Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1>ClCCCl>[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:8](=[O:10])[CH3:9])[CH2:30]1
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc(C2CCCC(N)C2)c(OCOC)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2CCCC(NC(C)=O)C2)c(OCOC)c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Triethylamine (15 μl) and acetic anhydride (10 ml) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexylamine (29 mg) in anhydrous 1,2-dichloroethane (2 ml) at room temperature. After 0.5 hr, the reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml) and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (22 mg, 66%) and a mixture of diastereoisomers; m/z (ES+) 338 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=O)[N:12]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]1=[O:27].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[S:37])[N:12]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]1=[O:27]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)Cn1c(=O)c2ccccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(=S)c2ccccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 70.9 %

Procedure:
Into 100 ml of toluene was dissolved 3.80 g of ethyl 1-(2,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetate, and 5.70 g of Lawesson's reagent were added. After refluxed for 7 hours and 30 minutes, 1.90 g of Lawesson's reagent were further added and, after refluxed for 5 hours, solvent was distilled off. To the residue were added 10 ml of ethanol for washing, then it was further recrystallized from ethanol to obtain 2.80 g of title compound. m.p. 138°-139° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.ClCCl.C(N(CC)CC)C>CO>[C:13]([O:12][C:11]([NH:10][CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]([O:12][CH3:13])=[O:17])[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(C)NC(=O)OC(C)(C)C)c1
Reaction time: 17 h
Yield: 150.4 %

Procedure:
To a solution of tert-butyl 1-(3-bromophenyl)ethylcarbamate (300 mg, 1 mmol) in methanol (10 mL) was added [1,1′-bis(diphenyl-phosphino)ferrocene]palladium [II]chloride, 1:1 complex with dichloromethane (146 mg, 0.2 mmol) then triethylamine (0.28 mL, 2 mmol). The mixture was evacuated and backfilled with carbon monoxide four times and was then heated to reflux and stirred under an atmosphere of carbon monoxide for 17 hours. After this time the mixture was filtered through Celite to give a brown solid which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give methyl 3-{1-[(tert-butoxycarbonyl)amino]ethyl}benzoate (210 mg, 75%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=O)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=O)C.[CH3:27][NH:28][NH2:29].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:20]([C:6]12[C:4](=[O:3])[N:28]([CH3:27])[N:29]=[C:11]1[CH2:10][CH2:9][NH:8][CH2:7]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CNN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1N=C2CCNCC2(Cc2ccccc2)C1=O
Temperature: 65 °C
Reaction time: 7.5 h
Yield: 84.8 %

Procedure:
To a solution of 3-benzyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3ethyl ester (1935.97 g, 5.36 moo in toluene (9700 mL) was added methylhydrazine (299.2 mL, 5.63 mot), followed by acetic acid (325 mL, 5.68 mol) slowly at about 8° C. The reaction mixture was heated slowly to about 65° C. and stirred for about 7.5 hours. After cooling to room temperature, the organic layer was washed with 10% sodium bicarbonate, water and saturated NaCl solution and concentrated in vacuo to a low volume. The reaction was repeated at same scale, twice. The concentrated product solutions from the three reactions were combined and mixed with IPE (50 L), cooled to about 0° C., HCl gas was introduced repeatedly and stirred at room temperature overnight until the deprotection was complete. The mixture was concentrated in vacuo to about half of the original volume, methylene chloride (24 L) was added, followed by NH4OH (22 L). The mixture was then extracted with methylene chloride and concentrated to a low volume (6 to 7 L). Hexane (20 L) was added and the mixture was cooled to about 1520° C. The free base product was collected as crystals and dried under vacuum (2985 g total, yield 84.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.[P:24](Cl)([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>O1CCOCC1>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH2:20][CH3:21])=[CH:13][CH:14]=2)[N:9]([CH2:22][CH3:23])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][P:24](=[O:25])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:7][CH:6]=1)#[N:18]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(CC)c2c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(C#N)c(-c3ccc(NP(=O)(OCC)OCC)cc3)n(CC)c2c1
Temperature: 80 °C
Yield: 50.6 %

Procedure:
A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (148 mg, 0.484 mmol), diethyl chlorophosphate (0.086 mL, 0.58 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in 1,4-dioxane (5 mL) is stirred at ambient temperature for 12 hours, then heated to 80° C. for an additional 24 hours. The solution is cooled and poured into 50 mL of ethyl acetate. This is washed with water and saturated brine (50 mL each), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by flash chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford diethyl [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate (108 mg, 0.245 mmol, 51%) as a white powder after evaporation.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: COC(=O)C1Sc2cc(C)ccc2OCC1=O
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(C)ccc2OCC1=O

Procedure:
Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate (1.7 g) was reacted with 3-(4-phenylpiperazin-1-yl)propyl chloride in the same manner as in Reference Example 1 to give 0.9 g of colorless, oily methyl 7-methyl-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N:8]1[C:13]2[C:14]([C:17]([OH:19])=[O:18])=[CH:15][S:16][C:12]=2[CH:11]=[N:10][CH:9]=1>ClCCl.CO>[CH3:1][O:18][C:17]([C:14]1[C:13]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[S:16][CH:15]=1)=[O:19]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1csc2cncnc12
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1csc2cncnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylsilyldiazomethane (2 M in hexane, 1 mL) was added to a suspension of thieno[3,2-d]pyrimidine-7-carboxylic acid (50 mg) in a mixture of dichloromethane and methanol (95/5, 1 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated under reduced pressure and the crude residue was purified by flash chromatography (DCM/MeOH, 97/3) to give 40 mg of thieno[3,2-d]pyrimidine-7-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=2[N:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7](/[CH:23]=[CH:22]/[C:21]([O:25][CH3:26])=[O:24])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(O)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: C=CC(=O)OC
Product: COC(=O)/C=C/c1ccc2nc(N)c3ncn(CC(C)(C)O)c3c2c1

Procedure:
The method described in Example 15 Part E can be used to couple 1-(4-amino-8-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol with methyl acrylate to provide Methyl(2E)-3-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enoate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:21]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]4)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].[CH:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:41])[CH3:40].[CH3:48]CN(C(C)C)C(C)C>CN(C=O)C>[CH:39]([N:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]([C:12]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]5)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:9]=[CH:10][CH:11]=2)=[O:4])[CH2:44][CH2:43]1)([CH3:41])[CH3:40]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CCl)c4)nc4ccccc34)ccc21
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(CCC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A suspension of tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (112 mg, 0.223 mmol), 1-isopropylpiperazine (52 mg, 0.406 mmol), DIEA (51 mg, 0.402 mmol) in DMF (2 mL) was stirred at 75° C. for 4 h. The reaction mixture was cooled to RT and the residue was poured into ice-water. The resulting white solid was filtered and dried for several hours under high vacuum. The crude product was purified by prep TLC using CH2Cl2:MeOH, (9:1) as the mobile phase to afford tert-butyl 5-(2-(3-(3-(4-isopropylpiperazin-1-yl)propanamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (60 mg, 0.094 mmol, 42%)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[C:4](=[O:14])[C:3]=1[C:15](OCC)=[O:16].C(N(C(C)C)C(C)C)C.Cl.[NH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>O1CCOCC1.CCOC(C)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[C:4](=[O:14])[C:3]=1[C:15]([NH:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:16]
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O
Temperature: 80 °C
Yield: 49.5 %

Procedure:
Ethyl 4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (425 mg, 1633 μmol) was dissolved in 1,4-dioxane (1633 μL) and N-ethyl-N-isopropylpropan-2-amine (853 μL, 4898 μmol). tert-Butyl 2-aminoacetate hydrochloride (411 mg, 2449 μmol) was added, and the mixture was heated at 80° C. for 4 hours. The reaction mixture was then cooled, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (279 mg) as a white solid after purification via preparatory LC. MS (m/z)=290(M+H-tBu)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26]([NH:29][C:30]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:28])[CH3:27]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:33]2[CH2:32][CH2:31][C:30]([NH:29][C:26](=[O:28])[CH3:27])([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:35][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: COc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Product: COc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(NC(C)=O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 225.9 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.38 g) was coupled to 4-acetamido-4-phenylpiperidine (0.29 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.7 g); mp 182°-210° C. (d); MS: m/z=580(M+1); NMR(CD3OD): 2.1 (s,3), 2.3 (m,2), 2.9 (m,1), 2.6 (m,2), 2.7-3.0 (m,3), 3.1-3.3 (m,7), 3.6-3.7 (m,3), 3.95 (s,3), 4.9 (m,1), 6.7 (dd,1, J=8, 2), 6.9 (d,1, J=2), 7.2 (d,1, J=2), 7.2-7.4 (m,8), 7.8 (d,1, J=8), 7.8-8.1 (m,3). Analysis for C32H34Cl2N3O3.HCl.H2O: Calculated: C, 60.53; H, 6.03, N, 6.62; Found: C, 60.47; H, 5.93; N, 6.43.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH3:14]>>[C:1]12([NH:11][C:12]([NH2:14])=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Product: NC(=S)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-adamantyl isothiocyanate (4.83 g, 25.0 mmol, Aldrich) and ammonia (0.5 M solution in 1,4-dioxane, 100 mL, 50 mmol) was stirred at ambient temperature for 48 h. The solvents were removed in vacuo to give the title compound as a white solid. MS m/z: 211.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C@@H:4]([CH2:6][OH:7])[NH2:5].S=[C:11]1[CH2:15][S:14][C:13](=[O:16])[NH:12]1>C(O)C>[O:16]=[C:13]1[N:12]=[C:11]([NH:5][C@@H:4]([C:3]([N:2]([CH3:9])[CH3:1])=[O:8])[CH2:6][OH:7])[CH2:15][S:14]1
Reactant: CN(C)C(=O)[C@H](N)CO
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CN(C)C(=O)[C@@H](CO)NC1=NC(=O)SC1
Yield: 70.8 %

Procedure:
To a solution of N,N-dimethyl-D-serinamide (645 mg) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (650 mg), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (799 mg).
Reaction SMILES: [CH3:1][C:2](CCCC(C)COC1CCCCO1)=[CH:3][CH2:4][CH:5]([O:15][C:16](=[O:18])[CH3:17])C(C)=CC1N=C(C)SC=1.C(OC(CC=C(C)CCCC(C)COC1CCCCO1)C(=O)C)(=[O:34])C>>[C:16]([O:15][CH2:5][C:4](=[O:34])[CH2:3][CH2:2][CH3:1])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(CC=C(C)CCCC(C)COC1CCCCO1)C(C)=O
Reactant: CC(=O)OC(CC=C(C)CCCC(C)COC1CCCCO1)C(C)=Cc1csc(C)n1
Product: CCCC(=O)COC(C)=O

Procedure:
MS (CI): m/z (%)=43 (39), 45 (22), 57 (34), 91 (19), 119 (10), 145 (9), 173 (9), 189 (14), 190 (78), 191 (18), 233 (45), 246 (22), 251 (100), 252 (11), 307 (44).
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)(=O)C>[S:13]([C:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])([OH:3])(=[O:2])=[O:1]
Reactant: CCOC(=O)C1=C(S)CCCCC1
Reactant: O
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCCCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
Sodium peroxyborate tetrahydrate (6.8 g) was admixed with acetic acid (37 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-1-cycloheptene-1-carboxylate (3.0 g, synthesized in accordance with Tetrahedron, Vol.30, p.3753 (1974)) in acetic acid (15 ml) was added dropwise over 1 hour. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (100 ml) and stirred at room temperature for 3 hours and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (10 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (70 ml) and stirred at room temperature for 1 hour. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (100 ml) and the pellet which precipitated was isolated by a filtration to obtain ethyl 2-sulfo-1-cycloheptene-1-carboxylate as a white powder (3.4 g) containing inorganic substances. This (1.5 g) was dissolved in thionyl chloride (4 ml) and then stirred at 80 to 90° C. for 15 hours. The mixture was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (30 ml). The solution obtained was washed with saturated brine (30 ml×2) and then dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by flash chromatography on silica gel column (eluent: ethyl acetate/hexane=1/8) to yield ethyl 2-chlorosulfonyl-1-cycloheptene-1-carboxylate (590 mg) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10].[Cl-].[K+].C([O-])([O-])=O.[K+].[K+].C([O:21][CH:22](OCC)[CH:23]=[CH2:24])C>CN(C=O)C>[Cl:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:24]=[CH:23][CH:22]=[O:21]
Reactant: COc1ccc(Br)c(Cl)c1
Reactant: C=CC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=CC=O)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
To a mixture of 4-bromo-3-chloro anisole (35 g, 0.159 mol), KCl (11.9 g, 0.160 mol, 1 eq.), K2CO3 (33 g, 0.238 mol, 1.5 eq) in 400 mL DMF in a sealed tube was added acrolein diethylacetal (73 mL, 0.479 mol, 3 eq.) and Bu4NOAc (96 g, 0.318 mol, 2 eq.). N2 was bubbled through the mixture and Pd(OAc)2 (1.1 g, 4. mmol, 3 mol %) was added. The reaction mixture was heated in an oil bath for 6 hr at 100° C. then cooled in an ice-bath. 300 mL of water was then added, followed by 500 mL of 1N HCl. The ice-bath was removed and the mixture was stirred for 30 min. The solution was extracted with ethyl acetate once then with diethyl ether 3 times. The combined organic layer washed with water, brine, dried over MgSO4, filtered and concentrated to provide the crude product which was recrystallized from hot ethyl acetate-hexanes to provide 15.5 g of crystalline 3-(2-chloro-4-methoxy-phenyl)-propenal. The mother liquor was concentrated and chromatographed with 10% ethyl acetate to provide another 5.6 g of 3-(2-chloro-4-methoxy-phenyl)-propenal.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N=C=N[CH2:19][CH2:20][CH2:21]N(C)C)C.ON1C2C=CC=C[C:29]=2N=N1.C(=O)([O-])O.[Na+]>C(O)(C)(C)C.C(N(CC)CC)C>[OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:20]([CH3:21])([CH3:29])[CH3:19])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a solution of 2-hydroxy-4-nitrobenzoic acid (5.0 g) in tert-butyl alcohol (100 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.4 g), 1-hydroxybenzotriazole (3.7 g) and triethylamine (7.6 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.3 g).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]1=O)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1.CO>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]1=[S:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cccc(OC)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCn1cccc(OC)c1=S
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 1-butyl-3-methoxy-2-pyridone (2-034-02) (6.4 g) in toluene (150 mL) was added Lawesson's reagent (16.8 g), and the reaction mixture was heated under reflux. After the reaction mixture was stirred for 3 h, to the reaction mixture was added methanol (100 mL), and the reaction mixture was stirred for 30 min. After the solvent was evaporated under reduced pressure, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1-butyl-3-methoxypyridine-2-thione (2-034-03) (5.6 g, 80%) as an oil.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.CO[CH:16](OC)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1.ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:9][C:8]1[C:6]2[O:7][CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[O:5][C:4]=2[CH:3]=[C:2]([C:1]([O:12][CH3:13])=[O:11])[CH:10]=1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: COc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(O)c2c(c1)OC(c1ccc(OC)cc1)O2
Yield: 52.4 %

Procedure:
To a suspension of methyl gallate (10 g, 54.3 mmol) in toluene (25 ml), p-toluensulfonic acid (29 mg) and p-anisaldehyde dimethylacetal (11.56 ml, 67.88 mmol) were added. The reaction was refluxed for 1.5 hours with continuous removal of water. The mixture was diluted with dichloromethane (70 ml) and washed with a saturated aqueous NaHCO3 solution (100 ml) and extracted with ethyl acetate (3×50 ml) The organic layer was washed with water (100 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was crystallized by n-hexane. The product (8.6 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1c(F)cccc1Cl
Product: O=c1[nH]c2nccc(Nc3c(F)cccc3Cl)c2c2ccccc12
Yield: 69.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-chloro-6-fluoroaniline (82 mg, 0.56 mmol) to provide 207 (101 mg, 69% yield) as a white solid. LC-MS (M+H=340, obsd.=340).