Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][CH:22]([F:24])[F:23])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:13])[CH2:7]2.[Cl:25]CCl>CN(C=O)C.Cl[Cu]>[Cl:25][C:2]1[CH:3]=[C:4]([O:21][CH:22]([F:24])[F:23])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:13])[CH2:7]2
Reactant: CC(c1ccc(Cl)cc1)N1Cc2cc(OC(F)F)cc(I)c2C1=O
Reactant: ClCCl
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)N1Cc2cc(OC(F)F)cc(Cl)c2C1=O
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
A solution of the 7-iodo-2-[1-(4-chloro-phenyl)-ethyl]-5-difluoromethoxy-2,3-dihydro-isoindolone (0.122 g, 0.26 mmol) in DMF (5 mL) was treated with CuCl (0.130 g, 1.31 mmol) and stirred at 140° C. for 1-2 h. After this time, the reaction mixture was diluted with dichloromethane (15 mL) and the solids removed by filtration. The filtrate was concentrated. Silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded 7-Chloro-2-[1-(4-chloro-phenyl)-ethyl]-5-difluoromethoxy-2,3-dihydro-isoindolone (0.05 g, 52%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.66 (d, 3H), 3.94 (d, 1H), 4.27 (d, 1H), 5.74 (q, 1H), 6.54 (t, 1H), 7.17 (s, 1H), 7.26 (s, 1H), 7.31 (m, 4H). GC-MS: m/z 371 (M)+, 356 (M−15)+.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH2:25]O)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:28])([F:29])[F:30])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2
Reactant: BrP(Br)Br
Reactant: OCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1c(-c2onc3c2CCc2cc(CBr)ccc2-3)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of (3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (Preparation 6B, 700 mg, 1.698 mmol) in anhydrous dichloromethane (25 mL) was added phosphorous tribromide (0.240 mL, 2.55 mmol) slowly at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature overnight. Next, 10 mL of ice water was added at 0° C. to quench the reaction. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution (20 mL) and filtered over CELITE®. The aqueous layer was separated, combined with the aqueous layer from before and extracted with dichloromethane (2×20 mL). The combined organic solutions were dried over sodium sulfate, filtered through a silica gel pad that was rinsed with dichloromethane, and concentrated under reduced pressure to give 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (580 mg, 1.220 mmol, 71.9% yield) as a yellow solid. LC/MS M+1=477.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:9]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[N:10][C:11]([Br:18])=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[N+]=[N-]>C1COCC1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:18][C:11]1[CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:8]2[NH:5][C:20]3=[N:21][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:23][CH:24]=[C:19]3[C:9]=2[N:10]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)nc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCCCCCCC(=O)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1nc(N3CCOCC3)ccc12
Temperature: 80 °C
Yield: 74.7 %

Procedure:
1,2-Dichloroethane (0.4 mL) was added to a mixture of methyl 3-azido-6-bromo-6′-morpholino-2,3′-bipyridine-4-carboxylate (240 mg, 0.572 mmol), rhodium octanoate dimer (35.7 mg, 0.046 mmol) and crushed 4 A° molecular sieves (500 mg gm) and heated overnights at 80° C. The reaction was diluted with THF and filtered. The collected solid was washed with multiple portions of boiling THF to extract all of the product. The solvent was removed from the combined filtrates and the residue was suspended in MeOH and the product was collected by filtration. This left methyl 2-bromo-7-(4-morpholinyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (167 mg, 0.427 mmol, 745% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.75 (1H, s), 8.30 (1H, d, J=8.85 Hz), 7.72 (1H, s), 6.91 (1H, d, J=8.85 Hz), 4.01 (3H, s), 3.74 (8H, dd, J=15.56, 4.88 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1)[CH3:2].Cl[C:19](OCC)=[O:20].Cl>>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[N:9]=[C:10]([Cl:15])[CH:11]=[CH:12][C:13]=2[N:14]=[C:19]1[OH:20])[CH3:17]
Reactant: CCN(CC)CCCNc1nc(Cl)ccc1N
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCN(CC)CCCn1c(O)nc2ccc(Cl)nc21

Procedure:
The production was carried out in a manner analogous to Example 1 from 20 grams of 2-(3-diethylamino-propylamino)-3-amino-6-chloropyridine and 9 ml of ethyl chloroformate. M.P. of the hydrochloride of the title compound was 203°-205° C.; yield: 14 grams.
Reaction SMILES: Cl.[C:2]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][Cl:23])=[N:20][C:19]([C:24]([OH:26])=[O:25])=[N:18]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27]O>>[CH3:27][O:25][C:24]([C:19]1[N:20]=[C:21]([CH2:22][Cl:23])[N:17]([C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:2](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:18]=1)=[O:26]
Reactant: CO
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: Cl
Product: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 18 h

Procedure:
224 ml of a 6N solution of hydrogen chloride in methanol is added to a solution of 112.2 g (0.299 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid in 1120 ml of methanol, and the whole is refluxed for 21 hours. There is then distilled off 800 ml of methanol at normal pressure, and the concentrated solution is allowed to stand for 18 hours at room temperature. The product that has crystallised out is filtered off under suction and washed with cold methanol and hexane. After drying in vacuo, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 132°-134°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH2:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccncc2N)CC1
Reaction time: 16 h
Yield: 81.2 %

Procedure:
To a solution of 4-(3-nitro-pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (25.0 g, 77.55 mmol, 1.0 equiv) in ethanol (375 mL) was added palladium on activated charcoal 10% (2.5 g, 2.35 mmol, 0.03 equiv) and the reaction put under hydrogen (50 Psi) in a Parr shaker for 16 h. The reaction mixture was filtered through Celite and the filtrate evaporated under reduced pressure. The residue was triturated with diethyl ether, the organic layer decanted and the solid material dried under reduced pressure to yield 18.4 g (81%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.25-1.27 (m, 2H), 1.40 (s, 9H), 1.88-1.91 (m, 2H), 2.90 (br s, 2H), 3.49 (br s, 1H), 3.89 (br s, 2H), 4.57 (s, 2H), 5.05 (br s, 1H), 6.42 (d, J=4.3 Hz, 1H), 7.56 (d, J=4.3 Hz, 1H), 7.63 (s, 1H). MS (ISP): 293.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:14]2[CH:13]=[C:12]([Cl:11])[CH:17]=[C:16]([Cl:18])[CH:15]=2)(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 3,5-dichlorobenzenesulphonyl chloride (0.24 g). Yield 0.012 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[C:33]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:32]=2)[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:36])=[C:33]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:32]=2)[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCOCC3)c(OCc3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
Morpholine (19 mg, 0.2183 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55 mg, 0.2869 mmol) were added to a methylene chloride solution (10 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (60 mg, 0.1421 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (55 mg, 0.1120 mmol, 79%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([C:12]2[N:17]3[N:18]=[C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(O)[CH3:10])[CH:6]=[CH:5][N:4]=1.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]2[N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH:9]([C:7]4[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=4)[CH3:10])[N:17]3[N:18]=2)=[CH:23][CH:24]=1
Reactant: COc1cc(C(C)(O)c2cccc3nc(Nc4ccc(C(F)(F)F)cc4)nn23)ccn1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1cc[nH]c(=O)c1)c1cccc2nc(Nc3ccc(C(F)(F)F)cc3)nn12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 93 %

Procedure:
1-(2-Methoxypyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethanol. Methylmagnesium bromide (1.390 mL, 4.17 mmol, 3 M solution in diethyl ether) was added dropwise to a stirred solution of (2-methoxypyridin-4-yl)(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)methanone (0.431 g, 1.043 mmol) in tetrahydrofuran (20 mL) at 0° C. under nitrogen. The reaction instantly became red-colored upon addition of the methylmagnesium bromide but then became more yellow-colored. The resulting mixture was stirred at 0° C. under nitrogen for 50 min. Saturated aqueous ammonium chloride (2 mL) was added to quench the reaction. The resulting mixture was diluted with water and ethyl acetate and shaken in a separatory funnel. The layers were separated. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was dissolved in dichloromethane and purified using flash chromatography (Biotage) (20-90% ethyl acetate in hexane) to give the desired product (0.417 g, 0.971 mmol, 93% yield) as a yellow foam-solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.01 (s, 1H), 8.06 (d, J=5.47 Hz, 1H), 7.74 (dd, J=7.42, 8.59 Hz, 1H), 7.61 (dd, J=1.17, 8.98 Hz, 1H), 7.50-7.59 (m, 4H), 7.47 (dd, J=1.17, 7.42 Hz, 1H), 6.94 (d, J=0.78 Hz, 1H), 6.86 (dd, J=1.56, 5.47 Hz, 1H), 6.44 (s, 1H), 3.82 (s, 3H), 2.03 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ (ppm)-60.20 (s, 3F); MS (ESI) m/z 430.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[CH:5][C:3]=1[OH:4].Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1.[H-].[Na+]>>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([O:10][C:12]2[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)=[C:8]([CH3:9])[C:2]=1[CH3:1]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1c(O)ccc(O)c1C
Agent: [H-]
Agent: [Na+]
Product: Cc1c(O)ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c1C
Yield: 49.5 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2,3-dimethylhydroquinone (1.38 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.87 g) and anhydrous N-N-dimethylformamide (20 ml) and the reaction mixture was purified to give the title compound (1.92 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])([CH3:10])[CH3:9].[CH3:41][CH:42](N)[C:43]1C=CC=[CH:45][CH:44]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:34][O:33][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][C:28]=1[O:31][CH3:32])[C:21]([C:19](=[O:20])[C:18]1[CH:38]=[CH:39][CH:40]=[C:16]([O:15][CH2:14][C:12](=[O:13])[NH:11][CH:8]([C:10]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH3:9])[CH:17]=1)=[N:22][CH:23]=[C:24]2[C:35]([OH:37])=[O:36]
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)C)c3)c2cc1OC
Reactant: CC(N)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)c4ccccc4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropylcarbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.05 ml of α-methylbenzyl amine (0.4 mmol). The mixture was shaken for 15 minutes under argon at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 6,7-Dimethoxy-1-{3-[(1-phenyl-ethylcarbamoyl)-methoxy]-benzoyl}-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (30 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.C1(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[N:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([O:1][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(O)cc3c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2=O)c1
Temperature: 120 °C
Yield: 81.2 %

Procedure:
Methyl 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoate (529 mg), N-phenyltrifluoromethanesulfonamide (612 mg) and potassium carbonate (709 mg) were stirred in THF (15 ml) and heated under microwave irradiation (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 120° C. for 10 minutes. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water (×2), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography with a gradient of iso-hexane to 30% ethyl acetate/iso-hexane yielded methyl 4-methyl-3-[1-oxo-7-{[(trifluoromethyl)sulfonyl]oxy} isoquinolin-2(1H)-yl]benzoate as a white solid (613 mg); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 3.86 (s, 3H), 6.89 (d, 1H), 7.50 (d, 1H), 7.60 (d, 1H), 7.90 (s, 1H), 7.93 (d, 1H), 8.00 (m, 2H), 8.20 (s, 1H); Mass Spectrum: M+Na+ 464.
Reaction SMILES: [C:1]1([C:11]2O[C:15](=O)[C:14]([C:18]#[N:19])=[C:13]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+]>C1COCC1>[C:1]1([C:11]2[C:9]3[C:10]4[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=4)[CH2:11][C:15]=3[C:14]([C:18]#[N:19])=[C:13]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(naphthalen-1-yl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (330 mg), indanone-2 (132 mg) and NaH (41 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 148-149° C.; ESIMS 401 (M+1); IR (KBr) 2213 cm−1 (CN); 13C NMR (75.53 MHz, CDCl3): δ 22.84, 24.94, 36.08, 52.16, 100.72, 116.12, 118.56, 120.75, 123.36, 124.30, 124.48, 124.92, 125.0, 125.36, 125.43, 127.09, 127.29, 130.15, 132.29, 132.64, 136.40, 138.86, 138.99, 140.82, 148.79, 153.65.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:23])[C:21]=1[OH:22])[CH:17]=O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH:11]=[CH:17][C:16]1[CH:19]=[C:20]([CH3:23])[C:21]([OH:22])=[C:14]([CH3:13])[CH:15]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(=O)c1cc(C)c(C)cc1C
Product: Cc1cc(C)c(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1C

Procedure:
This compound was synthesized from 2′,4′,5′-trimethylacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([Br:20])=[C:16]([CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:34]S(C1C=CC(CN)=CC=1)(=O)=O.BrBr>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([Br:20])=[C:16]([CH3:21])[N:15]([CH:22]([C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)[CH3:34])[CH:14]=2)=[O:12])=[CH:31][CH:32]=1)(=[O:3])=[O:4]
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: BrBr
Agent: Cl
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1C(C)c1ccc(C#N)cc1

Procedure:
5-Bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide can be prepared as described for preparation 9, substituting methylamine with 4-methylsulfonylbenzylamine hydrochloride; ESI mass spectrum: [M+H]+=528 (bromine isotope pattern); Retention time HPLC: 0.95 min (Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[C:24]([O:25][C:26]2[N:31]=[C:30]3[S:32][C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])=[N:34][C:29]3=[CH:28][CH:27]=2)[CH:41]=[CH:42][C:43]=1[F:44])=[O:6]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (0.11 g, 0.5 mmol) produced in Example C62(ii) in oxalyl chloride (0.5 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in N,N-dimethylacetamide (1.0 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (0.115 g, 0.33 mmol) produced in Example C63(vi) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (50 μL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (80 mg, 44%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1)=O.O.[OH-].[K+]>C(O)C.[C].[Pd]>[C:25]([CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][CH:19]([CH:17]=[CH:9][C:8]([C:7]2[C:2]([OH:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:29][CH:28]=1)([OH:27])=[O:26]
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC1=CCC(C=CC(=O)c2c(O)cccc2OCC(=O)O)C=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a suspension of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (1 g) and 4-formylcinnamic acid (0.79 g) in ethanol (10 mL) were added water (2 mL) and potassium hydroxide (3 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% palladium-carbon powder (0.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure. To the residue was added 2 mol/L hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-(2-carboxyethyl)-2′-(carboxymethoxy)-6′-hydroxydihydrochalcone (1.55 g). This material was dissolved in acetic acid (12 mL). To the solution were added sodium acetate (8.6 g) and acetic anhydride (8.6 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice. To the extract was added 1 mol/L aqueous sodium hydroxide solution, and the aqueous layer was separated. The aqueous layer was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with diethylether. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.29 g).