Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]N1C(C)(C)CCC[C:3]1(C)C.[CH3:12][O:13][C:14]1[C:23]2[C:18](=[C:19]([CH3:28])[C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[C:16]([C:29]([OH:31])=[O:30])[CH:15]=1.CI.O>C1COCC1>[CH2:28]([C:19]1[C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=[C:23]2[C:18]=1[CH:17]=[C:16]([C:29]([OH:31])=[O:30])[CH:15]=[C:14]2[O:13][CH3:12])[CH3:3]
Reactant: COc1cc2c(OC)cc(C(=O)O)cc2c(C)c1OC
Reactant: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CCc1c(OC)c(OC)cc2c(OC)cc(C(=O)O)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
LTMP (7.5 mmol) is added at 0° C. to a solution of 4,6,7-trimethoxy-8-methyl-2-naphthoic acid (0.414 g, 1.5 mmol) in anhydrous THF (30 mL). The mixture is stirred for 2 h at 0° C. then trapped with MeI (0.943 mL, 15 mmol). After 2 h at 0° C., the reaction mixture is heated to ambient temperature and then hydrolysed with 30 mL of water. The aqueous phase is washed with ethyl ether (2×20 mL), acidified with 2M HCl (pH 1-2), then extracted with ethyl ether (3×30 mL). The combined organic phases are dried over MgSO4, filtered, then concentrated under reduced pressure. The residue is recrystallized (cyclohexane/ethyl acetate) to give 8-ethyl-4,6,7-trimethoxy-2-naphthoic acid (3) (0.392 g, 90%). 1H NMR (200 MHz, acetone-d6): 8.22 (s, 1H), 7.44 (s, 1H), 7.29 (s, 1H), 3.96 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.02 (q, 2H, CH2), 1.16 (t, 3H, CH3). 13C NMR (100 MHz, DMSO-d6): 167.8, 154.2, 153.2, 146.9, 132.9, 127.0, 126.5, 125.0, 118.5, 102.6, 99.6, 60.6, 55.6, 55.4, 18.6, 15.4. IR (cm−1): 2940, 2826, 2637, 1682, 1464. SMHR, [M+H]+ calculated for C16H19O5: 291.1232. Found: 291.1230.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[SH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: OCCCCCCS
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(C)cc(SCCCCCCO)c1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), 6-mercaptohexanol (137 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 6-(3,5-dimethylphenyl)mercaptohexanol (212 mg, 92% yield) as colorless oil. Column chromatographic solvent (hexane/ethyl acetate=3/1). Rf=0.4 (hexane/ethyl acetate=2/1). 1H NMR (CDCl3, 300 MHz) δ 6.92 (s, 2 H), 6.78 (s, 1 H), 3.62 (q, 2 H, J=4.8 Hz), 2.90 (t, 2 H, J=7.2 Hz), 2.27 (s, 6 H), 1.30-1.68 (m, 9 H). 13C NMR (CDCl3, 75 MHz) δ 138.6, 136.5, 127.8, 126.7, 63.2, 33.8, 33.0, 29.5, 28.9, 25.7, 21.7. IR (neat, cm−1) 3320 (broad), 3060, 3022, 2972, 2847. MS (EI) m/z (relative intensity) 238 (40), 138 (100). Anal Cald for C14H22OS, Cald. C, 70.54; H, 9.30. Found C, 70.29; H, 9.33.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15](Cl)=[O:16])[CH2:12][C:11]2([Cl:14])[Cl:13])=[CH:6][CH:5]=1)[CH3:2].[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][OH:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][O:29][C:15]([C:10]1([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH2:12][C:11]1([Cl:14])[Cl:13])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOc1ccc(C2(C(=O)Cl)CC2(Cl)Cl)cc1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccc(C2(C(=O)OCc3ccc(F)c(Oc4ccccc4)c3)CC2(Cl)Cl)cc1
Yield: 85.2 %

Procedure:
5.87 g (0.02 mole) of (±)-1-(4-ethoxyphenyl)-2,2-dichlorocyclopropane-1-carboxylic acid chloride and 4.36 g (0.02 mole) of 3-phenoxy-4-fluoro-benzyl alcohol were dissolved in 100 ml of anhydrous toluene, and 3 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20° to 25° C., while stirring. The reaction mixture was then stirred at 25° C. for a further 3 hours. It was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.1 g (85.3% of theory) of (±)-1-(4-ethoxy-phenyl)-2,2-dichlorocyclopropane- 1-carboxylic acid 3-phenoxy-4-fluorobenzyl ester were obtained as a yellow oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[F:28])[CH:12]=2)=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:30][NH2:31]>C(O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([F:28])=[C:21]([C:13]2[CH:12]=[C:11]([NH:10][C:9]3[C:4]([C:3]([NH:31][CH3:30])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:26]=1
Reactant: CN
Reactant: COC(=O)c1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Solvent: CCO
Product: CNC(=O)c1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Reaction time: 16 h

Procedure:
14.4 mg 4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-ylamino]-nicotinic acid methyl ester were treated with 250 μl of 33% methylamine in ethanol at 40° C. for 5 min and then at ambient temperature for 16 hrs. After evaporation the product was digerated with ether and dried to give 15.7 mg 4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-ylamino]-N-methyl-nicotinamide as a yellowish powder with Rt˜1.47 min and correct mass M+H˜408.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH3:20]>CN(C=O)C.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]2[CH3:1])[CH3:20])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Reactant: CC(Br)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C(C)c2ccc(Cl)cc2)c2ccccc12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of ethyl 2-methyl-1H-indole-3-carboxylate (250 mg, 1.23 mmol) in anhydrous DMF (2 mL) was added NaH (60% in mineral oil, 74 mg, 1.85 mmol) at room temperature under N2. The reaction was stirred at 50-60° C. for 30 min. Then the reaction was cooled to 0° C. and a solution of 1-(1-bromoethyl)-4-chlorobenzene (from Example 35; 400 mg, 1.85 mmol) in DMF (1 mL) was added drop-wise. The reaction was stirred at room temperature overnight. Then the mixture was diluted with water and extracted with EtOAc. The organic extract was combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography using an eluent of petroleum ether/EtOAc (60:1) to afford the title compound as a yellow oil. (210 mg, yield 50.1%) 1H NMR (Methanol-d4, 400 MHz) δ 8.07-8.04 (m, 1H), 7.33-7.29 (m, 2H), 7.16-7.15 (m, 2H), 7.14-7.08 (m, 1H) 7.07-6.96 (m, 2H), 5.97 (q, J=7.2 Hz, J2=14.4 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 2.76 (m, 3H), 1.95 (d, J=6.8 Hz, 3H), 1.43 (d, J=14.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]([C:12](=O)[CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:18][C:19]([NH2:26])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CN1CCOCC1>C(O)(C)C>[NH2:18][C:19]1[NH:26][C:12]([CH3:13])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COC(=O)C(=Cc1ccc(C)cc1)C(C)=O
Reactant: CCOC(=O)C=C(N)N
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)NC(C)=C(C(=O)OC)C1c1ccc(C)cc1
Yield: 84.7 %

Procedure:
A mixture of (E and Z) methyl 2-(4-methylbenzylidene)-3-oxobutanoate (887 mg, 4.06 mmol), ethyl 3,3-diaminoacrylate, hydrochloride (677 mg, 4.06 mmol), and N-methylmorpholine (447 μl, 4.06 mmol) in Isopropanol (7682 μl) was refluxed overnight. The reaction was then concentrated and purified with column chromatography (0-100% EtOAc/Hexane) to afford 3-ethyl 5-methyl 2-amino-6-methyl-4-(p-tolyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.1349 g, 3.44 mmol, 85% yield) as pale yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15 (d, J=8.0 Hz, 2 H), 7.01 (d, J=7.8 Hz, 2 H), 5.90 (br. s., 2 H), 5.64 (s, 1 H), 4.86 (s, 1 H), 4.07 (q, J=7.1 Hz, 2 H), 3.64 (s, 3 H), 2.32 (s, 3 H), 2.27 (s, 3 H), 1.23 (t, 3 H); LCMS (m/z) ES+=331 (M+1).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:18]=[C:17]3[C:12]([N:13]=[CH:14][CH:15]=[N:16]3)=[C:11]([NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]3)[CH:10]=1)[CH2:2]2.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[CH:18]=[C:17]3[C:12]([N:13]=[CH:14][CH:15]=[N:16]3)=[C:11]([NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]3)[CH:10]=1)[CH2:4]2.[F:37][C:36]([F:39])([F:38])[C:34]([O-:40])=[O:35]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2cc(N3CC4CCC(C3)O4)cc3nccnc23)CC1
Solvent: ClCCl
Product: NC1CCC(Nc2cc(N3CC4CCC(C3)O4)cc3nccnc23)CC1
Product: O=C([O-])C(F)(F)F
Reaction time: 2 h

Procedure:
As shown in step 4-iii of Scheme 4, to a solution of compound 1007 (141 mg, 0.295 mmol) in CH2Cl2 (2.5 mL) was added TFA (656 mg, 443 μL, 5.75 mmol) at RT. The resulting black solution was stirred for 2 hours and then the reaction was quenched by the addition of saturated NaHCO3 until the black color gradually turned into an orange color. The reaction mixture was extracted with CH2Cl2 (3×) and the combined organic extracts were dried over Na2SO4 and evaporated to dryness to provide N1-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinoxalin-5-yl)cyclohexane-1,4-diamine, trifluoroacetate (compound 1008): ESMS (M+H+)=354.20. This material was used in subsequent reactions without any further purification.
Reaction SMILES: C([N:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([S:23][C:24]#[N:25])[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=1)C(=O)O)(C)(C)C.FC1C=CC2N=CN(C3N=C(SC#N)C([N+]([O-])=O)=CN=3)C=2C=1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52].C(Cl)Cl>>[F:15][C:12]1[CH:11]=[C:10]([NH:16][C:17]2[N:22]=[C:21]([S:23][C:24]#[N:25])[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=2)[C:9]([NH2:5])=[CH:14][CH:13]=1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: CC(C)(C)N(C(=O)O)c1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Agent: N#CSc1nc(-n2cnc3ccc(F)cc32)ncc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CSc1nc(Nc2cc(F)ccc2N)ncc1[N+](=O)[O-]

Procedure:
6-Fluoro-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole tert-Butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (4.06 g) was dissolved in 30% TFA/DCM (50 mL) and stirred until no starting material remained (90 min). The reaction solvents were removed, to yield crude 5-fluoro-N1-(5-nitro-4-thiocyanatopyrimidin-2-yl)benzene-1,2-diamine (MH+=306) as a TFA salt that was used immediately as such in the next step. Trimethyl ortho formate (15 mL) and MeOH (100 mL) were added to the above diamine and the solution was stirred for 16 hrs. The resulting orange ppt was collected via filtration, washed with MeOH and dried under reduced pressure to yield the titled compound (2.62 g), 1H-NMR (400 MHz, d6-DMSO) δ 9.2 (s, 1H), 9.1 (s, 1H), 8.5 (dd, 1H), 7.8 (dd, 1H), 7.3 (dd, 1H) ppm; MH+=317.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:11][CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(OCC)(=O)CC(C)=O.[Br:21]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C1C=CC=CC=1>[Br:21][C:7]1[C:6](=[O:8])[N:5]2[CH:9]=[CH:10][S:11][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(=O)n2ccsc2n1
Solvent: CCOC(=O)CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Cc1nc2sccn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 127°-129° C., (4 g), prepared according to Example 1 using ethyl acetoacetate, dissolved in benzene (100 ml) was reacted with N-bromo-succinimide (4.7 g) under stirring at room temperature for 1 hour. The precipitate was dissolved by adding chloroform and the solution was washed with water: evaporation in vacuo to dryness and crystallization of the residue from methanol gave 6-bromo-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 233°-234° C. (5.1 g), which was reacted with 3-pyridine-carboxaldehyde (3.4 g) in methanol (190 ml) in the presence of sodium methoxide (2.2 g) under stirring at the reflux temperature for 2 hours. After cooling the precipitate was filtered and washed with water until neutral: crystallization from CH2Cl2 -methanol gave 5.18 g of 6-bromo-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 208°-209° C., NMR (CDCl3) δppm: 6.99 (d) (1H, C-2 proton), 7.33 (dd) (1H, C-5 pyridyl proton), 7.59 (d) (1H, β-ethenyl proton), 7.95 (d) (1H, α-ethenyl proton), 7.96 (d) (1H, C-3 proton), 7.98 (m) (1H, C-4 pyridyl proton), 8.58 (bd) (1H, C-6 pyridyl proton), 8.82 (bs) (1H, C-2 pyridyl proton); JHαHβ =16 Hz.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.O>[CH3:31][O:23][C:22](=[O:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: O=C(O)CCOCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)CCOCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 30 h

Procedure:
35 mg of 3-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]propanoic acid was dissolved in 0.4 ml of N,N-dimethylformamide, mixed with 28 mg of cesium carbonate and 50 μl of methyl iodide and stirred for 30 hours. Then, it was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [CH2:1]([N:7]([CH2:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.Cl>CO.O1CCCC1.[OH-].[Na+]>[CH2:1]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)=[CH:38][CH:39]=1)[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(Cc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Methyl 3-{4-[(4-{[hexyl(4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}propanoate (250 mg) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound (220 mg, yield 90%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:27][C:28]#[CH:29].CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH2:29][C:28]#[CH:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCCl
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(C)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC=C(C(=O)NCCc1ccc(OC)c(OC)c1)c1ccc(C)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
Five hundred miligrams (500 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide (1.47 mmol), 0.11 g (1.47 mmol) of 3-chloropropyne and 5 ml of anhydrous N,N-dimethylformamide were mixed and 64 mg (1.61 mmol) of 60% sodium hydride was added thereto at 0-5° C. The mixture was stirred at 0-10° C. for 30 minutes and then stirred at room temperature. Water was added to the reaction mixture, followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=1:1) to give 180 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(2-propynyloxy)-2-(4-methylphenyl)acrylamide (the present compound 1182).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.[CH3:12][I:13]>CC(C)=O>[IH:13].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[NH:11])[S:10][CH3:12])=[CH:6][CH:7]=1
Reactant: CI
Reactant: NC(=S)Cc1ccc(Cl)cc1
Solvent: CC(C)=O
Product: CSC(=N)Cc1ccc(Cl)cc1
Product: I

Procedure:
A solution of 4-chlorophenyl(thioacetamide) (14.8 g.) and methyl iodide (32 g.) in acetone (40 ml.) was heated to reflux for 20 minutes. The mixture was cooled and filtered to give pure methyl 4-chlorophenyl(thioacetimidate) hydriodide, m.p. 172°-174°.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[O:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH:5]2[O:4][CH:3]([CH2:2][O:1][S:16]([C:13]3[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=3)(=[O:18])=[O:17])[CH2:7][CH2:6]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCC1CCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34.0 g (261 mmol) of 2,5-bis(hydroxymethyl)tetrahydrofuran are dissolved in 260 ml of dichloromethane. A solution of 99.0 g (521 mmol) of p-toluenesulfonyl chloride in 52 ml of pyridine and 130 ml of dichloromethane is added dropwise thereto. After stirring at room temperature for 24 hours, the precipitate is filtered off with suction and washed with dichloromethane. The filtrate and the washing phases are combined, washed with dilute hydrochloric acid and then with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The crude product is recrystallized from ethanol.
Reaction SMILES: [Mg].[CH3:2][CH2:3][CH2:4]Br.[OH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[Cl-].[NH4+]>O1CCCC1>[OH:16][C:9]([C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=1[OH:6])([CH2:2][CH2:3][CH3:4])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=C(Cn1ccnc1)c1ccccc1O
Reactant: CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)(Cn1ccnc1)c1ccccc1O
Yield: 28.4 %

Procedure:
To a tetrahydrofuran solution of Grignard reagent prepared from 73 mg of magnesium and 369 mg of n-propyl bromide, 202 mg of 1-(2-hydroxyphenacyl) imidazole (II) was added dropwise under ice-cooled conditions while stirring, and the mixture was refluxed for 2 hours. After ice-cooling, an aqueous solution of ammonium chloride was added to the mixture to decompose the surplus amount of the Grignard reagent and addition salts produced in the reaction. Extraction with chloroform was performed on this mixture and the chloroform layer was washed with water, followed by drying over anhydrous magnesium sulfate. The extract thus obtained was purified by means of silica gel column chromatography (eluent: chloroform) to produce 70 mg of the title compound at a yield of 29%.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[C:28]1[CH:41]=[CH:40][C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1>>[ClH:19].[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH2:21][S:20][C:15]2[C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[CH:36][CH:35]=1)(=[O:33])[C:31]1[CH:40]=[CH:41][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Product: Cl
Product: O=C(c1ccccc1)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1

Procedure:
Use a method similar to the Example 380 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with 4-(bromomethyl)benzophenone. Purify by preparative reverse phase HPLC (Column: Xterra Prep RP18 19×250 mm; Solvent A: 10 mM aqueous ammonium carbonate, Solvent B: acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/ruin). Use a method similar to the General Procedure 2-2 to give the title compound as a white solid. MS (ES+) m/z: 408 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:12][CH2:11]CC2)=[C:4]([CH:17]=O)[CH:3]=1.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[C:4](/[CH:17]=[C:24]2\[C:25](=[O:29])[NH:26][C:27]3[C:23]\2=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=3)[CH:3]=1
Reactant: N#CC1(COc2ccc(Cl)cc2C=O)CCCC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: N#CC1(COc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 53.4 %

Procedure:
In a manner similar to the method described in Example 1b, 1-(4-chloro-2-formyl-phenoxymethyl)-cyclopentanecarbonitrile (4.7 g, 20 mmol) was reacted with 6-chlorooxindole (2.78 g, 16.67 mmol) and pyrrolidine (1.54 g, 21.67 mmol) in methanol to give the title compound as a yellow solid (3.43 g).
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].CC(C)([O-])C.[Na+]>C(O)CCC>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][CH2:22][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[S:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Reactant: CN(C)CCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-(2-phenylamino-thiazol-5-yl)-phenol (35 mg, 0.130 mmol), 1-chloro-3-dimethylaminopropane hydrochloride (27 mg, 0.170 mmol, 1.3 equiv), and sodium tert-butoxide (29.6 mg, 0.299 mmol, 2.3 equiv) in 1-butanol (0.2 mL) is heated to 100° C. (using a preheated oil bath) for 3.5 h. The reaction mixture is allowed to cool to RT and concentrated in vacuo. Purification of the crude material by silica gel (10 g) column chromatography (CH2Cl2/MeOH, 90/10→80/20) affords the title compound as a reddish solid: ES-MS: 354.0 [M+H]+; single peak at tR=6.27 min (System 1); Rf=0.09 (CH2Cl2/MeOH, 90/10).