Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])=[N:4][CH2:5][C:6]1([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O>[F:32][C:2]([F:1])([F:31])[CH:3]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[NH:4][CH2:5][C:6]1([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: N#Cc1cccc(C(=NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(C(NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)imino)ethyl)benzonitrile (600 mg, 1.3 mmol) was dissolved in MeOH—H2O (20 mL, 8:2 v/v) and cooled to 0° C. Sodium borohydride (250 mg, 6.6 mmol) was added to this solution portionwise. The reaction mixture was allowed to warm up to room temperature, stirred for 2 h, and then quenched with water and concentrated under reduced pressure to remove the MeOH. The aqueous mixture was diluted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluant 15-20% EtOAc in petroleum ether) to afford 3-(2,2,2-trifluoro-1-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)benzonitrile (300 mg, yield 50%). 1H NMR (300 MHz, CDCl3) δ 7.89-7.86 (m, 2H), 7.63-7.60 (dt, J=7.6 Hz, 1.4 Hz, 1H), 7.55-7.51 (m, 2H), 7.50 (s, 1H), 7.47-7.41 (m, 3H), 7.39-7.36 (m, 0.1H), 4.16-4.03 (m, 1H), 3.84-3.74 (m, 2H), 3.71-3.61 (m, 2H), 2.95 (d, J=11.4 Hz, 1H), 2.76 (d, J=11.4 Hz, 1H), 2.36-2.24 (m, 2H), 2.01-1.92 (ddd, J=13.5 Hz, 9.0 Hz, 4.1 Hz, 2H). MS (ESI) m/z: Calculated for C24H22F3N3OS: 457.14. found: 458.2 (M+H)+.
Reaction SMILES: BrC1C([C@H](OC(C)(C)C)C(OCC)=O)=C(C)C=[C:8]2C=1C=C[C:6](C)=[N+:7]2[O-].[C:26]([O:30][C@@H:31]([C:37]1[C:38]([C:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH2:48]O)[CH:41]=[CH:40]2)[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C@@H:31]([C:37]1[C:38]([C:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH2:48][N:7]([CH3:8])[CH3:6])[CH:41]=[CH:40]2)[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1C1=CCCCC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CN(C)C)ccc2c1C1=CCCCC1

Procedure:
(S)-Ethyl 2-tert-Butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetate was prepared following the procedure used to prepare compound (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetate of Example 20 except that (S)-ethyl 2-tert-butoxy-2-(5-cyclohexenyl-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate. LCMS-ESI+ (m/z): 439.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([O:13][C:9](=[O:12])[CH:10]=[CH:11][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C=Cc1ccc(N)nc1
Temperature: 110 °C

Procedure:
A mixture of 2-amino-5-bromo-pyridine (9-1) (10 g, 58 mmol), tert-butyl acrylate (50 mL, 344 mmol), triethylamine (50 mL, 359 mmol), tri-o-tolylphosphine (3.0 g, 9.8 mmol) and Pd(OAc)2 (1.0 g, 4.5 mmol) in 150 mL CH3CN was purged with argon for 5 min and subsequently refluxed at 110° C. for 20 hr. The mixture was then cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:1) to afford the desired product 9-2 as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH:22]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([CH:27]2[CH2:28][CH2:29][C:30]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26]2)[CH:8]=1
Reactant: OC1CCc2ccccc2C1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cn(C2CCc3ccccc3C2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a mixture of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (0.10 g), 1,2,3,4-tetrahydronaphthalen-2-ol (0.17 g), triphenylphosphine (0.29 g) and toluene was added DIAD toluene solution (1.9M, 0.59 mL) at 50° C., and the mixture was stirred at 50° C. for 1 hr and at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/n-heptane to give the title compound (27 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH:30]1[CH2:32][CH:31]1[CH3:33])[C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([N:21]([S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH3:22])[N:20]=1)[C:12](N(OC)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:12]([C:11]1[CH:10]=[C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:29][CH:30]2[CH2:32][CH:31]2[CH3:33])[N:20]=[C:19]([N:21]([CH3:22])[S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH:18]=1)(=[O:13])[CH3:34]
Reactant: CON(C)C(=O)c1cc(N(Cc2ccccc2)CC2CC2C)nc(N(C)S(=O)(=O)C(C)C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(N(Cc2ccccc2)CC2CC2C)nc(N(C)S(=O)(=O)C(C)C)c1
Temperature: 0 °C

Procedure:
To a −78° C. solution of 2-{benzyl[(2-methylcyclopropyl)methyl]amino}-6-[(isopropylsulfonyl)(methyl)amino]-N-methoxy-N-methylisonicotinamide (860 mg, 1.81 mmol) from Step A in 6 mL dry THF was added methylmagnesium bromide (3.62 mL, 10.8 mmol, 3M solution in diethyl ether). The reaction mixture was allowed to slowly warm to 0° C. over 1 h, at which time it was poured onto 20 mL of sat. ammonium chloride and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, and concentrated. Purification by automated flash chromatography (silica gel cartridge, 0-100% ethyl acetate/hexanes over 35 minutes) afforded N-(4-acetyl-6-{benzyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylpropane-2-sulfonamide as a bright yellow solid. LCMS [M+H]=430.1.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH2:2][CH3:3].[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH2:1][CH2:2][CH3:3])=[O:5])=[N:7]1)=[O:15])[CH3:12]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCS(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)c1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 4.8 g. 3-propylsulphinyl-1,2,4-triazole, 4.48 g. diethylcarbamoyl chloride, 40 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride. The filtrate was diluted with petroleum ether (b.p. 40° - 60° C.), causing the deposition of an oil which gradually solidified. The solid product was collected and recrystallized from a mixture of ether and petroleum ether (b.p. 40° - 60° C.) to give 1-diethylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 50.5° - 51.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9])[CH3:2].O.[NH2:17][NH2:18]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:17][NH:18][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CC(C(=O)CC)C(=O)CC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1c(CC)n[nH]c1CC
Yield: 98.4 %

Procedure:
Combine 4-oxo-3-propionylhexanoic acid ethyl ester (2.49 g, 11.6 mmol) and hydrazine hydrate (0.70 g, 13.9 mmol) in glacial acetic acid (20 mL) and stir at room temperature for 88 hr. Concentrate to an oil. Partition this residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate the organic layer; dry (sodium sulfate), filter and concentrate to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ 8.64 (bs, 1H), 4.08 (q, 2H), 3.35 (s, 2H), 2.61 (q, 4H), 1.21 (m, 9H).
Reaction SMILES: CNC1CCCCC1NC.O1CCOCC1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1/[CH:24]=[C:25]1/[C:26](=[O:37])[C:27]2[C:32]([CH2:33][CH2:34]/1)=[CH:31][C:30]([O:35][CH3:36])=[CH:29][CH:28]=2.[Na+].[I-:39]>[Cu]I.O>[I:39][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1/[CH:24]=[C:25]1/[C:26](=[O:37])[C:27]2[C:32]([CH2:33][CH2:34]/1)=[CH:31][C:30]([O:35][CH3:36])=[CH:29][CH:28]=2
Reactant: [I-]
Reactant: COc1ccc2c(c1)CC/C(=C\c1ccncc1Br)C2=O
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CC/C(=C\c1ccncc1I)C2=O
Temperature: 110 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
In a Schlenk tube, N,N′-dimethyl-1,2-cyclohexanediamine 85% (32 μL, 0.20 mmol) and dioxane (2 mL) were added to a mixture of CuI (19.2 mg, 0.1 mmol), compound 87 (688 mg, 2.0 mmol) and NaI (600 mg, 4.00 mmol). The Schlenk tube was sealed with a Teflon cap and the reaction mixture was stirred at 110° C. for 24 h. After cooling, the resulting suspension was poured into water (20 mL), and extracted with dichloromethane (3×). The combined organic phases were dried over magnesium sulfate and concentrated to dryness. The product was allowed to crystallize at room temperature. The residue was purified by column chromatography on SiO2 (gradient of EtOAc in petroleum ether) to afford the title compound 88 as a yellow solid (Yield 703.8 mg, 90%).
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:3][C:4]([O:6][CH3:7])=[O:5].[OH:24][CH2:25][CH:26](CO)[OH:27].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:3][C:4]([O:6][CH2:7][CH:25]([CH2:26][OH:27])[OH:24])=[O:5]
Reactant: OCC(O)CO
Reactant: COC(=O)C=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CC(=O)OCC(O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 12 h
Yield: 38.5 %

Procedure:
1.0 g (3.1 mmol) of methyl 3,7,11,15-tetramethylhexadec-2-enoate was added dropwise to a solution of 0.57 g (6.2 mmol) of glycerol and 0.85 g (6.2 mmol) of potassium carbonate in dry N,N-dimethylformamide (3 mL) at 80° C. After the reaction mixture was stirred at 100° C. for 12 hours, 1M hydrochloric acid was added. The resulting solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 459 mg of the title compound (35% yield) as a colorless viscous product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:20][CH:21]([OH:24])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:20][CH:21]([O:24][C:38](=[O:40])[CH3:39])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1
Reactant: CCC(O)CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Yield: 97 %

Procedure:
To a solution of 2-chloro-6-{3-[3-cyclohexyl-3-(2-hydroxybutyl)ureido]-propoxy}quinoline (6.3 g), 4-dimethylaminopyridine (0.1 g) and triethylamine (2.3 g) in methylene chloride (80 ml) is added dropwise with stirring acetic anhydride (1.8 g) at room temperature. The methylene chloride layer is washed successively with diluted hydrochloric acid, water and a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The resultant is concentrated under reduced pressure to remove the solvent to give 2-chloro-6-[3-[3-cyclohexyl-3-(2-acetyloxybutyl)ureido]-propoxy]quinoline (6.7 g) as a colorless oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH:20]=[O:21].O>C1COCC1>[CH:9]1([CH:12]([CH:20]([C:19]2[CH:22]=[CH:23][C:24]([F:25])=[C:17]([F:16])[CH:18]=2)[OH:21])[C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=C(O)CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(C1CC1)C(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of lithium diisopropylamide (2.0M in hexanes, 46.4 mL, 92.8 mmol) in 20 mL of THF at −40° C. under a nitrogen atmosphere was added cyclopropylacetic acid (4.65g in 20 mL of THF, 46.4 mmol), dropwise. The mixture was stirred in the cold for 15 minutes and warmed to ambient temperature. After 1 hour, the reaction slurry was cooled in an ice bath and 3,4-difluorobenzaldehyde (5.2 mL, 47.1 mmol) in 10 mL of THF was added dropwise. The mixture was warmed to ambient temperature and allowed to stir for 2 hours. The mixture was poured into 200 mL of cold water and the layers separated. The organic layer was washed with water (3X), and the combined aqueous layers were washed with ethyl ether (2X), and then acidified with 3N hydrochloric acid. The water layer was extracted with ethyl ether (3X) and the combined ether layers were dried over sodium sulfate, filtered, and evaporated to dryness to yield the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[O:8][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2ccc3ccccc3c2)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
Ethyl 3,5-difluoro-4-hydroxybenzenepropanoate (200 mg, 0.87 mmol) was dissolved in DMF (10 mL). 2-(Bromomethyl)naphthalene (212 mg, 0.96 mmol) and potassium carbonate (132 mg, 0.96 mmol) were added thereto, and then the mixture was stirred at 80° C. for 4 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 80:20) to give the title compound (298 mg, yield 93%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:4]=2[CH2:3]1.C([OH:24])C.[OH-].[K+]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:24])=[O:19])=[CH:16][C:4]=2[CH2:3]1
Reactant: CC(C(N)=O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Reaction time: 6 h
Yield: 64 %

Procedure:
To a mixture of 150 mg of 2-(10,11-dihydro-10-oxodibenzo[b,f]-thiepin-2-yl)-propionamide and 2 ml of ethanol was added 400 mg of potassium hydroxide in 2 ml of water, and the mixture was refluxed with stirring for 6 hours. After the completion of the reaction, ethanol was removed by distillation to obtain a residue to which was added water. The residue was washed with ethyl acetate, and an alkaline layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a brown oil substance, which was chromatographed over 4 g of silica gel and eluted with benzene-chloroform (1:1) to obtain a light yellow oil substance. This substance was recrystallized from benzene-n-hexane, thereby obtaining 96 mg (yield: 64%) of 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as pale yellow crystals having a melting point of 130.5°-131.5° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])C.[OH-].[Na+].CCOCC>ClC1C=CC=CC=1>[Br:13][C:8]1[C:7]2[O:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(COc1ccccc1Br)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: Brc1cccc2ccoc12
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A stirred mixture of polyphosphoric acid (˜5 g) and chlorobenzene (8 mL) was heated at reflux and a solution of 1-(2,2-diethoxyethoxy)-2-bromobenzene (2.62 g, 9.0 mmol) in chlorobenzene (3 mL) was added dropwise over 10 min. The mixture was heated at reflux for 1.5 h. The mixture was allowed to cool to rt and 1M aq NaOH (20 mL) was added, followed by ether (175 mL). The mixture was washed with water (2×20 mL) and brine (20 mL), and dried over MgSO4. Evaporation of the solvent left a residue which was purified by a chromatography on a 140-g silica cartridge eluted with hexanes and a 0-10% EtOAc in hexanes gradient. Appropriate fractions were pooled and concentrated to afford 7-bromobenzofuran (0.65 g, 38% from 2-bromophenol) as a clear colorless oil.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH:7]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[C:6]=2[CH:19]=1.N([O-])=[O:21].[Na+]>S(=O)(=O)(O)O.O>[OH:21][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH:7]([C:10]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])=[O:11])[C:6]=2[CH:19]=1
Reactant: CCCN(CCC)C(=O)C1CSc2ccc(N)cc21
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCN(CCC)C(=O)C1CSc2ccc(O)cc21

Procedure:
11.6 g of 5-amino-2,3-dihydro-N,N-dipropyl-3-benzothiophencarboxamide were dissolved in a mixture of 4 ml of conc. sulphuric acid and 40 ml of water. 3.1 g of sodium nitrite dissolved in 10 ml of water were added dropwise below 10° C. with stirring. After addition the mixture was stirred for further 0.5 hours. The diazonium solution was then added carefully to a pre-heated solution of 50 ml of conc. sulphuric acid in 40 ml of water at 115°-120° C. The resulting mixture was poured onto ice and subsequently extracted with dichloromethane. Yield of the title compound as a semicrystalline product: 8.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([OH:23])CCC>Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:23])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CCCCO
Reactant: CCCOc1ccccc1-c1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: O
Product: CCCOc1ccccc1-c1nc(O)cc(Cl)n1

Procedure:
A stirred solution of 4,6-dichloro-2-(2-propoxyphenyl)pyrimidine (16.68 g) in concentrated hydrochloric acid (40 ml), n-butanol (80 ml) and water (40 ml) was heated under reflux for 3 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was washed with water and diethyl ether and recrystallized from isopropanol to yield the title compound, 8.46 g, m.p. 115.5°-116.5° C. A sample (1 g) of this material was recrystallized twice from isopropanol to yield the pure title compound, 0.42 g, m.p. 118°-118.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c(Cl)nc(N)nc1OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1OCc1ccccn1

Procedure:
From 2-amino-4-chloro-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. ES-MS m/e (%): 356 (MNa+, 50), 334 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:40][O:41][CH3:42])[C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[N:3]([CH2:40][O:41][CH3:42])[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])[C@@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: O
Solvent: CC(C)OC(C)C
Product: COCN1C(C)=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 1.2 g of bis(pivaloyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 1 or 2 as a substrate. To the substrate solution was added 300 mg of Lipase B, and the reaction system was stirred at room temperature for 3 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 0.9 g (yield: 95%) of (S)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccc(Br)cc1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1ccc(Br)cc1)C2
Yield: 63.9 %

Procedure:
A mixture of 3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.049 ml), water (0.049 ml) and ethanol (30 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 35) (0.25 g) as colorless crystals.