Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([N:11]([CH3:24])[CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])=[C:4]([O:25][CH3:26])[CH:3]=1.[C:27]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:54])[O:35][CH:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][N:44]([CH3:53])[C:45](=[O:52])[CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=O)[CH2:38][CH2:37]1>>[C:27]1([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:54])[O:35][CH:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][N:44]([C:45](=[O:52])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH:1][C:2]2[CH:3]=[C:4]([O:25][CH3:26])[C:5]([C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][N:15]([C:16]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:22])[CH3:23])[CH3:24])=[CH:6][C:7]=2[Cl:8])[CH3:53])[CH2:38][CH2:37]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Product: COc1cc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(Cl)cc1C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C
Yield: 43.9 %

Procedure:
The compound (219 mg, 0.57 mmol) obtained in Example 96a and the compound (294 mg, 0.63 mmol) obtained in Example 4g were used to give the title compound (209 mg; yield, 17%) as a white solid according to the method described in Example 18b.
Reaction SMILES: [OH-].[K+].COC(=O)[C:6]([C:16](=[O:18])[CH3:17])([CH2:13][CH2:14][CH3:15])[CH:7]([CH3:12])[C:8]([O:10]C)=[O:9]>CO.O>[C:16]([CH:6]([CH2:13][CH2:14][CH3:15])[CH:7]([CH3:12])[C:8]([OH:10])=[O:9])(=[O:18])[CH3:17]
Reactant: CCCC(C(C)=O)(C(=O)OC)C(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(C(C)=O)C(C)C(=O)O
Temperature: 105 °C

Procedure:
KOH (6.9 g, 123 mmol) is added to a solution of 2-acetyl-3-methyl-2-propyl-succinic acid dimethyl ester (5.0 g, 20.5 mmol) in MeOH (25 ml) and water (25 ml). The mixture is refluxed overnight and excess MeOH is evaporated. The residue is acidified by concentrated HCl to pH=2 and is refluxed (oil bath 105° C.) overnight. The mixture is extracted with EtOAc (4×75 ml) and the combined extracts are extracted with 2N aqueous NaOH (4×50 ml). The NaOH solution is then cooled to 0° C. and acidified with concentrated HCl. The mixture is extracted with EtOAc (4×75 ml) and the combined extracts are washed with brine (100 ml), dried (Na2SO4) and evaporated in vacuo, providing 3-acetyl-2-methyl-hexanoic acid as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][NH:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:17][C:18]1[CH:25]=[C:24](F)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CN1CCOCC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:11]3[C:24]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([Cl:17])[CH:25]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(C)CNC(c2ccc3c(c2)OCO3)C1
Reactant: N#Cc1ccc(F)cc1Cl
Solvent: CN1CCOCC1
Product: CC1(C)CC(c2ccc3c(c2)OCO3)N(c2ccc(C#N)c(Cl)c2)C1
Yield: 36.3 %

Procedure:
Combine 2-(1,3-benzodioxol-5-yl)-4,4-dimethylpyrrolidine (338 mg, 1.54 mmol) with 2-chloro-4-fluorobenzonitrile (216 mg, 1.39 mmol) and N-methylmorpholine (0.169 mL, 1.54 mmol) and then heat to 100° C. in a microwave for 1 h. Purify by flash chromatography (12 g RediSep silica gel columns, 0:100 to 90:10 gradient of [cyclohexane: ethylacetate] then repeat using (12 g RediSep silica gel columns, 0:100 to 97:3 gradient of [cyclohexane: ethylacetate] to provide 179 mg (36%) of the title compound. MS: 355 [M Cl35+H]+ and 377 [M Cl35+Na]+; 1H NMR (300 MHz, CDCl3): δ 7.28-7.30 (m, 1H), 6.72-6.76 (m, 1H), 6.61-6.67 (m, 1H), 6.58 (s, 1H), 6.51 (s, 1H), 6.28-6.31 (m, 1H), 5.92-5.95 (m, 2H), 4.68-4.72 (m, 1H), 3.48-3.50 (m, 1H), 3.30-3.35 (m, 1H), 2.20-2.30 (1H, m), 1.75-1.81 (1H, m), 1.18 (s, 3H) and 1.09 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:52][CH3:53])([C:31]2[NH:32][N:33]=[C:34](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)[N:35]=2)[CH2:28][CH2:29]O)=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:52][CH3:53])[C:31]3[N:32]([N:33]=[C:34](/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][C:41]([N:44]5[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]5)=[C:40]([O:50][CH3:51])[CH:39]=4)[N:35]=3)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1
Reactant: COc1cc(/C=C/c2n[nH]c(C(CCO)(OC)c3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(/C=C/c2nc3n(n2)CCC3(OC)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 1.9 %

Procedure:
Triphenylphosphine (22 mg) was added to a suspension of 3-(4-fluorophenyl)-3-methoxy-3-(5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-2H-[1,2,4]triazol-3-yl)propan-1-ol (38 mg) in carbon tetrachloride (2 mL) and THF (2 mL), and the reaction solution was heated under reflux for seven hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and a saturated sodium bicarbonate solution were added to the resulting residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system), again purified with silica gel column chromatography (elution solvent: ethyl acetate-methanol system) and then purified by LC-MS. After concentrating the target fraction, ethyl acetate and a saturated sodium bicarbonate solution were added to the residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 0.69 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: OC(CCl)CCc1ccc(Cl)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A solution of 1-chloro-4-(4-chlorophenyl)-2-butanol (125 g) in acetone (200 ml) at 0° C. was treated with 570 ml of Jones reagent (from sodium dichromate dihydrate (100 g), concentrated sulfuric acid (136 g) and water to 500 ml) and stirred overnight at room temperature. The resulting solution was diluted with water (200 ml), extracted with ether (3×300 ml) and the extracts washed with water, aqueous sodium bicarbonate, and dried (MgSO4). Evaporation of the ether gave 121 g of 1-chloro-4-(4-chlorophenyl)-2-butanone. The analytical sample from hexane had m.p. 65°-67° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].IC.[C:16](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Br
Yield: 95.9 %

Procedure:
A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96%) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) δ8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm−1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261.
Reaction SMILES: C[Si]([CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[N:7]1)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[N:7]1
Reactant: C[Si](C)(C)Cn1cc(-c2ccccn2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccccn2)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 2-(1-trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)-pyridine (6.05 g, 26 mmol) in THF (435 mL) was added water (0.94 mL, 52 mmol) and then tetrabutylammonium fluoride (1 M in THF, 31.2 mL, 31 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was poured into water and then the THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (3.53 g, 85%) as a light brown solid. MS: m/e=161.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([C:9]#[N:10])=[CH:5][CH:6]([CH3:8])[CH3:7].[N+]([CH3:15])([O-])=O>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:9]#[N:10])[CH2:15][CH:5]1[CH:6]([CH3:8])[CH3:7])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C(C#N)=CC(C)C
Solvent: CC#N
Product: COC(=O)C1(C#N)CC1C(C)C
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 2-cyano-4-methyl-pent-2-enoic acid methyl ester (10.5 g, 68.3 mmol) in dry acetonitrile (60 mL) was added nitromethane (5.5 mL, 103 mmol) and a portionwise addition of alumina-supported potassium flouride (40% wt, 22 g). The reaction mixture was stirred under reflux for 2 hours and cooled to room temperature. The solid was removed by filtration through a short pad of celite and washed with acetonitrile. Excess of solvent was removed in vacuo and the residue was re-dissolved in ether. The ether layer was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using hexanes/EtOAc (8:2) as an eluent to afford 1-cyano-2-isopropyl-cyclopropanecarboxylic acid methyl ester (7.7 g, 68%) as colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.13 (t, J=7.2 Hz, 6H), 1.39-1.45 (m, 2H), 1.65-1.74 (m, 1H), 1.81 (dd, J=4.4, 8.9 Hz, 1H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 19.6, 21.8, 21.9, 25.3, 31.2, 39.3, 53.7, 117.6, 168.7.
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[CH2:10][CH2:9][N:8]=[C:7]1[C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].[OH-].[K+]>>[C:15]1([C:13]2([OH:14])[C:12]3[C:11](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]3=[N:6][CH2:10][CH2:9][N:8]23)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccccc1)c1ccccc1C1=NCCN1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: OC1(c2ccccc2)c2ccccc2C2=NCCN21
Temperature: 0 °C

Procedure:
Seventeen grams of the phthalimidine hydrochloride from above, 20 g. of p-butoxyphenylsulfonyl chloride and 200 ml. of pyridine are refluxed for two hours and then the mixture is evaporated to dryness. On recrystallization of the residue from ethanol there is obtained 9b-phenyl-1,2,3,9b-tetrahydro-1-(p-butoxyphenylsulfonyl)-1H-imidazo [2,1-a]isoindol-5-one which is admixed with 25 ml. of 95 percent sulfuric acid for one hour. The reaction mixture which contains the sulfate salt of 2-(2-imidazolin-2-yl) benzophenone is then cooled by the addition of ice water and made alkaline by the addition of a 5N potassium hydroxide solution. The product is then separated by filtration and recrystallized from dioxan to afford 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindol-5-ol, m.p. 207 C., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide and ethanol.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH2:27](Br)[CH3:28]>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH3:28])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C#N)(CC)c1cccc(Oc2ccccc2C)c1OC
Yield: 99 %

Procedure:
Sodium hydride (50%, 650 mg), ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (4 g) and ethyl bromide (3.35 g) were treated in a similar, manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]butyrate (4.3 g).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=2)[CH:10]=[C:9]1[CH3:21])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][S:17]([C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([CH3:21])[NH:8]2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1cc2ccc(S(C)(=O)=O)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2ccc(S(C)(=O)=O)cc2[nH]1
Reaction time: 8 h

Procedure:
The above product of step 2 was dissolved in 100 mL methylene chloride and treated with 12 mL TFA. After stirring overnight, the volatiles were removed and the product crystallized from 10:1 methylene chloride/MeOH. In this way 8.0 g of 6-methanesulfonyl-2-methyl-1H-indole was obtained.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([N+:6]([O-:21])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]3[N:9]2[CH2:12][CH2:13][N:14]=3)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:15]1([C:7]2[C:8]3[N:9]([CH2:12][CH2:13][N:14]=3)[C:10]3[C:5]([N+:6]=2[O-:21])=[CH:4][CH:3]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:11]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(F)ccc21
Product: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Yield: 91.2 %

Procedure:
Under a nitrogen atmosphere, 1,2-dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (40 g 0.142 mol) and piperazine (122 g, 419 mol) were heated at 9° C., for 3.5 hrs. The solvent was removed in vacuo and the resulting residue was dissolved in dichloromethane. The resulting solution was washed with water, dried over anhydrous magnesium sulphate and concentrated in vacuo to yield an orange solid. The orange solid was recrystallized from chloroform-ethyl acetate to yield 1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide, (45 g) as orange crystals, m.p. 209°-211° C. (Found: C, 68.56; H,6.06; N,19.99%; C20H21N5O.O.2H2O requires C, 68.43; H,6.14; N,19.95%) represented by the structural formula: ##STR24##
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH:2]=[CH2:3].CCN(CC)CC.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>C1COCC1>[CH2:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:8]=[CH:7][C:5]=1[NH:6][C:23](=[O:26])[CH:24]=[CH2:25])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(OC(F)(F)F)ccc1N
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCc1cc(OC(F)(F)F)ccc1NC(=O)C=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-allyl-4-(trifluoromethoxy)aniline (17.5 g, 80.6 mmol) in THF (1000 ml), cooled in a dry ice bath to a temperature below −10° C. was added Et3N (8.96 g, 17.3 mmol) and acryloyl chloride (7.98 g, 88.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. The resulting mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and brine. The organic portion was dried over Na2SO4, filtered and concentrated in under reduced pressure to give a white solid which was washed with ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH2:19])[CH2:3][O:4][CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:20]([NH:27][C@H:10]1[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C@H:5]1[O:4][CH2:3][C:2]([CH3:1])=[CH2:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=C(C)COC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Yield: 78.7 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-[(2-methyl-2-propen-1-yl)oxy]-4-oxopiperidine-1-carboxylate obtained in Example (117b) (3.43 g, 17.1 mmol), benzylamine (1.5 g, 14 mmol), sodium (triacetoxy)borohydride (4 g, 18.9 mmol) and 1,2-dichloroethane (30 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 3.97 g of the title compound as a colorless oily substance (86%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[Cl:7][C:8]1[CH:34]=[CH:33][C:11]2[CH:12]=[C:13]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])[CH2:14][O:15][C:10]=2[CH:9]=1.Cl.Cl[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[Cl:7][C:8]1[CH:34]=[CH:33][C:11]2[CH:12]=[C:13]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:41]5[CH:40]=[CH:39][N:38]=[CH:37][CH:42]=5)[CH2:30][CH2:31]4)[C:21](=[O:32])[CH2:20]3)(=[O:17])=[O:18])[CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1CCNCC1
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 39.9 %

Procedure:
To sodium bicarbonate solution were added 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (1.4 g) and chloropyridine hydrochloride (1.02 g), and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (50 ml), and the mixture was allowed to react at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1 N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane: methanol containing 10% ammonia solution=20: 1) to give colorless solid 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (608 mg).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1.[C:19](B1OC(C)(C)C(C)(C)O1)([CH3:21])=[CH2:20].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:21][C:19]([C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1)=[CH2:20]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1csc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (334 mg) obtained in Example 1, steps 1-3, isopropenylboronic acid pinacol ester (168 mg), saturated aqueous sodium carbonate solution (6 ml), tetrakis(triphenylphosphine)palladium (32.5 mg) and DME (9 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere, and poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→30% ethyl acetate/hexane) to give the title compound (270 mg, 91.5%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[C:26](Cl)(=[O:28])[CH3:27]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C.O>[C:26]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[CH:17]=1)[N:5]=2)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
N-{5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (1.8 g, 4.63 mmol) and N,N-dimethylpyridine-4-amine (566 mg, 4.63 mmol) were dissolved in pyridine (9.25 mL), acetyl chloride (0.658 mL, 9.25 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate (80 mL)/water (50 mL), and the organic layer was collected, and washed with saturated brine (50 mL). The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was crystallized from toluene/diisopropyl ether (1:3), collected by filtration, and dried to give the title compound (1.69 g, 85%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[C:18]=3[OH:27])[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:26]=[CH:25][C:20]5[O:21][CH2:22][CH2:23][O:24][C:19]=5[C:18]=4[O:27][CH2:35]3)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2ccc3c(c2O)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c2ccc2c1OCCO2

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one was obtained (85%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.22 (m, 12H), 7.10 (ddd, J=7.8, 7.8, 1.2 Hz, 1H), 6.99 (dd, J=7.4, 7.4 Hz, 1H), 6.88 (s, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.32 (d, J=8.3 Hz, 1H), 6.04 (d, J=8.3 Hz, 1H), 4.93 (d, J=9.5 Hz, 1H), 4.81 (d, J=9.5 Hz, 1H), 4.27 (s, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.8, 148.8, 144.7, 142.0, 137.6, 137.5, 131.6, 129.3, 128.7, 128.5, 128.3, 128.1, 127.9, 127.7, 127.6, 123.9, 122.9, 122.4, 113.8, 111.0, 109.9, 80.1, 64.1, 63.9, 58.1, 57.1; MS (ES+) m/z 461.9 (M+1).