acetate. The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound (414 mg, 100%) as a solid. +ESI (M+H) 204.1; 1H NMR (400 MHz, DMSO-d6, δ): 13.24 (s, 1H), 8.76 (d, J=0.8 Hz, 1H), 8.18 (dd, J=8.6, 1.8 Hz, 1H), 8.11 (d, J=5.9 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.45 (d, J=5.9 Hz, 1H), 4.07 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([C:11](=[O:20])[C:12]3[C:18](Br)=[CH:17][S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([C:11](=[O:20])[C:12]3[C:18]([CH3:21])=[CH:17][S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Zn]C
Reactant: O=C1c2c(Br)csc2C2CN(Cc3ccccc3)CC12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1csc2c1C(=O)C1CN(Cc3ccccc3)CC21
Temperature: 22 °C
Yield: 97 %

Procedure:
A solution of the product from step e) (2.4 g, 6.89 mmol) in dioxane (34.5 ml) was treated with Pd(dppf)2Cl2 (337 mg, 0.41 mmol) and a 2M solution of dimethylzinc in toluene (6.89 ml, 13.78 mmol) at 102° C. for 1 hour. The reaction was cooled to 22° C. and carefully quenched with sat. NH4Cl (20 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic layers were dried (MgSO4) and passed through a plug of silica-gel using 50:50 hexanes:EtOAc to give the subtitle compound (1.9 g, 97%). MS calculated for C17H17NOS+H 284, observed 284.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].OO.[C:11]([OH:14])(=[O:13])[CH3:12]>C(OC(=O)C)(=O)C>[C:11]([O:14][CH2:8][C:2]1[C:3]([CH3:7])=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: Cc1cccnc1C
Agent: OO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ncccc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2,3-lutidine (4.8363 g, 45.13 mmol) in glacial acetic acid (30 mL) at room temperature was added 30% H2O2 (4.6 mL) and the resultant solution was heated to 70° C. After 6 hours, the reaction mixture was cooled to room temperature, additional H2O2 (4.6 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved in CHCl3 (100 mL) and treated with solid Na2CO3 (14.12 g). After 1 hour, the supernatant was decanted and the residue was washed with warm CHCl3 (3×50 mL). The combined. supernatants were filtered and concentrated to provide 4.6951 g as a yellow solid. The solid was dissolved in acetic anhydride (38 mL) and heated at 90° C. overnight. The mixture was cooled to room temperature and concentrated and the crude product was filtered through a silica plug (33 g silica, ethyl acetate) to give 6.13 g of 2-acetoxymethyl-3-methyl-pyridine as an orange oil.
Reaction SMILES: C[Si](I)(C)C.C[O:7][CH2:8][C@H:9]([CH3:37])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15].O>C(#N)C>[OH:7][CH2:8][C@H:9]([CH3:37])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 83.9 %

Procedure:
Trimethylsilyl iodide (11.06 ml, 76.25 mmol) was added to a solution of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (7.00 g, 15.25 mmol) in dry acetonitrile (100 ml) under argon for 21 h. Water (40 ml) was added to quench the reaction and the acetonitrile was removed in vacuo. The residue was diluted with ethyl acetate (200 ml) and 1M aqueous hydrochloric acid and the organic layer was separated and further washed with 10% w/v aqueous sodium thiosulfate pentahydrate to remove residual iodine. The organic layer was separated, dried (MgSO4), filtered and evaporated and purified by column chromatography (eluting with 3% to 5% methanol: dichloromethane) to give the title compound (5.70 g, 84%) as a white foam. Recrystallisation from hot ethanol (125 mg/ml) afforded the title compound as colourless needles (87% recovery); 1H NMR (300 MHz, CDCl3) δ: 1.33 (d, 3H), 2.10 (t, 1H), 3.08 (s, 3H), 3.78 (m, 2H), 3.82 (s, 3H), 4.57 (m, 1H), 6.80 (m, 2H), 7.15 (m, 3H), 7.25 (m, 2H), 7.93 (d, 2H), 8.43 (s, 1H); m/z 444 (M−H)−.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[C:39]([O:43][C:44]([N:46]1[C@H:51]([CH3:52])[CH2:50][CH2:49][C@H:48]([C:53](O)=[O:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C[C@H]1NC[C@@H](C(O)=O)CC1>ClCCl.O>[CH3:52][C@H:51]1[CH2:50][CH2:49][C@@H:48]([C:53]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:54])[CH2:47][N:46]1[C:44]([O:43][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:45]
Reactant: C1CCNC1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[C@@H]1CC[C@H](C(=O)O)CN1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](C(=O)N2CCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (7.50 g, 19.72 mmol), diisopropylethylamine (7.08 mL, 39.45 mmol) and pyrrolidine (1.40 g, 19.72 mmol) were added to a solution of cis-1-(tert-butoxycarbonyl)-6-methylpiperidine-3-carboxylic acid (synthesized by N-Boc protection of cis-6-methylpiperidine-3-carboxylic acid, analogously prepared by the method described in J. Med. Chem. 2011, 54, 1871-1895.) (4.0 g, 16.44 mmol) in anhydrous dichloromethane (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. Water was added and the mixture was extracted with dichloromethane. The organics were dried over sodium sulfate and concentrated under reduced pressure to afford cis-tert-butyl 2-methyl-5-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (4.0 g). The material was used without further purification.
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:31][CH3:32])=[N:25][C:26]([O:29][CH3:30])=[N:27][CH:28]=1)O.[Cl-:33].[NH4+]>ClCCl>[Cl:33][C:15]1([C:23]2[C:24]([O:31][CH3:32])=[N:25][C:26]([O:29][CH3:30])=[N:27][CH:28]=2)[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=2)[NH:17][C:16]1=[O:21]
Reactant: COc1ncc(C2(O)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ncc(C2(Cl)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyridine (0.28 ml) and thionyl chloride (0.18 ml) were added successively to an ice-cold solution of the intermediate from step A (0.64 g, 2.0 mmol) in dichloromethane (20 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude intermediate was rapidly employed without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[F:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:26][CH2:25][C:24]1[C:19]([C:16]2[CH:17]=[N:18][C:13]([F:12])=[CH:14][CH:15]=2)=[N:20][CH:21]=[CH:22][CH:23]=1)=[S:11]
Reactant: NCc1cccnc1-c1ccc(F)nc1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Product: Fc1ccc(-c2ncccc2CNC(=S)Nc2cccc(Cl)c2Cl)cn1
Yield: 72 %

Procedure:
The title compound was synthesized by general procedure 1 using 2,3-dichlorophenylisothiocyanate and C-(6′-fluoro-[2,3′]bipyridinyl-3-yl)-methylamine (Example 192F) to give 0.974 g (72%) of 1-(2,3-dichloro-phenyl)-3-(6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-thiourea as a white powder. 1H NMR (DMSO-d6, 400 MHz) 4.74 (d, J=4.1 Hz, 2H), 7.31 (dd, J=2.5, J=8.2 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.49 (dd, J=4.7 Hz, J=7.9 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.87 (dd, J=1.5 Hz, J=7.9 Hz, 1H), 8.17 (dt, J=2.5 Hz, J=8.2 Hz, 1H), 8.39 (bs, 1H), 8.41 (d, J=2.5 Hz, 1H) 8.60 (dd, J=1.6 Hz, J=4.7 Hz, 1H), 9.49 (bs, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min), then 100% acetonitrile isocratic 2 minutes, Rt 10.30 min. (94.3%); MS: M+H+ 407.