Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:13][C:14]1([CH3:45])[CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:32]#[C:33][C:34]3[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][CH:35]=3)[CH:20]=2)[O:15]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].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>[C:2]1([C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:32]#[C:33][C:34]4[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][CH:35]=4)[CH:20]=3)[O:15][C:14]([CH3:13])([CH3:45])[CH:23]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CC(C)(C)O3)cc1
Temperature: 25 °C

Procedure:
A solution of bromobenzene (250.0 mg, 1.59 mmol) in 3.0 mL of THF was cooled to -78° C. and tert-butyllithium (203.7 mg, 3.18 mmol, 1.9 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (440.0 mg, 3.18 mmol) in 5.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-chromen-6-ylethynyl)-benzoate (Compound 264, 150.0 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 110.0 mg (87%), was isolated by column chromatography (2.5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.99 (2H, d, J=8.3 Hz), 7.51 (2H, d, J=8.3 Hz), 7.47-7.35 (6H, m), 7.21 (1H, d, J=2.0 Hz), 6.88 (1H, d, J=8.4 Hz), 5.66 (1H, s), 4.38 (2H, q, J=7.1 Hz), 1.52 (6H, s), 1.40 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][CH:16]=1)=O)(C)(C)C.CCCCCC>O1CCOCC1.CCOC(C)=O>[NH2:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC2CCCCC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NCc1ccc(CC2CCCCC2)nc1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Add 4N hydrogen chloride in dioxane (10 mL) to a solution of 3-tert-butoxycarbonylaminomethyl-6-cyclohexylmethyl-pyridine (345 mg, 1.13 mmol) in EtOAc (10 mL) and stir overnight. Concentrate in vacuo, suspend the solid obtained in diethyl ether and add hexane. Filter and wash the solid with hexane. Suspend the solid into dichloromethane, add saturated aqueous NaHCO3 and stir until both phases are clear (15 min). Extract the aqueous phase twice with dichoromethane. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound as an oil (205 mg, 97%) that was used without any further purification. MS (ES+) n7/z: 205 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)=O.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+].CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[N:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: O=C(c1cc2ccccc2o1)c1nc2ccccc2s1
Reactant: CN1CCC(N)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(N=C(c2cc3ccccc3o2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (benzofuran-2-yl)(benzothiazol-2-yl)methanone (1.4 g) and 4-amino-1-methylpiperidine (0.57 g) in tetrahydrofurane (8 mL) is added dropwise titanium tetraisopropoxide (1.78 g). The suspension is stirred for 24 h at room temperature, diluted with ethyl acetate and 1N sodium hydroxide. The precipitate is filtered over a clarcel pad and rinsed with ethyl acetate. The pooled filtrates are washed with saturated sodium chloride solution, dried and concentrated under reduced pressure. The residue is purified over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to afford [(benzofuran-2-yl)(benzothiazol-2-yl)methylene](1-methylpiperidin-4-yl)amine.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:21][O:20][CH2:19][CH2:18][CH2:17][N:8]1[C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=[C:9]1[C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=2)[CH2:12]1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2cccc(Cl)c21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21

Procedure:
((R)-7-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (0.111 mmol max, about half of crude oil from Step E) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.122 mmol, 0.040 g) and N-methylmorpholine (0.555 mmol, 0.061 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.122 mmol, 0.046 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (20-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (30F) as a clear oil that was used directly onto the next step. ESI-ESI-MS: m/z 619.5 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.[OH:20][C:21]([CH3:28])([CH3:27])[CH2:22][NH:23][C:24]([NH2:26])=[NH:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:7][N:26]=[C:24]([NH:23][CH2:22][C:21]([CH3:28])([OH:20])[CH3:27])[N:25]=2)[CH2:2][CH2:3]1
Reactant: CSc1nccc(/C(=C/N(C)C)C(=O)CC2CC2)n1
Reactant: CC(C)(O)CNC(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(methylthio)pyrimidin-4-yl)but-3-en-2-one (3) in DMF (4 mL), 1-(2-hydroxy-2-methylpropyl)guanidine (529 mg, 3.15 mmol) and potassium carbonate (872 mg, 6.31 mmol) were added, and the reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was purified by a reverse-phase Gilson HPLC [30-90% organic phase over 15 min] followed by a Biotage silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a glassy solid (90 mg, 21% yield). MS (ES+): m/z=392.2/393.2/394.3 (100/40/10) [MH+]. HPLC: tR=1.12 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CNNC.C>CO.[Fe](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccccn1
Agent: Cl[Fe](Cl)Cl
Agent: CNNC
Solvent: CO
Product: COc1cc(N)ccc1-c1ccccn1
Temperature: 65 °C

Procedure:
To a solution of 2-(2-methoxy-4-nitrophenyl)pyridine (5.4 g, 23.3 mmol), dimethyl hydrazine (14 mL, 233 mmol), charcoal (0.7 g), in methanol (200 mL) was added iron trichloride (0.075 g, 0.46 mmol), then heated at 65° C. overnight. The reaction mixture was quenched with H2O (50 mL), then extracted with EtOAc (3×50 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica (EtOAc/Hexane 3/7) to give 3-methoxy-4-pyridin-2-ylaniline.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=O)[CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:52]1[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][NH2:60])[CH2:54][CH2:53]1>>[N:55]1([CH2:58][CH2:59][NH:60][C:15]([C@@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=5[N:19]=4)[CH:5]=3)[CH2:10]2)=[O:17])[CH2:56][CH2:57][O:52][CH2:53][CH2:54]1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)C1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NCCN1CCOCC1)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Method K—Step a To a mixture of (R)-1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 3,4, step e) (0.01 g, 0.27 mmol) in dcm (2 mL), HATU (0.10 g, 0.28 mmol), TEA (0.08 mL, 0.56 mmol) and 2-morpholinoethylamine (0.04 g, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with ammonium chloride solution (2 mL), filtered through a phase separator and organic solvent was removed. The crude was then purified by SCX column and flash chromatography (eluent: gradient from EtOAc to EtOAc:NH3 in MeOH (2M)/10:1) to obtain 0.05 g of the title compound (40%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:19][CH:20](Cl)[CH2:21][CH3:22].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:5]([N:8]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1OCC1CCCC1
Reactant: CCC(Cl)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cnc(N2CCCC2)c(OCC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of 0.544 g (0.0020 mol) 5-bromo-3-cyclopentylmethoxy-pyrazin-2-ylamine in 10 mL dimethylformamide was added 0.349 g (0.0080 mol) sodium hydride 55% in oil and the mixture was stirred at room temperature for 20 min. To the resulting suspension was added 0.345 mL (0.0030 mol) 1-bromo-2-chlorobutane and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was washed with water and 10% aqueous sodium bicarbonate, dried over sodium sulfate, evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to yield 0.579 g (0.0018 mol) of the title compound as yellowish crystals melting at 54-55° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:26][CH:27]([CH3:29])[CH3:28])[CH:24]=3)[CH2:19][C:18](=[O:32])[NH:17]2)=[CH:12][CH:11]=1.I[C:34]1[CH:39]=[CH:38][C:37]([C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=2)([OH:42])[CH3:41])=[CH:36][CH:35]=1.N[C@@H]1CCCC[C@H]1N>C(OCC)(=O)C.[Cu]I.O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]2[C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:26][CH:27]([CH3:28])[CH3:29])[CH:24]=3)[CH2:19][C:18](=[O:32])[N:17]2[C:34]2[CH:35]=[CH:36][C:37]([C:40]([OH:42])([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=3)[CH3:41])=[CH:38][CH:39]=2)=[CH:14][CH:15]=1
Reactant: COc1cccc(C(C)(O)c2ccc(I)cc2)c1
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)NC(=O)C2
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(C(C)(O)c2ccc(N3C(=O)Cc4cc(OC)c(OC(C)C)cc4[C@@H]3c3ccc(Cl)cc3)cc2)c1

Procedure:
A dry 10 ml microwave vial was charged with K3PO4 (123 mg, 0.578 mmol), (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,2-dihydroisoquinolin-3(4H)-one (100 mg, 0.289 mmol), 1-(4-iodophenyl)-1-(3-methoxyphenyl)ethanol (113 mg, 0.318 mmol), trans-1,2-diaminocyclohexane (6.95 μl, 0.058 mmol) and dioxane (3 ml). The reaction mixture was degassed with argon in a sonic bath during 5 minutes. Then copper(I)iodide (11.01 mg, 0.058 mmol) was added. The vial was sealed and heated for 8 hrs to 100° C. in a metal heating block. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain a brown oil as crude material which was purified by preparative HPLC (reversed phase). Fractions containing the products were pooled and worked up (addition of NaHCO3, removal of acetonitrile followed by extraction with DCM). The residue was dissolved in 1,4-dioxane and freeze dried overnight to obtain the title compound as yellowish solid.
Reaction SMILES: [CH:1]1([NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]3[N:14]=[CH:13][C:12]=2[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH:1]1([NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([C:20]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:21])=[C:15]3[N:14]=[CH:13][C:12]=2[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnn2c(NC3CCc4ccccc43)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NC3CCc4ccccc43)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 56.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,3-dihydro-1H-inden-1-ylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.104 mmol) obtained in step 2 and methanesulfonamide (39 mg, 0.42 mmol), the title compound (33 mg, 57%) was obtained.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[C:9]([O:10][C:11]2[C:25]([O:26][C:27]3[CH:28]=[N:29][C:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])=[CH:31][CH:32]=3)=[CH:24][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22]C=C[N:19]=4)=[N:17][C:13]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:39][N:40]1C=CC(C(O)=O)=N1>>[F:1][CH:2]([F:38])[O:3][C:4]1[C:9]([O:10][C:11]2[C:25]([O:26][C:27]3[CH:28]=[N:29][C:30]([S:33]([CH2:36][CH3:37])(=[O:34])=[O:35])=[CH:31][CH:32]=3)=[CH:24][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][N:40]([CH3:39])[N:19]=4)=[N:17][C:13]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2OC(F)F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2cccnc2OC(F)F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2-difluoromethoxy-pyridin-3-yloxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 247 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+]>CO>[CH:7]1([CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([OH:22])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105.2 %

Procedure:
A solution of the isomeric mixture of 3-cyclopentyl-2-(4-meth-anesulfonyl-phenyl)-acrylic acid ethyl ester [65.02 g, 0.202 mol, (E):(Z)=1.63:1] in methanol (504 mL) was treated with a 1N aqueous sodium hydroxide solution (423 mL, 0.423 mol). The reaction mixture was stirred at 25° C. for 20 h, at which time, thin layer chromatography indicated the presence of starting material. The reaction mixture was then concentrated in vacuo to remove some of the methanol (300 mL). The resulting reaction mixture was heated under reflux for 1 h, at which time, thin layer indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×1 L). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylic acid (62.58 g) as a cream solid consisting of a 16.2:1 mixture of (E):(Z) isomers. The cream solid was treated with ethyl acetate (200 mL), and the resulting slurry was heated to a boil. The resulting white solid surrounded by a light yellow liquid of ethyl acetate was allowed to cool to 25° C. The solid was filtered to afford pure (E)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylic acid (41.18 g, 69%) as a white solid: mp 200-202° C.; EL-HRMS m/e calcd for C15H18O4S (M+) 294.0926, found 294.0921.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.Cl.[NH2:20][C@@H:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:18])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:23])[NH2:24]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Product: NC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC(F)(F)F)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and (S)-2-amino-2-phenyl-acetamide hydrochloride (CAN 60079-51-8) as starting materials, MS (EI): m/e=394.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)[CH3:30]>COCCOC.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].C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5]([C:34]2[CH:33]=[N:32][N:31]([CH2:29][CH3:30])[CH:35]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CCn1cc(-c2cnc(N)c(-c3ccc(C(=O)OC(C)(C)C)c(F)c3)c2)cn1
Temperature: 120 °C
Yield: 76.9 %

Procedure:
To tert-butyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate (200 mg, 0.544 mmol) (See Scheme 101, Step 2 for synthesis) in DME (3 mL) and 2 M sodium carbonate (1.5 mL, 3.0 mmol) was added 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (182 mg, 0.816 mmol) followed by PdCl2(dppf)-CH2Cl2 adduct (44.5 mg, 0.054 mmol). The reaction mixture was microwave heated at 120° C. for 20 min. The reaction mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography eluting with 0-50% of EtOAc (contains 10% MeOH)/heptane yielding tert-butyl 4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-fluorobenzoate (160 mg, 77%). LCMS (m/z): 383.2 (MH+), 0.782 min.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[S:25][CH2:24][C:23](=[O:26])[NH:22][C:21]=2[CH:27]=1>CCO.O>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[CH2:13][NH:16][C:17]1[CH:18]=[CH:19][C:20]2[S:25][CH2:24][C:23](=[O:26])[NH:22][C:21]=2[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 42 %

Procedure:
A solution of 2-[4-[(tert-butyl)dimethylsiloxy]butyl]oxirane (10.0 g) and 6-amino-4H-benzo[1,4]thiazin-3-one (7.81 g; commercial) in EtOH/water (300 mL; 9:1) was refluxed for 2 days. The solvents were removed under reduced pressure and the residue was taken up in EA/Hex (1:1; 100 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by CC (EA/Hex; 1:1), affording an orange solid (7.40 g; 42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14]1.[I:20]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([I:20])[C:15]([CH3:19])=[N:14]1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(C)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: CC#N
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C)c1I

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3,5-dimethylpyrazole (0.218 g) in acetonitrile (3 ml) at room temperature was added dropwise a solution of N-iodosuccinimide (0.158 g) in acetonitrile (2 ml). After 27 hours the mixture was evaporated to dryness and the residue purified by column chromatography on silica gel (5 g) eluted with dichloromethane. Combination and evaporation of suitable fractions provided the title compound as yellow oil.