Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 72 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(4-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]([CH2:21][CH3:22])[CH:19]([CH3:23])[CH:18]([CH2:24][OH:25])[CH2:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C)C.[OH-:29].[Na+].OO>C1COCC1.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH:20]([CH2:21][CH3:22])[CH:19]([CH3:23])[CH:18]([CH2:24][OH:25])[CH2:17][CH:16]2[OH:29])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CCC1C(c2ccc(OCc3ccccc3)cc2)=CCC(CO)C1C
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: O
Product: CCC1C(C)C(CO)CC(O)C1c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the solution of [4-(4-benzyloxy-phenyl)-5-ethyl-6-methyl-cyclohex-3-enyl]-methanol (3.1 g, 6.8 mmol) in THF (50 mL) was added BH3.S(CH3)2 solution (1.0 M in THF, 10.3 mL, 1.5 eq.) at 0° C. The reaction mixture was refluxed for 4 h and then cooled to 0° C. NaOH (20% aqueous, 30 mL) and H2O2 (50% in H2O, 21 mL) were added at 0° C. The reaction mixture was then stirred at 0˜25° C. for 4 h. The reaction mixture was then diluted with ethyl acetate/H2O (400 mL/200 mL). The organic layer was separated, dried over MgSO4 and purified on SiO2 (50˜100% ethyl acetate/hexane) to yield 2-(4-benzyloxy-phenyl)-3-ethyl-5-hydroxymethyl-4-methyl-cyclohexanol.
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[N:10]([CH3:16])[N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:29]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH:43]=[CH2:44])[C:33]1=[O:34])[CH:30]=[CH2:31]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:13]([C:11]3[N:10]([CH3:16])[N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:40][C:39]=2[N:32]([CH2:29][CH2:30][CH3:31])[C:33]1=[O:34])[CH2:43][CH3:44]
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Reactant: CCC(Oc1cc(C(=O)O)n(C)n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.[Na+].[Cl-]>[Cl:25][C:8]1[N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnn(C2CCOCC2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2CCOCC2)c1Cl
Temperature: -78 °C
Yield: 63.2 %

Procedure:
To a solution of 4-nitro-1-tetrahydropyran-4-yl-pyrazole (1.32 g; 6.69 mmol) in THF (15 mL) was added dropwise LHMDS (1 mol/L) in THF (2.0 equiv.; 13.4 mmol) at −78° C. The reaction was stirred at −78° C. for 30 minutes before the addition of hexachloroethane (2.4 g, 10 mmol) in THF (5 mL). The reaction was stirred at −78° C. before warming to room temperature. The reaction was diluted with sat. NaCl and extracted with EtOAc (3×). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to give 5-chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.98 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]2.C1C(=O)N([Br:21])C(=O)C1.OS(O)(=O)=O>O>[Br:21][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:13])[CH3:12])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC2(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc2c(cc1Br)C(C)(C)CC2
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
To a suspension of 5-methoxy-1,1-dimethyl-indan (2.16 g, 12.25 mmol) (prepared following the procedures described in U.S. Pat. Appl. Publ., 2006100460) in water (120 ml), NBS (2.2 g, 12.3 mmol) was added. The reaction mixture was heated to 60° C. while stirring. Concentrated H2SO4 (1.3 ml, 40% aq. solution) was then added and stirring was continued for 5 hours. The reaction mixture was cooled to rt. The mixture was extracted with diethyl ether three times. The combined organic extract was washed with brine and dried (Na2SO4). Silica gel chromatography (ethyl acetate/heptane) provided 2.78 g (89%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C.CN(C1C=CN=CC=1)C>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2[nH]c(=O)c(=O)n(C3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
18.3 g (70 mmol) of 7-amino-1-cyclohexylquinoxaline-2,3(1H,4H)-dione (product e2 from Example 2) were dissolved in 250 ml of acetic acid and, after a spatula tip of 4-(N,N-dimethylamino)pyridine had been added, 7.2 g (70 mmol) of acetic anhydride were added dropwise. The mixture was then stirred at room temperature for 30 min. The resulting precipitate was then filtered off with suction and dried to yield 20.8 g (98%) of the product. Melting point 227°-230° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N+:3]=1[O-:12].[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.CCN(C(C)C)C(C)C.O>CCCCO.CN(C1C=CN=CC=1)C>[O-:12][N+:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: [O-][n+]1ccc2ccccc2c1Cl
Agent: CN(C)c1ccncc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2c3ccccc3cc[n+]2[O-])C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
To a solution of the compound from Step 2 1-chloroisoquinoline 2-oxide (1.2 g, 6.68 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (2.0 g, 10.02 mmol) in n-BuOH (20 mL) was added DIPEA (0.95 g, 7.35 mmol) and DMAP (81 mg, 0.668 mmol). The mixture was stirred at 120° C. for 16 h. The mixture was then poured into water (20 mL) and extracted with EtOAc (3×10 mL). The combined layers organic were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash column chromatography eluting with a gradient of petroleum ether: EtOAc (1:1 to 0:1) to afford the title compound (0.8 g, 35%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:33]([Cu])#[N:34]>N1C=CC=CC=1>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:17][N:16]=[C:15]3[C:33]#[N:34])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(NCc3ccccc3)nnc(I)c2c1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: N#Cc1nnc(NCc2ccccc2)c2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc12
Temperature: 90 °C
Yield: 50.8 %

Procedure:
To a solution of 1-benzylamino-4-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (62 mg, 0.11 mmol) in pyridine was added CuCN (30 mg, 0.34 mmol). The solution was heated to 90° C. for 1 hour, then concentrated under vacuum. Flash chromatography (hexanes/EtOAc) was used to obtain 4-Cyano-1-benzylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (25 mg, 50%) as a yellow solid. 1H-NMR (DMSO-d6) δ: 4.94 (d, 2H), 7.26 (m, 1H), 7.34 (t, 2H), 7.43 (d, 2H), 7.52 (d, 1H), 7.66 (t, 1H), 8.10 (d, 1H), 8.26 (s, 1H), 8.52 (m, 2H), 8.65 (d, 1H), 9.21 (t, 1H), 11.0 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([NH2:10])=[S:9].Br[CH2:12][C:13](=O)[C:14]([OH:16])=[O:15]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH:12]=[C:13]([C:14]([OH:16])=[O:15])[N:10]=1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)NCc1ccco1
Product: O=C(O)c1csc(NCc2ccco2)n1
Yield: 98.2 %

Procedure:
2-[(Furan-2-ylmethyl)-amino]-thiazole-4-carboxylic acid (220 mg) was prepared according to General Procedure B using furan-2-ylmethyl-thiourea (156 mg) and 3-bromo-2-oxo-propionic acid (167 mg).
Reaction SMILES: II.[C:3]1([CH3:25])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C([O:28][P:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])C>>[C:3]1([CH3:25])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][P:29](=[O:28])([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccccc1N(c1ccc(CO)cc1)c1ccccc1C
Agent: II
Product: CCOP(=O)(Cc1ccc(N(c2ccccc2C)c2ccccc2C)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodine (6.6 mmol) was added to a mixture of 4-(N,N-di-tolylamino)-benzyl alcohol (6.6 mmol) and triethylphosphite (10 mL) at 0° C. The reaction was allowed to warm to 25° C. and stirred for two hours. Excess triethylphosphite was distilled away from the reaction under reduced pressure, and the residue was partitioned between ether and water. The organic extracts were dried and concentrated to an oil, which was then purified by column chromatography to yield 1.6 g of diethyl 4-(N,N-di-tolylamino)-benzylphosphonate. The product was a pale, viscous oil. H1 NMR and mass spectra data were consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH:12]1C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cc(Br)ncc1F
Reactant: c1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Br)ncc1F
Yield: 88.4 %

Procedure:
To a cooled solution of 2-bromo-5-fluoroisonicotinic acid (3.0 g, 13.6 mmol) in benzene (20 ml) and methanol (10 ml) is dropwise over a period of 15 min added under stirring and cooling (trimethylsiliyl)diazomethane (2 M in ether, 14 ml, 28 mmol). The yellow solution is stirred for 1.5 h without cooling and evaporated to dryness. Purification of the residue (3.3 g) by chromatography on a 50 g Silicycle silica cartridge using a heptane/ethyl acetate 10-50% gradient affords methyl 2-bromo-5-fluoroisonicotinate (2.82 g, 88.4%) as a light yellow solid. mp.: 43-6° C. MS: m/z=233.9 (M+H+).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([NH:40][C@@H:41]1[CH2:46][CH2:45][C@@H:44]([C:47]([OH:49])=O)[CH2:43][C@@H:42]1[NH:50][C:51]([C:53]1[S:54][C:55]3[CH2:56][N:57]([CH3:62])[CH2:58][CH2:59][C:60]=3[N:61]=1)=[O:52])=[O:39])=[CH:32]2>C(Cl)(Cl)Cl.C(N(CC)CC)C>[ClH:28].[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([NH:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([C:47]([N:3]([CH3:4])[CH3:2])=[O:49])[CH2:43][C@H:42]1[NH:50][C:51]([C:53]1[S:54][C:55]3[CH2:56][N:57]([CH3:62])[CH2:58][CH2:59][C:60]=3[N:61]=1)=[O:52])=[O:39])=[CH:32]2
Reactant: CNC
Reactant: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 72 h
Yield: 118.7 %

Procedure:
Triethylamine (0.25 mL), dimethylamine hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (53 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg) were added to a chloroform suspension (10 mL) of the compound (168 mg) obtained in Example 56, and the mixture was stirred for 72 hours. The solvent was distilled away under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The resultant organic layer was washed with saturated brine and dried over magnesium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the resultant residue was purified by silica gel column chromatography (methylene chloride:methanol=93:7). The thus-obtained colorless solids (135 mg) were suspended in ethanol (5 mL), and then 1N HCl in ethanol (0.5 mL) was added. The mixture was stirred for 2 hours, and the solvent was distilled away to give the title compound (112 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2)[CH3:2].[NH4+].O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:28])=[O:14])=[CH:8]2)[CH3:2]
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a solution of 7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (3.4 g) in N,N-dimethylformamide (40 mL) were added under ice-cooling 1-hydroxybenzotriazole ammonium salt (2.2 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g), and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (3.4 g, yield 100%) as a pale-yellow amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])#[N:2].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6])#[N:2]
Reactant: N#Cc1ccccc1C(=O)O
Reactant: Oc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
2-Cyanobenzoic acid (1.00 g, 6.80 mmol), phenol (576 mg, 6.12 mmol) and PyBOP (3.90 g, 7.48 mmol) were dissolved in DMF (12 mL), and triethylamine (2.10 mL, 15.0 mmol) was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:2) to afford phenyl 2-cyanobenzoate (1.24 g, 82%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]([C:15]1[N:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([CH3:28])=[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>O>[C:11]([C:15]1[N:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([CH3:28])=[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:16]=1[CH:8]=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(CCc2ccccc2)c1C
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C=O)c(C(C)(C)C)n(CCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 0.72 ml of phosphorus oxychloride was added to 4 ml of N,N-dimethylformamide at an inner temperature of from 10 to 20° C., followed by stirring at room temperature for 15 minutes. A 5 ml portion of N,N-dimethylformamide solution of 2.00 g ethyl 5-tert-butyl-2-methyl-1-(2-phenylethyl)-1H-pyrrole-3-carboxylate was added to this solution under ice-cooling at an inner temperature of from 10 to 20° C., followed by stirring overnight at 60° C. Water was added at 0° C., pH was adjusted to 8 with potassium carbonate, and extraction was carried out with diethyl ether. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:8-1:7) to obtain 1.63 g of ethyl 5-tert-butyl-4-formyl-2-methyl-1-(2-phenylethyl)-1H-pyrrole-3-carboxylate as a light yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13].[N:24]#[C:25]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])[C:25]#[N:24]
Reactant: N#CBr
Reactant: O=C(CNc1nc2ccccc2s1)N1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CN(CC(=O)N1CCCc2ccccc21)c1nc2ccccc2s1
Reaction time: 12 h
Yield: 21.9 %

Procedure:
To a suspension of compound 83 (340 g, 1.05 mmol) in dry CH3CN (10 mL) were added cyanogen bromide (5M in CH3CN) (0.42 mL, 2.1 mmol) and K2CO3 (580 g, 4.2 mmol). The reaction was heated to reflux for 4 h under N2. 0.84 mL (4.2 mmol) of cyanogen bromide was added and the reflux was continued for 12 h. The reaction mixture was diluted with EtOAc (50 mL). The solids were filtered off, filtrate was concentrated, and the yellow residue was purified by column chromatography (20% EtOAc in hexanes) to afford 84 as an off-white solid (80 mg, 28%). MS m/z: 349 (M+H)+. Anal. Calcd. For, C19H16N4OS.0.6 H2O: C, 63.53; H, 4.83; N, 15.60; S, 8.92. Found: C, 63.24; H, 4.67; N, 15.25; S, 8.76.
Reaction SMILES: [CH2:1]([C:5](=[CH2:11])[C:6]([O:8]CC)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl>[OH-].[K+]>[CH2:1]([C:5](=[CH2:11])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: C=C(CC(C)C)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: C=C(CC(C)C)C(=O)O
Yield: 99.1 %

Procedure:
Saponification of 6.32 g (40.4 mmol) ethyl 2-isobutylacrylate was carried out 50 ml of 20% aqueous KOH at reflux. The obtained mixture was acidified by aqueous HCl to pH=5-6, and the product was extracted by 2×100 ml of dichloromethane. The organic extract was evaporated to dryness to give 5.13 g (99%) 2-isobutylacrylic acid which was further used without an additional purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23]CC)=[O:22].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)COc1ccc(-n2ncc(C(=O)O)c2N)cc1C#N
Yield: 41 %

Procedure:
To a solution (17 ml) of ethyl 5-amino-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylate (1.7 g) in ethanol was added 2 N aqueous sodium hydroxide solution (3 ml) with stirring, and the mixture was refluxed under heating for 2 hours. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of dioxane and water to give 0.64 g of 5-amino-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid, melting point 212° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][C:21]=1O)=[O:19].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:16][O:17][C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][C:21]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1c(O)cnc2ccc(OC)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)cnc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Trifluoromethanesulfonic anhydride (3.35 mL, 19.94 mmol, 1.5 eq) is added at room temperature to a stirred solution of 3-hydroxy-6-methoxy-quinoline-4-carboxylic acid methyl ester (3.1 g, 13.29 mmol, 1.0 eq) in dichloromethane (30 mL), followed by triethylamine (5.6 mL, 39.88 mmol, 3.0 eq). After 1 hour stirring at room temperature, solvent is removed and the residue is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 6-methoxy-3-trifluoromethanesulfonyloxy-quinoline-4-carboxylic acid methyl ester as a yellow solid (3.69 g, 76% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:24])[CH:5]=1.Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:12]=2[CH3:24])[CH:5]=1
Reactant: CCn1cc(Br)cn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(S(C)(=O)=O)ccc23)c1
Product: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)OC)c3)c3ccc(S(C)(=O)=O)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-methanesulfonyl-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.