Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:31]1(=[O:35])[CH2:34][CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1>[OH:35][C:31]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2(O)CCC2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
To a solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol) in tetrahydrofuran (3 ml) was added 1.6N solution of n-butyllithium in hexane (0.829 ml, 1.33 mmol) at −78° C., and the mixture was stirred at −78° C. for 15 min. At −78° C., a solution of cyclobutanone (0.0747 ml, 1.00 mmol) in tetrahydrofuran (1 ml) was added, and the mixture was stirred at −78° C. for 30 min. Saturated aqueous ammonium chloride solution (3 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (108 mg, 33.8%) as an oil.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH3:2].[NH2:9][C:10]1[C:11]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:12][C:13]([CH3:31])=[C:14]([CH3:30])[C:15]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:15]2[C:14]([CH3:30])=[C:13]([CH3:31])[N:12]=[C:11]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:10]=2[N:9]=1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCNC(=O)OC(C)(C)C)c1C
Reactant: COC(C)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCCNC(=O)OC(C)(C)C)c2c1C
Yield: 83.1 %

Procedure:
Trimethyl orthoacetate (3.55 mL, 28.27 mmol), tert-butyl 2-{2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethoxy}ethylcarbamate (11.21 g, 26.92 mmol), pyridine hydrochloride (1.12 g) and toluene (120 mL) were combined and heated at reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water (3×100 mL) and brine (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 9.85 g of tert-butyl 2-[2-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethylcarbamate.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[O:21][C:20]=2[CH3:32])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[O:21][C:20]=2[CH3:32])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccc(OC)cc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(C(Oc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)o2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of cyclohexyl[5-(4-methoxyphenyl)-2-methylfuran-3-yl]methanol (601 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (365 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (1.0 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.0 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 12% ethyl acetate/hexane) to give methyl 4-{cyclohexyl[5-(4-methoxyphenyl)-2-methylfuran-3-yl]methoxy}benzoate as an amorphous compound. The obtained methyl 4-{cyclohexyl[5-(4-methoxyphenyl)-2-methylfuran-3-yl]methoxy}benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (362 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1
Reactant: CCCc1nc(O)c2cc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc(Cl)c2cc(Cl)ccc2n1
Yield: 58.1 %

Procedure:
6-Chloro-2-propyl-quinazolin-4-ol (810 mg, 3.64 mmol, 1 eq.), phosphorous oxychloride (3.30 mL, 35.1 mmol, 9.64 eq.) and triethylamine (1.63 mL, 11.7 mmol, 3.21 eq.) were refluxed for 2 hours. Stripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated sodium bicarbonate, 1× with brine. Dried and stripped in vacuo to give an amber oil. Purified over silica gel in 9:1 Hexanes/EtOAc. Obtained 510 mg of off-white solids as product. The product was used immediately in Example 121 Part D.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CCCC(=O)Cl
Product: CCCC(=O)NCCCCn1c(C)nc2c(N)nc3ccccc3c21
Yield: 51.8 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with butyryl chloride (0.43 mL, 4.1 mmol) to provide 0.65 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]butanamide as an off white solid, m.p. 169.4-170.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[N:5](C(=O)C(F)(F)F)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:19][CH2:20]3)=[O:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCN(C(=O)C(F)(F)F)c2cc(NC(=O)N3CCN(c4ncccc4Cl)CC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)CCNc2cc(NC(=O)N3CCN(c4ncccc4Cl)CC3)ccc21
Temperature: 50 °C

Procedure:
A suspension of N-(4,4-dimethyl-1-trifluoroacetyl-1,2,3,4-tetrahydroquinol -7-yl)-4-(3-chloro-2-pyridyl)-piperazine-1-carboxamide (125 mg, 0.253 mmol) and potassium carbonate (105 mg, 0.758 mmol) in methanol (5 ml) and water (5 ml) was heated at 50° C. for 3 h. After this period, the solvents were evaporated in vacuo and the residue partitioned between DCM (50 ml) and water (50 ml). The aqueous layer was re-extracted with DCM (2×50 ml) and then the combined organic layers dried (Na2SO4) and the solvents evaporated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.19 (dd, 1H), 7.61 (dd, 1H), 7.07 (d, 1H), 6.87 (dd, 1H), 6.75 (d, 1H), 6.41 (dd, 1H), 6.19 (br, 1H), 3.85-3.95 (br, 1H), 3.60-3.70 (m, 4H), 3.30-3.40 (m, 4H), 3.25-3.35 (m, 2H), 1.65-1.75 (m, 2H), 1.26 (s, 6H). MS (ES): MH+ 400/402.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH:56](=O)[CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH2:56]([N:53]1[CH2:54][CH2:55][N:50]([C:41]2([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:40][CH:39]=3)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]2=[O:49])[CH2:51][CH2:52]1)[CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCC=O
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCN1CCN(C2(c3ccc(OCc4cc(C)nc5ccccc45)cc3)C(=O)NC(=O)NC2=O)CC1
Yield: 63.2 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with hexanal (18.8 mg, 1.5 eq) to provide the title barbituric acid (70.0 mg, 63%). MS found: (M+H)+=544.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N+:13]([O-])[CH:14]=[CH:15][CH:16]=[C:11]3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:39])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N:13][C:14]([Cl:39])=[CH:15][CH:16]=[C:11]3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1cccc(-c2n[nH]c3ccc(Cl)nc23)c1

Procedure:
To 100 mg of 3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxide in toluene was acted phosphorus oxychloride in toluene in the same manner as described in Production example 28, to afford 30 mg of 3-(3-fluorophenyl)-5-chloro-1H-pyrazolo[4,3-b]pyridine described in Example 38 described below as a colorless powder, as well as 60 mg of a crude product of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2].Br[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=[C:3]([CH2:1][CH3:2])[CH:12]=2)=[CH:16][CH:17]=1)#[N:28]
Reactant: N#Cc1ccccc1Br
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
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: Cc1ccccc1
Product: CCc1cc(OCc2ccc(-c3ccccc3C#N)cc2)c2c(n1)CCCC2
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium (40 mg) was added to a suspension of 4-[(2-ethyl-5,6,7,8-tetrahydroquinolin-4-yl)oxymethyl]-phenylboronic acid (200 mg) and 2-bromobenzonitrile (106 mg) in toluene (2 ml) ethanol (0.5 ml) and 2M aqueous sodium carbonate (0.58 ml). The mixture was degassed and placed under an atmosphere of argon, then heated under reflux for 12 hours. The resulting solution was cooled to ambient temperature, and dichloromethane (30 ml) and water (10 ml) were added. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (3:1 v/v), and the product triturated with ether/hexane to give 4-[(2'-cyanobiphenyl-4-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline (106 mg) as a white solid, m.p. 147°-148° C.; NMR (CDCl3): 1.29(t,3H), 1.7-1.95(m,4H), 5.17(s,2H), 6.57(s,1H), 7.4-7.7 (complex m,7 H), 7.78(d,1H); mass spectrum (+ve CI) 369 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[C:5](F)[CH:4]=1.[CH3:16][S:17](C1C=C(C=CC=1)C#N)(=[O:19])=[O:18]>>[OH:15][N:14]=[C:2]([C:3]1[CH:12]=[CH:11][CH:6]=[C:5]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=1)[NH2:1]
Reactant: CS(=O)(=O)c1cccc(C#N)c1
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Product: CS(=O)(=O)c1cccc(C(N)=NO)c1
Yield: 75 %

Procedure:
The title compound was obtained following procedure described for Intermediate 1 step 2 but starting from 3-methylsulfonylbenzonitrile (3.03 g; 16.72 mmol) to give the title compound as a white powder (2.69 g, 75%). 1H NMR (DMSO-d6, 300 MHz) δ 9.88 (s, 1H), 8.21 (t, J=1.68 Hz, 1H), 8.00 (dt, J=1.44, 7.93 Hz, 1H), 7.91 (dt, J=1.49, 7.80 Hz, 1H), 7.66 (t, J=7.84 Hz, 1H), 6.03 (s, 2H), 3.23 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([CH3:25])=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:18]([OH:20])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[C:34](=[O:35])[CH:33]=[C:32]([CH3:36])[NH:31][C:30]=1[CH3:37].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C)C=O>[Cl:24][C:22]1[CH:21]=[C:17]([C:18](=[O:20])[NH:27][CH2:28][C:29]2[C:34](=[O:35])[CH:33]=[C:32]([CH3:36])[NH:31][C:30]=2[CH3:37])[C:16]([CH3:25])=[C:15]([CH:23]=1)[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: Cc1cc(=O)c(CN)c(C)[nH]1
Reactant: Cc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(C)[nH]1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
A solution of 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5-chloro-2-methylbenzoic acid (140 mg, 0.379 mmol), 3-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one, hydrochloride (71.4 mg, 0.379 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (77 mg, 0.568 mmol), EDC (109 mg, 0.568 mmol) and N-methylmorpholine (166 μl, 1.514 mmol) was stirred for 18 h at RT in N,N-Dimethylformamide (DMF) (3619 μl) under nitrogen. Upon completion, the reaction was poured into stirring ice-water. White solid precipitated out of solution, which was filtered and dried under high vacuum to give tert-butyl 4-(5-chloro-3-(((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenoxy)piperidine-1-carboxylate (0.095 g, 0.189 mmol, 50% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.41 (s, 9 H) 1.50-1.60 (m, 2 H) 1.79-1.90 (m, 2 H) 2.06 (s, 3 H) 2.16 (s, 3 H) 2.31 (s, 3 H) 3.20-3.31 (m, 2 H) 3.49-3.63 (m, 2 H) 4.19 (d, J=4.80 Hz, 2 H) 4.59-4.78 (m, 1 H) 5.87 (s, 1 H) 6.81 (d, J=2.02 Hz, 1 H) 7.15 (d, J=1.77 Hz, 1 H) 8.22 (t, J=5.05 Hz, 1 H) 11.01 (br. s., 1 H). MS(ES) [M+H]+ 504.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]4[C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=[C:13]4[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C>[Br:31][C:10]1[N:9]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]3[C:17]([C:20]([F:22])([F:21])[F:23])=[N:18][N:19]=[C:13]3[CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: FC(F)(F)c1nnc2n1CCC(c1ncc3c(Cl)nccn13)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCC(c1nc(Br)c3c(Cl)nccn13)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
To a solution of 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (335 mg, 0.978 mmol) in DMF (4.9 mL) was added NBS (226.19 mg, 1.271 mmol) at ice water, the resulting solution was stirred at this temperature for 10 minutes. The reaction was quenched with water, then extracted with EA and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to give 7-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (0.41 g, yield 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg. 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (53 mg, 45%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([C:34]=4[F:35])=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:38].[ClH:40].CCOCC>>[ClH:38].[ClH:40].[ClH:38].[F:35][C:34]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[N:26][C:25]=1[C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:18]=2)[CH:24]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4ncc5ccccc5c4F)c3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1ncc2ccccc2c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[6-amino-5-(4-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (16.0 mg, 0.0327 mmol) in DCM (0.60 mL, 9.4 mmol) was added 1.0 M of HCl in Et2O (0.90 mL, 0.90 mmol), and the mixture was stirred at ambient temperature for 2 h. Almost immediately a pale yellow solid precipitated. The solvents were evaporated, and the residue was transferred into a vial and dried in vacuo overnight, yielding the title compound as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=14.6 (very brs, 1H), 9.38 (s, 1H), 9.08-8.99 (brm, 1H), 8.91-8.80 (brm, 1H), 8.53 (brs, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.24 (dd, J=8.2, 0.8 Hz, 1H), 8.06 (d, J=0.4 Hz, 1H), 8.03 (ddd, J=0.8, 7.0, 8.2 Hz, 1H), 7.92 (ddd, J=1.0, 7.0, 8.2 Hz, 1H), 7.88 (brs, 1H), 4.54-4.45 (mc, 1H), 3.38 (brd, J=13.2 Hz, 2H), 3.09 (brq, J=11.6 Hz, 2H), 2.27-2.08 (m, 4H). MS(ES+): m/z=389.18 (18) [MH+], 306.13 (100) [MH+-piperidine]. HPLC: tR=1.69 min (polar—5 min, ZQ2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[CH3:16][NH:17][NH2:18]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:14])[N:17]([CH3:16])[N:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CNN
Solvent: CC(C)O
Product: COc1ccc(C2=NN(C)C(=O)CC2)cc1

Procedure:
In a 500 mL round bottom flask, 4-(4-methoxyphenyl)-4-oxobutyric acid (27 g, 132 mmol) and methylhydrazine (7.3 g, 8.5 mL, 159 mmol) in 2-propanol (150 mL) were stirred at reflux 12 h. The solvent was concentrated to about 50 mL, ether was added (˜50 mL) and the product collected by filtration, washed 1× with ether and dried under house vacuum. Yield 27 g (94%, purity >95%), mp 133-135° C. 1H NMR (CDCl3) δ 2.57 (m, 2H), 2.9 (m, 2H), 3.4 (s, 3H), 3.8 (s, 3H), 6.9 (d, 2H), 7.6 (d, 2H). MS m/z=218 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.[F:11][C:12]([F:51])([F:50])[C:13]1[CH:14]=[C:15]([C@H:23]2[O:27][C:26](=[O:28])[N:25]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=3B3OC(C)(C)C(C)(C)O3)[C@H:24]2[CH3:49])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[F:51][C:12]([F:11])([F:50])[C:13]1[CH:14]=[C:15]([C@H:23]2[O:27][C:26](=[O:28])[N:25]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=3[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=3)[C@H:24]2[CH3:49])[CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:18]=1
Reactant: C=C(C)c1cccc(Br)n1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
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: CCO
Solvent: COCCOC
Product: C=C(C)c1cccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 100 °C

Procedure:
In a tube were placed 2-bromo-6-isopropenylpyridine (17.5 mg, 0.0878 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (26.2 mg, 0.0439 mmol), DME (190 μL), EtOH (62 μL), and 1M aqueous Na2CO3 (100 μL, 0.1 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (9 mg, 7.8×10−3 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 100° C. for 2 hours. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.15 (15% EtOAc/hexanes). LCMS=589.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.81-7.85 (m, 2H), 7.74 (s, 1H), 7.69-7.69 (m, 3H), 7.58 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 5.94 (s, 1H), 5.48 (d, J=7.7 Hz, 1H), 5.36 (s, 1H), 5.06 (d, J=16.0 Hz, 1H), 4.47 (d, J=16.1 Hz, 1H), 3.91 (m, 1H), 2.23 (s, 3H), 0.50 (d, J=6.6 Hz, 3H).