Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([CH3:37])[C:17]2[CH:18]=[N:19][C:20]([N:31]3[CH2:36][CH2:35]S[CH2:33][CH2:32]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[CH3:30])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[O:43][S:44]([O-:46])=O.[K+].S([O-])(O)=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([N:31]3[CH2:32][CH2:33][S:44](=[O:46])(=[O:43])[CH2:35][CH2:36]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[CH3:30])[CH3:37])=[O:15])[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
5.0 g (8.3 mmol) 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-isobutyramide was suspended in 50 ml methanol and treated at room temperature with 6.4 g (10.4 mmol) oxone™. The suspension was stirred for 16 hours at room temperature, cooled to 0° C. and 3.4 ml (16.7 mmol) sodium hydrogen sulfite solution was added dropwise. The stirring was pursued for 30 minutes at room temperature and the pH adjusted to ca. 8.5 with saturated aqueous sodium carbonate. The methanol was evaporated under reduced pressure and the residue was extracted with dichloromethane. The organic phase was washed with half-saturated aqueous sodium chloride. The solvent was exchanged under reduced pressure in a rotary evaporator with 60 ml isopropanol and the volume reduced to ca. 40 ml. The solution was cooled to room temperature under stirring within 2 hours and stirred further for 1 hour. The precipitate formed was filtered off, washed with 5 ml isopropanol and dried under high vacuum to yield 4.4 g (83.5%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxothiomorpholin-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide as a white powder of m.p.=135–138° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][OH:15])[O:10][C@H:9]1[N:16]1[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18])#[N:2].O1CCCC1.N1C=CC=CC=1.[CH3:36][O:37][C:38]1[CH:59]=[CH:58][C:41]([C:42](Cl)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1>CO>[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([C:42]([O:15][CH2:14][C@H:11]2[O:10][C@@H:9]([N:16]3[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]3=[O:18])[C@H:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][C:1]#[N:2])[C@@H:12]2[OH:13])([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:41]2[CH:58]=[CH:59][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)=[CH:48][CH:47]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCOCCC#N)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To the 2′-O-(2-cyanoethoxymethyl)-5-methyluridine (20.7 g, 60.6 mmol) obtained in Step 2 was added anhydrous tetrahydrofuran (150 mL), anhydrous pyridine (150 mL), activated Molecular Sieves 4A (50 g), and 4,4′-dimethoxytrityl chloride (22.6 g, 66.7 mmol), and the mixture was stirred overnight at room temperature. After completion of the reaction, methanol (5 mL) was added to the reaction solution and the mixture was stirred for 15 min. The reaction solution was then filtered under aspiration and washed with ethyl acetate, and the filtrate was concentrated. To the residue was added aqueous saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel chromatography to give 5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl)-5-methyluridine (35.6 g; yield 91.2%).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH2:7][CH:8]=[CH2:9])[NH:5][C:4](=[O:10])[CH2:3]1.F[B-](F)(F)F.[CH3:16][O+](C)C>>[CH3:16][O:10][C:4]1[CH2:3][CH:2]([CH3:1])[CH:6]([CH2:7][CH:8]=[CH2:9])[N:5]=1
Reactant: C[O+](C)C
Reactant: C=CCC1NC(=O)CC1C
Agent: F[B-](F)(F)F
Product: C=CCC1N=C(OC)CC1C

Procedure:
The product of EXAMPLE 265 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:1][N:2]=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1
Reactant: NNc1ccccn1
Reactant: CC(C)c1ccc(C=O)cc1
Solvent: CCO
Product: CC(C)c1ccc(C=NNc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 76 %

Procedure:
In 20 ml of ethanol was dissolved 5.46 g of 2-hydrazinopyridine. With 7.41 g of 4-isopropylbenzaldehyde added, the solution was agitated. Fine crystals started precipitating within about 30 seconds and the entire solution solidified within about 1 minute. 10 ml of ethanol was added to the mass, which was refluxed at 100° C. for 40 minutes. The reaction solution was allowed to cool at room temperature and further cooled down to 5° to 10° C. to cause crystals to fully precipitate, which were collected by suction filtration. The crystals were washed with ethanol and dried in vacuum for 40 minutes, obtaining 9.09 g (yield 76%) of pale yellow acicular crystals.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].Cl>N1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([S:27]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:28])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.43 g of 3,4-dimethoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated as an oil upon neutralization and was thereupon treated once more with active charcoal. The product separated upon renewed neutralization with concentrated hydrochloric acid. Recrystallization from 25 ml of 60% ethanol yielded 0.12 g of 3,4-dimethoxy-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as colourless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[OH-].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(Br)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.13 h
Yield: 42 %

Procedure:
A solution of 5-bromo-2-methylpyridin-3-amine (187 mg, 1.0 mmol) and diisopropylethylamine (523 uL, 3.0 mmol) in dichloromethane (5 mL) was cooled to 0° C., and then methanesulfonyl chloride (155 uL, 2.0 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 8 min and was then warmed to rt. After stirring for 1 h, the volatile materials were removed in vacuo. The residue was then dissolved in methanol (2.5 mL) and aqueous sodium hydroxide (2 M, 1.5 mL, 3 mmol) was added. The reaction mixture was stirred for 1 h 40 min at rt. Water was then added to the mixture which was subsequently extracted twice with dichloromethane. The combined organic extracts were extracted with aqueous citric acid (10%). The organic phase was discarded, and the aqueous phase was basified to pH ˜7.5 with aqueous sodium hydroxide (1 M). The aqueous mixture was extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (50% hexanes:50% ethyl acetate) to provide N-(5-bromo-2-methylpyridin-3-yl)methanesulfonamide (111 mg, 0.42 mmol, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 3.10 (s, 3H), 2.47 (s, 3H); MS (EI) for C7H9BrN2O2S: 265, 267 (Br isotopes, MH+).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.I([O-])(=O)(=O)=O.[Na+].CO>O>[OH:3][CH:2]1[C@H:1]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[CH:4]([OH:5])[N:18]1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1ncccn1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: Nc1ccn([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)c(=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of cytidine (2.43 g) and 2-aminopyrimidine (0.95 g) in water (15 ml) was added sodium metaperiodate (2.13 g) at 15° C. The solution was stirred at ambient temperature for four hours. To the reaction mixture was added methanol (20 ml). A precipitate was filtered off and the filtrate was condenced in vacuo. The condenced solution was lyophilized to give white powder of 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]cytosine (3.20 g).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH2:14]([N:16]([CH2:43][CH3:44])[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[C:28](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:29](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[Cl:30])=[CH:24][CH:23]=1)[CH3:15]>C(O)C>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH2:43]([N:16]([CH2:14][CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[C:28](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:29](\[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)/[Cl:30])=[CH:24][CH:23]=1)[CH3:44]
Reactant: CCN(CC)CCCCOc1ccc(/C(=C(\Cl)c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Product: CCN(CC)CCCCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Temperature: 4 °C
Reaction time: 18 h

Procedure:
Combine citric acid (164.7 mg, 0.86 mmol) and ethanol (3 mL) and heat until the solid dissolves. Combine (Z)-1-[4-(4-diethylaminobutoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene (372.6 mg, 0.86 mmol) and warm ethanol (3 mL) and add with stirring to the citric acid solution prepared above. Cool to 4° C. and allow to stand for 18 hours. Filter to give the title compound as a solid: mp; 127°-130° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][C:29]2=[O:32])=[CH:25][CH:24]=1.Cl[CH2:34][C:35](=[O:37])[CH3:36].[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH3:21][O:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH:28]([CH2:34][C:35](=[O:37])[CH3:36])[C:29]2=[O:32])=[CH:25][CH:24]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(=O)C(CC(C)=O)C2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A lithium diisopropylamide solution, freshly prepared from 3.12 ml of diisopropylamine and 13.8 ml of 1.6N n-butyllithium in hexane, in 40 ml of anhydrous tetrahydrofuran was added dropwise while stirring to a solution, cooled to -70°, of 2.96 g of 6-methoxy-1-indanone in 300 ml of anhydrous tetrahydrofuran. The mixture was stirred at this temperature for an additional 30 minutes and a solution of 1.62 ml of chloroacetone dissolved in 40 ml of anhydrous tetrahydrofuran was subsequently added dropwise over 10 minutes. The reaction mixture was left to come to room temperature over 90 minutes and was stirred at this temperature for an additional 45 minutes. Subsequently, the reaction mixture was poured on to 100 ml of ice, 100 ml of saturated sodium chloride were added and the organic phase was separated. The aqueous phase was extracted once with 300 ml of diethyl ether. The combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. The red oil obtained was purified by column chromatography on silica gel (hexane/diethyl ether 3:2). There were obtained 2.24 g (56%) of (RS)-6-methoxy-2-(2-oxopropyl)-1-indanone as a yellow solid which was used without further recrystallization in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)[C:5]([O:25][CH3:26])=[CH:4][C:3]=1[N:27]1[CH2:32][CH2:31]S[CH2:29][CH2:28]1.[OH:33][S:34]([O-:37])(=O)=O.OS(O[O-])(=O)=O.OS(O[O-])(=O)=O.[O-]S([O-])(=O)=O.[K+].[K+].[K+].[K+].[K+].S(=O)(O)[O-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)[C:5]([O:25][CH3:26])=[CH:4][C:3]=1[N:27]1[CH2:32][CH2:31][S:34](=[O:37])(=[O:33])[CH2:29][CH2:28]1
Reactant: O=S(=O)([O-])O
Reactant: COc1cc(N2CCSCC2)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: O=S(=O)(O)O[O-]
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])O
Solvent: CO
Solvent: O
Product: COc1cc(N2CCS(=O)(=O)CC2)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a suspension of 4-{2-fluoro-5-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine (400 mg, 0.88 mmol) in methanol (6 mL) and water (0.3 mL) was added potassium monopersulfate triple salt (1.09 g, 1.77 mmol) under an atmosphere of nitrogen and the mixture was heated for 18 h at 80° C. The reaction mixture was cooled to ambient temperature, sodium bisulfite (38% in water, 3 mL) was added and stirred for 0.5 h at ambient temperature. The resulting suspension was extracted with dichloromethane (20 mL) and washed with aqueous sodium carbonate (half saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 10:70:20) afforded the title compound (228 mg, 53%) as a white solid. MS: m/e=485.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9](Br)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6].C(N(CC)CC)C.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6]
Reactant: CC(C)(C)COC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)COC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Yield: 70.6 %

Procedure:
Following General Procedure D and using 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid 2,2dimethylpropyl ester (Intermediate 46, 0.54 g, 1.4 mmol), triethyl amine (3 mL), copper(I)iodide (0.10 g, 0.52 mmol), trimethylsilyl acetylene (0.8 mL, 5.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.35 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound (0.396 g, 71%) was obtained as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](O)(=[O:15])C.C1N2CN3CN(C2)CN1C3>O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]=[O:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
6-Nitroindole (1.0 g, 6.2 mmol) was successively added with acetic acid (2.5 mL), water (5.0 mL), and hexamethylenetetramine (1.2 g, 8.4 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was added with water, and the precipitated solid was collected by filtration, and then dried to obtain 6-nitro-1H-indole-3-carboxaldehyde (0.91 g, 77%).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:23])[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:7]2[C:16]([CH3:22])=[CH:17][C:18]([CH3:21])=[C:19]([CH3:20])[C:6]=2[O:5]1.C([O-])(=O)C.[Na+].C(#N)C>O>[Br:1][C:17]1[C:18]([CH3:21])=[C:19]([CH3:20])[C:6]2[O:5][C:4]([CH3:23])([CH3:3])[CH:8]([C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[C:7]=2[C:16]=1[CH3:22]
Reactant: Cc1ccc(C2c3c(C)cc(C)c(C)c3OC2(C)C)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C2c3c(C)c(Br)c(C)c(C)c3OC2(C)C)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Bromine (29.3 mL) was added dropwise to a mixture of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (145 g), sodium acetate (50.9 g) and acetonitrile (2175 mL) at 0 to 5° C. The mixture was stirred at 0 to 10° C. for 1 hour and water (725 mL) was added thereto. Precipitated crystals were filtered to obtain the title the compound (175 g, 94.2%).
Reaction SMILES: [OH-].[K+].[CH3:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:36])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[C:16]([O:34][CH3:35])[CH:15]=2)[CH2:6][CH2:5]1.Cl>CO>[CH3:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11](=[O:36])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]3)=[C:16]([O:34][CH3:35])[CH:15]=2)[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1CCN(CCOc2ccc(C=CC(=O)N[C@H]3CC[C@H](C)CC3)cc2OC)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCC(C(=O)O)CC1

Procedure:
10 ml of 2 M aqueous potassium hydroxide solution was added to a solution of 0.5 g of N-(trans-4-methylcyclohexyl) -4-{2-[4-(ethoxycarbonyl)piperidino]ethoxy}-3-methoxycinnamamide (Example 168) in 50 ml of methanol. The solution was reacted for 1 hours, while it was refluxed. After reaction, 2 N hydrochloric acid to the reaction solution, acidifying the solution. The solution was then extracted twice with 50 ml of methylene chloride. The organic layer obtained was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The product obtained was recrystallized from methanol/ether, yielding 0.43 g of N-(trans-4-methylcyclohexyl)-4-[2(4-carboxypiperidino)ethoxy]-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34]>>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]([NH:34][CH2:33][C:32]([O:31][CH3:30])=[O:35])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN
Reactant: CN1CCN(CCC(=O)CN(Cc2ccc(F)cc2)C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: COC(=O)CNC(CCN1CCN(C)CC1)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl-4-fluorobenzyl[4-(4-methylpiperazin-1-yl)-2-oxobutyl]carbamate and glycine methyl ester hydrochloride using a procedure essentially the same as that in Example 6, Step 6. 1H NMR (400 MHz, CDCl3) δ 7.19 (br s, 2H), 7.00 (t, J=8.4 Hz, 2H), 4.50-4.46 (m, 1H), 4.39 (d, J=15.6 Hz, 1H), 4.05 (d, J=4.8 Hz, 1H), 3.77 (s, 1H), 3.72 (s, 3H), 3.56-3.38 (m, 2H), 3.27-3.05 (m, 2H), 2.82-2.77 (m, 2H), 2.55-2.43 (m, 8H), 2.29 (s, 3H), 2.05 (s, 2H), 1.45 (d, J=13.2 Hz, 9H). ES MS (M+1)=467.4.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[CH3:28])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[F:27][C:23]1[C:22]([CH3:28])=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:13]2[N:8]([C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: COC(=O)c1c(Cc2cccc(F)c2C)c(-c2ccccc2)n2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(C(=O)O)c2ccccn2c1-c1ccccc1
Temperature: 90 °C
Yield: 107.1 %

Procedure:
The compound of step 3 (250 mg, 0.67 mmol) was dissolved in dioxane (10 ml) and treated with 10 ml of an aqueous 10 N solution of sodium hydroxide. The mixture was heated to 90° C. for 12 h, cooled to room temperature and neutralized with dilute hydrochloric acid. The aqueous phase was extracted with DCM and the combined organic phases dried over sodium sulfate and filtered. The solution was evaporated to give 258 mg of the crude title compound which was used in the next step without purification.
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1.C1(C)C=CC=CC=1.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[C:4]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)#[CH:3]
Reactant: CC(C)(O)C#Cc1ccc(OCCCCCO)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C#Cc1ccc(OCCCCCO)cc1
Yield: 98.1 %

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 5.41 g (20.6 mmol) of 5-[4-(3-methyl-3-hydroxybutyne-1-yl)phenoxy]pentanol and 70 ml of toluene under a nitrogen atmosphere. To the flask, 1.65 g (41.2 mmol) of sodium hydroxide was added, and stirred under reflux for 4 hours. After the completion of the reaction, water, 1N hydrochloric acid, and ethyl acetate were added to the reactant to adjust the pH to an acidity and effect ethyl acetate extraction. The resulting organic phase was washed with NaCl saturated water, dried over anhydrous sodium sulfate, filtered, and concentrated to thereby obtain 4.13 g of 5-(4-ethynylphenoxy)pentanol in the form of a brown oil in a 98% yield.