Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]2[C:4]=1[C:5](=[O:30])[C:6]([C:25]([O:27]CC)=[O:26])=[CH:7][N:8]2[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[N:17]=1>C(O)(=O)C>[NH2:2][C:3]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]2[C:4]=1[C:5](=[O:30])[C:6]([C:25]([OH:27])=[O:26])=[CH:7][N:8]2[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[N:17]=1
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(F)c(F)c(F)c(N)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(F)c32)c(F)cc1F
Yield: 95.4 %

Procedure:
To 1.5 ml of the mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 145 mg of ethyl 5-amino-1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 17 hours with stirring and allowed to cool. The precipitate was collected by filtration, and washed with ethanol and to obtain 129 mg of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[S].[OH2:10]>>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]([S:5][CH2:4][C:3]([OH:2])=[O:10])=[CH:7][CH:8]=1
Reactant: O
Reactant: COCc1cccs1
Agent: [S]
Product: COCc1ccc(SCC(=O)O)s1
Reaction time: 2 h
Yield: 18 %

Procedure:
Using a similar procedure to that described in Example 32, part (i), 2-methoxymethylthiophene (10.09 g) was lithiated and reacted with sulphur at 25°-30° C. After stirring the reaction mixture for 2 hours, the mixture was poured into water (150 ml) and the aqueous layer separated. A solution of potassium carbonate (5.45 g) and chloroacetic acid (7.45 g) in water (25 ml) was added to the aqueous layer, and the mixture allowed to stand for 18 hours. The mixture was acidified to pH 2 with 2 M hydrochloric acid and extracted with ether (2×150 ml). The organic extracts were combined, dried (MgSO4), treated with activated carbon, and evaporated, to give 2-(2-methoxymethylthien-5-ylthio)acetic acid as a viscous brown oil (3.1 g, 18% yield); NMR: 3.26(s,2H), 3.6(s,2H), 4.52(s,2H), 6.95(d,1H), 7.09(d,1H); m/e (chemical ionisation) 236 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([CH2:27]O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:27][CH:24]3[CH2:25][CH2:26][N:22]([C:20]([O:19][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:21])[CH2:23]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Product: COc1cc2ncnc(Cl)c2cc1OCC1CCN(C(=O)OC(C)(C)C)C1
Yield: 114.6 %

Procedure:
4-Chloro-7-methoxy-6-hydroxyquinazoline (2.5 g) was reacted with 1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidine (3.58 g) to give 4-chloro-7-methoxy-6-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methoxy}quinazoline (5.36 g, 100%); 1H NMR Spectrum: (DMSO d6) 1.39 (s, 9H); 1.45-1.79 (m, 2H); 1.97-2.08 (m, 1H); 2.65-2.74 (m, 1H); 2.91-3.17 (m, 2H); 3.40-3.52 (m, 1H); 4.01 (s, 3H); 4.15-4.22 (m, 2H); 7.42 (s, 1H); 7.45 (s, 1H); 8.86 (s, 1H); Mass Spectrum: (M+H)+ 394.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([OH:12])C.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>O>[NH2:1][C:2]1[N+:7]([O-:12])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CCO
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: -10 °C
Reaction time: 7 h

Procedure:
75 G. of 2,4-diamino-6-chloropyrimidine are dissolved in 1500 ml. of ethanol at 35° C. The solution is cooled to -10° C. and a solution of 100 g. of 3-chloroperbenzoic acid in 500 ml. of ethanol is slowly added dropwise in the course of 1 hour. The suspension is subsequently stirred at -10° C. for 7 hours and left to stand at 5° C. overnight. The suspension is neutralized with 24 g. of sodium hydroxide in 100 ml. of water. The solid material is filtered off and recrystallized from ethanol, there being obtained pure 2,4-diamino-6-chloropyrimidine-3-oxide.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:15]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1N
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccccc1NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3.24 g of ortho-phenylenediamine was dissolved in 30 ml of dimithylformaide, to the solution were added 2.07 g of potassium carbonate and 1.52 g of cinnamyl chloride, and the mixture was stirred overnight at a room temperature. After adding 100 ml of water, the reaction mixture was extracted twice with 100 ml and 50 ml of chloroform, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure The resulting residue was applied to a silica gel column and eluted with chloroform, to obtain 2.0 g of the title compound as light brown crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F-].[K+]>O>[Cl:8][C:3]1[C:2]([NH:1][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [F-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)N1CCC(Nc2cccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 1 L three-neck RB-flask equipped with a mechanical agitator and temperature probe was charged 3-amino-2-chloropyridine (37.9 g, 0.294 mol, 100 mol %) and ethyl 4-oxo-1-piperidinecarboxylate (55.5 g, 0.324 mol, 110 mol %) followed by IPAC (500 mL). The mixture became homogeneous after 5 min agitation (16° C.). Trifluoroacetic acid (44 mL, 0.590 mol, 200 mol %) was charged to the mixture over 30 s, causing an increase in temperature to 25° C. (no cooling used). Sodium triacetoxyborohydride (75.0 g, 0.354 mol, 120 mol %) was added as a solid over 5 min and a further increase in temperature to 56° C. was observed. After 10 min agitation, the mixture was clear and homogeneous. LC analysis indicated consumption (<0.5 A %) of 3-amino-2-chloropyridine and formation of the alkylated product. A solution of 10 wt % aqueous NaOH was added to the mixture at 50° C. over 10 min. When the pH of the mixture was 8-9, the phases were allowed to separate. The organic phase washed with brine (200 mL). The separated aqueous phase was 580 mL-100 μL sample was diluted in 100 mL MeOH and LC analysis indicated 0.23 g, 0.3% of product was present. The brine was assayed as above and contained negligible product. Azeotropic drying with IPAC was conducted at atmospheric pressure under constant volume conditions until the water content was <500 ppm by KF titration. The solution was concentrated to a volume of 170 mL then THF (35 ppm H2O, 230 mL) was added. This solution was used directly for the subsequent step. LC analysis gave 84 g, 101% AY of the desired reductively alkylated product and KF titration gave water content as <500 ppm.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1cccc(C(F)(F)F)c1)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1cccc(C(F)(F)F)c1

Procedure:
A solution of ethyl 8-acetyl-12-hydroxy-13-(3-trifluoromethylphenoxy)tridecanoate (17.4 g., 0.038 mole) and sodium hydroxide (4 g., 0.1 mole) in water (30 ml.) and methanol (120 ml.) is heated at 60° for 16 hours. Most of the methanol is then removed by distillation in vacuo. The residue is dissolved in 150 ml. of water and extracted with ether. The aqueous solution is acidified with concentrated hydrochloric acid. The oily product is taken up in ether and dried over sodium sulfate. Ether is evaporated in vacuo to leave the title compound as a viscous oil weighing 12.9 g. The product is purified by column chromatography on 200 g. of silica gel with 2% methanol in chloroform as eluant; pmr (CDCl3) δ 2.10 (3H, s CH3CO); 3.95 (3H, broad s CHO and CH2O); 6.75 (2H, s OH and CO2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]([Si:10]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH3:20])=[CH:14][CH:13]=1)([CH3:9])[CH3:8]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH:25]([Si:10]([CH:7]([CH3:9])[CH3:8])([CH:22]([CH3:24])[CH3:23])[O:11][C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:19]\[CH3:20])=[CH:16][CH:17]=1)([CH3:27])[CH3:26]
Reactant: C1COCCN1
Reactant: CCC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C/C=C(\c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)N1CCOCC1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
Titanium tetrachloride (28 mL) and morpholine (mL) were added in that order to a toluene (1.5 L) solution of 1-{4-[(triisopropylsilyl)oxy]phenyl}propan-1-one (130 g, 0.424 mol) synthesized in Reference Example 1-2-(1), and stirred at 130° C. for 12 hours. After cooled with ice, the insoluble matter in the reaction liquid was removed by filtration through Celite, and the mother liquid was concentrated to obtain a crude product (193 g) of the intended compound.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 104.7 %

Procedure:
304 g (2 mol) of 4-formylbenzoic acid were dissolved in 1 l of dimethylformamide (DMF), 304 g (2.2 mol) of potassium carbonate were added and then over a period of 30 min 261 ml (2.2 mol) of benzyl bromide were added at about 40° C. (exothermic reaction). The mixture was stirred for further 4 h at 40° C. to 45° C. Then the reaction mixture was poured into 3 l of ice-water and extracted for times with 1 l each of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the ethyl acetate removed in a rotary evaporator at reduced pressure. 503 g of an oil were obtained. The crude product was used directly in the next reaction step.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][C:2]1=[O:9].[OH-].[CH2:11]([P+:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>CO>[NH:1]1[C@H:5]([C:6]([O-:8])=[O:7])[CH2:4][CH2:3][C:2]1=[O:9].[CH2:24]([P+:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: O=C1CC[C@@H](C(=O)[O-])N1
Reaction time: 0.05 h
Yield: 98 %

Procedure:
5.0 g of (S)-(−)-2-pyrrolidone-5-carboxylic acid (by Wako Pure Chemical Industries) was suspended in 30 ml of methanol, and 26.8 g of aqueous 40% tetrabutylphosphonium hydroxide (by Aldrich) was dropwise added thereto at 0° C., taking 3 minutes. After being stirred for 10 minutes, this was concentrated under reduced pressure at 40° C., using an evaporator. 50 ml of methanol was added to the residue, and the mixture was concentrated under reduced pressure in the same manner. 100 ml of toluene was added to the obtained residue, and the resulting mixture was concentrated under reduced pressure; and this operation was repeated twice. Next, this was concentrated in ultra-high vacuum at from room temperature to 50° C. for 15 hours. 15.3 g of tetrabutylphosphonium (S)-(−)-2-pyrrolidone-5-carboxylate (purity, 98.0%) was obtained as an oily compound. (This is an ionic liquid A.) In NMR analysis, neither toluene nor methanol was detected.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14](Cl)([CH3:16])[CH3:15])[CH3:11]>>[Br:1][C:2]1[C:3]([OH:8])=[CH:4][C:5]2[C:10]([CH3:18])([CH3:11])[CH2:12][CH2:13][C:14]([CH3:16])([CH3:15])[C:6]=2[CH:7]=1
Reactant: Oc1ccccc1Br
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Product: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Yield: 78.4 %

Procedure:
In a manner similar to that of Example 36(a), by reaction of 67.14 g (388.0 mmol) of 2-bromophenol with 71.10 g (388.0 mmol) of 2,5-dichloro-2,5-dimethylhexane, 86.13 g (78%) of the expected product are obtained in the form of a white solid with a melting point of 90–94° C.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29](CC5C=C(C=CC=5)C(OC)=O)[C:28](=O)[CH2:27]4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1.[C:44]1([CH3:54])[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51]>>[C:44]1([CH3:54])[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:17]([C:10]3[O:9][C:8]([N:4]4[CH2:3][CH2:2][CH2:7][CH2:6][CH2:5]4)=[N:12][C:11]=3[C:13]([F:15])([F:16])[F:14])=[O:18])=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)(=[O:52])=[O:51]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1cccc(CN2CCN(c3ccc(NC(=O)c4oc(N5CCCC(C)C5)nc4C(F)(F)F)cn3)CC2=O)c1
Product: Cc1ccccc1S(=O)(=O)N1CCN(c2ccc(NC(=O)c3oc(N4CCCCC4)nc3C(F)(F)F)cn2)CC1

Procedure:
Compound 9 was prepared by the general procedure for compound 8, by using intermediate C-3 and o-tolylsulfonyl chloride as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.33 (d, 1H, J=2.6 Hz), 7.82 (m, 2H), 7.59 (m, 1H), 7.45 (m, 2H), 6.87 (d, 1H, J=9.2 Hz), 3.60 (br s, 4H), 3.55 (m, 4H), 3.12 (m, 4H), 2.59 (s, 3H), 1.60 (br s, 6H). LCMS (ESI) Rt=3.89 min, [M+1]+ 579.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:17])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Br:26]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:26][CH2:17][C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][C:10]2[C:5]([C:6]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COC(=O)c1nc2ccc(OC)cc2c(-c2ccc(OC)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)c1nc2ccc(OC)cc2c(-c2ccc(OC)cc2)c1CBr
Temperature: 25 °C
Yield: 97.3 %

Procedure:
Methyl 6-methoxy-4-(4-methoxyphenyl)-3-methylquinoline-2-carboxylate (8.27 g) was dissolved in benzene (100 ml); N-bromosuccinimide (5.24 g) and 2,2′-azobis(isobutyronitrile) (0.40 g) were added; followed by refluxing for 2 hours. After cooling to room temperature, the resulting precipitate was filtered off. The filtrate was diluted with ethyl acetate (100 ml), after which it was washed with 1 N sodium hydroxide and brine successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure; the residue obtained was purified by column chromatography (silica gel: 50 g, eluent: ethyl acetate-hexane=1:2). The crude crystal obtained was recrystallized from ethyl acetate-hexane to yield the title compound (9.93 g) as a colorless needle crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:10]=[C:9]2/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:5])[CH3:2].Br[CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:31][CH2:33][CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[N:10]=[C:9]2/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)c1ccc2c(c(/C=C/c3ccc(F)cc3)nn2C(=O)OC(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c(/C=C/c3ccc(F)cc3)nn2C(=O)OC(C)(C)C)c1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of 200 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-ethyl ester in 13 mL of N,N-dimethylformamide were added 196.5 mg of 2-(2-bromoethoxy)-tetrahydropyran and 306.3 mg of cesium carbonate, stirred for 1 hour and 30 minutes at room temperature, stirred at 50° C. for 17 hours, added with 196.5 mg of 2-(2-bromoethoxy)-tetrahydropyran and 306.3 mg of cesium carbonate, stirred for 3 hours at room temperature and for 2 hours at 50° C., added with 554 mg of 2-(2-bromoethoxy)-tetrahydropyran, and further stirred at 50° C. for 4 hours. Then, the reaction solution was added saturated aqueous ammonium chloride, extracted twice with ethyl acetate, and the resultant organic layer was washed once with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography, to afford 147 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:13]2)=[CH:8][CH:7]=1)=[O:4].S(=O)(=O)(O)O.[CH2:40](O)C>>[CH2:1]([O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)[CH2:13]2)=[CH:8][CH:7]=1)=[O:4])[CH3:40]
Reactant: COC(=O)Cc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Yield: 56 %

Procedure:
A stirred, ice-cooled solution of 7-methoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline (0.202 g, 0.46 mmol) in ethanol (10 ml) was treated with concentrated sulfuric acid (0.53 ml, 0.53 mmol). The mixture was heated at reflux for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate solution (30 ml). The organic phase was separated and washed with brine. Drying (Na2SO4) and evaporation in vacuo afforded an orange oil which was chromatographed on silica using 50-100% ethyl acetate-pentane gradient elution to afford the title compound as a colourless oil (120 mg, 56%).
Reaction SMILES: [CH3:1][C:2]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:26])[CH2:3][CH2:4][CH2:5][C:6]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1)(C(OCC)=O)C(OCC)=O.S(=O)(=O)(O)O.[Cl-].[Na+]>C(O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:1])([CH3:26])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)C(C)(C)CCCC(C(=O)OCC)(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCc1ccc([N+](=O)[O-])cn1
Yield: 15.3 %

Procedure:
9.71 g of triethyl 5-methyl-1-(5-nitropyridin-2-yl)hexane-1,1,5-tricarboxylate was treated in the same manner as the one of Production Example 149 to thereby give 2.87 g of a yellow oily substance. A 1.82 g portion of this product was dissolved in 30 ml of ethanol. After adding 3 ml of conc. sulfuric acid, the resulting mixture was heated under reflux for 7 hours. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 1.0 g of the title compound as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.P(=O)(O)(O)O>C1(C)C=CC=CC=1.O1CCCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([B:26]([OH:31])[OH:27])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(B(O)O)c2)CC1
Temperature: -70 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-(3-bromophenyl)piperazine-1-carboxylate (3.8 g, 11.14 mmol, 1.00 equiv) in toluene/tetrahydrofuran=1:1 (40 mL). This was followed by the addition of n-BuLi (4.9 mL, 2.5M/L) dropwise with stirring at −70° C. The resulting solution was stirred for 30 min at −70° C. To this was added triisopropyl borate (2.5 g, 13.30 mmol, 1.19 equiv) dropwise with stirring at −70° C. The mixture was warmed to 0° C., the reaction was then quenched by the addition of 13 mL of saturated ammonium chloride and 3.4 mL of water. Phosphoric acid (85 wt %, 1.5 g, 1.2 equiv) was added and the mixture was stirred for 30 min. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 20 mL of toluene. The product was precipitated by the addition of 80 mL of heptane. The solids were washed with 20 mL of heptane and collected by filtration. This resulted in 2.9 g (85%) of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1.[NH:15]1[CH2:20][CH:19]=[C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6]3)[CH2:16][CH:17]=2)=[CH:22]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: O=c1n(CCCCl)nc2ccccn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1n(CCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12
Reaction time: 18 h
Yield: 58.9 %

Procedure:
2-(3-Chloro-propyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one 211 mg (1 mmol) was loaded into a round bottomed flask, followed by 396 mg (2 eq) of 3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indole, 1.0 gram of potassium iodide, 1.0 gram of potassium carbonate, 100 ml acetone. The mixture was stirred under nitrogen for 18 hours. It was then poured into about 300 ml water and extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulfate and filtered and concentrated. Flash column chromatography using 10% ˜100% ethyl acetate/hexane and yielded 220 mg of product (59%). mp: 173.3° C. M+: 374.0; (300 MHz, CDCl3): 8.60 (s, 1H, NH), 7.90 (d, 1H), 7.75(d, 1H), 7.34(d, 1H), 7.11(m, 5H), 6.44(m, 1H), 6.16(s, 1H), 4.12 (t, CH2), 3.22 (d, CH2), 2.70 (t, CH2) 2.60(m, 4H), 2.17 (t, CH2).