Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[C:18]([CH2:28][CH2:29][C:30](OCC)=[O:31])=[CH:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:36])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[C:18]([CH2:28][CH2:29][CH2:30][OH:31])=[CH:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:36])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)CCc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(CCCO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a 8 ml THF solution of 400 mg of ethyl 3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]propanoate was added 40 mg of lithium aluminum hydride at 0° C., followed by stirring for 2 hours. Water was added to the reaction mixture, followed by and filtration through celite. After evaporation under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 288 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(3-hydroxypropyl)quinolin-4(1H)-one.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9]P(=O)(OCC)OCC)[N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:8]=1)([CH3:2])[CH3:3]
Reactant: CCOP(=O)(Cc1csc(C(C)C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C(C)C)n1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of diethyl [(2-isopropyl-1,3-thiazol-4-yl)methyl]phosphonate (2.47 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.36 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.72 g) was added to the reaction mixture and the mixture was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give 2-isopropyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as pale-yellow oil (1.59 g, yield 60%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=[O:4].[H-].[Na+].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:35]3[CH2:40][CH2:39][C@H:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([N:25]=[CH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])=[C:21]([Cl:34])[CH:20]=3)[C:11]=12>CS(C)=O>[C:28]([OH:33])(=[O:4])[CH3:29].[Cl:34][C:21]1[CH:20]=[C:19]([C:18]2[C:11]3[C:12](=[N:13][CH:14]=[N:15][C:10]=3[NH2:9])[N:16]([C@H:35]3[CH2:36][CH2:37][C@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:39][CH2:40]3)[N:17]=2)[CH:24]=[CH:23][C:22]=1[NH:25][CH:26]1[CH2:2][O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]1=2
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N=Cc5ccccc5O)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NC5COc6ccccc65)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Salicylaldehyde (0.033 g, 0.000274 mol) and trans-3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.115 g, 0.000261 mol) were combined in absolute ethanol and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)imino]methylphenol which was used without further purification. Trimethylsulfoxonium iodide (0.110 g, 0.0005 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and 60% dispersion of sodium hydride in paraffine (0.02 g, 0005 mol) was added at once. After 10 min., the solution of trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)imino]methylphenol in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (50 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[3-chloro-4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.044 g, 0.000071 mol) as a white solid.
Reaction SMILES: CCC1C=CC(=O)[C:5]2=C[C:7]3[CH2:25][N:24]4[C:10](=[CH:11][C:12]5[C@@](O)(CC)C(=O)OC[C:13]=5[C:22]4=O)[C:8]=3[NH:9][C:4]=12.[CH2:30]([Cl:32])Cl.CC(N(C)C)=[O:35].N1C=CC=CC=1>C(N(CC)CC)C>[N:24]1([CH:25]2[CH2:5][CH2:4][N:9]([C:30]([Cl:32])=[O:35])[CH2:8][CH2:7]2)[CH2:22][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)N(C)C
Reactant: CCc1ccc(=O)c2cc3c([nH]c1-2)-c1cc2c(c(=O)n1C3)COC(=O)[C@]2(O)CC
Reactant: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Cl)N1CCC(N2CCCCC2)CC1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
In a suitable vessel were charged 7-Ethyl-10-hydroxycamptothecin (1 g), methylene dichloride, dimethyl acetamide (0.221 gm) and pyridine (3 ml) under nitrogen atmosphere. A solution of [1,4′]bipiperidinyl-1′-carbonyl chloride (0.88 g), methylene dichloride and triethylamine (1 ml) was prepared and added to the above suspension and stirred at 30-40° C. for 2 hours. The solvent was distilled out under reduced pressure at 50° C. and hexane was added under stirring as an antisolvent to isolate crystalline compound which was then filtered, washed with hexane and dried under reduced pressure at 50° C. The yield was 1.25 g (83.55%); HPLC purity-99.9%
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][S:5][C:6]1[N:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:8]([C:11](O)=[O:12])=[CH:9][N:10]=1.[CH2:26](CN)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH2:35]([N:37](CC)CC)C.CCCP(=O)=O>ClCCl>[CH2:26]([N:37]([CH3:35])[C:11]([C:8]1[N:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6]([S:5][CH2:4][C:3]2[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:2]=2[Cl:1])=[N:10][CH:9]=1)=[O:12])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Reactant: NCCc1ccccc1
Agent: CCCP(=O)=O
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)c1cnc(SCc2c(F)cccc2Cl)n1-c1ccc(F)cc1

Procedure:
A solution of 2-((2-chloro-6-fluorobenzyl)thio)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (88) (50 mg, 0.13 mmol), N-benzylmethylamine (16 mg, 0.13 mmol), triethylamine (0.12 mL, 0.79 mmol) and propylphosphonic anhydride (T-3-P)(50% in ethyl acetate, 0.12 mL, 0.20 mmol) in dichloromethane (1.5 mL) was stirred overnight at room temperature. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (50%-100% EtOAc in hexanes) to give N-benzyl-2-((2-chloro-6-fluorobenzyl)thio)-1-(4-fluorophenyl)-N-methyl-1H-imidazole-5-carboxamide (500). 1H NMR (400 MHz, CDCl3) δ: 7.37-7.25 (m, 4H), 7.20-6.99 (m, 8H), 6.93-6.90 (m, 1H), 4.64 (s, 2H), 4.45 (s, 2H), 2.96 (s, 3H). LC-MS ESI m/z; found 484.1 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:8]([C@H:20]([OH:22])[CH3:21])[C:7]1=[O:23].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[OH:22][C@@H:20]([CH:8]1[CH:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[NH:6][C:7]1=[O:23])[CH3:21]
Reactant: COc1ccc(CN2C(=O)C([C@@H](C)O)C2C(=O)OCc2ccccc2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@H](O)C1C(=O)NC1C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3(a) 14 g of benzyl 1-(2,4-dimethoxybenzyl)-3-[(R)-1-hydroxyethyl]-2-oxoazetidine-4-carboxylate [which had been synthesized according to a procedure similar to that described in Tetrahedron 46, 1795 (1984)] were dissolved in a mixture of 420 ml of acetonitrile and 420 ml of water. 66.1 g of potassium persulfate and 23.3 g of dibasic potassium phosphate were added to the solution, and the mixture was stirred at 70° C. for 60 minutes. At the end of this time, insoluble materials were filtered off, and the filtrate was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed from the solvent by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel to afford 6.1 g of benzyl 3-[(R)-1-hydroxyethyl]-2-oxoazetidine-4-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([S:8][C:9]([CH3:27])([CH3:26])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>C(#N)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:10]([OH:17])([C:9]([CH3:27])([S:8][C:5]1[N:6]=[N:7][C:2]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)=[CH:3][CH:4]=1)[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Sc1ccc(Cl)nn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC#N
Product: CC(C)(Sc1ccc(-n2cncn2)nn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 93 %

Procedure:
A mixture consisting of 3.0 g (7.3 mmol) of (+)-3-(6-chloropyridazin-3-ylthio)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 2.0 g(29 mmol) of 1,2,4-triazole, and 1.5 ml of acetonitrile was heated at reflux for 19 hours. After allowing the mixture to cool, the solvent was removed by distillation under reduced pressure, and the residue was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution and dried. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using a mixed solvent of chloroform and methanol (100:1). The solvent was removed from the effluent by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform and diethyl ether to obtain 3.0 g (93%) of (+)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-3-(6-(1H- 1,2,4-triazol-1-yl)pyridazin-3-ylthio)butan-2-ol as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:2]2[CH:10]=[CH:9][CH:5]=[CH:4][CH:3]=2)=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-Bromo-2-nitro-benzoic acid (1.33 g, 0.0054 mol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL) and aluminum trichloride (0.676 g, 0.0051 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCC(c2ccc(Br)cc2)CC1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
4-(4-Bromo-phenyl)-1-methyl-piperidine; hydrochloride was prepared from 4-(4-bromo-phenyl)-piperidine; hydrochloride (1.0 g, 3.6 mmol) in a manner analogous to Step 34c. The reaction product was isolated an off-white solid (0.94 g) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.58 (br s, 1H), 7.54 (d, J=7.2 Hz, 2H), 7.21 (d, J=7.3 Hz, 2H), 3.46 (d, J=11.4 Hz, 2H), 3.09-2.97 (m, 2H), 2.83-2.70 (m, 4H), 2.00-1.87 (m, 4H). MS=254, 256 (MH)+. 50b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(1-methyl-piperidin-4-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-phenyl)-1-methyl-piperidine; hydrochloride (100.0 mg, 0.3441 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.070 g, 58%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.8 Hz, 1H), 8.23 (d, J=8.2 Hz, 2H), 8.08 (d, J=8.1 Hz, 2H), 7.65 (d, J=7.4 Hz, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.01 (t, J=6.7 Hz, 1H), 6.85 (s, 1H), 3.10 (s, 3H), 3.01-2.94 (m, 2H), 2.51-2.41 (m, 1H), 2.33 (s, 3H), 2.10-2.01 (m, 2H), 1.87-1.77 (m, 4H). MS=462 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](I)=[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]5[CH:31]=[C:32]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[O:33][C:26]=45)=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:40])=[CH:4][CH:3]=1.[O-:41][CH2:42][CH3:43].[Na+]>>[C:34]1([C:32]2[O:33][C:26]3[C:27](=[N:28][CH:29]=[CH:30][C:25]=3[O:24][C:21]3[CH:22]=[CH:23][C:18]([NH:17][C:15]([C:10]4[C:9](=[O:40])[N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[CH:13]=[CH:12][C:11]=4[O:41][CH2:42][CH3:43])=[O:16])=[CH:19][CH:20]=3)[CH:31]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)cc1)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a dry 5 mL sealed tube with stirbar was added 1-(4-fluorophenyl)-4-iodo-2-oxo-N-{4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]phenyl}-1,2-dihydropyridine-3-carboxamide (46.30 mg; 0.07 mmol; 1.00 eq.) and the vial was sealed and flushed with N2. To the vial was added dry THF (1.00 ml) via syringe and then sodium ethoxide (0.04 ml; 0.09 mmol; 1.30 eq.) (21% solution in ethanol) was slowly added via syringe and the reaction mixture was stirred at room temperature for 1 h. The solution was concentrated, taken up in EtOAc and washed with sat. aq. NaHCO3. The organic layer was collected, extracting aqueous layer with EtOAc (3×). Combined organic layers were dried (Na2SO4) and concentrated on rotary evaporator to afford the title compound as a beige solid (40 mg, 100%). (HPLC (method F): 99%, RT: 6.08 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.41 (s, 1H), 8.34 (d, J=5.5, 1H), 7.97-7.90 (m, 2H), 7.86 (d, J=7.8, 1H), 7.83-7.77 (m, 2H), 7.69 (s, 1H), 7.58-7.50 (m, 2H), 7.50-7.43 (m, 3H), 7.41-7.35 (m, 2H), 7.34-7.27 (m, 2H), 6.71 (d, J=5.5, 1H), 6.52 (d, J=7.9, 1H), 4.26 (q, J=7.0, 2H), 1.30 (t, J=7.0, 3H); MS (m/z) 562 [M+H]+, RT: 3.5 min.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1O[S:5]([CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=[O:7])=[O:6].[N:31]1([CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[N:31]1([CH2:36][CH2:37][CH:38]2[CH2:39][CH2:40][N:41]([S:5]([CH2:8][CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]3)(=[O:6])=[O:7])[CH2:42][CH2:43]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCS(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)C1
Reactant: C1CCN(CCC2CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CCS(=O)(=O)N2CCC(CCN3CCCC3)CC2)C1

Procedure:
tert-Butyl 3-(2-(perfluorophenoxysulfonyl)ethyl)piperidine-1-carboxylate (0.5 g, 1.09 mmol) and 4-(2-pyrrolidinoethyl)piperidine (0.4 g, 2.18 mmol) were dissolved in tetrahydrofuran (10 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 ml, 3.27 mmol) was added under an inert gas and the mixture was refluxed for 2 h. Ethyl acetate and saturated sodium bicarbonate solution (20 ml of each) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/ammonia (25% aq) (300:100:1). Yield: 0.32 g (64%)
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[C:13]1([C:19](OC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:13]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:19](=[O:20])[N:11]=1
Reactant: COC(=O)C1(Br)CCCCC1
Reactant: NC(=S)NC1CC2CCC1C2
Product: O=C1N=C(NC2CC3CCC2C3)SC12CCCCC2

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and methyl 1-bromocyclohexanecarboxylate according to Method D.
Reaction SMILES: [F:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]C)=[O:5].O[C@@H](CCCC)CC(OC)=O>>[F:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC[C@@H](F)CC(=O)OC
Agent: CCCC[C@H](O)CC(=O)OC
Product: CCCCC(F)CC(=O)O

Procedure:
Incidentally, methyl (R)-3-fluoroheptanoate derived from methyl (S)-3-hydroxyheptanoate (98.8% ee, [α]D20 =9.07) was hydrolyzed to obtain 3-fluoroheptanoic acid, which was then reacted with R-(+)-1-(1-naphthyl)ethylamine to form a diastereomer. The resulting diastereomer was found to have an optical purity of 98.7% ee by liquid chromatography, indicating that no racemization took place at all.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.OCCCS[C:14]1[C:22]2[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]=2[S:16][C:15]=1[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.[O:37]1CCCC1>>[CH3:24][N:20]1[C:21](=[O:23])[C:22]2[C:14]([S:3][C:4]3[S:5][CH:6]=[CH:7][CH:8]=3)=[C:15]([C:30]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:37])[S:16][C:17]=2[N:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]1=[O:25]
Reactant: C1CCOC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(Cc3cccnc3)sc21
Reactant: Sc1cccs1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccs3)c(C(=O)c3cccnc3)sc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Prepared according to the method described in Example 38 from sodium hydride (0.068 g), 2-mercaptothiophene (0.15 ml), dry tetrahydrofuran (60 ml) and 5-bromo-3-methyl-1-(2-methylpropyl)-6-[(pyridin-3-yl)carbonyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.60 g, Example 39) with stirring at room temperature for 18 hours. After work up, the residue was purified by column chromatography over silica eluting with ethyl acetate:isohexane (1:1) to give the title compound as a yellow solid (0.46 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:17]1[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C.O>[CH2:3]([N:17]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCn1ccc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCn1ccc(C(=O)O)c1
Yield: 79.9 %

Procedure:
To a solution of 2.58 g (61.3 mmol) of 95% sodium hydroxide in 100 ml of ethanol and 40 ml of water was added 5.43 g (15.3 mmol) of ethyl 1-tetradecylpyrrole-3-carboxylate obtained in Example 56. After the mixture was heated under reflux for 5 hours, the ethanol was removed under reduced pressure and 100 ml of water was added thereto. Then the mixture was acidified with concentrated hydrochloric acid to precipitate crystals, which were extracted with 70 ml and with 50 ml of ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the remaining crystals were recrystallized from hexane to give 3.76 g (79.9% yield) of 1-tetradecylpyrrole-3-carboxylic acid as white crystals, m.p. 66°-67° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:36]1([C:42]2([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([N:45]1[CH2:46][CH2:47][C:42]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43][CH2:44]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCOC(=O)C1(C2CCCCC2)CCNCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To 3.22 g (10.9 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-propionic acid dissolved in 20 ml of DMF are added 2.29 g (12.0 mmol) of EDC, 1.62 g (12.0 mmol) of HOBt, 2.62 g (10.9 mmol) of ethyl 4-cyclohexylpiperidine-4-carboxylate and 4.6 ml (32.7 mmol) of triethylamine. After stirring for 2 hours 30 minutes, the reaction is stopped by adding aqueous 1N sodium hydroxide solution and the organic products are extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated. The crude product obtained is chromatographed on silica gel (eluent: 7/3 heptane/EtOAc). 3.70 g of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate in the form of a white powder are obtained in a yield of 66%.