Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:32]=[O:33].C(N(CC)CC)C.O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[N:28]5[CH2:32][OH:33])=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: C=O
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Temperature: 80 °C

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (1 g) synthesized in the same manner as in WO2006/112464 (Example 11) in DMF (10 ml) were added 37% aqueous formalin solution (3.7 ml) and triethylamine (0.05 ml), and the mixture was heated at 80° C. for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give a mixture (1 g, 3:2) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one and 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([F:17])[C:3]=1[O:18][CH3:19].ClC1C=CC=C(F)C=1OC.C([Li:34])CCC>>[Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([F:17])[C:5]([Li:34])=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Agent: COc1c(F)cccc1Cl
Product: [Li]c1ccc(Cl)c(OC)c1F

Procedure:
Another embodiment of the present disclosure includes a method of forming 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane that comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole. The 6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reacted with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with 2,3-dimethyl-2,3-butanediol.
Reaction SMILES: O(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:22][CH:23]=[C:24]2[C:29](=[O:30])OC(C)(C)OC2=O)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19]([C:29]([OH:30])=[CH:24][CH:23]=[N:22]2)=[CH:20][CH:21]=1
Reactant: COc1cccc(NC=C2C(=O)OC(C)(C)OC2=O)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2c(O)ccnc2c1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a solution of Ph2O (500 g) heated to 250° C. was added 108.7 g (392 mmol) of 5-[(3-Methoxyphenyl-amino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione in portions over a 30 min period. The mixture was heated an additional 15 min, cooled to rt, diluted with hexanes (800 mL) and the resulting slurry stirred overnite. The hexanes was decanted off, the solid residue dissolved in 600 mL of MeOH at reflux, cooled to rt and the resulting solid filtered and washed with minimal CH2Cl2. The analogous recrystallization procedure was followed to afford a total of 20.73 g (30%) of 7-methoxyquinolin-4-ol as a light brown solid. 1H NMR (methanol-d4) δ 3.87 (s, 3H), 6.23 d, J=7.3 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.96 (dd, J=9.0, 2.4 Hz, 1H), 8.11 (d, J=9 Hz, 1H); LC-MS (retention time: 0.77, method D), MS m/z 176 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[CH:7][C:2]([NH:20][C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: Cn1nccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNC(=O)c1ccccc1Nc1cc(Nc2ccnn2C)ncc1Cl
Temperature: 150 °C
Yield: 28.2 %

Procedure:
A mixture of 2-[(2,5-dichloro-4-pyridinyl)amino]-N-methylbenzamide (100 mg, 0.338 mmol), 5-amino-1-methyl-1H-pyrazole (65.6 mg, 0.675 mmol), Cs2CO3 (220 mg, 0.675 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 61.8 mg, 0.068 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 48.8 mg, 0.084 mmol) was heated at 150° C. in a microwave oven for 30 min. The reaction mixture was filtered, and the filtrate was concentrated, and the resulting crude product was purified by reverse phase HPLC and the product was treated with 2 N HCl to give 34 mg of product as an HCl salt (24%). LCMS (ES) m/z=357.1 (M+H); 1H NMR (400 MHz, methanol-d4) δ ppm 8.01 (s, 1H), 7.76-7.74 (m, 1H), 7.62-7.61 (m, 2H), 7.55 (d, J=2 Hz, 1H), 7.42-7.39 (m, 1H), 6.52 (s, 1H), 6.33 (d, J=2 Hz, 1H), 3.76 (s, 3H), 2.91 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:16])[CH:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8](=[O:22])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1F.[F:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[CH3:31].O>CS(C)=O.ClCCl>[F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:16])[CH:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8](=[O:22])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[N:35]1[CH2:34][CH2:33][N:32]([C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([F:24])[CH:26]=2)[CH2:37][CH2:36]1
Reactant: CCOC(=O)c1cn(C)c2cnc3c(F)c(F)ccc3c2c1=O
Reactant: Cc1ccc(N2CCNCC2)cc1F
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)c2cnc3c(F)c(N4CCN(c5ccc(C)c(F)c5)CC4)ccc3c2c1=O
Temperature: 100 °C
Yield: 23.7 %

Procedure:
A stirred suspension of 3 g of ethyl 7,8-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 3.9 g of 1-(3-fluoro-4-methylphenyl)piperazine in 30 cm3 of dimethyl sulphoxide was heated at a temperature in the region of 100° C. for about 100 hours. The reaction mixture was treated with 150 cm3 of water in the region of 10° C. and the precipitate was taken up in 100 cm3 of dichloromethane, dried with 10 g of magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa). The yellow powder obtained was chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 80 cm), eluted at an argon pressure of 1 bar with a mixture of dichloromethane and methanol (98/2 mixture by volume), and 200 cm3 fractions were collected. Fractions 16 to 23 were combined and then concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained was washed with 10 cm3 of diethyl ether, filtered and dried. 1.1 g of ethyl 7-fluoro-8-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a yellow solid, which melted at a temperature in the region of 290° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].CC1(C)OB([C:29]2[CH:30]=[N:31][N:32](C(OC(C)(C)C)=O)[CH:33]=2)OC1(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:29]3[CH:30]=[N:31][NH:32][CH:33]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A 500-mL round-bottom flask was purged with nitrogen and charged with cyclobutyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (15.0 g, 40.9 mmol), tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (20 g, 68 mmol), cesium carbonate (40.0 g, 123 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.0 g, 2.45 mmol), 1,4-dioxane (150 mL), and water (15 mL). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:3, ethyl acetate/petroleum ether) to afford cyclobutyl (S)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (9.0 g, 62%) of as a yellow solid. MS (ESI, pos. ion) m/z 355 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:21])[CH:8]=2)[N:3]=1.C(OC([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=2)[C:31](=[O:39])[NH:30]1)=O)(C)(C)C.C1COCC1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH:18]1([C:16]2[CH:17]=[C:13]([NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([I:21])[CH:8]=4)[N:3]=[C:2]([NH:38][C:35]4[CH:36]=[C:37]5[C:32]([C:31](=[O:39])[NH:30][NH:29]5)=[CH:33][CH:34]=4)[N:11]=3)[NH:14][N:15]=2)[CH2:20][CH2:19]1
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(I)ccc2n1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(I)ccc4n3)ccc12
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To (2-Chloro-6-iodo-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (208 mg, 0.606 mmol) in NMP (1 mL) was added 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (252 mg, 1.01 mmol) and THF (3 mL) and the solution was heated to 100 C in a sealed tube. After 4 h, the solution was poured into sat. NaHCO3, and extracted with ethyl acetate, dried (Na2SO4) and concentrated in vacuum to give the title compound as a white solid (300 mg, 95% yield). LCMS m/e: 625.2 (M+H), 623.2 (M−H).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[N+:16]([C:19]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=2)=[CH:22][C:20]=1[NH2:21])([O-:18])=[O:17].C(Cl)(Cl)Cl>CC(C)=O>[Cl:33][C:32]1[C:27]([O:26][C:23]2[CH:24]=[CH:25][C:19]3=[N+:16]([O-:18])[O:17][N:21]=[C:20]3[CH:22]=2)=[N:28][CH:29]=[C:30]([Cl:34])[CH:31]=1
Reactant: Nc1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Solvent: Ic1ccccc1
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1onc2cc(Oc3ncc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To iodobenzene diacetate (3.9 g, 12 mmol) in 100 ml of acetone is added at RT 2-nitro-5-(3,5-dichloro-2-pyridyloxy)aniline (3.0 g, 10 mmol), neat, in portions over 10 minutes. The reaction is stirred at RT overnight and is then stripped. Chloroform is added to the residue, and this mixture is filtered through celite. The filtrate is washed with water (2X) and with brine, dried over sodium sulfate and stripped to give 5-(3,5-dichloro-2-pyridyloxy)benzo-2,1,3-oxadiazole N-oxide. (D; X=H, Y=Cl, Z=Cl).
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.ClC(N(C)C)=C(C)C.[C:27]([O:36][CH3:37])(=[O:35])[C:28]1[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH2:30].N1C=CC=CC=1>C(Cl)Cl.O>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[C:27]([O:36][CH3:37])=[O:35])=[O:18])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Reactant: COC(=O)c1ccccc1N
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a suspension of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 500 mg, 2.0 mmol) in CH2Cl2 (10 mL) at room temperature is added 1-chloro-N,N,2-trimethylpropenylamine (0.98 mL, 7.2 mmol). After stirring for 3 h, methyl anthranilate (1.3 mL, 10.2 mmol) and pyridine (0.66 mL, 8.2 mmol) are added. The mixture is stirred for another 16 h at room temperature. Water (100 mL) is added and the mixture is extracted with EtOAc (3×100 mL). The organic layers are combined, dried and evaporated. Methanol (50 mL) is added to the oily residue, and a white solid is formed. The solid is filtered to afford the title compound (503 mg, 65%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7](#[N:10])[CH2:8]O.CCOCC>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:8][C:7]#[N:10])[CH3:6]
Reactant: N#CCO
Reactant: CNCCOC
Solvent: CCOCC
Solvent: O
Product: COCCN(C)CC#N
Temperature: 70 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
2-Methoxy-N-methylethanamine 266 (10.0 g, 112 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 12.0 mL, 123 mmol) at 0° C. and the mixture stirred at 70° C. for 1 h. The solution was cooled to 20° C., and Et2O (150 mL) and water (100 mL) were added. The aqueous layer was extracted with Et2O (3×40 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 267 (6.46 g, 45%) as a colourless oil: 1H NMR [(CD3)2SO] δ 3.63 (s, 2H, CH2CN), 3.50 (t, J=5.1 Hz, 2H, CH2O), 3.37 (s, 3H, OCH3), 2.69 (t, J=5.1 Hz, 2H, CH2N), 2.42 (s, 3H, NCH3); HRMS calcd for C6H12N2O (M+) m/z 128.0947, found 128.0946.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:25][CH2:26][CH:27]3[CH2:29][CH2:28]3)=[N:10][CH:11]=[C:12]([CH:24]=2)[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18]/[C:17]/2=[N:22]\[OH:23])=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[F:32][C:33]([F:44])([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:25][CH2:26][CH:27]3[CH2:28][CH2:29]3)=[N:10][CH:11]=[C:12]([CH:24]=2)[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18]/[C:17]/2=[N:22]\[O:23][CH2:34][C:33]([F:44])([F:43])[F:32])=[O:14])=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(N[C@H]1CCCC/C1=N\O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCCC/C1=N\OCC(F)(F)F)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
To a solution of 0.100 g 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-{(S)-2-[(E)-hydroxyimino]-cyclohexyl}-nicotinamide in 1.0 ml dimethylformamide was added 0.012 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 30 min. To the resulting solution was added 0.037 ml (0.062 g, 1.1 equivalents) 2,2,2-trifluoroethyl-trifluoro-methanesulfonate and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 0.040 g of the title compound as light yellow oil. MS (EI): 496.3 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:7]=[C:8]([S:13][Si](C)(C)C)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(#N)C.CN(C)P(=O)(N(C)C)N(C)C>[Cl:5][C:6]1[CH:7]=[C:8]([S:13][CH2:2][C:3]#[N:4])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: N#CCCl
Reactant: C[Si](C)(C)Sc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CCSc1ccc(Cl)c(Cl)c1
Reaction time: 0.03 h
Yield: 96.9 %

Procedure:
3.5 ml (55 mmoles) of chloroacetonitrile were added to a refluxing solution of 11.0 g (44 mmoles) of 3,4-dichlorophenylthio(trimethyl)silane in a mixture of 25 ml of acetonitrile and 10 ml of hexamethylphosphoric triamide and the reaction was complete with 2 minutes. The residue obtained after evaporation of the acetonitrile was dissolved in ethyl acetate, and the solution was washed with water, dried and evaporated to dryness to obtain 9.30 g (93% yield) of (3,4-dichlorophenylthio)acetonitrile boiling at 127°-130° C./0.4 mm Hg and having a refractive index of nD25 =1.5920.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:21][C:22]([C:24]1[CH:35]=[C:34]([CH3:36])[C:27]2[N:28]=[C:29]([CH2:31][CH2:32][CH3:33])[NH:30][C:26]=2[CH:25]=1)=[O:23])[CH2:9][C:10](=[O:20])[NH:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[N:57](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:56]=[N:55][N:54]=2)=[CH:43][CH:42]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[CH2:1]([C@@H:8]([NH:21][C:22]([C:24]1[CH:35]=[C:34]([CH3:36])[C:27]2[N:28]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[C:53]4[NH:54][N:55]=[N:56][N:57]=4)=[CH:43][CH:42]=3)[C:29]([CH2:31][CH2:32][CH3:33])=[N:30][C:26]=2[CH:25]=1)=[O:23])[CH2:9][C:10](=[O:20])[NH:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc2c(C)cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCc1nc2cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 6 h

Procedure:
To a cold solution of 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid ((R)-1-benzyl-2-benzyloxycarbamoylethyl)amide (800 mg, 825 μmol) in DMF (50 mL) in ice bath was added NaH (60% dispersion in oil; 99 mg, 2.5 mmol) in small portions. After stirring for 30 minutes at the same temperature, 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole (460 mg, 825 μmol) was added to the mixture, and the final mixture was stirred at room temperature for 12 hours, then at 70° C. for 6 hours. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaCl. The organic layer was dried over MgSO4, and evaporated in vacuo, affording a pale yellow oil. The oil was dissolved in DCM (10 mL), followed by the addition of TFA (10 mL). The final mixture was stirred at room temperature for 1 hour, and concentrated to dryness, yielding a pale yellow oil. The oil was rinsed with ether and dried. The crude material was found to contain two regioisomeric N-alkylation products, compound 5a (a major product) and compound 5b (a minor desired product). ESMS [M+H]+ calcd for C43H42N8O3, 719.35. found 719.3.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([CH3:17])[C:11]3=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:38])[C:29]5[C:34]([CH:35]=4)=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:39][CH3:40])[CH:19]=3)[N:9]=2)[CH2:4][CH2:3]1.[CH:41]1([N:46]=[C:47]=[O:48])[CH2:45][CH2:44][CH2:43][CH2:42]1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH:41]1([NH:46][C:47](=[O:48])[O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[N:12]4[CH:13]=[CH:14][N:15]=[C:16]([CH3:17])[C:11]4=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[N:28]([CH3:38])[C:29]6[C:34]([CH:35]=5)=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][CH:30]=6)=[O:26])=[C:20]([O:39][CH3:40])[CH:19]=4)[N:9]=3)[CH2:4][CH2:3]2)[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: COc1cc(-c2nc([C@H]3CC[C@H](O)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Reactant: O=C=NC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nc([C@H]3CC[C@H](OC(=O)NC4CCCC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(4-(3-((trans)-4-hydroxycyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (0.037 mmol, 20 mg) and N,N-dimethylpyridin-4-amine (7.41 μmol, 0.906 mg) in dichloromethane (2 ml) was added cyclopentyl isocyanate (0.185 mmol, 20.60 mg) and the mixture was stirred at room temperature overnight. Then pyridine (2 ml) was added and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate and the obtained suspension was filtered. The filtrate was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 5% methanol) to give (trans)-4-(1-(3-methoxy-4-(4-methoxy-1-methyl-1H-indole-2-carboxamido)phenyl)-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl cyclopentylcarbamate (6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:21]#[C:22][Si](C)(C)C)[N:6]=1)=[O:4].[OH:27]S(O)(=O)=O>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:21](=[O:27])[CH3:22])[N:6]=1)=[O:4]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1nc(C#C[Si](C)(C)C)c(Cl)c(F)c1Nc1ccccc1F
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-4-fluoro-3-(2-fluorophenylamino)-6-trimethylsilanylethynyl-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), HgSO4 (1.00 equivalent), and conc. H2SO4 (2.00 equivalents) in acetone-water is refluxed with stirring for 3 hours. The reaction mixture is concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vauco to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: Cl.Cl.[N:3]1([C:10]2[CH:11]=[C:12]([CH2:20][CH3:21])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[CH2:23][C:24]1[N:25]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH2:20]([C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([N:3]3[CH2:9][CH2:8][CH2:7][N:6]([CH2:23][C:24]4[N:25]=[C:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[S:27][CH:28]=4)[CH2:5][CH2:4]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[CH3:21]
Reactant: CCc1cc(N2CCCNCC2)c2ncccc2c1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 51.3 %

Procedure:
A mixture of 8-[1,4]-diazepan-1-yl-6-ethylquinoline dihydrochloride (0.32 g, 1 mmol, 1 equiv), 4-chloromethyl-2-phenylthiazole (0.21 g, 1 equiv) and Cs2CO3 (1.63 g, 5 equiv) in 5 mL of DMF was heated at 60° C. for 3 hours and then cooled to room temperature. EtOAc (˜70 mL) was added and the mixture washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 40% EtOAc in hexanes. Silica gel chromatography was repeated using 5% to 10% MeOH in EtOAc to afford the title compound as a light tan solid (0.22 g). 1H NMR (400 MHz, CD3OD) δ 8.65 (dd, 1H, J=1.8 and 4 Hz), 8.04 (dd. 1H, J=1.5 and 8.4 Hz), 7.91 (m, 1H), 7.90 (d, 1H, J=2.2 Hz), 7.41 (m, 3H), 7.36 (s, 1H), 7.31 (dd, 1H, J=4 and 8 Hz), 7.11 (s, 1H), 6.98 (s, 1H), 3.89 (s, 2H), 3.69 (m, 2H), 3.57 (t, 2H, J=5.87 Hz), 3.11 (m, 2H), 2.92 (t, 2H, J=5.3 Hz), 2.72 (q, 2H, J=7.0 Hz), 2.10 (m, 2H), 1.28 (t, 3H, J=7.0 Hz). MS (ES) m/z 429.2 (M+H+).