Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[OH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:26][C:25]2=[O:38]>>[CH3:18][O:17][CH:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[O:28][C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][C:25]3=[O:38])=[C:7]([O:19][CH3:20])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc2oc(-c3ccccc3)cc(=O)c2c1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 6-Hydroxy-2-phenyl-chromen-4-one following the Standard Procedure J. 1H-NMR (200.15 MHz, CDCl3): 8.0–7.9 (m, 2H), 7.6–7.5 (m, 5H), 7.30 (dd, 1H, J=9.0, 3.0), 6.9–6.8 (m, 4H), 4.3–4.2 (m, 4H), 4.00 (dd, 1H, J=7.2, 4.6), 3.83 (s, 3H), 3.41 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.2, 7.2), 2.33 (qn, 2H, J=6.2) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:32][C:31]([C:33]2[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=2)[C:36]#[N:37])=[CH:30][C:29](=O)[O:28]1>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]=1[NH:24][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[C:35]([C:36]#[N:37])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-pyrrol-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example J3) (186 mg, 0.54 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (153 mg, 0.67 mmol) according to the general procedure M. Obtained as a beige solid (179 mg).
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:26])[C:10]([CH3:27])=[N:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].Cl.C(O)C>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11](=[O:26])[C:10]([CH3:27])=[N:9][NH:8]2
Reactant: Cc1ccc(-c2cccc3c2c(=O)c(C)nn3Cc2ccccc2)c(C)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2cccc3[nH]nc(C)c(=O)c23)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
To 0.122 g (0.34 mmol) of 1-benzyl-5-(2,4-dimethylphenyl)-3-methylcinnolin-4(1H)-one and 0.14 g (0.10 mmol Pd) of 10% Pearlman's catalyst was added 4 mL of ethanol and two drops of concentrated HCl. The reaction vessel was charged with hydrogen via a balloon and stirred at room temperature for 3 h. The catalyst was removed by filtration, the filtrate was concentrated and the residue was purified by flash chromatography eluting with a 33% ethyl acetate/hexanes mixture to give 0.047 g (52%) of product as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:17][C:18]2[CH:42]=[CH:41][C:21]([C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:25]=3)=[O:23])=[CH:20][CH:19]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:25]=3)=[O:23])=[CH:41][CH:42]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCC(Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCC(Oc1ccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 4-[3-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol-1-yl]butyrate (270 mg) in ethanol (3 ml) and 1,4-dioxane (3 ml) was added 1 N aqueous solution of sodium hydroxide (1.5 ml). The mixture was stirred at room temperature for 3 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[3-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol-1-yl]butyric acid (230 mg) as powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)=[CH:33][CH:32]=1>O1CCOCC1>[F:27][C:26]([F:29])([F:28])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)=[O:39])=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)([OH:30])[C:22]([F:23])([F:24])[F:25]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 100 °C
Yield: 33.6 %

Procedure:
2-(4-((4-(4-Aminophenyl)piperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (0.231 mmol, 0.1 g) and phenyl pyridin-4-ylcarbamate (0.346 mmol, 0.074 g) were combined in dioxane (1 mL) in a Reactivial and heated to 100° C. for 2 days. The reaction mixture was concentrated at reduced pressure. The resulting residue was taken up in dichloromethane, washed with water, dried over sodium sulphate and concentrated at reduced pressure. The residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (43 mg). MS (ESI) m/z 555.2 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:34][N:35](C=O)C>[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N.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>[C:34]([C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH3:25])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1)#[N:35]
Reactant: CN(C)C=O
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(Br)c3)oc2c1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: O
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(C#N)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl ((2S)-1-((2-(3-bromo-4-(cyclopropylmethoxy)phenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (200 mg) in DMF (5 mL) were added zinc cyanide (227 mg) and tetrakis(triphenylphosphine)palladium(0) (44.7 mg), and the mixture was stirred at 100° C. for 18 hr under an argon atmosphere. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (27.8 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:40])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[N:27](C(OC(C)(C)C)=O)[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:40])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: CCOC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
1-t-Butyl 2-ethyl 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1,2-dicarboxylate (9.44 g, 16.5 mmol) synthesized in Example (17c) was dissolved in dichloromethane (90 mL), and cooled to 0° C. Trifluoroacetic acid (45 mL) was added dropwise with stirring under nitrogen atmosphere, and stirring was carried out at room temperature for 1 hour. The solvent was distilled off under reduced pressure, followed by dilution with ethyl acetate (300 mL), a saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (6.34 g, yield 81%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][C:12]=2[F:27])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].S(=O)(=O)(O)O.[CH3:38]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][CH3:38])=[O:23])[CH:17]=3)=[CH:13][C:12]=2[F:27])=[CH:4][C:3]=1[C:29]([F:31])([F:32])[F:30]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)ccn1
Yield: 80 %

Procedure:
4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)picolinic acid (1 g, 2.13 mmol) was suspended in methanol (20 mL). Concentrated sulfuric acid (5 mL) was added at room temperature. The resulted mixture was refluxed for 3 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=10:1) to give methyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)picolinate B8 (0.83 g, purity 97%, yield 80%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+].[NH2:24][CH2:25][CH:26]([OH:28])[CH3:27]>O>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(O)CN
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(O)CNc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
27 g of 4-chloro-5-trifluoromethyl-1,3-dinitrobenzene are initially introduced into 100 ml of water with 5.3 g of Na2CO3, and 13.5 g of 1-aminopropan-2-ol are added at 80° C. in the course of 30 minutes. The mixture is subsequently stirred at 80° C. for one hour and then cooled to room temperature, and the product which has precipitated is filtered off and dried in a vacuum drying cabinet.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][N:16]=2)[CH:6]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c([N+](=O)[O-])c2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c(N)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
First, 79 mg of 10% palladium/carbon was added to a solution of 0.30 g of 3-(4-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-13) in 12 ml of ethyl acetate under an atmosphere of nitrogen, which was then replaced with hydrogen under a pressure of 1 atm., and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.13 g (yield, 47%) of 3-(5-amino-4-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-19).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC.O>O1CCCC1.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>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3cccs3)cc12
Yield: 45.4 %

Procedure:
A solution of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), tri-n-butyl(2-thienyl)tin (0.32 ml, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in tetrahydrofuran (20 ml) was refluxed for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.22 g, 45.8%) as crystals.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:25].C(=O)(O)[O-].[Na+]>O>[Cl:25][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 60 °C
Yield: 63 %

Procedure:
A mixture of 5,6-diphenylfuro[2,3-d]pyrimidin-4(3H)-one (3 g) and POCl3 (30 mL) was heated at 55-65° C. for 3 h. Water was then added followed by sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (95:5), to give white solid 4-chloro-5,6-diphenylfuro[2,3-d]pyrimidine (2 g, 63%). 1H NMR (300 MHz, CDCl3): δ 8.77 (s, 1H), 7.61-7.58 (m, 2H), 7.52-7.46 (m, 5H), 7.35-7.32 (m, 3H). LC-MS (ESI) m/z 307.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]#[CH:25]>CC(C)=O>[C:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)#[C:24][CH3:25]
Reactant: O=c1c2ccccc2oc2cc(O)ccc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)c3ccccc3oc2c1

Procedure:
A mixture of 3-hydroxyxanthen-9-one (2.12 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.25 g of a product with the following characteristics: m.p.142-144° C.; 1H NMR (CDCl3) δ: 2.61 (m, 1H), 4.84 (s, 2H), 6.98-8.38 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Cl.[C:15]([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:15][O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: O=C([O-])O
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 4-(4-aminophenyl)-butyric acid (5 g, 27.90 mmol) in MeOH (100 mL) at room temperature was added HCl conc. (37% 15 mL). The resulting mixture was stirred overnight at 50° C. then treated with a saturated aqueous solution NaHCO3 and Na2CO3 solid until pH 9. The solvent was evaporated under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The crude material was purified by flash chromatography using CH2Cl2/MeOH as solvent mixture yielding 40 (4.93 g, 91%) as orange solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[C:23]#[N:24])[NH:19][CH:18]=[CH:17]3)=[CH:10][CH:9]=1.CN([CH:28]=[O:29])C>>[CH:28]([C:17]1[C:16]2[C:20](=[CH:21][C:22]([C:23]#[N:24])=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)[CH:15]=2)[NH:19][CH:18]=1)=[O:29]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3cc[nH]c3cc2C#N)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Phosphorous oxychloride (84.3 mg, 0.54 mmol) was added to DMF (1 mL) at 0° C. and the reaction mixture was stirred for 15 minutes. To this solution was added 5-(4-methoxy-phenyl)-1H-indole-6-carbonitrile (150.0 mg, 0.60 mmol) in DMF (1 mL) and the reaction mixture was stirred at 40° C. for 1 hour. The reaction mixture was cooled to room temperature, treated with additional phosphorous oxychloride (84.3 mg, 0.54 mmol) and stirred at 45° C. for an additional hour. The reaction mixture was cooled to room temperature, and quenched with water (10 mL). The solution was concentrated in vacuo, and the residue was partitioned between water (10 mL) and EtOAc (10 mL). The layers were separated and the organic layer was concentrated in vacuo. The crude material was slurried in CH2Cl2, and the resulting solid was filtered and air dried to give the title compound (85 mg, 51% yield). MS (ES−) 275.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (br. s., 1H), 10.00 (s, 1H), 8.58 (d, J=3.12 Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.51 (d, J=8.59 Hz, 2H), 7.09 (d, J=8.80 Hz, 2H), 3.83 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]([CH3:22])[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:27]=[O:28]>>[CH2:6]([N:13]([CH3:22])[C:14]1[CH:15]=[C:16]([Cl:21])[C:17]([CH:27]=[O:28])=[C:18]([Cl:20])[CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CN(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(Cc1ccccc1)c1cc(Cl)c(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphoryl chloride (12.7 ml) was dropwise added to N,N-dimethylformamide (70 ml), and the mixture was stirred for 30 minutes at ambient temperature. A solution of N-benzyl-3,5-dichloro-N-methylaniline (7.26 g) in N,N-dimethylformamide (30 ml) was dropwise added thereto, and the mixture was stirred for 30 minutes at ambient temperature and then for 30 minutes at 50° C. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a flash chromatography (ethyl acetate: n-hexane=1:6, V/V) to give N-benzyl-3,5-dichloro-4-formyl-N-methylaniline (5.70 g).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]>[C].[Pd]>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][C:15]=2[CH3:18])=[CH:25][CH:24]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cc1
Yield: 100.1 %

Procedure:
Using 3-(1-cyano-1-methylethyl)-N-[4-methyl-3-(4-nitrophenoxy)phenyl]benzamide (2.08 g, 5.0 mmol) and 10%-palladium carbon (0.5 g), and in the same manner as in Example A25(iv), the title compound (1.93 g, quantitative) was obtained as a pink amorphous substance.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.[CH3:20][NH2:21]>CO>[CH3:20][NH:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1
Reactant: CN
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Solvent: CO
Product: CNCc1ccc2c(c1)N(COC)c1nccnc1S2

Procedure:
8-Chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was stirred in a solution of methylamine in methanol at room temperature over day and night. Then the reaction mixture was distilled under reduced pressure and the residue was distributed into sodium hydroxide and ethyl acetate. The organic layer was extracted and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give the title compound as a yellow oily substance.