Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[OH:36][CH2:37][CH:38]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:38][CH2:37][OH:36])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=CCO
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CCO)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), and hydroxy-acetaldehyde according to the procedure in Example 21. 1H-NMR (400 MHz, CD3OD): δ 8.18 (d, 1H), 8.02 (s, 1H), 7.22 (dd, 1H), 7.14 (d, 2H), 5.82 (m, 1H), 3.94 (m, 2H), 3.74 (m, 2H), 3.30 (m, 2H), 3.18 (t, 2H), 2.92 (m, 1H), 2.30 (m, 4H), 2.20-1.98 (m, 4H), 1.96-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H29N5O2, 420.2 (M+H), found 420.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:45])[C:9]([C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)([CH3:34])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:32])=[O:31])([CH3:29])[CH3:28])[CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:12]=2)=[CH:4][CH:3]=1.[CH3:46][Mg]I>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:45])([C:9]([C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)([CH3:34])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:31])=[O:32])([CH3:28])[CH3:29])[CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:12]=2)[CH3:46])=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: CC(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)(C(=O)c1ccc(F)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(F)cc1)C(C)(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 21 °C
Reaction time: 12 h

Procedure:
To a solution of Example 19 (93 mg, 0.144 mmol) in CH2Cl2 (4 mL) at −78° C. was added methyl magnesium iodide (3M, Et2O, 0.24 mL, 0.8 mmol) dropwise. The resulting reaction mixture was stirred at 21° C. for 12 h, then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with dichloromethane/methanol, 99:1, 2×), then stirring vigorously the resulting residue in hexane/ethyl acetate/ether for 1 h and then filtration afforded the title compound as a white powder (mixture of diastereoisomers; 1:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][NH2:26]>CO.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:22]([CH3:23])=[N:25][NH:26][C:19]=2[CH3:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)C(Cc1cn(C(=O)OC(C)(C)C)c2ncccc12)C(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1n[nH]c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Reaction time: 2 h

Procedure:
To 3-(2-acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (513, 1.20 g, 3.63 mmol) in methanol (15.0 mL), cooled to −20° C. under an atmosphere of nitrogen, was added hydrazine (0.128 g, 4.00 mmol) in dichloromethane (6.0 mL). The reaction was stirred for 2 hours. The reaction was concentrated to remove the solvents, and the residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 60% ethyl acetate in hexane to give a white solid (514, 1.0 g, 84.4%). MS (ESI) [M+H+]+=327.4.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH2:20])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]3[N:42]([CH3:43])[N:41]=[N:40][N:39]=3)[CH:33]=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH:20][C:30]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[N:42]([CH3:43])[N:41]=[N:40][N:39]=4)[CH:33]=3)=[O:29])[CH2:8]2)=[CH:21][CH:22]=1
Reactant: N[C@@H]1COCC[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CC#N
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2COCC[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine (44 mg, 143 μmol) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (47 mg, 158 μmol) were dissolved in acetonitrile (1 mL) and the mixture was stirred at room temperature. After 24 h, the mixture was concentrated, dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by reverse phase high pressure liquid chromatography (C18, 10-100% acetonitrile in water, containing 0.05% trifluoroacetic acid), then by flash column chromatography (5% methanol in dichloromethane, containing 0.5% ammonium hydroxide) to provide the product as a glass (16 mg, 23%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[NH:8][S:9](=[O:18])(=[O:17])[C:10]2[CH:16]=[CH:15][S:14][C:11]=2[C:12]=1[OH:13])=[O:5])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]([CH3:21])[S:9](=[O:17])(=[O:18])[C:10]2[CH:16]=[CH:15][S:14][C:11]=2[C:12]=1[OH:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC1=C(O)c2sccc2S(=O)(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1=C(O)c2sccc2S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.93 G. (7 mmol) of 3-ethoxycarbonylmethyl-4-hydroxy-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide are dissolved in 4 ml. of absolute dimethylformamide and added dropwise during 30 minutes at 0° C. to a stirred suspension of 0.185 g. (7.7 mmol) of sodium hydride in 2 ml. of absolute dimethylformamide. The mixture is stirred for a further 1 hour at room temperature. There are then added firstly 0.53 ml. (1.2 g.; 8.45 mmol) of methyl iodide and, after 30 minutes, a further 0.25 ml. (0.565 g; 4 mmol) of methyl iodide and the mixture is allowed to react for 1 hour. After distillation of the solvent, the residue is taken up in 30 ml. of 0.5-N hydrochloric acid and 30 ml. of methylene chloride, the organic phase is separated and the aqueous layer is back-extracted twice with a small amount of methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol. There is obtained 3-ethoxycarbonylmethyl-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide of melting point 161°-163° C. (crystal transformation at 151°-152° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:7])=[O:6].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>>[CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:23]=[O:24])(=[O:16])=[O:15])(=[O:6])=[O:7]
Reactant: CCCCN=C=O
Reactant: COCCS(=O)(=O)c1ccccc1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: COCCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C

Procedure:
A mixture of 2-[(2-methoxyethyl)sulfonyl]benzenesulfonamide (9.5 g, 0.034 mol), n-butylisocyanate (4.7 ml, 0.041 mol) and 1,4-diaza[2.2.2]bicyclooctane (0.1 g) in mixed xylenes (58 ml) was heated to 140° with stirring under nitrogen. Liquid phosgene (2.7 ml, 0.039 mol) was added at a rate to maintain an internal temperature between 125°-135°. When the addition was complete, the solution was refluxed for 2 hours, cooled to room temperature under nitrogen purge and then filtered under a nitrogen atmosphere. Removal of solvent in vacuo gave 2-[(2-methoxyethyl)sulfonyl]benzenesulfonyl isocyanate, which was used immediately in Example 5 below, without further purification.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1CCSC(C)=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(CCSC(C)=O)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.8 %

Procedure:
To a solution of methyl 3-[2-(acetylthio)ethyl]-1H-indole-2-carboxylate (0.364 g, 1.31 mmol), phenylboronic acid (0.239 g, 1.97 mmol), and copper(II)acetate (0.237 g, 1.31 mmol) in dichloromethane (10 mL) was added pyridine (0.91 mL, 6.55 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was passed through a column of silica gel (EtOAc/hexanes, 1:9) to afford 3-(2-acetylthioethyl)-1-phenyl-1H-indole-2-carboxylic acid, methyl ester (0.153 g, 0.43 mmol, 33%) as a clear oil: 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.20–3.24 (m, 2H), 3.39–3.43 (m, 2H), 3.75 (s, 3H), 7.07 (d, J=8.2 Hz, 1H), 7.20–7.32 (m, 4H), 7.42–7.53 (m, 3H), 7.87 (d, J=7.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[H-].[Na+].Br.Cl[C:12]1[CH:13]=[C:14]([CH3:22])[C:15]2[N:16]([C:18]([NH2:21])=[N:19][N:20]=2)[N:17]=1.O>CN(C=O)C>[CH3:22][C:14]1[C:15]2[N:16]([C:18]([NH2:21])=[N:19][N:20]=2)[N:17]=[C:12]([O:7][CH2:6][C:2]2([CH3:1])[CH2:5][O:4][CH2:3]2)[CH:13]=1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: CC1(CO)COC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC2(C)COC2)nn2c(N)nnc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
(3-Methyloxetan-3-yl)methanol (1.74 g) was initially charged in DMF (30 ml), admixed under argon with sodium hydride (408 mg) and stirred at 45° C. for 0.5 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g) was dissolved in DMF (30 ml) and one equivalent of the alkoxide solution (10 ml) was added. After stirring at 45° C. for 30 min, a further 0.5 equivalent of alkoxide solution was added, followed by 0.5 eq. each after a further 30 and 60 min. Then the mixture was admixed with water, and the reaction mixture was dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 758 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1ccc[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 50 %

Procedure:
3-Methylpyridine 1-oxide (2 g, 18.3 mmol, Step a) was added slowly to the round bottom flask containing sulfuric acid (7 mL, 128 mmol). The mixture was cooled to 0° C. and nitric acid (5.7 mL, 128 mmol) was added drop wise. The resulting reaction mixture was heated at 90-100° C. for 2 hours. The reaction mixture was poured onto crushed ice and sodium carbonate was added portion wise. The aqueous phase was extracted with chloroform. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to get 3-methyl-4-nitropyridine 1-oxide (1.4 g, 50%).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12].C[Si](C)(C)N[Si](C)(C)C>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[CH2:9]([NH:13][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CONC(=O)N1
Reactant: CCCCN
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCCCNC1=NC(=O)NOC1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg of ammonium sulfate, 0.88 g (0.012 mole) of n-butylamine and 20 ml hexamethyldisilazane in 40 ml freshly distilled dry dioxane is refluxed for 17 hours. After cooling to room temperature, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 1.02 g (87 percent) of 5-butylamino-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH:37][C:38]1([C:45]2[S:46][CH:47]=[CH:48][N:49]=2)[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>>[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:33][N:34]([CH:41]3[CH2:40][CH2:39][C:38]([OH:37])([C:45]4[S:46][CH:47]=[CH:48][N:49]=4)[CH2:43][CH2:42]3)[CH2:35]2)=[N:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1CCC(O)(c2nccs2)CC1
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:4])=[O:3].[NH3:14]>C(Cl)(Cl)Cl>[S:2]([C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=[O:4])(=[O:3])[NH2:14]
Reactant: COC(=O)c1cscc1S(=O)(=O)Cl
Reactant: N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cscc1S(N)(=O)=O
Reaction time: 3 h

Procedure:
39.9 g (0.166 mole) of methyl 4-chlorosulfonylthiophene-3-carboxylate (VIII) is dissolved in 400 ml of absolute chloroform; ammonia is passed in at room temperature until the mixture has an alkaline reaction. After the mixture has been stirred for a further 3 hours (care being taken that the solution remains alkaline) it is extracted with water and the organic phase is dried and evaporated. The crystalline residue can be recrystallized from ethanol; however, for further use, digestion with ether is sufficient.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:3]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: Fc1cccc(COc2cccc(Br)n2)c1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2cccc(-c3cc(F)ncc3Cl)n2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A mixture of 2-bromo-6-(3-fluorobenzyloxy)pyridine (145 mg, 0.514 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (144 mg, 0.822 mmol), PalladiumTetrakis (71.3 mg, 0.062 mmol), DME (3 ml), and t 2M sodium carbonate (1.028 ml, 2.056 mmol) was reaction mixture was stirred at 100° C. for 3 hr, followed by LCMS. The reaction mixture was cooled, diluted with 10 ml of ethyl acetate, filtered and concentrated to yield a crude product, which was purified by silica gel chromatography using a 12 g column eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 100 mg of titled compound as a free base. LCMS (m/z): 333.1 (MH+), retention time=1.26 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[CH:14][C:13]=1[F:22].C1COCC1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: COCc1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Yield: 98.2 %

Procedure:
The methyl 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylate was treated with THF (2 mL), MeOH (2 mL) and 1.0 M aq. NaOH (2 mL, 2 mmol) at room temperature for 1 h. The volatile solvents were removed under reduced pressure. The residue was neutralized to pH around 5-6 with 1N HCl. The solids that precipitated were collected by filtration, rinsed with water, and dried to give the sub-title compound as a white solid (374 mg, 98.2%). LCMS calc. for C14H11F3NO3 (M+H)+ m/z=298.1. found: 298.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:31][CH:32]([CH3:34])[CH3:33].[F:35][C:36]([F:47])([F:46])[C:37]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:39](O)=[O:40]>C(#N)C>[F:35][C:36]([F:46])([F:47])[C:37]([C:42]([F:43])([F:44])[F:45])=[CH:38][C:39]([NH:16][C@:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:31][CH:32]([CH3:34])[CH3:33])[CH:4]=1)([C:17]1[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:40]
Reactant: O=C(O)C=C(C(F)(F)F)C(F)(F)F
Reactant: CC(C)Oc1cc([C@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: CC#N
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C=C(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
A round bottom flask was charged with IIDQ polystyrene resin (493 mg, 1.5 mmol/g, 0.74 mmol) and acetonitrile (5 mL) and sealed with a rubber septum. The suspension was vacuumed and reflushed with argon three times. To the resulting slurry was added a solution of (R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedures 109, 110, 111, 112, 113, 114, (180 mg, 0.37 mmol) and 4,4,4-trifluoro-3-(trifluoromethyl)crotonic acid (93 mg, 0.45 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and purified by ISCO chromatography (40 g column) using hexane/EtOAc (0-15% over 30 min) to give (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide (Example 291) as a white solid at a retention time of 20 min (199 mg, 74% yield). LCMS: RT=2.18 min [M+H] 674.33 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.25 min, Purity 98% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 3H, m; 7.02 ppm, 1H, dd, J=10.55, 8.79 Hz; 6.95 ppm, 3H, m; 6.85 ppm, 1H, s; 6.67 ppm, 3H, d, J=7.03 Hz; 6.62 ppm, 1H, m; 6.13 ppm, 1H, s; 5.88 ppm, 1H, tt, J=53.00, 2.86, 2.75 Hz; 4.36 ppm, 1H, ddd, J=11.97, 6.15, 6.04 Hz; 3.99 ppm, 1H, d, J=13.18 Hz; 3.71 ppm, 1H, d, J=13.18 Hz; 1.26 ppm, 6H, m.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:17][C:18]1[C:19]([Sn](CCCC)(CCCC)CCCC)=[N:20][CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[C:19]([C:11]2[N:12]=[N:13][CH:14]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:21]4[C:22]([F:24])=[CH:23][C:18]([F:17])=[CH:19][N:20]=4)[CH:3]=3)[N:10]=2)=[N:20][CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(F)cc1F
Reactant: CSc1nncc(-c2ccc(F)c(Br)c2)n1
Product: Fc1cnc(-c2nncc(-c3ccc(F)c(-c4ncc(F)cc4F)c3)n2)c(F)c1

Procedure:
A solution of 5-(3-bromo-4-fluorophenyl)-3-methylsulfanyl-[1,2,4]triazine and 3,5-difluoro-2-tributylstannylpyridine were coupled together by the method of Example 36 to give 3-(3,5-difluoropyridin-2-yl)-5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-[1,2,4]triazine: δH (500 MHz, CDCl3) 7.38-7.46 (3H, m), 8.44-8.48 (1H, m), 8.50 (1H, dd, J 2.3, 6.7 Hz), 8.52 (1H, d, J 2.3 Hz), 8.63 (1H, s), 9.77 (1H, s); m/z (ES+) 402.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([CH:23]=3)[NH2:22])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:26]1[CH:30]=[C:29]([CH2:31][C:32](Cl)=[O:33])[S:28][CH:27]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([NH:22][C:32](=[O:33])[CH2:31][C:29]4[S:28][CH:27]=[CH:26][CH:30]=4)[CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1N
Reactant: O=C(Cl)Cc1cccs1
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Yield: 83.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)aniline (400 mg, 1.14 mmol) and thiophene-2-acetyl chloride (148 mL, 1.50 mmol) were coupled according to the procedure of Example 56, Step G to give the desired product (454 mg, 84%). 1H NMR (400 MHz, d6-DMSO) δ 9.51 (s, 1H), 8.87 (D, J=7.2 Hz, 1H), 8.42-8.38 (m, 2H), 8.27 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.37-7.36 (m, 1H), 7.30 (dd, J=8.4 and 2.0 Hz, 1H), 7.19-7.16 (m, 2H), 7.09 (d, J=5.6 Hz, 1H), 6.96-6.94 (m, 2H), 3.98 (s, 2H), 3.91 (s, 3H) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])=[C:10]([F:25])[CH:9]=[C:8]([Cl:26])[C:6]=2[CH:7]=1.[CH3:27][O-:28].[Na+].O>O1CCCC1>[Cl:26][C:8]1[C:6]2[CH:7]=[C:3]([CH2:2][O:28][CH3:27])[O:4][C:5]=2[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[C:13]2=[O:24])=[C:10]([F:25])[CH:9]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(CBr)oc23)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
1.5 g (3.3 mmol) of 3-(2-bromomethyl-4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 30 ml of tetrahydrofuran, and 0.7 g (3.6 mmol) of sodium methoxide (28% methanol solution) was dropwise added thereto under cooling with ice. After stirring at room temperature for 5 minutes, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.75 g (yield: 56.0%) of the desired product as a yellowish brown glassy substance. Refractive index: 1.5389 (20° C.).