Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].I[C:23]1[C:27]([CH2:28][N:29]([CH3:41])[CH2:30][CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:26][N:25]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[CH3:12][CH:10]([C:8]1[CH:7]=[C:6]([C:23]2[C:27]([CH2:28][N:29]([CH3:41])[CH2:30][CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:26][N:25]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[N:24]=2)[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:9]=1)[CH3:11]
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Reactant: CC(C)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)c1cc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cc(C(C)C)c1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A mixture of 2-(3,5-diisopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (288 mg, 1.00 mmol, 1.00 equiv), tert-butyl N-[2-([[3-iodo-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl](methyl)amino)ethyl]-N-methylcarbamate (479 mg, 1.00 mmol, 1.00 equiv), K3PO4 (636 mg, 3.00 mmol, 3.00 equiv) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (65 mg, 0.10 mmol, 0.10 equiv) in ethylene glycol dimethyl ether (5 mL) was stirred under nitrogen in a 10-mL sealed tube for 12 h at 85° C. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (39:1 with 0.1% triethylamine) to obtain 100 mg (20%) of tert-butyl N-[2-[([3-[3,5-bis(propan-2-yl)phenyl]-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl)(methyl)amino]ethyl]-N-methylcarbamate as a black solid. 1H NMR (300 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.49 (s, 2H), 7.07 (s, 1H), 5.45-5.35 (m, 1H), 4.01-3.88 (m, 1H), 3.71-3.60 (m, 1H), 3.40 (s, 2H), 3.24 (s, 2H), 3.00-2.80 (m, 2H), 2.68 (s, 3H), 2.49-2.40 (m, 2H), 2.23 (s, 3H), 2.15-1.85 (m, 3H), 1.80-1.60 (m, 1H), 1.31 (s, 9H), 1.23 (d, J=6.9 Hz, 12H) ppm. LCMS (method D, ESI): RT=1.41 min, m/z=513.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([OH:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][CH2:45][CH2:46][CH2:47]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([O:13][CH2:47][CH2:46][CH2:45][O:44][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][O:38]3)[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(O)c2)n1
Reactant: OCCCOC1CCCCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of 5-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol (WO2011/154734A1, which is incorporated herein by reference in it is entirety; 500 mg, 1.88 mmol), and Ph3P (986 mg, 3.76 mmol) in dry THF (10 mL) was added 3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (Can. J. Chem. Vol. 73, 1195, pp 1682, which is incorporated herein by reference in it is entirety; 452 mg, 2.82 mmol). The resulting mixture was cooled to 0° C. using an ice bath and diethylazodicarboxylate (0.69 mL, 3.76 mmol) was added to the chilled mixture which was allowed to warm up to RT. The volatiles were removed under reduced pressure. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (739 mg, 96%). LCMS (Method 1): Rt 3.63 min, m/z 408 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:5][C:4]=1[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1)[CH3:2].ClC(Cl)C.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:37]([N:22]1[CH2:21][CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:6]3[C:7]([C:9]([NH2:11])=[O:10])=[N:8][C:3]([CH2:1][CH3:2])=[C:4]([NH:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]4)[N:5]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(C3CCNCC3)cc2)nc1N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCc1nc(C(N)=O)c(Nc2ccc(C3CCN(C(C)=O)CC3)cc2)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide (Example 358) (43 mg) and dichloroethane (1 mL), pyridine (0.01 mL) and acetic anhydride (0.01 mL) were added under ice cooling and stirred at room temperature for 20 minutes. After addition of saturated aqueous sodium hydrogen carbonate, the reaction liquid was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the organic layer was concentrated, and the resulting residue was solidified with ethyl acetate-hexane to give 3-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (26 mg) as a white solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C>[ClH:32].[C:23]1([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
(R)-1-(2-((2,2-Diphenylethenyl)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (Example 50) (3.0 g, 0.079 mol) was dissolved in ethanol (20 ml) and 12 N sodium hydroxide solution (2.0 ml) was introduced. After stirring the solution at room temperature for 2.5 h, 37% hydrochloric acid (ca. 2.2 ml) was added, with acidity measured at pH 2. Dichloro-methane (300 ml) was introduced, and the mixture was dried (MgSO4). Filtration and evaporation of the filtrate gave a solid, which was triturated with diethyl ether, to give the title compound (2.65 g, 86%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([NH2:29])=[O:28])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2ccnc(N)c2)c1-c1ccc(F)cc1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: Cn1cnc(-c2ccnc(NC(N)=O)c2)c1-c1ccc(F)cc1
Temperature: 50 °C
Yield: 65.4 %

Procedure:
4-[5-(4-Fluoro-phenyl)-1-methyl-1H-imidazol-4-yl]-pyridin-2-ylamine (72 mg, 0.27 mmol) and benzoyl isocynate (59 mg, 0.40 mmol) are mixed in DCM (2.0 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (2.0 mL) and potassium carbonate (56 mg, 0.40 mmol). The mixture is then heated at 80° C. for 35 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (45 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is washed with methanol (3×5 mL) and dried to give 55 mg of the titled product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[C:7]1[CH:12]=[C:11]([C:13]2[C:17](C)=[CH:16]S[CH:14]=2)[CH:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]=2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C1C=C(OCCCCCCC2C=CC=C(OCCCC(OCC)=O)C=2CCC(OCC)=O)C=C(Br)C=1)(C)(C)C.[O:92]1[C:97]2C=CC(B(O)O)=C[C:96]=2[O:95][CH2:94][CH2:93]1>>[C:1]([O:5][C:6](=[O:48])[C:7]1[CH:8]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]=2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:10]=[C:11]([C:13]2[CH:14]=[CH:94][C:93]3[O:92][CH2:97][CH2:96][O:95][C:16]=3[CH:17]=2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)OC(C)(C)C)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC

Procedure:
The title compound was prepared by the same method as 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid tert-butyl ester starting from 3-bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester and 1,4-benzodioxane-6-boronic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[NH:21]1[CH:25]=[C:24]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:23]=[CH:22]1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[NH:21]1[CH:25]=[C:24]([C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)([OH:30])[CH:27]([CH3:29])[CH3:28])[N:23]=[CH:22]1
Reactant: COc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)C(=O)c1c[nH]cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
4-Bromo-4′-methoxy-1,1′-biphenyl (1.95 g) was dissolved in THF (40 ml) and the mixture was cooled to −78° C. A solution (1.6 M; 5.5 ml) of n-butyllithium in hexane was added dropwise, and the mixture was stirred at −78° C. for 1 h. Then, a solution (10 ml) of 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (335 mg) in THF was slowly added dropwise. The reaction mixture was heated from −78° C. to room temperature and saturated aqueous ammonium chloride solution was added to the reaction mixture. The mixture was extracted with ethyl acetate and the organic layer was dried and concentrated. The obtained residue was recrystallized from ethyl acetate to give the title compound (322 mg) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.[CH:16](O)=[O:17].O>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]([CH:16]=[O:17])[CH2:6][C:7]1[CH:8]=[C:9]([F:14])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=CO
Reactant: COC(=O)CNCc1cc(F)cc(F)c1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)CN(C=O)Cc1cc(F)cc(F)c1
Yield: 99.3 %

Procedure:
A solution of N-(3,5-difluorobenzyl)-glycine methyl ester (7.61 g, 0.0352 mole) and formic acid (1.33 ml, 0.0352 mole) was heated at reflux in xylene (60 ml) with azeotroic removal of water for 2.5 hours and the solvent was removed under vacuum to give the product as an oil (8.50 g, 99%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:28]>CCCCCC>[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:20][CH2:19][C:6]3([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCc1ccc(N)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Product: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 251 step A) from 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, dimethylaluminium chloride in hexane and 4-ethyl-phenylamine, with concomitant cleavage of the Boc protecting group under the conditions. MS (ESI): 259.1 (MH+).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].[Na+].[CH2:27]1[O:30][CH:28]1[CH3:29]>O>[C:1]([CH2:4][N:5]1[CH2:16][CH2:15][N:14]([CH2:27][CH:28]([OH:30])[CH3:29])[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 96 %

Procedure:
To a solution of 194.0 g (0.56 mol) of 15 in 450 mL of water is added sufficient NaOH to adjust the pH to 12.0 to 12.5 (the temperature is maintained below 30° C. during the addition). Propylene oxide (65 g, 1.12 mols) is added to the basic solution. After 6 hours at ambient temperature the excess propylene oxide and solvent is removed under reduced pressure. The product is precipitated from a minimal amount of methanol to afford 16 in 96% yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=O)=O.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F-].[K+]>C1(C2(C3C=CC=CC=3)CC2(P(C(C)(C)C)C(C)(C)C)C)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, 4-trifluoromethane-sulfonyloxyanisole (0.49 g, 1.9 mmol), phenylboronic acid (0.29 g, 2.4 mmol), potassium fluoride (0.24 g, 4.2 mmol), (π-allyl)palladium chloride (3.6 mg, 0.01 mmol), 2,2-diphenyl-1-(di-tert-butylphosphino)-1-methylcyclopropane (14.0 mg, 0.04 mmol) obtained in Example 4 and toluene (4 ml) were placed in a reaction flask and stirred for 1.5 hours at 80° C. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the concentrate was purified by column chromatography to give the title compound (0.34 g, 96%) as white crystal.
Reaction SMILES: [O:1]1[C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1C(=O)N([I:18])C(=O)C1>C(#N)C>[I:18][C:9]1[CH:8]=[N:7][C:6]([NH2:10])=[C:5]2[O:1][CH:2]=[CH:3][C:4]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2ccoc12
Solvent: CC#N
Product: Nc1ncc(I)c2ccoc12
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of furo[2,3-c]pyridine-7-ylamine (1.5 g, 11.2 mmol) in acetonitrile (40 mL) was added NIS (3.02 g, 13.4 mmol) portionwise over a period of 15 min. The resultant mixture was stirred at RT for 16 h. The reaction mixture was quenched with 20% aqueous sodium thiosulfate solution (20 mL) and stirred for 10 min. The mixture was extracted with ethyl acetate (70 mL). The organic layer was washed with aqueous 20% sodium thiosulfate solution (20 mL), water (2×50 mL), and brine (40 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (25% ethyl acetate:hexanes) afforded 2.5 g (86%) of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([C:35]2([OH:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>CS(C)=O>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:38]1[CH2:37][CH2:36][C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:42])[F:43])[CH:30]=2)([OH:41])[CH2:40][CH2:39]1)[O:14]3
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)CO3
Temperature: 80 °C

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.43 g, 1.14 mmole) and 4-[3-(trifluoromethyl)phenyl]-4-piperidinol (0.84 g, 3.43 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated to 80° C. under nitrogen for 4 hours. After completion, the reaction was allowed to cool to room temperature and was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.33 g of the (S)-enantiomer of the title compound, m.p. 148-151° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]([NH:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([CH3:25])[N:18]=2)=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[C:2]=[O:3].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:2](=[O:3])[NH:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]([NH:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([CH3:25])[N:18]=2)=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc(N=C=O)c2)n1
Reactant: CC(C)(C)N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc(NC(=O)NC(C)(C)C)c2)n1

Procedure:
To a solution of 3-isocyanato-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide prepared as in Example 3 was added 0.8 g of tert-butylamine at ambient temperature with stirring. After sixteen hours, filtration of the reaction mixture and evaporation of the filtrate yielded the desired product which after trituration with ethyl ether and isolation by filtration melted at 137°-145°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=O)[NH:21][C:20]=1[CH3:27])=[O:18])[CH3:12]>N1CCCCC1.C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[NH:21][C:20]=1[CH3:27])=[O:18])[CH3:29]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Yield: 55.5 %

Procedure:
A mixture of 1,3-dihydro-indol-2-one (266 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90° C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 422 mg (55%) of the title compound as a light yellow solid.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][CH:43]3[CH2:49][CH2:48][CH:47]4[CH:45]([C:46]4([F:51])[F:50])[CH2:44]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[CH2:30][CH2:29]1.CS(N)(=O)=O.[CH:57]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58]1>>[CH:28]1([C:31]2[C:32]([O:41][CH2:42][CH:43]3[CH2:49][CH2:48][CH:47]4[CH:45]([C:46]4([F:50])[F:51])[CH2:44]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([NH:63][S:60]([CH:57]2[CH2:59][CH2:58]2)(=[O:62])=[O:61])=[O:37])[CH2:30][CH2:29]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a colorless solid (0.012 g, 11%): 1H NMR (300 MHz, CDCl3) δ11.80 (br s, 1H), 7.10 (d, J=8.2 Hz, 1H), 7.02-6.87 (m, 1H), 4.14-3.78 (m, 2H), 3.12-2.50 (m, 2H), 2.42-2.05 (m, 2H), 2.05-1.27 (m, 5H), 1.28-1.14 (m, 2H), 1.15-0.95 (m, 4H), 0.95-0.74 (m, 2H), 0.70-0.54 (m, 2H); MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].N1C=CC=CC=1.[CH2:22]([C:29](O)([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([OH:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([C:29]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([OH:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCC(O)(Cc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(Cc1ccccc1)(OS(=O)(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Triflic anhydride (71 mmoles, 20 g) was added at -27° C. to a solution of pyridine (74 moles, 5.9 g) in 150 ml methylene chloride with vigorous stirring. The solution was warmed to room temperature. Benzyl 2-hydroxyhexanoic acid (57 moles, 12.65 g) in 15 ml methylene chloride was added over 2 minutes. The solution was stirred for 1 hour and filtered. The filtrate was concentrated, filtered through silica gel eluted with hexane, and evaporated to yield 17.0 g of benzyl 2-(trifluoromethanesulfonylhydroxy)hexanoic acid. (MS)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([Li])CCC.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1.CCCCCC>[F:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:3][C:2]=1[C:24](=[O:26])[CH3:25]
Reactant: Fc1ccc(CN2CCOCC2)cc1Br
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: -75 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
4-(3-Bromo-4-fluorobenzyl)morpholine (Preparation 1, 35.5 g) is dissolved in THF (400 mL) and cooled to −75° C. A solution of n-butyllithium in hexane (2.5 M, 57.0 mL) is added via addition funnel, maintaining the temperature below −68° C. A solution of N-methoxy-N-methylacetamide (16.0 g) in THF (50 mL) is added via addition funnel, maintaining the temperature below −65° C. The reaction is stirred at −75° C. for 1 h and allowed to warm to rt overnight. The reaction is quenched with 1 N HCl (150 mL) and poured into ethyl acetate (400 mL). The aqueous layer is separated, made basic with sat. aq. NaHCO3, and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL). The combined aqueous washes are back-extracted with ethyl acetate (100 mL). The organic layers are combined, dried (Na2SO4), and concentrated in vacuo to a yellow oil. The crude product is distilled (135° C., 0.3 Torr) to afford 19.7 g (64%) of the title compound as a clear, colorless oil. Physical characteristics: B.p. 135° C. (0.3 Torr); 1H NMR (300 MHz, DMSO-d6) δ 7.72, 7.61-7.56, 7.31, 3.56, 3.48, 2.58, 2.34; IR (liq.) 1996, 1979, 1919, 1688, 1612, 1492, 1417, 1361, 1291, 1281, 1212, 1118, 865 cm−1; MS (ESI+) m/z 238 (M+H)+. Anal. Calcd for C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.43; H, 6.75; N, 5.84.