Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=[O:24])[CH2:15][CH2:14]1)(=[O:12])=[O:11].Br[CH2:26]Br.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([O:24][CH2:26]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:12])=[O:11]
Reactant: BrCBr
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
50 mg (0.133 mmol) of ethyl 6-[1-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 0.01 ml (0.146 mmol) of dibromomethane were dissolved in 1 ml of tetrahydrofuran, and 0.18 ml (0.279 mmol) of n-butyllithium/hexane solution (1.58 M) was added dropwise thereto at −78° C., followed by stirring at room temperature for 4 hours. After the reaction solution was cooled with ice, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=2:1) to give 7 mg of the title compound as a yellow oil (yield: 14%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+].O>CS(C)=O>[N:13]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+:14]=[N-:15]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCC(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of 4-chloro-1-phenylbutan-1-one (26.4 mL, 164 mmol) in DMSO (200 mL) was added sodium azide (12.8 g, 197 mmol). The solution was warmed to 55° C. and stirred for 16 hours. The cooled mixture was then treated with water and extracted with ether. The combined organics were washed with water and brine, then dried over MgSO4 and concentrated to provide the product as an orange oil (30.7 g, 99%).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH3:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.[NH3:20]>>[NH2:20][CH:11]([CH3:18])[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cc2cccs2)cc1
Reactant: N
Product: CC(N)Cc1cccs1
Temperature: 80 °C
Yield: 53 %

Procedure:
Into a 1000 ml autoclave, are added 1-(2-thienyl)-2-propanol p-toluenesulfonate (75 g) and ammonia (600 ml). The whole is heated to 80° C. during 15 hours. After cooling, the autoclave is opened and the ammonia is allowed to evaporate. After adding water (100 ml) and a 1N sodium hydroxide solution (175 ml), the resulting material is extracted with ether. The ether phase is separated and then mixed with 1N hydrochloric acid (75 ml). The aqueous phase is made alkaline and is then extracted with ether. The ether extract is washed with a 5% sodium bicarbonate solution, and then with a saturated sodium chloride solution, after which it is dried over sodium sulfate. After evaporation, the residue is distilled in vacuo, to give 19 g 2-amino-1-(2-thienyl)-propane (Yield: 53%) boiling at 84°-86° C. under 12 mm Hg.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:16])[C:13](O)=[O:14])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:16])[C:13]([Cl:26])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 50 ml volume four-necked flask, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetic acid (8-a) (0.94 g), toluene (anhydrous) (3.0 ml) and dimethylformamide (anhydrous) (0.2 m) were added under a nitrogen atmosphere and the internal temperature was raised to about 50° C. Thionyl chloride (0.45 ml) was added thereto and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was concentrated under reduced pressure, and azeotropically distilled with toluene to give 0.96 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N:13]([CH2:18][CH3:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][N:10]2[N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]([C:23](=[O:26])[NH:24][CH3:25])=[C:9]2[CH:8]=1)(=O)=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1([NH:45][C:46](=[O:62])[C:47]2[CH:52]=[CH:51][CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)[CH2:44][CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[CH2:18]([N:13]([C:12]1[C:7]([C:51]2[CH:50]=[CH:49][CH:48]=[C:47]([C:46](=[O:62])[NH:45][C:42]3([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)[CH2:43][CH2:44]3)[CH:52]=2)=[CH:8][C:9]2[N:10]([N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]=2[C:23]([NH:24][CH3:25])=[O:26])[CH:11]=1)[S:14]([CH3:17])(=[O:15])=[O:16])[CH3:19]
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OS(=O)(=O)C(F)(F)F)S(C)(=O)=O
Reactant: CC1(C)OB(c2cccc(C(=O)NC3(c4ccccn4)CC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)NC2(c3ccccn3)CC2)c1)S(C)(=O)=O

Procedure:
6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.1 g, 0.17 mmol, 1 eq), N-(1-(pyridin-2-yl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.0.65 g, 0.18 mmol, 1.1 eq), tetrakistriphenylphosphine palladium (0.0058 g, 0.0051 mmol, 0.03 eq) and cesium carbonate (0.165 g, 0.51 mmol, 3 eq) were dissolved in 1,4-dioxane (10 ml) and water (2 ml) and the reaction was heated at 90° C. for 14 hours. The solution was filtered through celiete. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield: 22 mg (26%) 1HNMR (400 MHz, CD3OD): δ 1.05 (t, J=8 Hz, 3H), 1.65-1.66 (m, 2H), 1.78-1.82 (m, 2H), 2.89 (s, 3H), 3.20 (s, 3H), 3.62 (br s, 2H), 7.28-7.30 (t, J=7.76 Hz, 2H), 7.57 (br s, 1H), 7.67 (t, J=7.72 Hz, 1H), 7.75 (d, J=8.20 Hz, 1H), 7.86-7.88 (m, 3H), 7.96 (s, 1H), 8.02 (d, J=2.09 Hz, 1H), 8.18 (br, 1H), 8.23 (s, 1H), 8.55 (d, J=5.32 Hz, 1H), 8.98 (s, 1H). LCMS: (ES+) m/z=627.2 (M+H); Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH; Flow: 1 mL/Min; RT min: 1.768;
Reaction SMILES: [Cl:1]CCl.[OH:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1.S(Cl)(Cl)=O>C(N(CC)CC)C>[OH:4][C:5]1[C:10]([C:11]([Cl:1])=[O:13])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cnccc1O
Reactant: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cnccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 80 ml. of dichloromethane solution containing 9.8 g. of 4-hydroxynicotinic acid and 10 ml. of triethylamine was added dropwise 7 ml. of thionyl chloride with stirring under ice-cooling over a period of 20 minutes and the mixture was stirred for 2 hours at room temperature. The crystals thus formed were recovered by filtration, washed with a small amount of dichloromethane, and then dried to provide 4-hydroxynicotinoyl chloride.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[Cl:14])=O.[Br:15][C:16]1[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=1>C(O)C>[Br:15][C:16]1[CH:17]=[N:18][C:19]2[N:20]([CH:2]=[C:3]([C:5]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=3[Cl:14])[N:22]=2)[CH:21]=1
Reactant: O=C(CBr)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1ncc(Br)cn1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1
Yield: 48.2 %

Procedure:
A solution of 2-bromo-1-(2-chloro-5-nitrophenyl)ethan-1-one (I-2) (30 g, 108 mmol, 1.00 equiv) and 5-bromopyrimidin-2-amine (15 g, 88 mmol, 0.81 equiv) in ethanol (300 ml) was stirred for 12 h at 75° C. and then concentrated under vacuum. The residue was diluted with 200 ml of water and extracted with 3×100 ml of ethyl acetate. The combined organic layers was washed with brine, dried over Na2SO4 and concentrated under vacuum to give 15 g (39%) of 6-bromo-2-(2-chloro-5-nitrophenyl)imidazo[1,2-a]pyrimidine (I-3) as a brown solid.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH:11](O)[CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC>[Br:2][CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(O)c1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCCCC(Br)c1ccccc1

Procedure:
PBr3 (0.171 mL, 1.82 mmol, Aldrich) was added to a solution of 1-phenylpentan-1-ol (0.500 g, 3.04 mmol, Alfa Aesar) in Et2O (3.2 mL) at 0° C. The reaction was allowed to reach ambient temperature and then was quenched with ice water and diluted with hexanes. The layers were separated and the organic layer was washed with water and then with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with hexanes afforded product (0.15 g, 22%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=1>CN(C)C=O>[CH3:24][C:17]1[CH:16]=[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 44.7 %

Procedure:
Sodium hydride (60% in mineral oil; 0.599 g) was suspended in dimethylformamide (10 mL), and to this was added dropwise a solution of diethyl malonate (2.00 g) in dimethylformamide (10 mL) under ice-cooling. After the foam generation was finished, a solution of 4-fluoro-2-methylnitrobenzene (1.94 g) in dimethylformamide (5 mL) was added thereto. The reaction temperature was raised to 100° C., the mixture was stirred for 6 hours. The resulting reaction mixture was concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to give the title compound (1.65 g) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C=O)C>[Cl:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN3C(=O)c4ccccc4C3=O)c2F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
3-{[3-(Bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.8 g, 4.8 mmol) was dissolved in DMF (50 mL) and potassium phthalimide (2.25 g, 12.0 mmol) was added. The reaction mixture was placed in an oil bath at 60° C. and stirred for 2-3 h. The reaction mixture was cooled to RT and the solvent was evaporated. Purification was accomplished by column chromatography (CH2Cl2/MeOH) to afford the title compound (1.9 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.70-7.98 (m, 6H), 7.39-7.49 (m, 2H), 7.35 (dd, 1H), 4.81 (s, 2H). MS: m/z 463.2 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:8][C:9]([C:13]([OH:15])=O)=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[CH3:12][C:11]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[CH:8]=[C:9]([C:13](=[O:15])[NH:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[N:10]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)O)nc1C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)NCCN2CCOCC2)nc1C

Procedure:
Ethyl 2-methyl-6-(2-morpholinoethylcarbamoyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate, which was obtained according to a similar manner to that of Example 11 from 5-ethoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2--pyridinecarboxylic acid (1.3 g) and 2-morpholinoethylamine (1.28 g), was treated with a solution of hydrogen chloride in ethanol to give ethyl 2-methyl-6-(2-morpholinoethylcarbamoyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][NH2:28])=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][NH:28][C:4]([C:3]2[C:2]([NH2:1])=[N:10][CH:9]=[C:8]([Br:11])[CH:7]=2)=[O:6])=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)c2cc(Br)cnc2N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-bromo-nicotinic acid (1.2 g, 5.53 mmol) in DMF (30 mL) were added 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 6.173 mmol), HATU (2.35 g, 6.184 mmol) and DIPEA (4 mL, 23.56 mmol) at RT. The reaction mixture was stirred for 18 h at RT. The reaction mixture was poured into ice-water (30 mL), extracted with ethyl acetate (3×50 mL), organic layer was washed with brine dried over anhydrous sodium sulphate concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 60% EtOAc in petroleum ether to afford the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.[ClH:37]>C(OCC)(=O)C.CC(O)C>[ClH:37].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccoc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccoc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
To a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (253 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as a white solid (yield 134 mg, 62%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1.[CH2:17](I)[CH3:18]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([CH2:17][CH3:18])[C:13]2=[O:16])=[CH:8][CH:7]=1
Reactant: CCI
Reactant: O=c1[nH]ccc2ccc(OCCCCl)cc12
Product: CCn1ccc2ccc(OCCCCl)cc2c1=O

Procedure:
By a similar method as in Reference Example 7,7-(3-chloropropoxy)-2-ethyl-2H-isoquinolin-1-one in the form of a colorless oil was prepared from 7-(3-chloropropoxy)-2H-isoquinolin-1-one using ethyl iodide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([NH2:26])[S:25][C:21]=2[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([NH:26][C:14](=[O:16])[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:12][CH:11]=3)[S:25][C:21]=2[CH:20]=1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)cc1
Reactant: COc1ccc2nc(N)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(NC(=O)Cc3ccc(-c4ccncc4)cc3)sc2c1

Procedure:
To a mixture of 2-(4-(pyridin-4-yl)phenyl)acetic acid 3-1 (45 mg, 0.21 mmol), 6-methoxybenzo[d]thiazol-2-amine 3-2 (36 mg, 0.20 mmol), and DIEA (32 mg, 0.25 mmol) in DMF (0.5 mL) under stirring was added HATU (84 mg, 0.22 mmol). The solution was stirred for 2 hours before it was subject to reverse phase HPLC for purification to give compound 3 as white solid. MS m/z 376.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 12.60 (s, 1H), 8.70 (m, 2H), 7.87 (m, 2H), 7.78 (m, 2H), 7.72 (d, 1H, J=8.8 Hz), 7.63 (d, 1H, J=2.8 Hz), 7.58 (m, 2H), 7.11 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 3.96 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=CC(C(O)=O)=[C:4](C)[CH:3]=1.B.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:13]([CH2:17][OH:16])[CH:14]=[CH:15][C:3]=1[CH3:4]
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: Cc1ccc(CO)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 4-chloro-2-methylbenzoic acid (800 mg, 4.69 mmol) in THF (8 mL) that was cooled at 0° C., BH3.THF (14 mL, 1M in THF) was added into the solution drop wise. The mixture was then stirred at r.t. overnight. Add methanol to the system at 0° C. slowly until no gas released. Remove the solvent and the residue was extracted with ethylacetate, concentrated the organic phase to give 894 mg of the title compound (85%). 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 4.63 (2H, s), 7.13-7.22 (2H, m), 7.35 (1H, s).
Reaction SMILES: [NH:1]([C:3](=[O:14])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5])[NH2:2].[C:15](F)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([NH:2][NH:1][C:3](=[O:14])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:5])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NN
Reactant: O=C(F)c1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of (S)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate (293 mg, 1.44 mmol, 1.0 equv. in 3 ml of DCM) was added benzoyl fluoride (179 mg, 1.44 mmol in 2 ml of DCM), the reaction solution was stirred at room temperature for 50 min., the solvent was removed to yield the desired product. 1H NMR (400 MHz, CDCl3) δ 7.89-7.78 (m, 2H), 7.54 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.6 Hz, 2H), 5.32 (b, 1H), 4.45 (b, 1H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[Br:20]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>CO>[Br:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)cc1-c1ccc2c(Br)c(N)ncc2c1
Yield: 68.9 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (51.3 mg, 203 μmol) and N-bromosuccinimide (36.4 mg, 204 μmol) were dissolved together in methanol (2.0 mL) at ambient temperature. After 10 mins the mixture was poured into water and saturated aqueous sodium bicarbonate (1 mL), extracted twice into dichloromethane. The combined organic phases were washed with brine containing sodium thiosulfate (1 mL, 1M), dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by flash chromatography (silica, ISCO, 0-10% methanol in dichloromethane) to yield the title compound as a white solid (46.3 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.92 (t, J=9 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J=9 Hz, 1H), 7.27-7.22 (m, 1H), 7.03-6.95 (m, 2H), 5.04 (s, 2H), 2.24 (s, 3H). LCMS: M+H+=331 & 333.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[CH2:65][C:66]([NH:68][CH:69]2[CH2:72]N[CH2:70]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:68]([CH2:66][CH3:65])[CH:69]([CH3:70])[CH3:72])([CH3:31])[CH3:4]
Reactant: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.43 g) in anhydrous acetonitrile (22 ml), N,N-carbonyldiimidazole (545 mg) was added. The resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture, N,N-diisopropylethylamine (581 μl) and a solution of the compound (2.78 g), which had been obtained in (2), in anhydrous acetonitrile (23 ml) were added and the mixture was stirred overnight at room temperature. To the reaction mixture, dichloromethane was added. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure, whereby 2.57 g of the title compound were obtained as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[OH-].[K+].[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH3:10])[N:5]=[C:6]([O:16][CH2:15][C:14]([F:18])([F:17])[F:13])[N:7]=1
Reactant: OCC(F)(F)F
Reactant: CNc1nc(N)nc(Cl)n1
Agent: [K+]
Agent: [OH-]
Product: CNc1nc(N)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-chloro-6-methylamino-1,3,5-triazine (0.2 mole) was slurried in 80 ml of 2,2,2-trifluoroethanol at room temperature. Potassium hydroxide pellets (0.2 mole) were added portionwise and the mixture was stirred at room temperature overnight. The following day the reaction was heated at gentle reflux for 2 hours during which time the solids gradually dissolved. The solution was cooled and the solvent was removed under vacuum. The residue was washed with water and filtered to give 20.9 g shining off-white crystals of the product named above with the following characteristics: m.p. 204°-205° C. NMR (DMSO-d6): δ2.75, d, (NHCH3); 4.8, q, (OCH2CF3); 6.5-7.3, m, (NH2 +NHCH3).