Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13](COCC[Si](C)(C)C)[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([Cl:26])[N:5]=2.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[NH:16][CH:15]=[CH:14][N:13]=1)=[CH:8][CH:7]=[C:6]([Cl:26])[N:5]=2
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(Cl)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
2-Amino-7-chloro-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one (1.0 g, 2.38 mmol) was dissolved in 30 mL of dichoromethane. 30 mL of trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for 3 h, until analytical HPLC showed complete consumption of the starting material. Solvents were removed under reduced pressure, and ethyl acetate was added to the residue. The solution was washed with saturated aqueous sodium bicarbonate. The formed precipitate was collected by filtration, then put to dry out overnight at 40° C. under vacuum, yielding 574 mg of beige powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][O:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:10]=2[C:9]2[CH:8]=[C:7]([CH2:28][CH2:29][N:30]3C(=O)C4C(=CC=CC=4)C3=O)[CH:6]=[CH:5][C:4]=2[N:3]=1.O1CCCC1.O.NN>C(O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][O:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:10]=2[C:9]2[CH:8]=[C:7]([CH2:28][CH2:29][NH2:30])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3ccc(CCN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COCCc1nc2c(N)nc3ccc(CCN)cc3c2n1CCCN1CCCC1=O
Temperature: 25 °C
Yield: 38.6 %

Procedure:
2-(2-{4-Amino-2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethyl)-1H-isoindole-1,3(2H)dione (2.2 g, 4.1 mmol) was dissolved in 2:1 ethanol:tetrahydrofuran (40 mL), combined with hydrazine hydrate (410 mg, 8.2 mmol) and heated at reflux temperature for three hours. Additional hydrazine hydrate (0.25 mL) was added and the solution was refluxed for an additional 1.5 hours. The reaction was cooled to ambient temperature, filtered and the filtrate concentrated under reduce pressure. Purification by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-40% CMA:chloroform gradient over 3.8 L) provided 650 mg of 1-{3-[4-amino-8-(2-aminoethyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as an off-white solid. MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([C:28]([OH:30])=O)[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl.[F:33][C:34]([F:45])([F:44])[C:35]1[N:40]=[CH:39][C:38]([C@H:41]([NH2:43])[CH3:42])=[CH:37][N:36]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:18]1[CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:15]=[C:16]([C:28]([NH:43][C@@H:41]([C:38]2[CH:37]=[N:36][C:35]([C:34]([F:45])([F:44])[F:33])=[N:40][CH:39]=2)[CH3:42])=[O:30])[CH:17]=1
Reactant: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(-c3ccc(F)cc3F)c2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(-c2ccc(F)cc2F)cc(N2CCNCC2)c1)c1cnc(C(F)(F)F)nc1
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a solution of 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2′,4′-difluorobiphenyl-3-carboxylic acid (30.0 mg, 0.072 mmol), in N,N-dimethylformamide (1.0 mL) was added (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine dihydrochloride (22.7 mg, 0.086 mmol), EDC (17.8 mg, 0.093 mmol), HOBT (11.0 mg, 0.072 mmol) and diisopropylethylamine (0.038 mL, 0.215 mmol). After 16 h, the mixture was acidified with hydrochloric acid gas. After 15 min, the mixture was concentrated and purified by reverse phase HPLC (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (28.4 mg). HRMS 492.1833 (M+1). 1H NMR (500 MHz, CD3OD): δ 9.00 (s, 2H); 7.57-7.50 (m, 1H); 7.47-7.43 (m, 2H); 7.24 (q, J=1.7 Hz, 1H); 7.09-7.03 (m, 2H); 5.33 (q, J=7.1 Hz, 1H); 3.25 (t, J=4.9 Hz, 4H); 3.00 (t, J=4.7 Hz, 4H); 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([O:14][CH3:15])=[C:6]([CH:8]([C:11](=O)[CH3:12])[C:9]#[N:10])[CH:7]=1.Cl.[C:25]([NH:29][NH2:30])([CH3:28])([CH3:27])[CH3:26]>C(O)C>[CH3:26][C:25]([N:29]1[C:9]([NH2:10])=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:5]=2[O:14][CH3:15])[C:11]([CH3:12])=[N:30]1)([CH3:28])[CH3:27]
Reactant: COc1c(OCc2ccccc2)cc(F)cc1C(C#N)C(C)=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Product: COc1c(OCc2ccccc2)cc(F)cc1-c1c(C)nn(C(C)(C)C)c1N
Temperature: 75 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 2-{5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}-3-oxobutanenitrile (5.7 g, 18.1 mmol) in ethanol (60 mL) was added t-butylhydrazine hydrochloride (6.8 g, 54 mmol). The mixture was stirred for 2 h at 75° C. before cooling to rt and stirring for an additional 14 h. The volatile materials were removed in vacuo. To the residue was added water, and the resulting aqueous mixture was extracted with ethyl acetate 3 times. The organic extracts were combined and washed with 1 N HCl (aq) followed by aqueous NaHCO3 (sat). The organics were then dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 1-(1,1-dimethylethyl)-4-{5-fluoro-2-(methyloxy)-3-[{phenylmethyl)oxy]phenyl}-3-methyl-1H-pyrazol-5-amine as a pale yellow syrup (6.81 g, 17.8 mmol, 98% yield). 1H NMR (400 MHz, CDCl3): δ 7.45-7.32 (m, 5H), 6.60 (dd, 1H), 6.53 (dd, 1H), 5.10 (s, 2H), 3.91 (br s, 2H), 3.55 (s, 3H), 2.20 (s, 3H), 1.67 (s, 9H); MS (EI) for C22H26FN3O2: 384 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:17]([O:24][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Nc1nc(OCc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, benzyl alcohol and DBU in THF. ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:5][CH:6]=1.[CH3:14][O:15][C:16]1[C:17]([NH2:31])=[N:18][CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:5][CH:6]=[C:2]([C:20]3[CH:21]=[C:16]([O:15][CH3:14])[C:17]([NH2:31])=[N:18][CH:19]=3)[N:3]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: Fc1ccc(-c2nc(Br)cs2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2csc(-c3ccc(F)cc3)n2)cnc1N
Yield: 30.1 %

Procedure:
A mixture of 4-bromo-2-(4-fluorophenyl)thiazole (450 mg, 1.7 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (400 mg, 1.6 mmol), and aqueous 2.0 M Na2CO3 solution (2.3 mL, 4.6 mmol) in DME (6.8 mL) was sparged with Ar for 3 min. Tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.1 mmol) was added and the reaction mixture was sparged with Ar for 1 min. The reaction was sealed and irradiated at 115° C. for 25 min in a microwave reactor. The reaction mixture was partitioned with EtOAc (50 mL) and saturated aqueous NaHCO3 solution (100 mL). The separated organic layer was washed with saturated aqueous NaHCO3 solution (50 mL). The organic layer was extracted with aqueous 0.5 N HCl solution (2×25 mL). The combined acidic aqueous portions were washed with EtOAc (30 mL), neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography over silica gel (SiO2, 100% EtOAc) to furnish 145 mg (88% purity) of 5-(2-(4-fluorophenyl)thiazol-4-yl)-3-methoxypyridin-2-amine which was directly used in the next step: LCMS (m/z): 302.1 (MH+), tR=0.75 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][CH3:44])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:42]([O:41][CH2:40][CH2:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:37][CH:36]=1)[CH2:43][CH3:44]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (6.5 g) was added toluene/ethanol/water (10/1/1,188 ml) and then were added 4-(2-propoxyethoxy)phenyl borate (5.3 g) and potassium carbonate (6.0 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.9 g), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/2) to give methyl 7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (6.5 g).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.C(O[CH:18]=[C:19]([C:25]([CH3:27])=O)[C:20]([O:22]CC)=[O:21])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:27][C:25]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:13])([F:14])[F:2])=[CH:10][CH:9]=2)[N:12]=[CH:18][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ccc(OC(F)(F)F)cc1
Temperature: 76 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
4-Trifluoromethoxyphenylhydrazine hydrochloride (4.0 g) and ethyl 2-ethoxymethylene-acetoacetate (3.26 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), were added to a mixed solvent of water (10 ml) and ethanol (10 ml), and stirred at 76° C. for two hours. Sodium hydroxide (1.40 g) was added to the reaction solution and the mixture was further stirred at the same temperature for an hour. Ethanol was evaporated in vacuo, hydrochloric acid (1 mole/1) was added to the aqueous solution and the precipitated solid was recrystallized from ethyl acetate to give the titled compound (3.56 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([NH2:9])[CH2:6][CH2:7][CH3:8])[CH3:2].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([N:9]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(N)C(=O)OCC
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCC(N=Cc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A solution of 11.90 g of the product from stage 1 in 150 ml of diethyl ether was combined in succession with 8.3 ml of benzaldehyde, 23 ml of triethylamine and 7.0 g of anhydrous magnesium sulphate. The mixture was stirred for 24 hours at room temperature, then filtered and washed with diethyl ether. Once the solvent had been removed by distillation, 18.40 g of 2-(benzylideneamino)pentanoic acid ethyl ester (96% of th.) were obtained in the form of a yellowish, viscous mass.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.C(=O)([O-])[O-:10].[K+].[K+]>CO>[OH:10][CH:2]1[CH2:3][CH2:4][CH:5]2[CH:1]1[CH2:8][CH2:7][CH2:6]2
Reactant: C1CC2CCCC2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC1CCC2CCCC12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of (E)-6-acetoxy-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxyoct-1-enyl]bicyclo[3,3,0]octane (530 mg; prepared as described in Reference Example 24 and predominantly in the 2β-configuration) in methanol (10 ml) was treated with anhydrous potassium carbonate (193 mg). The mixture was heated at 40° C., with stirring, for 24 hours. The methanol was then removed in vacuo and the residue was extracted with dichloromethane (3×10 ml). Concentration of the extract in vacuo gave (E)-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxyoct-1-enyl]-6-hydroxybicyclo[3,3,0]octane (430 mg), predominantly in the 2β-configuration.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:35])([F:34])[F:33])[CH:15]=1.C(CN)O>>[Cl:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:33])([F:35])[F:34])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Solvent: NCCO
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxo-thiazolidin-3-yl)-methanesulfonamide (from Example 360) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure E. The compound was made as an ethanolamine salt following General Procedure T.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[F:45][C:46]([F:56])([F:55])[C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[C:47]([C:46]([F:45])([F:55])[F:56])[CH:48]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4cccc(C(F)(F)F)c4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 38.1 using 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine and 3-trifluormethylbenzyl chloride to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH2:22])[N:15]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[N:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([C@H:23]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:24]3)[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:21]=12
Reactant: COc1cc(C#Cc2nn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CC[C@H](n2nc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)C1

Procedure:
In accordance with Example 1, (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and propionyl chloride were used to obtain the title compound as a white solid. Table 2 shows the physical properties thereof.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=1.[NH:16]1[C:24]2[C:19](=[C:20]([CH2:25][NH2:26])[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=[C:2]([NH:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH:18]=[CH:17][NH:16]3)[CH:7]=1
Reactant: Cc1cccc(-c2nc(Cl)cc(Cl)n2)n1
Reactant: NCc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(-c2nc(Cl)cc(NCc3cccc4[nH]ccc34)n2)n1
Temperature: 25 °C

Procedure:
A solution of 4,6-dichloro-2-(6-methyl-pyridin-2-yl)-pyrimidine (Intermediate E) (1 eq, 0.417 mmol, 0.1 g) and C-(1H-indol-4-yl)-methylamine (1 eq, 0.417 mmol, 61 mg) and K2CO3 (1 eq, 0.417 mmol, 58 mg) in NMP (1 ml) is heated using microwave radiation at 120° C. for 1 hour. After cooling to room temperature, the mixture is partitioned between DCM/water and the organic portion is separated and concentrated in vacuo. The crude brown oil is purified by flash chromatography on silica eluting with 100% DCM and the appropriate fractions are combined and concentrated in vacuo. The resulting oil is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and the residue is dissolved in DCM and concentrated in vacuo once again. The resulting solid is dried under vacuum to afford the title compound [M+H]+=350/352.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:17]([NH2:19])=[O:18])=[CH:7][CH:8]=2)[N:3]=1.I[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([NH:19][C:17]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][C:2]([CH3:1])=[N:3]3)=[CH:8][CH:7]=2)=[O:18])=[CH:22][CH:23]=1)#[N:26]
Reactant: N#Cc1ccc(I)cc1
Reactant: Cc1cc(N2CCCC2)c2ccc(C(N)=O)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cc(N2CCCC2)c2ccc(C(=O)Nc3ccc(C#N)cc3)cc2n1
Temperature: 50 °C
Reaction time: 22 h
Yield: 25.3 %

Procedure:
A suspension of 2-methyl-4-pyrrolidin-1-yl-quinoline-7-carboxylic acid amide (50 mg, 0.20 mmol), 4-iodobenzonitrile (45 mg, 0.20 mmol), xantphos (6.8 mg, 12 μmol), cesium carbonate (89 mg, 0.27 mmol), and palladium(II) acetate (1.8 mg, 8 μmol) in 1,4-dioxane (0.5 mL) was stirred under argon at 50° C. for 22 h, then the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) afforded the title compound (18 mg, 26%). Light yellow solid, ISP-MS: m/e=357.3 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:43]=[CH:42][C:37]([C:38](OC)=[O:39])=[CH:36][CH:35]=2)=[CH:16][CH:15]=1.Cl>O1CCCC1.COCCOC>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:38](=[O:39])[CH2:3][S:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:6])=[O:5])=[CH:42][CH:43]=2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C(CS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is added a solution of 5.0 g. of methyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate in 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield 4'-[13-(4-chlorophenyl)tridec-12-ynylamino]-2-(phenylsulfonyl)acetophenone.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Br-:12].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:12][C:9]1[C:2]([F:1])=[C:3]([CH:6]=[C:7]([F:11])[C:8]=1[OH:10])[CH:4]=[O:5]
Reactant: [Br-]
Reactant: O=Cc1cc(F)c(O)cc1F
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(F)c(O)c(Br)c1F
Temperature: 40 °C
Reaction time: 7 h
Yield: 86169.1 %

Procedure:
To a solution of 2,5-difluoro-4-hydroxybenzaldehyde (37.5 g, 0.237 mmol) in dichloromethane (1.5 L) was added pyridinium tribromide (75.9 g, 0.237 mmol). The reaction mixture was stirred at 40° C. for 7 hrs then at room temperature overnight. The reaction was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give 48.4 g of crude 3-bromo-2,5-difluoro-4-hydroxybenzaldehyde use as this in the next step.