Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].N[CH2:12][C:13](=O)[CH2:14]CC(O)=O>C(O)CC.Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:12][CH2:13][CH3:14])=[O:8]
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Solvent: CCCO
Product: CCCOC(=O)CCC(=O)CN
Temperature: 75 °C
Reaction time: 20 h

Procedure:
0.5 g 5-aminolevulinic acid hydrochloride was dissolved in 100 ml dry n-propanol containing 1-2 drops of conc. hydrochloride in a 250 ml glass reactor equipped with a stirrer, reflux condenser and a thermometer. The reaction mixture was stirred at 70-80° C. for approx. 20 hours. After all the 5-aminolevulinic acid was converted to its n-propylester (followed by 1H-NMR), the excess propanol was removed, and the product dried under high vacuum (<1 mBar) at 40-50° C. The reaction gave 0.49 g propyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C([Li])CCC.Cl[CH2:26][O:27][CH3:28]>C1COCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:26][O:27][CH3:28])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: COCCl
Reactant: COc1ccc(CNC(=O)OC(C)(C)C)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCN(Cc1ccc(OC)cc1OC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 104.4 %

Procedure:
Tert-butyl 2,4-dimethoxybenzylcarbamate (3.96 g, 14.8 mmol) was dissolved in THF (74 mL) and cooled to −78° C. The solution was treated with butyl lithium (7.44 mL, 16.3 mmol) dropwise over a five minute period to afford a pale-yellow solution. The solution was allowed to stir for 15 minutes before the chloro(methoxy)methane (1.35 mL, 17.8 mmol) was added dropwise (neat). The reaction was stirred at −78° C. for 10 minutes, then allowed to warm slowly to ambient temperature overnight. The reaction was concentrated in vacuo to afford a yellow gel which was partitioned between half-saturated NH4Cl solution and ether. The aqueous layer was extracted once, and the organics were combined. The organic layer washed with water, then brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo. 1H NMR supports the desired near-pure (>90%) tert-butyl 2,4-dimethoxybenzyl(methoxymethyl)carbamate (4.81 g, 104% yield) as a pale-yellow oil which was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: O=C(O)Cc1ccccc1O
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)Cc2ccccc2O)cc1
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
2-hydroxyphenylacetic acid (10 g, 66 mmol) was dissolved in N,N-dimethyl-formamide (100 ml) and cooled on ice-bath. Potassium tert-butoxide (8.85 g, 78 mmol) was added. The mixture was left for 30 min and allowed to reach room temperature. 4-Methoxy-benzylchloride (11.7 g, 72 mmol) in N,N-dimethyl-formamide (30 ml) was then added dropwise, under nitrogen atmosphere and left over-night. The solvent was evaporated under reduced pressure and the crude mixture was dissolved in ether (100 ml) and washed with water (25 ml), brine and dried over sodium sulphate. Chromatography (hexane-ethyl acetate, 2:1) followed by recrystallization hexane-ethyl acetate) gave the title compound (7.6 g, 42%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.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>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: OB(O)c1ccc(F)cc1F
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+]
Product: Cc1nc(-c2ccc(F)cc2F)n2c1c(C)nc1ccc(F)cc12
Yield: 50.1 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2,4-difluorophenylboronic acid (48 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (41 mg, 50% yield). EIMS 328.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[NH2:17])=[N:6][CH:7]=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1.ClCCl>[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:17][C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:18])=[O:28])=[C:25]([O:32][CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Cl)CC1
Reactant: Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2cc(Cl)ccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-2-amino-4-chlorobenzamide (0.74 g, 26.5 mmol) in pyridine (1 mL) and dichloromethane (20 mL) at 0° C. was added a solution of 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride (1.05 g, 26.5 mmol) in dichloromethane (10.5 mL). The cold bath was then removed and after 72 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with water, followed by satd aq NaHCO3 and then brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a solution of 20% ethyl acetate in hexanes.
Reaction SMILES: [OH:1][C@@:2]([CH3:31])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[C:27]3[S:28][CH:29]=[CH:30][C:26]=3[O:25][N:24]=2)[CH:18]=1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([NH:39][CH2:3][C@@:2]([CH3:31])([OH:1])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[C:27]3[S:28][CH:29]=[CH:30][C:26]=3[O:25][N:24]=2)[CH:18]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@](C)(O)COc2cccc(-c3noc4ccsc34)c2)cc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: C[C@@](O)(CNCc1ccccc1)COc1cccc(-c2noc3ccsc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir a solution of toluene-4-sulfonic acid (S)-2-hydroxy-2-methyl-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl ester (intermediate prepared as described in example 6, 2.45 g, 0.00533 g) and tetrahydrofuran (40 mL), and treat dropwise at 0° C. with a solution of benzylamine (0.57 g, 0.00533 mol, Aldrich Chemical Company) and tetrahydrofuran (10 mL). Stir overnight at room temperature, concentrate in vacuo and partition the residue between ethyl acetate (100 mL) and water (100 mL). Separate the organic phase, dry (MgSO4), filter and concentrate in vacuo. Purify the residue by flash chromatography (silica gel, elute with 9:1 dichloromethane:methanol) to give the free base of the title compound. The maleate salt may be prepared as described for example 66.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH2:23])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)(=[O:33])=[O:32])[N:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CN)n1
Reactant: O=S(=O)(Cl)c1ccccn1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2ccccn2)n1
Yield: 85.7 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 12-(d) except for using tert-butyl[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate (1.20 g, 3.56 mmol) obtained in Reference Example 12-(c), and using 2-pyridylsulfonyl chloride (640 mg, 3.60 mmol) in place of 3-pyridylsulfonyl chloride to afford the title compound (1.46 g) as a white solid. (Yield: 86%)
Reaction SMILES: [C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[H][H]>O1CCOCC1.[Pd]>[C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)OCc3ccccc3)cc2cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)O)cc2cc1Cl

Procedure:
7-Butyryloxy-3-carboxymethylaminocarbonyl-6-chlorocoumarin was prepared as follows. 920 mg (2 mMol) 7-butyryloxy-3-benzyloxycarbonylmethylaminocarbonyl-6-chlorocoumarin were dissolved in 50 ml dioxane. 100 mg palladium on carbon (10%) and 100 microliters acetic acid were added to the solution and the suspension stirred vigorously in a hydrogen atmosphere at ambient pressure. After the uptake of hydrogen seized the suspension was filtered. The product containing carbon was extracted five times with 25 ml boiling dioxane. The combined dioxane solutions were let to cool upon which the product precipitated as a white powder. Reduction of the solvent to 20 ml precipitates more product. The remaining dioxane solution is heated to boiling and to heptane is added until the solution becomes cloudy. The weights of the dried powders were 245 mg, 389 mg and 58 mg, totaling 692 mg (1.88 mMol, 94%) of white product. 1H NMR (dDMSO): 102 ppm (t, 3H, J=7.4 Hz, butyric methyl), 1.73 ppm (m, 2H, J1 J2=7.3 Hz, butyric methylene), 2.70 ppm (t, 2H, J=7.2 Hz, butyric methylene), 4.07 ppm (d, 2H, J=5.6 Hz, glycine methylene), 7.67 ppm (s, 1H, coumarin), 8.35 ppm (s, 1H, coumarin), 8.90 ppm (s, 1H, coumarin), 9.00 ppm (t, 1H, J=5.6 Hz, amide).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7](F)=[C:6]([F:12])[CH:5]=1)=[O:3].[CH3:13][S-:14].[Na+]>C(#N)C>[F:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=[C:8]([F:10])[C:7]=1[S:14][CH3:13]
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC#N
Product: CSc1c(F)cc(C(C)=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
The 3,4,5-triflouroacetophenone (9.50 g, 54.6 mmol) and sodium thiomethoxide (4.60 g) were mixed together in acetonitrile (80 mL). The solution was stirred for 2 hour at ambient temperature. Solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was extracted with water (2×100 mL), saturated ammonium chloride (2×100 mL) and dried over sodium sulfate. Solvent was removed in vacuo to yield 1-[3,5-difluoro-4-(methyl-thio)phenyl]ethanone as a yellow oil (8.08 g, 73%). 1H NMR (CDCl3/300 MHz) 7.46-7.43 (m, 2H), 2.58 (s, 3H), 2.56 (t, 3H, J=1). ESHRMS m/z 203.0357 (M+H+, Calcd 203.0342).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[N:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(F)cc2)cc(C(F)(F)F)[nH]1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1

Procedure:
The title compound was prepared from 4-(4-fluoro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (15.5 g, 0.06 mol) and phosphoroxychloride (155 mL) according to the general procedure I. Obtained as a light yellow solid (16.5 g, 99%). MS (EI) 276.1 [(M)+]; mp 67° C.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:44])([C:22]([F:43])([F:42])[C:23]([F:41])([F:40])[C:24]([F:39])([F:38])[C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C1C=C(C)C=CC=1S([O-])(=O)=O>O1CCCC1>[F:3][C:4]([F:44])([C:22]([F:43])([F:42])[C:23]([F:41])([F:40])[C:24]([F:39])([F:38])[C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:2][CH3:1]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Solvent: C1CCOC1
Product: CNCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
3.78 g of methylamine is condensed in a solution of 5.72 g of 7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-heptadecafluoro-tetradecyl-tosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred overnight in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 4.29 g of (7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-heptadecafluoro-tetradecyl)-methyl-amine is obtained as a crude product.
Reaction SMILES: [CH3:1][C:2]1OC(=O)[CH:6]([C:10]([CH3:12])=O)[C:4](=[O:5])[CH:3]=1.[NH3:13]>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[CH:6]=[C:10]([CH3:12])[N:13]=1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Reactant: N
Product: Cc1cc(O)cc(C)n1

Procedure:
Five separate batches of dehydroacetic acid (1.5 g, 8.92 mmol) are each suspended in conc. ammonia (4 mL) and irradiated at 120° C. for 20 minutes (150 W, Discover® System microwave reactor by CEM Corporation, Matthews, N.C., USA) in the microwave. Once cooled, the solutions are combined and evaporated to dryness to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>CN(C=O)C>[Cl:21][CH2:20][CH2:19][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[NH2:11]
Reactant: Nc1nc(N)c2[nH]cnc2n1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2ncn(CCCl)c2n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 72 %

Procedure:
10 g (66.6 mmol) 2,6-diaminopurine were suspended under argon in 300 ml DMF and 21.6 g (156.5 mmol) potassium carbonate and 24 ml 1-bromo-2-chloroethane were added. The mixture was stirred for 64 hours at room temperature. The light yellow suspension was filtered and the solids were washed with 30 ml DMF and subsequently triturated with 100 ml water for 30 minutes. The mixture was filtered and the solids were washed with 50 ml water and dried in vacuo to give 10.15 g (72%) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:49]([CH2:51][NH2:52])[OH:50]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:52][CH2:51][CH2:49][OH:50])=[O:20])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 62.7 %

Procedure:
A dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added triethylamine (80 μl, 0.566 mmol), 4-dimethylaminopyridine (15 mg, 0.118 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.283 mmol) and ethanolamine hydrochloride (28 mg, 0.283 mmol). The resulting mixture was stirred at room temperature for 17.5 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give the title compound (69 mg, 0.148 mmol, 63%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:24](=[O:31])[NH:25][C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[C:5]2[N:9]=[C:8]([NH:10][C:11]([C:13]3[N:14]=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[NH:7][C:6]=2[CH:23]=1.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>N1C=CC=CC=1>[NH:30]1[CH:29]=[CH:28][N:27]=[C:26]1[NH:25][C:24]([C:4]1[C:5]2[N:9]=[C:8]([NH:10][C:11]([C:13]3[N:14]=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[NH:7][C:6]=2[CH:23]=[C:2]([NH:1][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:3]=1)=[O:31]
Reactant: Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
20 mg (0.04 mmol) of isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (Example 129) was dissolved in pyridine (2 mL). To this stirring solution at 0° C., 5.6 mg (0.053 mmol) of isobutyryl chloride was added in one portion. The reaction mixture was stirred for 10 min at 0° C. and warmed to room temperature. The pyridine was evaporated and water (5 mL) was added to the reaction mixture. The mixture was stirred for 10 min. and the resulting solid was filtered, washed with water (2 mL) and diethyl ether (5 mL), and dried to provide 15.5 mg (66.5%) of isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-6-isobutyrylamino-1H-benzoimidazol-2-yl]-amide. LCMS: 483 (M+1)+. 1H NMR (CD3OD, 400 MHz): δ 9.43 (s, 1H), 8.77 (s, 1H), 8.06-8.31 (m, 5H), 7.80-7.93 (m, 3H), 7.08 (s, 2H), 2.45 (m, 1H), 1.1 (d, 6H) ppm.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[N:8]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[C:9]=[S:10]>CCOC(C)=O>[NH2:7][C:6]1[S:10][C:9]([NH:8][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:1][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: N#CC(N)C(N)=O
Reactant: S=C=Nc1cccc2ccccc12
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Nc2cccc3ccccc23)sc1N
Yield: 48.7 %

Procedure:
To a suspension of 2-amino-2-cyanoacetamide (0.25 g, 2.53 mmol) in EtOAc (8 mL), was added 1-isothiocyanatonaphthalene (0.467 g, 2.53 mmol), and the mixture was refluxed for 30 min. The solvent was evaporated under reduced pressure, and the resulting crude residue was purified by silica gel column chromatography eluted with 2% MeOH in DCM to give 0.35 g (48% yield) of the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:39][C:38]1([CH3:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=2)[NH:30][CH:29]1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:24]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: O=C(O)c1cnccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of pyrazine-2-carboxylic acid (1.26 g, 10 mmol) and 1,1′-carbonyldiimidazole (2.14 g, 13 mmol) in N,N-dimethylformamide (8 mL) was stirred at 70° C. for 1 h. Then a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3 g, 10 mmol) in N,N-dimethylformamide (5 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyrazine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.82 g, 45%) as a light yellow solid: LC/MS m/e calcd for C23H22N4O3 (M+H)+: 403.46, observed: 403.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:41]([O:47][CH2:48][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (57 μL, 0.41 mmol) in DMF (1 mL) was added chloromethyl pivalate (35 μL, 0.25 mmol) at rt. The reaction was stirred at rt for 24 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 1/1) to afford (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl pivalate (30 mg, 23%) and (N-(3-(5-(4-chlorophenyl)-1-((pivaloyloxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propylsulfonamido) methyl pivalate (20 mg, 13.3%) as white solids. The title compounds were characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][NH:14][CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14]([CH2:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)[CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2
Reactant: ClCc1ccncc1
Reactant: O=C1Nc2cc(F)ccc2N2CCNCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cc(F)ccc2N2CCN(Cc3ccncc3)CC12

Procedure:
A solution of 2 g. (0.008 mole) of 8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one and 1.6 g. (0.01 mole) of 4-picolyl chloride, 3.5 g. of potassium carbonate and 0.5 ml. of triethylamine was stirred and refluxed in 100 ml. of acetone for 48 hours, cooled and filtered. The solvent was removed under reduced pressure. The residue was dissolved in ethanol and treated with dry hydrogen chloride saturated ether. The product hydrochloride was filtered and recrystallized from ethanol-water to yield 1.25 g. of the title compound as the dihydrochloride, m.p. 269°-272° C.