Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[Cl:9][C:10]1[C:18]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([CH3:27])=[O:26])[CH:20]=2)=[C:17]([Cl:28])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C>[Cl:9][C:10]1[C:18]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([CH3:27])=[O:26])[CH:20]=2)=[C:17]([Cl:28])[CH:16]=[CH:15][C:11]=1[C:12]([O:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1)=[O:13]
Reactant: CC(=O)c1cc(-c2c(Cl)ccc(C(=O)O)c2Cl)n(C)n1
Reactant: CCn1nccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCn1nccc1OC(=O)c1ccc(Cl)c(-c2cc(C(C)=O)nn2C)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
0.21 g (1.9 mmol) of 1-ethyl-5-hydroxy-1H-pyrazole and 0.39 g (1.9 mmol) of N,N-dicyclohexylcarbodiimide were added to 0.59 g (1.9 mmol) of 2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoic acid in 8 ml of acetonitrile. The mixture was stirred at room temperature for 12 hours and 25 ml of 5% strength sodium carbonate solution and 50 ml of ethyl acetate were added, insoluble components were filtered off and the organic phase was separated off, dried and concentrated. The residue was subsequently chromatographed over silica gel (eluent: ethyl acetate:cyclohexane=1:1). 0.21 g (27% of theory) of (1-ethylpyrazol-5-yl) 2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoate was obtained.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[C:15]([F:20])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:21]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[C:15]([F:20])[CH:14]=2)[CH2:8]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 75 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
[(5R)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (Intermediate 4, 6.14 g, 14.7 mmol) was dissolved in N,N-dimethylformamide (50 ml). Sodium azide (1.92 g, 29.6 mmol) was added and the reaction was stirred at 75° C. overnight. The yellow mixture was poured into half-saturated sodium bicarbonate and extracted using ethyl acetate. The organic layer was washed three times with water, dried (magnesium sulfate), filtered, and concentrated to give the title compound as a yellow solid (4.72 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14]CC)=O)=[CH:5][CH:4]=1.[O-]CC.[Na+]>C1(C)C(C)=CC=CC=1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][C:12](=[O:14])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(CCC(=O)OCC)c1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CN(c2ccc(OC)cc2)CCC1=O
Temperature: 110 °C

Procedure:
32.3 g of diethyl 3,3'-[(4-methoxyphenyl)-imino]dipropionate in 40 ml of xylene were added under argon to a freshly prepared solution of sodium ethoxide in absolute ethanol (2.3 g of sodium in 55 ml of ethanol). The mixture was heated slowly to about 110° C., by which means the ethanol was distilled off. Thereafter, the mixture was heated for a further 2 hours. The mixture was cooled to room temperature and poured on to ice. After neutralization with concentrated hydrochloric acid, the mixture was extracted with ether. The extract was washed three times with water, dried over sodium sulfate and evaporated. The product was chromatographed on silica gel with hexane/ethyl acetate (9:1) and yielded ethyl 1-(p-methoxyphenyl)-4-oxo-3-piperidinecarboxylate as a yellow oil.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH2:22][CH2:21][N:20](C(OC)=O)[CH2:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N1CC=C(CCOC(c2ccccc2)c2ccccc2)CC1
Solvent: CCO
Product: C1=C(CCOC(c2ccccc2)c2ccccc2)CCNC1
Yield: 88.5 %

Procedure:
To a stirred solution of methyl 4-(2-(benzhydryloxy)ethyl)-5,6-dihydropyridine-1(2H)-carboxylate (6.5 g, 18.49 mmol) in ethanol (25 ml) was added Claisen's alkali (6.457 g KOH dissolved in 5 ml water and 20 ml methanol). The solution was refluxed overnight, concentrated in vacuo, cooled and diluted with water (40 ml) and extracted with ether (3×30 ml). The combined ethereal extract was dried (Na2SO4) and evaporated to afford viscous liquid. The product was purified by column chromatography over silica gel (ethyl acetate:methanol:triethylamine 20:10:2.5) to obtain compound 5 as yellowish viscous liquid (4.8 g, 88%). 1H-NMR (CDCl3; 400 MHz): 2.03 (brm, 2H, H-3), 2.29-2.32 (t, 2H, J=6.4 Hz, OCH2CH2), 2.92-2.95 (t, 2H, J=5.6 Hz, H-2), 3.31 (brs, 2H, H-6), 3.49-3.53 (t, 2H, OCH2CH2), 5.32 (s, 1H, PhCH(O)Ph), 5.41 (brs, 1H, CH═C), 5.76 (brs, 1H, —NH), 7.17-7.33 (m, 10H, ArH).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7]2[CH:17]=[C:18]([CH2:21][N:22]([CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[C:23](=[O:34])CC3C4C(=CC=CC=4)NN=3)[CH:19]=[CH:20][C:6]1=2)[CH3:4].CI.O>CN(C=O)C>[CH2:3]([N:5]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7]2[CH:17]=[C:18]([CH2:21][N:22]([CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH:23]=[O:34])[CH:19]=[CH:20][C:6]1=2)[CH3:4]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)Cc3n[nH]c4ccccc34)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(C=O)CCc3cccnc3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
Sodium hydride (55% in oil) (52 mg) was suspended in DMF(7 ml), and cooled to 0° C. in an ice water bath. N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)acetamide(210 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 30 minutes followed at room temperature for 30 minutes. Methyl iodide(0.03 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=85:15). The purified product was condensed to dryness to give the title compound(17 mg) as a pale yellow white amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([CH3:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH:39]1([NH2:43])[CH2:42][CH2:41][CH2:40]1>O1CCCC1>[CH:39]1([NH:43][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([O:4][C:3]3[C:16]([CH3:23])=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:2]=3[CH3:1])[CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCC1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)NC1CCC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 71.6 %

Procedure:
To a solution of 5-(2,6-Dimethyl-4-nitro-phenoxy)-2-methoxy-benzoic acid (2.0 g, 6.3 mmol) in tetrahydrofuran (60 mL) at 0° C. under nitrogen was added N-methylmorpholine (1.4 mL) and isobutyl chloroformate (1.3 g, 9.5 mmol). The resulting mixture was stirred for 25 minutes at 0° C., and cyclobutyl amine (0.9 g, 13 mmol) was added in a single portion at 0° C. The reaction solution was stirred for another 30 minutes at 0° C. and warmed to room temperature over 1 hour. The solution was then concentrated to a viscous oily solid which was partitioned between water (25 mL) and methylene chloride (25 mL). The organic phase was separated and the aqueous phase was extracted with methylene chloride (10 mL). The combined organic extracts were washed with saturated aqueous NaHCO3, 1N hydrochloric acid and brine, dried over Na2SO4, filtered, and concentrated. To the residue was purified by column chromatography (Et2O/methylene chloride/hexane=1/7/12) to afford the title compound (1.67 grams) as a crude product. 1H NMR (400 MHz, CDCl3) δ8.04 (br s, 1H), 7.98 (s, 2H), 7.54 (d, 1H), 6.90 (d, 1H), 6.86 (dd, 1H), 4.51-4.49 (m, 1H), 3.94 (s, 3H), 2.41-2.38 (m, 2H), 2.17 (s, 6H), 1.95-1.90 (m, 2H), 1.80-1.75 (m, 2H). MS (APCI+) Calc: 370.4, Found: 371.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[Cl:34].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>FC(F)(F)CO>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:34][C:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:21]3[C:16]4[CH:15]=[C:14]([C:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH:12]=5)[NH:23][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:26]=2)[NH:30][N:29]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: Clc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Temperature: 100 °C
Reaction time: 120 h

Procedure:
Into a 10 mL sealed tube, to a suspension/solution of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (85.3 mg, 0.229 mmol, 1 eq) and 5-amino-3-chloroindazole (3) (43.3 mg, 0.258 mmol, 1.13 eq) in 2,2,2-trifluoroethanol (TFE) (6 mL), trifluoroacetic acid (TFA) (88 μL, 1.1 mmol, 5 eq) was added and the reaction was allowed to stir for 5 d at 100° C. The reaction was cooled to rt and concentrated under reduced pressure. Purification of the crude material most likely to have been problematic-N-BOC protection carried out for easier purification by chromatography on silica gel. MS (ES+): m/z 365.98/367.98 (30/10) [MH+]. HPLC: tR=0.48 & 1.57 min (ZQ2000, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][C:37]([NH:40][CH2:41][CH2:42][CH2:43][NH2:44])([CH3:39])[CH3:38]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][CH2:41][NH:40][C:37]([CH3:39])([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC(C)(C)NCCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCCNC(C)(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 75.1 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added N-(1,1dimethylethyl)-1,3-propanediamine (0.028 mL, 0.177 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (17 mg, 75%). LC-MS m/z 566 (M+H)+; 1H-NMR (MeOD) δ 1.11 (s, 9H), 1.27 (d, 6H), 1.60 (m, 2H), 2.31 (s, 3H), 2.45 (m, 2H), 3.15 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
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[C:5]([F:20])=[CH:4][CH:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH:21]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[C:5]([F:20])=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)ccc(F)c2C1
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCOc2c(C3CC3)ccc(F)c2C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
A mixture of tert-butyl 9-bromo-6-fluoro-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.16 mmol), cyclopropylboronic acid (298 mg, 3.47 mmol), saturated aqueous sodium carbonate solution (6 ml), and tetrakis(triphenylphosphine)palladium(0) (36.1 mg, 0.0313 mmol) in dimethoxyethane (10 ml) was stirred under a nitrogen atmosphere at 90° C. for 12 hr. The reaction mixture was poured into water, and the 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, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (270 mg, 75.7%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH:16]12[NH:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([O:24][CH2:25][C:26]1[C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][C:41]([F:44])([F:43])[F:42])=[N:28][O:29][C:30]=1[CH:31]1[CH2:33][CH2:32]1)[CH2:17]2.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].O1CCOCC1>[CH:31]1([C:30]2[O:29][N:28]=[C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][C:41]([F:42])([F:43])[F:44])[C:26]=2[CH2:25][O:24][CH:18]2[CH2:17][CH:16]3[N:23]([C:2]4[CH:7]=[CH:6][N:5]5[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]5[CH:3]=4)[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH2:32][CH2:33]1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Reactant: CCOC(=O)c1cnc2cc(Br)ccn12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)ccn12
Temperature: 120 °C

Procedure:
A sealable vessel was charged with ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (67 mg, 0.25 mmol), 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (I-1H) cesium carbonate (122 mg, 0.38 mmol), 1,4-dioxane (2 mL). The mixture was degassed (argon bubble, 10 min) and then tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.025 mmol) were added. The reaction flask was evacuated and backfilled with Ar three successive times, and then heated to 120° C. for 12 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (8 mL) and filtered through a CELITE® pad, the filtrate was washed with water (7 mL), dried over magnesium sulfate, concentrated, and chromatographed on silica using linear gradient, 0-100%, EtOAc in Hexanes) to give the desired product as a waxy solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:18][C@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH2:21])(=O)=O)=CC=1.Cl.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([C:41]2[C:49]3[C:48]([NH2:50])=[N:47][CH:46]=[N:45][C:44]=3[NH:43][CH:42]=2)[CH:32]=1.O>CN(C=O)C>[Si:23]([O:22][C@H:19]([CH:20]=[CH2:21])[CH2:18][N:43]1[C:44]2[N:45]=[CH:46][N:47]=[C:48]([NH2:50])[C:49]=2[C:41]([C:33]2[CH:32]=[N:31][C:40]3[C:35]([CH:34]=2)=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:42]1)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25]
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)O[Si](C)(C)C(C)(C)C
Reactant: Nc1ncnc2[nH]cc(-c3cnc4ccccc4c3)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@H](Cn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)O[Si](C)(C)C(C)(C)C
Temperature: 90 °C
Reaction time: 20 h
Yield: 73.3 %

Procedure:
Potassium carbonate (4.0 g) and (R)-2-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl 4-methylbenzenesulfonate (1.43 g) were added to a solution of 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (1.22 g) obtained in Step 4 in DMF (12.2 ml) at room temperature, and the mixture was stirred at 90° C. for 20 hours. After the reaction mixture was cooled, water (49 ml) was added thereto, and the resulting mixture was stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: methanol/ethyl acetate) to obtain the title compound (1.31 g) as a light-yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1>>[F:22][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][NH:1][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[C:15]1[S:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=1
Reactant: O=C(O)C1CC1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Product: O=C1CSC(c2ccc(N3C[C@H](CNC(=O)C4CC4)OC3=O)cc2F)=NN1

Procedure:
Prepared from 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.30 g, 0.925 mmol and cyclopropanecarboxylic acid (0.0812 ml, 1.02 mmol) according to the method of Example 15 (0.30 g, 84%); 1HNMR (300 MHz, DMSO-d6) δ 0.59-0.68 (m, 4H), 1.53-1.62 (m, 1H), 3.44 (t, J=5.2 Hz, 2H), 3.58 (s, 2H), 3.72 (dd, J=6.3, 9.1 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.72-4.78 (m, 1H), 7.41 (dd, J=2.2, 8.5 Hz, 1H), 7.53 (dd, J=2.2, 14 Hz, 1H), 7.68 (t, J=8.8 Hz, 1H), 8.46 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 239-40; MS (m/z): [M+H]+=393.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].IC1C=C2C(=CC=1)N=C(C(O[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=O)C=N2>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:6]
Reactant: O=C(O)c1ccnc(F)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cnc2cc(I)ccc2n1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccnc(F)c1
Yield: 61 %

Procedure:
This compound was prepared starting from compound 27 (1.00 g, 7.09 mmol), according to the procedure developed for compound 24. Reaction time at reflux: 3.5 h, reaction time at 50° C.: 12 h to give compound 35 (1.14 g, 4.35 mmol) as a white solid. Yield 61%; mp 148-150° C.; IR (KBr) ν 1220, 1283, 1406, 1525, 1742 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.44 (d, 2H, J=9.3 Hz), 7.66 (m, 1H), 7.91 (td, 1H, 5JH-F=1.5 Hz, J=1.5, 5.1 Hz), 8.36 (d, 2H, J=9.3 Hz), 8.50 (d, 1H, J=5.1 Hz); MS m/z 262 (M+, 4), 124 (100), 96 (59), 76 (18), 69 (16), 63 (12), 51 (10).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]([CH3:15])[CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])(C)C.N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]([CH3:15])[CH2:12][CH2:13][O:14][SiH2:17][C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CCO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](CCO[SiH2]C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.6 %

Procedure:
(3-Hydroxy-1-(S)-methyl-propyl)-carbamic acid benzyl ester (8.02 g, 35.9 mmol) was taken up in DMF (75 mL). tert-Butyl-dimethylsilyl chloride (8.12 g, 53.9 mmol) was added to the solution followed by imidazole (4.15 g, 61.0 mmol). The reaction was stirred at rt and monitored by TLC. The reaction was determined to be complete at 1 h by TLC. The reaction was taken up in EtOAc (200 mL) and partitioned between 5% LiCl(aq) (200 mL). The aqueous was back extracted with EtOAc. The organics were combined and washed with 3×200 mL 5% LiCl(aq), and dried over Na2SO4. Solids were filtered and solvent removed under reduced pressure. [3-(tert-Butyl-silanoxy)-1-(S)-methyl-propyl]-carbamic acid benzyl ester (12.73 g, 100%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=CC=1.COC1C=CC(CNC2C3C(=CC=C(N(C)C)C=3)C=C(C3C=CC=C(OC)C=3)N=2)=CC=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2nccc3ccccc23)cc1
Agent: COc1ccc(CNc2nc(-c3cccc(OC)c3)cc3ccc(N(C)C)cc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2ccccc12
Yield: 71 %

Procedure:
A reaction mixture of N1-(4-methoxy benzyl)-isoquinolinamine compound III (300 mg, 0.73 mmol) and trifluoroacetic acid (5 mL) in methylene chloride (5 mL) was refluxed for 2 days. A solution of NaHCO3 was added and the reaction mixture was extracted with methylene chloride. The combined organic extracts were washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel with n-hexane-ethyl acetate (1:1) to afford 1-amino isoquinoline (151 mg, 71%). The 1-amino compound was dissolved in acetone (5 mL) and 5 drops of concentrated HCl was added. The hydrochloride salt was filtered and filter cake was washed with acetone. After drying, 120 mg of 1-amino isoquinoline hydrochloride was obtained (Compound 13, 50%). 1H NMR (300 MHz, DMSO-d6) δ: 13.57 (s, 1H), 9.37 (s, 2H), 7.79 (d, 1H), 7.55-7.39 (m, 6H), 7.02 (m, 1H), 3.87 (s, 3H), 3.06 (s, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]([F:41])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:43]=1>O>[F:41][CH:11]([F:10])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][N:32]([S:48]([C:44]4[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=4)(=[O:50])=[O:49])[CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)c3cccnc3)CC2)n1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 86 %

Procedure:
DIPEA (0.78 mL, 4.48 mmol) was added to a mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (200 mg, 0.449 mmol) and 3-pyridinesulfonyl chloride (159 mg, 0.859 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 18.5 hrs. Water was added and the phases were separated. The organic phase was dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (99:1), gave 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(3-pyridinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (227 mg, 86%).