Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([CH2:25][CH:26]([C:31]([F:34])([F:33])[F:32])[CH2:27][C:28]([OH:30])=[O:29])=[O:24].[C:35](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([CH2:25][CH:26]([C:31]([F:34])([F:33])[F:32])[CH2:27][C:28]([O:30][CH3:35])=[O:29])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(Cl)cc2F)c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CC(CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 214.2 %

Procedure:
To a mixture of 0.20 g of 4-(N-(2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl)carbamoyl)-3-trifluoromethylbutyric acid, 0.06 g of potassium carbonate and 4 ml of N,N-dimethylformamide was added 0.05 g of methyl iodide at room temperature and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and washed successively with water and a saturated saline solution, and dried over anhydrous sodium carbonate followed by removing ethyl acetate by distillation to obtain 0.44 g of the desired compound as crystal.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH:31]2[CH2:33][CH2:32]2)[C:13]([C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:19][CH:20]=2)=[O:14])[CH2:8][CH2:7]1)#[N:5].C(N(C(C)C)C(C)C)C>C(O)C>[CH:31]1([N:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4](=[NH:5])[NH:2][OH:3])[CH2:7][CH2:8]2)[C:13]([C:15]2[CH:20]=[N:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:17][CH:16]=2)=[O:14])[CH2:33][CH2:32]1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C(=N)NO)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hydroxylamine hydrochloride (21 mg) is added to 2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide (130 mg, Intermediate 22) and ethyldiisopropylamine (634) in ethanol (30 mL) and the mixture is refluxed for 4 h. Another 10 mg hydroxylamine hydrochloride is added and the mixture is refluxed for 1 h and stirred at room temperature for 12 h. The solvent is removed in vacuo and the residue is purified by preparative HPLC (MeOH/H2O/TFA) to yield 2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carboxylic acid cyclopropyl-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-amide as an intermediate. Subsequently 50 mg of the aforementioned intermediate are added to tetrahydrofuran (10 mL) followed by ethyldiisopropylamine (28 μL) and cyclopropanecarbonyl chloride (10 μL). The mixture is stirred at room temperature for 3 h. Acetonitrile is added and the mixture is refluxed for 12 h. After removal of the solvents the residue is purified by HPLC (MeOH/H2O/ammonia) to yield the desired product. LC (method 16): tR=1.17 min; Mass spectrum (ESI+): m/z=509 [M+H]+.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.N1CCCCC1.C(O)(=O)C>CC(O)C>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[C:11]([C:10]([CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]2[C:1]1=[O:22])=[O:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)CC(=O)COCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Temperature: 37.5 °C
Reaction time: 2 h

Procedure:
85 g of methyl 4-(2-(phthalimido)ethoxy)acetoacetate was agitated with 31.7 ml of 2-chlorobenzaldehyde and 37 ml of 2-propanol at 20-25° C. The solution of 1.1 ml of piperidine in 14 ml of 2-propanol was added dropwise during 1.5 hour. The mixture was than agitated for 2 hours at the same temperature and for 2 hours at 35-40° C. The mixture was acidified with 1.5 ml of acetic acid, 140 ml of 2-propanol was added and the solution was cooled to 0-5° C. The isopropanolic layer was separated and the organic layer was again washed with 53 ml of 2-propanol. The organic layer, containing the desired product, was evaporated to dryness in order to remove the residual solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[O:23][C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[N:15][N:14]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(C(=O)NNC(=O)c3ccccc3)oc12
Solvent: O=S(Cl)Cl
Product: COc1cccc2cc(-c3nnc(-c4ccccc4)o3)oc12
Temperature: 80 °C
Yield: 78.6 %

Procedure:
N′-(7-Methoxybenzo(b)furan-2-ylcarbonyl)benzohydrazide (5.0 g) was dissolved in thionyl chloride (20 ml) and the mixture was stirred with heating at 80° C. for 1 hr. Thionyl chloride was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (3.7 g) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=1>C(O)C.O.NN>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([C@@H:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-tert-butyl (1-(3-bromo-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (30E, 1.5 g, 2.7 mmol) in 27 ml of ethanol, 0.9 ml of hydrazine monohydrate was added and stirred at room temperature for 2 hours. To the reaction mixture, ethanol was added and filtrated, and the filtrate was concentrated. The residue was diluted with ethyl acetate, and washed with water and then with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the title product. MS (m/z) 427.83 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.CN(C)P(N(C)C)(N(C)C)=O.[Cl:30][C:31]#[C:32]Cl>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[CH3:18][O:17][C:15]([C:12]1([C:32]#[C:31][Cl:30])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]1)=[O:16]
Reactant: COC(=O)C1CCOCC1
Reactant: ClC#CCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)C1(C#CCl)CCOCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
Into an oven dried, argon purged flask tetrahydrofuran (50 mL) was added and the solution was cooled with an ice bath. A 1.8 M solution of lithium diisopropylamide (7.2 mL, 13 mmol) in tetrahydrofuran/heptane/ethylbenzene was added. The resulting solution was cooled to −78° C., and treated dropwise with methyl tetrahydro-2H-pyran-4-carboxylate (Sigma-Aldrich) (1.20 mL. 1.30 g, 9 mmol) followed by hexamethylphosphoramide (1.56 mL, 1.61 g, 9 mmol). The resulting solution was warmed to 0° C., stirred for 20 min., cooled to −78° C., and treated dropwise with pre-cooled (0° C.) solution of 1,2-dichloro-ethyne (ca. 10 mmol). The reaction mixture was stirred at −78° C. for 30 min and then allowed to warm to room temperature. After 4 hours at room temperature, the reaction mixture was poured into crushed ice and extracted with diethyl ether (200 mL) (5 mL of brine was added to support the separation). The organic phase was separated and washed with water (200 mL). This water phase was extracted with diethyl ether (100 mL). The combined organic fractions were washed with brine (100 mL), dried over magnesium sulfate, filtered through a 2 cm layer of silica gel (silica gel layer was washed with 50 mL of ethyl acetate), and then concentrated under reduced pressure. The crude product was subjected to silica gel chromatography (gradient from 0-15% ethyl acetate in iso-hexanes) to afford the title compound (1.22 g, 67%) as a colorless oil. Rf=0.48, 30% ethyl acetate in iso-hexanes, phosphomolybdic acid in ethanol. LCMS (m/z) 203.2/205.3 [M+H]′ Tr=3.12 min (Gemini 5u C18 110 Å, 50×4.60 mm 5 micron column, 3.5 min, 2 ml/min, 5-100% acetonitrile/water, 0.1% acetic acid modifier gradient). 1H NMR (400 MHz, CDCl3): δ 3.79-3.65 (m, 4H), 3.72 (s, 3H), 1.97 (m, 2H), 1.78 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 99 %

Procedure:
To a solution of 10.0 g (49.6 mmol) of 4-chloro-3-nitrobenzoic acid in 100 ml of methanol was added dropwise 11.8 g (99.2 mmol) of thionyl chloride at 0° C. The reaction mixture was refluxed for 2 hours and the solvent was then distilled off under reduced pressure. Ice water was added to the resulting residue. The mixture was made basic by the addition of concentrated ammonium hydroxide. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to give 10.9 g (>99%) of the desired methyl 4-chloro-3-nitro-benzoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[F:30])=[C:18]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:17]=1>>[CH3:34][C:31]([C:18]1[CH:17]=[C:16]([CH2:15][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:21]=[CH:20][C:19]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[F:30])([CH3:32])[CH3:33]
Reactant: COC(=O)CCc1cccc(O)c1
Reactant: COc1ccc(F)c(-c2ccc(CCl)cc2C(C)(C)C)c1
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(C(C)(C)C)c2)c1
Yield: 83 %

Procedure:
Methyl 3-(3-hydroxyphenyl)propanoate (commercially available from Aagile Labs Division of Tyger Scientific) (0.025 g, 0.14 mmol) was alkylated by reaction with compound 8.10 (0.043 g, 0.14 mmol) according to the method given in Example 1 to give compound 34.1 as a clear oil (0.052 g, 83% yield). MS ESI (pos.) m/e: 473.2 (M+Na)+, 468.2 (M+H2O)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[C:8]([OH:16])([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.[Br:24]Br.[OH-].[Na+]>O1CCOCC1>[Br:24][C:11]#[C:10][CH2:9][C:8]([CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=1)[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)([OH:16])[C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: C#CCC(O)(C(Oc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)C(O)(CC#CBr)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
14 g (0.04 mol) of 4-((4-chlorophenoxy)-(1H-1,2,4-triazol-1-yl)-methyl)-5,5-dimethyl-hex-1-yn-4-ol (obtained as described in Example 1), dissolved in 75 ml of dioxane, were added dropwise to a solution of 7.7 g (0.048 mol) of bromine in 40 ml of 10% strength sodium hydroxide solution at 0° C. After five hours, the reaction mixture was stirred into ice water. The precipitated product was filtered off under suction, washed with water and dried. 14.2 g (86.1% of theory) of 1-bromo-4-((4-chlorophenoxy)-(1H-1,2,4-triazol-1-yl)-methyl)-5,5-dimethyl-hex-1-yn-4-ol of melting point 156° to 160° C. were obtained.
Reaction SMILES: C(OC([N:11]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:14][N:13]=1)=O)C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1)[CH2:27][NH:11][C:12]1[N:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][N:17]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OCc2ccccc2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Ethyl 4-{2-[benzyloxycarbonyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (3.0 g) is dissolved in tetrahydrofuran (20 ml) and thereto is added 10% palladium-carbon (500 mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 2 hours and 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to give ethyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (2.22 g). MS (m/z): 452 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].O.C(=O)(O)[O-].[Na+]>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.O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH:18]=[C:19]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cn2)CC1
Temperature: 90 °C
Reaction time: 7 h
Yield: 90.1 %

Procedure:
To 2,5-dibromopyridine (5.0 g), tetrakis(triphenylphosphine)palladium(0) (1.22 g), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (8.16 g) were added 1,4-dioxane (42 ml) and 2M aqueous solution of sodium carbonate (26 ml), and stirred at 90° C. for 7 hours. To the reaction solution was added saturated sodium bicarbonate water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate) to give 4-(5-bromopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (6.45 g) as a pale yellow oil.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[CH3:31]C1C=C(C=CC=1)C=O>>[CH3:31][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:3]=1)[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-methylbenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (1H, br. s.) 10.26 (1H, s) 7.96-8.06 (1H, m) 7.75 (1H, d, J=5.47 Hz) 7.44 (1H, d, J=5.27 Hz) 7.25-7.32 (1H, m) 6.93-7.17 (2H, m) 6.78 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.51, 1.76 Hz) 3.61 (2H, s) 3.31-3.36 (2H, m) 2.60 (2H, t, J=6.54 Hz) 2.22 (3H, s)
Reaction SMILES: [S].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>>[CH:3]1[C:4]2[C:5](=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH:6]=[CH:7][C:2]=1[OH:8]
Reactant: Oc1ccccc1
Agent: [S]
Product: Oc1ccc2ccccc2c1

Procedure:
346 Grams of a sulfur-containing phenol resin (softening point, 107° C.) was obtained in completely the same manner as in Reference Example 1 except that 144 g (1 mole) of β-naphthol was used in place of resorcin.
Reaction SMILES: I[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[S:20][C:19]3[N:21]=[CH:22][CH:23]=[N:24][C:18]=3[N:17](COC)[C:16]=2[CH:28]=1.IC1N=CN=C2C=1N=CN2CC1C=CC2SC3N=CC=NC=3NC=2C=1.[CH3:54][C:55]([OH:59])([C:57]#[CH:58])[CH3:56]>>[N:24]1[C:18]2[NH:17][C:16]3[CH:28]=[C:12]([CH2:11][N:6]4[CH:5]=[N:4][C:3]5[C:7]4=[N:8][CH:9]=[N:10][C:2]=5[C:58]#[C:57][C:55]([CH3:56])([OH:59])[CH3:54])[CH:13]=[CH:14][C:15]=3[S:20][C:19]=2[N:21]=[CH:22][CH:23]=1
Reactant: COCN1c2cc(Cn3cnc4c(I)ncnc43)ccc2Sc2nccnc21
Reactant: C#CC(C)(C)O
Agent: Ic1ncnc2c1ncn2Cc1ccc2c(c1)Nc1nccnc1S2
Product: CC(C)(O)C#Cc1ncnc2c1ncn2Cc1ccc2c(c1)Nc1nccnc1S2

Procedure:
8-(6-Iodopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was treated by the same method as the one of Example 9 to thereby give 8-(6-iodopurin-9-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine. Next, this product was treated with 2-methyl-3-butyn-2-ol by the same method as the one of Example 1417 to thereby give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)CCl.O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:34]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[CH:43]=[N:42][CH:41]=[CH:40]3)=[O:35])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][CH:19]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH2:25][NH:26][C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[C:34]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[CH:43]=[N:42][CH:41]=[CH:40]3)=[O:35])=[CH:22][CH:23]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Reaction time: 8 h

Procedure:
To 2,4-dimethylbenzoic acid in pyridine was added EDC, DMAP, and tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139), and the solution was capped and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E145).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[CH:13]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C=O)C.C1C=CC=CC=1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:11]#[N:12])=[CH:6][CH:5]=1
Reactant: BrC1CCCCC1
Reactant: N#CCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#CC(c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of NaH (1.1 g, 27.5 mmol) in DMF (15 mL) and benzene (30 mL) at 0° C. was treated dropwise with 4-bromophenylacetonitrile (5.0 g, 25.5 mmol), stirred for 45 minutes, treated portionwise with cyclohexyl bromide (3.15 mL, 25.5 mmol), warmed to room temperature, stirred for 90 minutes, treated with water, and extracted with diethyl ether. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([OH:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)[O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Ethyl 7-bromoheptanoate and 3,5-bis(trifluoromethyl) phenol were added to dimethylformamide (DMF). The solution was added with potassium carbonate and stirred at room temperature. The solution was added with water and extracted twice with ethyl acetate. After the organic layer was washed three times with water and dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography to obtain ethyl 7-(3,5-bis (trifluoromethyl)phenoxy)heptanoate.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][S:6]([C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[Cl:26])=[C:11]([Cl:27])[CH:10]=2)(=[O:8])=[O:7])[CH2:3][CH2:2]1.[Br:28][C:29]1C=CC(CN)=[CH:31][CH:30]=1>>[Br:28][C:29]1[CH:3]=[CH:2][C:1]([CH2:4][NH:5][S:6]([C:9]2[CH:10]=[C:11]([Cl:27])[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[Cl:26])=[C:13]([Cl:15])[CH:14]=2)(=[O:8])=[O:7])=[CH:31][CH:30]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)NCC3CC3)cc2Cl)c(Cl)c1
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)NCc3ccc(Br)cc3)cc2Cl)c(Cl)c1

Procedure:
This compound was prepared according to the procedure for the preparation of 120 using 4-bromobenzylamine resin in place of the cyclopropylamino methyl resin.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[C:17]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:23])[CH3:22]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-chloroaniline (1.16 g) in methylene chloride (26 mL) were sequentially added triethylamine (1.52 mL) and ethyl chlorooxoacetate (1.11 mL) under ice cooling, and the thus-obtained mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture to partition the mixture. The organic layer was sequentially washed with 10% aqueous citric acid and saturated brine, and was dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and hexane was added to the residue. The precipitated crystals were collected by filtration, and were dried, to thereby give the title compound (1.89 g).