Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10]C(=O)OC(C)(C)C)=[N:7][C:8]=1[CH3:9].N1C(C)=CC(C)=CC=1C.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]1[CH2:39][C:40]1[O:44][C:43]([C:45](O)=[O:46])=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:10][C:6]1[N:7]=[C:8]([CH3:9])[C:3]([CH2:2][NH:1][C:45]([C:43]2[O:44][C:40]([CH2:39][N:30]3[CH:31]=[CH:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:28])=[CH:41][CH:42]=2)=[O:46])=[C:4]([CH3:18])[CH:5]=1
Reactant: O=C(O)c1ccc(Cn2ccc3ccccc3c2=O)o1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1cc(N)nc(C)c1CNC(=O)c1ccc(Cn2ccc3ccccc3c2=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 5-(aminomethyl)-4,6-dimethylpyridin-2-ylcarbamate (41.1 mg, 0.163 mmol) in THF (5 ml) were added collidine (0.022 ml, 0.163 mmol), 5-((1-oxoisoquinolin-2(1H)-yl)methyl)furan-2-carboxylic acid (44.0 mg, 0.163 mmol) and HATU (81.0 mg, 0.212 mmol). After stirring for 18 h at rt, all volatiles were removed in vacuo. The crude intermediate was purified by column chromatography (CombiFlash Companion, 12 g SiO2, heptane to EA), dissolved in DCM (1 ml) and TFA (1 ml), kept for 1 h at rt, and concentrated. Purification by preparative HPLC (Waters Sunfire Prep C18 OBD 5 um, 100×19 mm, A: H2O+0.1% TFA, B: MeCN+0.1% TFA, 6-36% B in 10 min, 30 ml/min, rt) afforded the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.37 (s, 3H), 4.28 (d, 2H), 5.23 (s, 2H), 6.45 (d, 1H), 6.62 (s, 1H), 6.68 (d, 1H), 7.06 (d, 1H), 7.49-7.59 (m, 4H), 7.65-7.76 (m, 2H), 8.21 (d, 1H), 8.52 (t, 1H), 13.33 (s, 1H). LCMS RtM=1.50 min, [M+H]+=403.3.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:8][C:9]1[C:22]([Br:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:10]=1[C:11]([NH:13][CH:14]([CH:16]1[CH2:18][CH2:17]1)[CH3:15])=[O:12].[Br:25][C:26]1[CH:30]=[C:29]([C:31](OC2C=CC=CC=2)=[O:32])[N:28]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=2)[N:27]=1.CC(C)([O-])C.[K+]>O.CS(C)=O>[Br:25][C:26]1[CH:30]=[C:29]([C:31]([NH:8][C:9]2[C:10]([C:11](=[O:12])[NH:13][CH:14]([CH:16]3[CH2:18][CH2:17]3)[CH3:15])=[CH:19][C:20]([Cl:24])=[CH:21][C:22]=2[Br:23])=[O:32])[N:28]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=2)[N:27]=1
Reactant: CC(NC(=O)c1cc(Cl)cc(Br)c1N)C1CC1
Reactant: O=C(Oc1ccccc1)c1cc(Br)nn1-c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(NC(=O)c1cc(Cl)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 55.9 %

Procedure:
0.45 g of anhydrous sodium sulfate was added to a mixed solution comprising 0.23 g of 2-amino-3-bromo-5-chloro-N-(1-cyclopropylethyl)benzamide, 0.27 g of phenyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate and 5 ml of dimethyl sulfoxide at room temperature, and 0.16 g of potassium tert-butoxide was added, followed by reaction for one hour. Then, the reaction liquid was slowly added to water. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 4/6) to obtain 0.24 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11](=[O:28])[CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[S:5][C:6]=1[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:63][C:64]([O:67][C:68]([NH:70][CH2:71][C@H:72]([NH2:77])[C:73]([O:75][CH3:76])=[O:74])=[O:69])([CH3:66])[CH3:65].Cl.C(N(CC)CC)C>CN(C=O)C>[CH3:76][O:75][C:73](=[O:74])[C@@H:72]([NH:77][C:7]([C:6]1[S:5][C:4]([NH:10][C:11](=[O:28])[CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[N:3][C:2]=1[CH3:1])=[O:8])[CH2:71][NH:70][C:68]([O:67][C:64]([CH3:63])([CH3:66])[CH3:65])=[O:69]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: Cc1nc(NC(=O)Cc2cccc3c2cnn3C2CCCCO2)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(NC(=O)Cc2cccc3c2cnn3C2CCCCO2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a solution of 4-Methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carboxylic acid (540 mg, 1.348 mmol) in anhydrous DMF (25 mL) was added HBTU (614 mg, 1.619 mmol), HOBt (219 mg, 1.621 mmol), H-DAP(BOC)-OME HCL (515 mg, 2.022 mmol) and triethylamine (0.9 mL, 6.457 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated under reduced pressure to remove most of the DMF. The residue was diluted with ethyl acetate (200 mL), washed with 1/1 water/brine (40 mL), aqueous 1N HCl (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (40% to 100% EtOAc in hexanes) to give (S)-3-tert-Butoxycarbonylamino-2-[(4-methyl-2-{2-[1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carbonyl)-amino]-propionic acid methyl ester (548.6 mg, 68%) as an off white foam. MS m/e 617.4 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:27]I.Cl>CN(C)C=O>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[N:15]([C:16](=[O:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:27])([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)Cc2ccccc2)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(N(C)C(=O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.924 g of ethyl 4-nitro-3-phenylacetylaminobenzoate in 10 ml of N,N-dimethylformamide were added 0.166 g of 60% sodium hydride while being cooled with ice, and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.50 ml) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was poured into cold 1-N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 1-N hydrochloric acid and then with water, and was dried. The solvent was distilled off under reduced pressure. The residue was purified through silica-gel column chromatography (developing eluent: a mixture of ethyl acetate and hexane at a ratio of from 1:10 to 1:4) to obtain 0.510 g of ethyl 4-nitro-3-[N-(methyl)phenylacetylamino]benzoate. To 0.148 g of this compound were added 2 ml of ethanol, 1 ml of acetic acid and 0.240 g of reduced iron, and the mixture was refluxed for 2 hours. The solid material was separated through filtration. The filtrate was concentrated, and was then purified through preparative thin-layer silica-gel chromatography (eluent: a mixture of chloroform and ethyl acetate at a ratio of 2:1) to give 0.090 g of 2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole (115).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([N:32]3[CH2:31][CH2:30][NH:29][CH:28]([CH3:27])[CH2:33]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CNCCN1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Product: CC1CN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccccc4)c3)cn2)CCN1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.18 mmol) was used in general procedure 3 with 2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 450.1 (M)+
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13](N)[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.N([O-])=O.[Na+].O.[ClH:38]>>[C:1]([C:9]1[CH:14]=[C:13]([Cl:38])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ccc(N)cc2C(=O)c2ccccc2)n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)OC)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
To a solution of 13.1 g. (34.5 mmol) of the final product of Example 2 in 50 ml. HOAc and 75 ml. of 3 N HCl, stirred at 3°, was added dropwise so as to maintain a temperature of 3°-6°, a solution of 2.50 g. (36.3 mmol) of sodium nitrite in 25 ml. H2O. When the addition was complete, the reaction was stirred at 3° for 20 minutes. A fresh solution of cuprous chloride in concentrated hydrochloric acid (prepared from 27 g. cupric sulfate pentahydrate*) was mixed with an equal volume of water and cooled to 3°. The diazotized solution, which had to be kept cold (<5°) at all times, was slowly poured into the vigorously stirred 5° cuprous chloride solution in several portions, in order to control foaming.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4](=[O:13])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].BrBr.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[H-].[Na+]>C(Cl)(Cl)(Cl)Cl.CN(C)C=O.O>[CH3:3][C:2]([CH3:14])([C:4](=[O:13])[CH:5]=[C:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:1]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C(=O)C=Cc1ccccc1
Agent: BrBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)C(=O)C=C(c1ccccc1)n1cncn1

Procedure:
2,2-Dimethyl-5-phenylpent-4-ene-3-one (9.48 g) in carbon tetrachloride (60 ml) was treated dropwise with bromine (8.0 g). The solution was evaporated in a vacuum and the pale yellow residue of 4,5-dibromo-2,2-dimethyl-5-phenylpentan-3-one (12.6 g) collected. The dibromo compound so prepared (6.96 g) was dissolved in dry dimethylformamide (20 ml) and added dropwise to a mixture obtained by adding 1,2,4-triazole (2.76 g) to a suspension of sodium hydride (1.92 of 50% dispersion in mineral oil, washed free of oil with dry petrol) in dimethylformamide (10 ml). The resulting mixture was heated on a steambath for 15 minutes and poured into cold water (200 ml). The mixture was extracted with ether and the ether extracts dried and evaporated to give a pale yellow oil. This oil crystallised from petrol to give 2,2-dimethyl-5-phenyl-5-(1,2,4-triazol-1-yl)pent-4-en-3-one (compound no. 1 of Table I) having a melting point of 70°- 73° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.Cl.[C:25](O)(=O)[CH3:26]>C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][C:25]([CH3:26])=[N:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(=O)O
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc2c(ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc32)[nH]1
Temperature: 120 °C

Procedure:
7,8-Diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (80 mg, 0.243 mmol) is dissolved in glacial acetic acid (1.5 ml), dilute hydrochloric acid (2M, 0.1 ml) is added, and the mixture is heated at 120° C. for 90 min. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (3×40 ml), water (40 ml) and saturated brine (40 ml). The organic layer is dried (MgSO4), filtered and evaporated to give a brown solid. This is triturated with ethyl acetate containing a few drops of methanol and filtered to give a pale yellow powder.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:6])=O.C1(NO)C=CC=CC=1.CC[O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1.C(O)C>[O:23]=[C:24]1[O:6][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:31]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: NN
Agent: ONc1ccccc1
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccccc2)oc1=O
Temperature: 27.5 °C
Reaction time: 12 h

Procedure:
Hydrazine hydrate (1.7 g) was added dropwise over 30 min to a stirred suspension of 5% Rh—C (wet, 110 mg) and nitrobenzene (4.1 g) in THF (20 mL) at 15° C. controlled by ice-bath. The reaction mixture was warmed to 25-30° C. for 2 h, followed by filtration. The filtrate was diluted with an equal volume of dichloromethane, dried over sodium sulfate, then condensed to a small volume. Addition of petroleum ether to this solution led to the formation of a needle-like white solid as the fairly pure product of phenyl hydroxyamine (3.2 g, 86%). The reaction mixture of phenyl hydroxyamine (2.675 g, 25 mmol), diethyl ethoxymethylene malonate (4.324 g, 20 mmol) and ethanol (20 mL) was stirred at RT for 12 h to form a large amount of solid, which after warming on a water-bath for 3 h disappeared and reappeared when the reaction mixture was cooled down to RT. Filtration and washing with ethanol provided the title compound as white crystal like solid (4.25 g, 91%). 1H NMR (200 MHz, CDCl3) δ (ppm): 8.40 (s, 1H), 7.46-7.28 (m, 5H), 4.23(q, J=7.1 Hz, 2H). 1.31 (t, J.=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12](C(OCC)C)[CH:13]=2)[C:5]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:4]([CH:27]([NH2:29])[CH3:28])[CH:3]=1.Br[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][NH:35]2.C(N(CC)C(C)C)(C)C.Cl.O>C(O)C.O1CCCC1.CO>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)[C:5]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:4]([CH:27]([NH:29][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][NH:35]3)[CH3:28])[CH:3]=1
Reactant: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)N)c2-c2cc(F)cc(F)c2)cn1
Reactant: Brc1ncnc2[nH]cnc12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cc(F)cc(F)c2)c1-c1cn[nH]c1
Temperature: 100 °C

Procedure:
A mixture of 1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluoro-5-methylbiphenyl-2-yl}ethanamine (0.074 g, 0.18 mmol), 6-bromo-9H-purine (0.053 g, 0.26 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) in ethanol (0.6 mL) was heated at 100° C. overnight. The residue was concentrated and treated with 1.0 M hydrogen chloride in water (1.0 mL, 1.0 mmol) in tetrahydrofuran (1 mL) overnight. The mixture was diluted with MeOH and purified on prep LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to afford the desired product. LCMS calculated for C23H19ClF2N7 (M+H)+: m/z=466.1. found: 466.1.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:29])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:29])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: O=C(NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 55.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide (0.160 g), KOH (0.050 g), water (2 mL) and THF (10.0 mL) to afford 0.070 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[CH:5][C:6]([CH3:12])=[N:7]2.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([N:13]1[CH2:18][CH2:17][N:16]([C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:28])[CH2:15][CH2:14]1)=[CH:5][C:6]([CH3:12])=[N:7]2
Reactant: Cc1cc(N2CCNCC2)c2c(Cl)cccc2n1
Reactant: O=C=Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2c(Cl)cccc2n1

Procedure:
5-Chloro-2-methyl-4-(piperazin-1-yl)quinoline (0.18 g, 0.7 mmol), 4-fluorophenyl isocyanate (91 μL, 0.8 mmol), and DMAP (5 mg) in CH2Cl2 (10 mL) are reacted according to method C yielding the product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][O:13][C:12]([CH3:15])=[N:11]2)=[CH:4][CH:3]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][O:13][C:12]([CH3:15])=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC1=NC(C=Cc2ccc(Br)cc2)(CO[Si](C)(C)C(C)(C)C)CO1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CC1=NC(CCc2ccc(Br)cc2)(CO[Si](C)(C)C(C)(C)C)CO1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
4-[2-(4-Bromophenyl)vinyl]-4-(t-butyldimethylsilanyloxymethyl)-2-methyl-4,5-dihydrooxazole (3 mmol) is dissolved in ethanol (15 mL) and hydrogenated at atmospheric pressure in the presence of chlorotris(triphenylphosphine)rhodium(I) (10%). The mixture is stirred at 40° C. for 12 h. After filtration and concentration, the crude product is obtained as colorless oil, which is used directly in the next step without further purification. MS: (ES+): 412.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2=[O:15].C(=O)([O-])[O-].[K+].[K+].I[CH:23]([CH3:25])[CH3:24]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:23]([CH3:25])[CH3:24])[O:8][C:7]([CH3:13])([CH3:14])[CH2:6][C:5]2=[O:15]
Reactant: CC(C)I
Reactant: CC1(C)CC(=O)c2cc(Br)c(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc2c(cc1Br)C(=O)CC(C)(C)O2

Procedure:
As described in General Procedure A, 6-bromo-7-hydroxy-2,2-dimethyl-chroman-4-one, (Compound 3, 1.0 g, 3.8 mmol) in acetone (50 mL) was treated with anhydrous potassium carbonate (2.1 g, 14.9 mmol) and 2-iodopropane (0.7 mL, 7.5 mmol) to give the title compound as a white solid after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)[C:12]([C:24]3[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=3)=[N:11]2)=[CH:5][CH:4]=1.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)[C:12]([C:24]3[CH:30]=[CH:29][C:27]([NH:28][C:38]([NH:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:39])=[CH:26][CH:25]=3)=[N:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc(N)cc3)n2)cc1
Reactant: O=C=Nc1ccccc1
Product: COc1ccc(Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc(NC(=O)Nc4ccccc4)cc3)n2)cc1

Procedure:
Following the procedure described in Example 1 with crude 4-[1-{[4-(methyloxy)phenyl]methyl}-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and phenyl isocyanate provided the title product. ESMS [M+H]+: 515.4
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[N:12]=[CH:13][C:14]([F:25])=[C:15]3[C:19]([C:20](=[O:24])[C:21](O)=[O:22])=[CH:18][NH:17][C:16]=23)[CH:7]=1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:57]1([C:63]2[C:67]([N:68]3[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]3)=[CH:66][NH:65][N:64]=2)[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C>[F:25][C:14]1[CH:13]=[N:12][C:11]([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:10][N:9]=2)=[C:16]2[NH:17][CH:18]=[C:19]([C:20](=[O:24])[C:21](=[O:22])[N:71]3[CH2:72][CH2:73][N:68]([C:67]4[C:63]([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)=[N:64][NH:65][CH:66]=4)[CH2:69][CH2:70]3)[C:15]=12
Reactant: c1ccc(-c2n[nH]cc2N2CCNCC2)cc1
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)O)c[nH]c23)n[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5c[nH]nc5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 48.8 %

Procedure:
To a solution of 2-(7-(5-(ethoxycarbonyl)-1H-pyrazol-3-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.017 g, 0.049 mmol) in DMF (1.5 mL) was added TBTU (0.017 g, 0.054 mmol), diisopropylethylamine (0.15 mL), and 1-(3-phenyl-1H-pyrazol-4-yl)piperazine (0.011 g, 0.049 mmol). The mixture was stirred under N2 at rt for 14.5 h and was quenched with 10 mL of H2O. The solvent was removed under reduced pressure, and the residue was dissolved in DMF. The DMF solution was passed though a plug of celite to remove solids, and the DMF solution was purified by prep HPLC to give the title compound as a white solid (13.3 mg). LCMS: m/e 557.4 (M+H)+, ret time 1.79 min (method 1). 1H NMR (500 MHz, MeOD) δ ppm 8.44 (s, 1H) 8.31 (d, J=2.44 Hz, 1H) 7.95 (d, J=7.32 Hz, 2H) 7.63 (s, 1H) 7.56 (s, 1H) 7.46 (t, J=7.63 Hz, 2H) 7.36 (t, J=7.48 Hz, 1H) 4.46 (q, J=7.22 Hz, 2H) 3.88-3.92 (m, 2H) 3.65-3.70 (m, 2H) 3.00-3.04 (m, 2H) 2.91-2.95 (m, 2H) 1.45 (t, J=7.02 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)=[CH:40][CH:39]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccc(Cl)cc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 4-chlorophenylboronic acid were processed as described in Example 85 to provide the title compound.