Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ccn2)CC1
Temperature: 25 °C

Procedure:
Stir a solution of 2,4-dichloro-pyridine (6.7 mmol, 1 g), N-Boc piperazine (8.1 mmol, 1.5 g), sodium tert butoxide (9.5 mmol, 0.9 g), palladium (II) acetate (0.7 mmol, 0.15 g) and 2-(di-tbutylphosphino)biphenyl (0.7 mmol, 0.2 g) dissolved in toluene under nitrogen at 100° C. for 4 hours. Cool down to room temperature and add water. Extract in ethyl acetate washing the organic layer with water and saturated aq. sodium chloride. Dry organic layer over sodium sulfate, filter, and concentrate under reduced pressure to give 4-(4-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester as a residue. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 10% to 50%). MS(ES): m/z=298 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[CH:3]=1.[N+](=[CH2:21])=[N-].C(OCC)C>CO.C1(C)C=CC=CC=1>[CH3:21][O:17][C:16]([CH:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)[CH2:11][CH2:12]1)=[O:18]
Reactant: COc1nc(Cl)cc(N2CCC(C(=O)O)CC2)n1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CCN(c2cc(Cl)nc(OC)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 1-(6-chloro-2-methoxy-pyrimidin-4-yl)-piperidine-4-carboxylic acid [131 mg, 0.48 mmol] in MeOH (1 mL) and toluene (1 mL) is added a solution of 2 M diazomethane in diethylether (0.48 mL, 0.96 mmol). The solution is stirred for 2 h at ambient temperature and concentrated. The residue is subjected to chromatography on silica gel eluting with 40% ethyl acetate:heptane to afford 1-(6-chloro-2-methoxy-pyrimidin-4-yl)-piperidine-4-carboxylic acid methyl ester [103 mg, 75%] as a solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:5]=[CH:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4cn(CC)cn4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1cnc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)c1
Reaction time: 8 h
Yield: 101.5 %

Procedure:
A mixture of ethyl (4-{4-[(4-[({4-[(E)-2-(1-ethyl-1H-imidazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl)phenyl)acetate (485 mg), 8N aqueous sodium hydroxide solution (1 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was heated under reflux for 30 min. After cooling, to the reaction mixture was added 1N hydrochloric acid (8 mL) and the mixture was left standing overnight. The precipitated crystals were collected by filtration and recrystallized from methanol-diethyl ether to give (4-{4-[(4-[({4-[(E)-2-(1-ethyl-1H-imidazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetic acid as colorless crystals (472 mg, yield 100%). melting point: 194-196° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Cl:20]OC(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Cl:20][C:14]1[C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:13]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)COc1ccc(CCO)cc1OCC
Reactant: CC(C)(C)OCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1cc(Cl)c(CCO)cc1OCC
Reaction time: 0.25 h

Procedure:
To a stirred solution of ethyl 2-[2-ethoxy-4-(2-hydroxyethyl)phenoxy]acetate (1.15 g) in dichloromethane (4.3 ml) was added tert-butyl hypochlorite (478 μl) at room temperature, and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of sodium sulfite (542 mg) in water (5 ml), and the resulting mixture was stirred for 10 minutes at room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave ethyl 2-[5-chloro-2-ethoxy-4-(2-hydroxyethyl)phenoxy]acetate (1.28 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:20].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CN)ccc1Cl
Yield: 202.9 %

Procedure:
A solution of methyl 5-(((tert-butoxycarbonyl)amino)methyl)-2-chlorobenzoate (100 mg, 0.334 mmol) in EtOAc saturated with HCl (1 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and was triturated with pentane to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.20 (br s, 3H), 7.95 (s, 1H), 7.67 (s, 2H), 4.00 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[CH:14][NH:13][CH:12]=1)=[O:10])[CH3:7].[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:22]=[O:23])[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c[nH]cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c[nH]c(C=O)c1C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
POCl3 (4 mL, 1.1 eq) added to 9 mL (3 eq) of DMF cooled in an ice bath. After 15 mins, a solution of the 4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (6 g, 39.2 mmol) in DMF (2M, 20 mL) was added to the reaction and stirring continued at rt. After 2 hr, the reaction mixture was diluted with water (100 mL) and basified to pH=11 with 1N NaOH. The aqueous layer was extracted into DCM (2×250 mL), washing the combined organic layers with water (2×400 mL), dried (MgSO4), filtered through a plug of silica and concentrated to afford a pinkish solid. Trituration with hexanes afforded 3.3 g (46%) of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a tan solid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCN2CCCC2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (90 mg, 77%).
Reaction SMILES: CN(CCCN=C=NCC)C.[C:12]([O:16][C:17](=[O:26])[CH2:18][C@@H:19]([CH2:23][CH:24]=[CH2:25])[C:20]([OH:22])=O)([CH3:15])([CH3:14])[CH3:13].[CH2:27]([O:34][C:35](=[O:42])[C@H:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[CH3:39][C:38]([CH3:41])([CH3:40])[C@H:36]([NH:37][C:20]([C@H:19]([CH2:23][CH:24]=[CH2:25])[CH2:18][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:26])=[O:22])[C:35]([O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:42]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
N-(Dimethylaminopropyl)-N′-ethylcarbodiimide (2.298 g, 12 mmol) was added to a stirred mixture of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]pent-4-enoic acid (2.13 g, 10 mmol tert-leucine benzyl ester (2.834 g, 11 mmol)(N. Moss et al., J. Med. Chem., 1996, 39, 2178), N-methylmorpholine (2.40 mL, 22 mmol) and 1-hydroxybenzotriazole hydrate (1.836 g, 12 mmol) in anhydrous dichloromethane (50 mL) under nitrogen at 0° C. The mixture was allowed to warm slowly to room temperature with the cooling bath in place. After 20 h, the mixture poured into ethyl acetate (250 mL) and washed with 5% aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (2×70 mL), brine (70 mL), dried (MgSO4), and concentrated under reduced pressure. The residual oil crystallised upon addition of pentane. The solid was filtered and dried to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)hex-5-enoate (4.068 g, 97%), as a colourless solid.
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=O)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:23]1[CH:28]=[CH:27][C:26](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:4]([N:11]1[CH2:12][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2ccccc2)CN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a solution of sodium hydride (60% in oil, 6.36 g) in DMF (100 mL) was added ethyl 1-benzyl-3-oxopiperidine-4-carboxylate monohydrochloride (19.0 g) at 0° C., and the mixture was stirred for 5 min. N-phenylbis(trifluoromethanesulfonimide) (25.0 g) was added, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into ice water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried, and the solvent was evaporated under reduced pressure. To a mixture of the obtained residue in a mixed solvent of toluene (125 mL) and water (7.5 mL) were added dihydroxyphenylborane (5.82 g), potassium carbonate (4.40 g) and tetrakis(triphenylphosphine)palladium(0) (3.67 g), and the mixture was stirred under an argon atmosphere at 100° C. for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→20% ethyl acetate/hexane) to give ethyl 1-benzyl-5-phenyl-1,2,3,6-tetrahydropyridine-4-carboxylate (10.2 g) as a pale yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].NCCC(O)=O>C(O)CCC>[N+:14]([C:17]([CH3:18])=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)([O-:16])=[O:15]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: NCCC(=O)O
Solvent: CCCCO
Product: CC(=Cc1ccc(-n2ccnc2)cc1)[N+](=O)[O-]
Yield: 20.2 %

Procedure:
A mixture of 292 g (1.70 mole) of 4-(1H-imidazol-1-yl)benzaldehyde, 153.7 g (1.97 mole) of nitroethane (96%), and 15.4 g (0.173 mole) of β-alanine in 1000 ml n-butanol is refluxed for nine hours. The reaction mixture is allowed to cool overnight, the solid collected, and washed successively with ether and water to give 78.7 g of dark yellow crystals, mp 119°-120° C. Concentration of the filtrate to approximately 500 ml and cooling at 0° gave a second crop (87.2 g) of the product, mp 116°-118° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[NH:21][N:22]=[C:23]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+].IC.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:21]([CH3:32])[N:22]=[C:23]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)cc4)c3c2cc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OCc1ccccc1
Reaction time: 18 h
Yield: 69.4 %

Procedure:
4-(8-Benzyloxy-7-methoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (2.50 g, 6.15 mmol) is dissolved in N,N-dimethylformamide (72 ml). K2CO3 (1.70 g, 12.3 mmol) and iodomethane (421 μl, 6.76 mmol) are subsequently added at room temperature, and the reaction mixture is stirred for 18 h (TLC (HPTLC) monitoring). The mixture is then added to water (500 ml) and stirred for 30 min. The precipitate obtained is filtered off with suction and chromatographed over flash silica gel (120 g, solvent gradient cyclohexane/0-100% by vol. of ethyl acetate/0-40% by vol. of ethanol). The residue from the product fractions is suspended in 2-propanol, filtered off with suction and dried in a high vacuum, giving 4-(8-benzyloxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (1.79 g, 4.27 mmol) as a solid having a melting point of 230.4° C. MS: 421.1 (M+H+), TLC (HPTLC): Rf=0.44 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:15]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.ClS([N:27]=[C:28]=[O:29])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[C:28](=[O:29])([O:1][CH2:2][CH2:3][CH:4]([NH2:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)[NH2:27]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)OCCC(N)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Of the compound from Example 128A, 827 mg (2.59 mmol) were introduced in 100 ml of acetonitrile. A solution of 676 μl (7.77 mmol) of chlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwise at −15° C. After 5 min, 50 ml of water were added and the mixture was then stirred at 60° C. overnight. The reaction mixture was admixed with saturated aqueous sodium hydrogen carbonate solution and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Drying of the residue in an HV gave 678 mg (quant.) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH3:11])C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[NH2:8][CH2:11]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Combine oxalyl chloride (2.71 g, 21.4 mmol) and toluene (20 mL). Cool to 0° C. Add N,N-dimethylformamide (1.62 g, 22.2 mmol) as a solution in toluene (2 mL). Warm to ambient temperature. After 10 minutes, cool to 0° C. Add (E)-2(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (4.0 g, 20.2 mmol) Warm to ambient temperature. After 18 hours, pour the reaction mixture into a saturated sodium chloride solution (100 mL). Extract the aqueous layer 3 times with toluene. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ2.52 (m, 2H), 2.75 (m, 2H), 3.91 (d, J=6 Hz, 2H), 6.65 (d, J=82.5 Hz, 1H), 6.95 (m, 2H), 7.15 (m, 2H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCBr
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCCc2ccccc21

Procedure:
Under the atmosphere of nitrogen, 4 parts of 1,2,3,4-tetrahydroquinoline, 6.4 parts of 1-bromooctane, 5 parts of dimethylformamide (DMF), and 5 parts of potassium carbonate were stirred at 130° C. for 4 hours. After the reaction, the resultant was extracted with water/ethyl acetate, and the ethyl acetate phase was dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was separated and purified by column chromatography to yield 3 parts of a precursor of the compound (301), 1,2,3,4-tetrahydro-1-octylquinoline as a colorless liquid. Next, 1.7 parts of phosphorus oxychloride were dropwise added to 10 parts of chloroform and 1 part of N,N-dimethylacrolein, the temperature of which was adjusted to 5° C., while the temperature of the reaction solution was kept at 10° C. or lower. The reaction solution was then stirred at 5° C. for 1 hour. Thereafter, 2.5 parts of 1,2,3,4-tetrahydro-1-octylquinoline described above were added thereto, and then the reactive components were caused to react at 25° C. for 1 hour. The reaction solution was then stirred at 70° C. for 1 hour. Thereafter, a 20% solution of sodium hydroxide in water was added to the reaction solution until the pH turned to 12. The precipitated crystal was filtrated, and the resultant crystal was washed with water. The crystal was then separated by column chromatography (hexane/ethyl acetate), and recrystallized from ethanol to yield 2.7 parts of the compound (301) as a yellow crystal.
Reaction SMILES: Cl.ClCC([NH:6][CH2:7][C:8]1[C:13]([C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16])=[CH:12][C:11]([C:19]([Cl:23])=[C:20]([Cl:22])[Cl:21])=[CH:10][C:9]=1[OH:24])=O>C(O)C>[NH2:6][CH2:7][C:8]1[C:13]([C:14]([Cl:18])=[C:15]([Cl:17])[Cl:16])=[CH:12][C:11]([C:19]([Cl:23])=[C:20]([Cl:21])[Cl:22])=[CH:10][C:9]=1[OH:24]
Reactant: O=C(CCl)NCc1c(O)cc(C(Cl)=C(Cl)Cl)cc1C(Cl)=C(Cl)Cl
Agent: Cl
Solvent: CCO
Product: NCc1c(O)cc(C(Cl)=C(Cl)Cl)cc1C(Cl)=C(Cl)Cl
Temperature: 85 °C

Procedure:
To a solution of 0.2 mL ethanol and 60 μL conc. hydrochloric acid was added 0.025 g (0.05 mmol) of the product of Step E and the reaction mixture was stirred and heated to 85° C. using an external oil bath overnight. The reaction mixture was then cooled to room temperature and evaporated in vacuo. The residue was triturated with ether and dried overnight in vacuo to afford the title compound as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:10][O:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)ccc1Cl
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 3-hydroxy-4-chlorotoluene (25 g, 0.175 mol) in 400 ml of acetone was added 30.11 g (0.22 mol) of milled potassium carbonate and 31.22 g (0.22 mol) of methyl iodide, and the mixture was refluxed with stirring for 16 hours. The mixture was cooled, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in ether, washed with water, and the organic layer was dried over sodium sulfate and concentrated in vacuo to afford 25.6 g of 3-methoxy-4-chlorotoluene as a solid.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=[O:7].[C:16]1(C(O)=O)[C:25]2[C:20](=CC=CC=2)[CH:19]=[CH:18][CH:17]=1>>[C:2]1([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[O:7])[C:25]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: O=C1CCCCCN1C(=O)c1ccco1
Product: O=C1CCCCCN1C(=O)c1cccc2ccccc12

Procedure:
Synthesized as for N-(2-furoyl)caprolactam (Example X) using 1-naphthoic acid in place of 2-furoic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:7]2[CH2:6]1>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]2[CH2:6]1
Reactant: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: COCCN1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of 133a (286 mg, 1.26 mmol) in methanol (10 mL) was added Pd/C (28.6 mg). The system was evacuated and then refilled with H2. After stirring at room temperature for 2 h, the mixture was filtered off. The filtrate was concentrated under reduced pressure to afford 133b as a yellow solid (240 mg, 97%), which was used in the next step without further purification. MS-ESI: [M+H]+ 197.0
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>C(#N)C>[CH2:24]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([F:1])([F:15])[C:3]([F:13])([F:14])[O:4][C:5]=2[CH:11]=1)[C:23]#[CH:22]
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 67.5 °C
Reaction time: 24 h

Procedure:
Another method to prepare the titled compound is as follows. 2,2,3,3-Tetrafluoro-6-aminobenzodioxane (50.2 g, 225 mmol) and potassium carbonate (43.54 g, 315 mmol) were suspended into acetonitrile (250 mL), stirred in a 1-liter three-necked flask equipped with an overhead mechanical stirrer, and treated with ˜80% propargyl bromide in toluene (33.5 g, ˜225 mmol). The mixture was slowly heated to 65-70° C. over about three hours. Stirring was continued at that temperature for 24 hours, at which time the heat was turned off and the mixture was permitted to cool to room temperature. The mixture was filtered through a glass flitted funnel, and the solids were rinsed with acetonitrile (300 mL). The filtrate was concentrated, reconcentrated thrice from hexanes, and chromatographed on silica (0 to 1 to 2 to 4% EtOAc/hexanes) to give the titled compound.