Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][CH:5]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39]Br>O1CCCC1>[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39][N:2]([CH3:1])[C:3](=[O:23])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: CNC(=O)c1cnc(N2CCOCC2)cc1-c1ccccc1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 0.27 g (0.87 mmol) N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide in 15 ml tetrahydrofuran, 1.12 ml of a 1 M solution (1.12 mmol) of potassium hexamethyldisilazide in tetrahydrofuran was added at 0° C. After 30 min, 0.16 ml (0.87 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added dropwise and the reaction mixture was allowed to warm to room temperature over night. Quenching with water was followed by extraction with ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography gave 0.20 g (44%) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[C:22]1([C:28]2[N:32]=[C:31]([SH:33])[NH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:28]2[N:32]=[C:31]([S:33][CH2:2][C:3]3[O:4][C:5]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)=[CH:6][C:7]=3[CH2:8][OH:10])[NH:30][N:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Sc1nc(-c2ccccc2)n[nH]1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)oc1CSc1nc(-c2ccccc2)n[nH]1

Procedure:
The title compound was prepared using methyl 2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 44) and 3-phenyl-1,2,4-triazole-5-thiol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[CH2:37][CH2:36][CH:35]([OH:38])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[CH2:37][CH2:36][CH:35]([OH:38])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2CCC3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2CCC3O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 2-(4-chlorophenyl)-3-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (49 mg, 0.09 mmol) in DCM (10 mL) was added HCl in dioxane (4M, 2 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford the 2-(4-chlorophenyl)-1-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (46 mg, 99%). 1H NMR (D2O, 400 MHz) δ 8.38-8.36 (m, 1H), 7.37-7.34 (m, 2H), 7.22-7.19 (m, 2H), 5.18-5.10 (m, 1H), 4.34-4.28 (m, 1H), 4.10-3.00 (m, 12H), 2.50-2.40 (m, 1H), 1.85-1.75 (m, 1H), 1.28-1.26 (m, 6H), 1.20-1.13 (m, 3H). MS (APCI+) [M+H] +444.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([C:19](Cl)=[O:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]2[CH:10]([C:19](=[O:20])[C:18]3[CH:17]=[CH:16][S:15][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CN(Cc2ccccc2)CCC1c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2ccsc2C2CCN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
A solution of the product from step d) (7.37 g, 20.7) mmol) in CH2Cl2 (103 ml) was added dropwise to a slurry of AlCl3 (8.26 g, 62 mmol) in CH2Cl2 (28 ml) at 22° C. After 45 minutes, the reaction mixture was poured into ice cold 2 M NaOH (100 ml) and extracted with CH2Cl2 (300 ml). The organic extract was dried (MgSO4) and purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 50% ethyl acetate) to give 4 g (68%) of the subtitle compound. MS calculated for C17H17NOS+H 284, observed 284.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12](OC2C=CC(NC)=C(N)C=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C([O:43][C:44]2[CH:62]=[CH:61][C:47]3[N:48]([CH3:60])[C:49]([NH:51][C:52]4[CH:57]=[CH:56][C:55]([Br:58])=[C:54]([CH3:59])[CH:53]=4)=[N:50][C:46]=3[CH:45]=2)C=CN=1)=O)(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:49]2[N:48]([CH3:60])[C:47]3[CH:61]=[CH:62][C:44]([O:43][C:8]4([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][NH:9]4)=[CH:45][C:46]=3[N:50]=2)=[CH:53][C:54]=1[CH3:59]
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Reactant: Cc1cc(Nc2nc3cc(Oc4ccnc(C(=O)OC(C)(C)C)c4)ccc3n2C)ccc1Br
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CI
Product: Cc1cc(Nc2nc3cc(OC4(C(=O)O)C=CC=CN4)ccc3n2C)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-bromo-3-methylphenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=452
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=2)[C:7]([OH:9])=O)[CH2:3][CH2:2]1.FC1C=C(C=C(C(F)(F)F)C=1)[C:21]([N:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[O:38][CH3:39])C)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=2)[C:7]([N:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:30]=2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[O:38][CH3:39])[CH3:21])=[O:9])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C2CC2)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C2CC2)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 3-cyclopropyl-5-methanesulfonyl-benzoic acid (119 mg, 495 μmol) and 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) after a reaction time of 19.5 hours. The compound was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Off-white solid (0.082 g; 36%). MS (ESI): m/z=455.14 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:14][C:15]([OH:17])=[O:16])[N:12]=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:16][C:15](=[O:17])[CH2:14][N:13]1[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=2)=[N:10][N:11]=[N:12]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1cccc(C(F)(F)F)c1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 88.9 %

Procedure:
To a solution of 300 mg (1.10 mM) of [5-(3-trifluoromethylphenyl)tetrazol-1-yl] acetic acid in 2 ml of ethylene glycol was added 0.2 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=20/1) for separation and purification, to give 310 mg (yield 88.9%) of [5-(3-trifluoromethylphenyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:3]([CH2:2][Cl:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc[n+]([O-])c1CCl
Product: COC(=O)c1ccc(Cl)nc1CCl
Yield: 77.6 %

Procedure:
The crude of 2-(chloromethyl)-3-(methoxycarbonyl)pyridine-1-oxide (20 g, 99.5 mmol) was added in small portion to POCl3 (200 g) at room temperature. The mixture was refluxed for 3 hours before it was concentrated in vacuo. The residue was poured into ice-water, neutralized with NaHCO3 solution, and extracted with AcOEt (125 mL×3). The combined organic layers were concentrated to give the crude title product (17 g, yield 78%), which was used in the next step reaction without further purification.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]=[O:23])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:24])[N:8]2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]([Mg]Br)[CH:27]=[CH2:28].CCOCC.[NH4+].[Cl-]>C1COCC1>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]([OH:23])[CH2:28][CH:27]=[CH2:26])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:24])[N:8]2[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC[Mg]Br
Reactant: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C
Temperature: 25 °C

Procedure:
A solution of N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-formyl-4-methylisoxazole-3-carboxamide (53 mg, 0.153 mmol) in THF (1.5 mL) was cooled to 0° C. and 1M allylmagnesium bromide in Et2O (337 μl, 0.337 mmol) was added dropwise over 15 mins. The reaction mixture was warmed to room temperature and saturated NH4Cl (aq) was added. The aqueous layer was extracted with DCM (×3). The combined organic extracts were passed through a phase separating cartridge and the organic solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 50-100% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[N:15]=C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH2:15])=[O:4]
Reactant: COC(=O)c1c(N=C(c2ccccc2)c2ccccc2)ccc2c1CCCC2
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c(N)ccc2c1CCCC2
Reaction time: 1 h
Yield: 61.5 %

Procedure:
2-(Benzhydrylideneamino)-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 6, 8.2 g) was dissolved in THF (100 mL) and 1N hydrochloric acid was added (100 mL). The mixture was stirred for 1 hour and then passed through an SCX-2 SPE column. The column was washed with acetonitrile and then the desired product was eluted with a solution of 2M ammonia in methanol. Evaporation of the solvent gave the title compound as a clear oil (2.8 g) which was used without further purification or analysis.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[C:24]([CH3:28])[NH:23][N:22]=1>>[CH3:28][C:24]1[C:25]([C:26]#[N:27])=[C:21]2[N:20]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]2[N:23]=1
Reactant: Cc1[nH]nc(N)c1C#N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc2c1C#N
Yield: 63.2 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (234 mg, 63%). MS (ISP) 371.1 [(M+H)+]; mp 184° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]#[N:8])[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[N+:17]([O-])=O)=[N:3]1>C(O)C.Cl>[NH2:8][C:7]1[C:5]2[C:4](=[N:3][N:2]([CH3:1])[CH:6]=2)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[N:17]=1
Reactant: Cn1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])n1
Agent: Cl
Solvent: CCO
Product: Cn1cc2c(n1)Nc1ccc(Cl)cc1N=C2N

Procedure:
To 1-methyl-3-(4-chloro-2-nitroanilino)pyrazole-4-carbonitrile (16 g) stirred in ethanol (500 ml) was added a solution of anhydrous stannous chloride (33.1 g) in concentrated hydrochloric acid (176 ml). The mixture was heated under reflux for 2 hours, cooled, filtered and crystallised from methylated spirits (1 liter) to give the title compound as its hydrochloride salt m.p.>260° C. 2.0 g of the hydrochloride salt was partitioned between dilute ammonia solution and chloroform. The organic phase was washed with water, dried with magnesium sulphate, evaporated and the residue crystallised from chloroform-n-hexane to give the title compound as the free base m.p. 240° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH2:14])[C:6]([NH2:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:21][C:22](=O)[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[OH:38][CH2:37][C:33]1[CH:32]=[C:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:21])[NH:13][C:6]4[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:4][C:5]=4[N:14]=3)[CH:30]=[CH:29][CH:28]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(C(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 4,5-bis-trifluoromethyl-benzene-1,2-diamine [CAS-No. 30454-92-3] (244 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) in toluene (10 ml) under reflux conditions for 2 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (291 mg, 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][CH2:11][C:12]2[NH:13][C:14](=[O:22])[C:15]3[CH2:21][O:20][CH2:19][CH2:18][C:16]=3[N:17]=2)[CH3:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:41]=[CH:40][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([CH:30]2[CH2:31][CH2:32][N:33]([CH2:36][C:37]([N:10]([C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:11][C:12]3[NH:13][C:14](=[O:22])[C:15]4[CH2:21][O:20][CH2:19][CH2:18][C:16]=4[N:17]=3)=[O:38])[CH2:34][CH2:35]2)=[O:29])=[CH:40][CH:41]=1
Reactant: C[C@@H](NCc1nc2c(c(=O)[nH]1)COCC2)c1ccc(F)cc1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: C[C@H](c1ccc(F)cc1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (26.9 mg) from (R)-2-((1-(4-fluorophenyl)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C30H32FN4O4 550.6. found 551.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.97 (dd, J=8.84, 5.31 Hz, 2H) 7.31 (dd, J=8.59, 5.05 Hz, 1H) 7.13-7.27 (m, 3H) 6.88 (t, J=7.83 Hz, 1H) 6.03 (q, J=7.07 Hz, 1H) 4.27-4.57 (m, 5H) 4.11 (br. s., 2H) 3.85-4.03 (m, 4H) 3.36 (br. s., 1H) 3.30 (br. s., 2H) 2.97 (s, 1H) 2.70 (br. s., 2H) 2.59 (d, J=4.04 Hz, 1H) 2.12 (s, 4H) 1.68 (d, J=7.07 Hz, 1H) 1.49 (d, J=7.07 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.[F-].[Cs+]>C(COC)OC.CO.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:39]([F:50])([F:49])[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CCOC(=O)c1c(-c2ccccc2C(F)(F)F)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 135B (30 mg), 2-(trifluoromethyl)phenylboronic acid (15.3 mg), tetrakis(triphenylphosphine)palladium(0) (3.1 mg) and cesium fluoride (16.3 mg) in dimethoxyethane (1.4 ml) and methanol (0.7 ml) was heated at 100° C. in a microwave reactor (CEM Discover) for 30 minutes and was concentrated. The residue was purified by flash chromatography, eluting with 0%-100% dichloromethane in hexane, to provide ethyl 5-(benzyloxy)-1-(3-(naphthalen-1-yloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 12.67 (s, 1H), 8.04-8.40 (m, 1H), 7.87 (d, J=7.32 Hz, 1H), 7.82 (d, J=7.63 Hz, 1H), 7.69 (t, J=7.32 Hz, 1H), 7.57-7.65 (m, 2H), 7.44-7.56 (m, 3H), 7.26-7.41 (m, 7H), 6.97 (dd, J=9.00, 2.29 Hz, 1H), 6.85 (d, J=7.93 Hz, 1H), 6.55 (d, J=2.14 Hz, 1H), 4.83-4.98 (m, 4H), 4.05-4.24 (m, 2H), 2.28-2.40 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCOC1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C1CCOCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
A mixture of 4-methylaminopiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol), tetrahydropyran-3-one (187 mg, 1.87 mmol), 4 Å powdered molecular sieves (550 mg) and DIPEA (323 μl, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 4-[Methyl(tetrahydropyran-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester as an oil (101 mg, 36%). 1H NMR (CDCl3, 300 MHz): δ 4.24-4.07 (m, 2 H); 4.06-3.96 (m, 2 H); 3.43-3.32 (m, 2 H); 2.78-2.63 (m, 4 H); 2.25 (s, 3 H); 1.77-1.60 (m, 8 H); 1.46 (s, 9 H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18](O)=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45].C([O-])([O-])=O.[Na+].[Na+]>CC1OCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18]([NH:45][CH2:44][C:43]([F:47])([F:46])[F:42])=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1
Reactant: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)NCC(F)(F)F
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
To (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (limiting reagent) charge 2-methylTHF (7.5 vol), then charge T3P® (2.0 eq, 50% w/w in 2-MeTHF). Heat the mixture to 60-65° C. and maintain this temperature for no less than 3 hrs and the solids are completely dissolved. Cool to 20-25° C. then charge 2,2,2-trifluoroethylamine (2.0 eq). Continue agitation for no less than 6 hrs at 20-25° C. and until HPLC analysis showed <1.0% of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a). Slowly charge a Na2CO3 solution (15 vol, 1.165M) while maintaining a batch temperature <30° C. Stir the mixture for 30 min then separate the phases. Wash the organic phase with water (4 vol). Emulsions have been observed at this point and can be addressed through addition of NaCl solution. Charge methanol (7 vol) then distill to 4 vol. Repeat 3 times. Prior to crystallization, adjust the total volume to approximately 11 vol. Heat the mixture to 50-55° C. then add water (2.45 vol, final solvent composition 22% water in methanol) over 30 min. Seed the batch with (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia) (1 wt % seed based on the compound of Formula (4a)). Stir for 4 hrs at 50-55° C. then add water over 24 h until the mixture is approximately 58 wt % water in methanol. Cool to 20-25° C., stir 1 h, then filter. Wash the cake with water (2 vol). Dry the solids at 60-65° C. to give (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1ccsc1
Product: Clc1cc(-c2ccsc2)nc2c1CCC2
Yield: 70 %

Procedure:
Following general procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with thiophen-3-ylboronic acid (0.112 g, 0.88 mmol) to afford the title compound (0.132 g, 70%) as a white solid. MW=235.73. 1H NMR (CDCl3, 500 MHz) δ 7.88-7.82 (m, 1H), 7.61-7.56 (m, 1H), 7.40-7.34 (m, 1H), 3.11 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.16 (quin, J=7.5 Hz, 2H); APCI MS m/z 236 [M+H]+.