Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BrH:13].BrBr.S([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[Br:13][CH2:11][C:10]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1)=[O:12]
Reactant: CC(=O)c1cnn(C(C)(C)C)c1
Reactant: Br
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)n1cc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.66 g (10.0 mmol) 1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone in 18 ml dichloromethane is added 5.86 μl (0.10 mmol) of a 32% solution of hydrobromic acid in acetic acid. Then a solution of 3.20 g (20 mmol) bromine in 5 ml dichloromethane is added dropwise. The reaction mixture is stirred for 3 days at room temperature. Then aqueous sodium hydrogen sulfite is added to reduce the excess bromine. The reaction mixture is reduced in volume under vacuum and it is then partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-bromo-1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone as yellow oil, which crystallizes on standing; HPLC/MS 2.28 min (B), [M+H] 245/247.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:14]2[C:15](=[O:29])[N:16](CC3C=CC(OC)=CC=3)[CH2:17][CH2:18][O:19][C:13]=2[N:12]=[CH:11][N:10]=1.C1(OC)C=CC=CC=1>>[NH2:8][C:9]1[C:14]2[C:15](=[O:29])[NH:16][CH2:17][CH2:18][O:19][C:13]=2[N:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CN2CCOc3ncnc(N)c3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1ncnc2c1C(=O)NCCO2
Temperature: 90 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
TFA (15 mL, 195 mmol) was added to a solution of 100E (2.5 g, 8.32 mmol) in anisole (1 mL, 9.15 mmol) at 0° C., and the mixture was stirred for 2 h at 90° C. for 16 h in sealed-tube. The reaction mixture was concentrated to get the residue and it was triturated with 25 mL (50%) ethyl acetate in hexane to afford to afford title compound (1.0 g, 66.7%) as an off-white-solid. 1H NMR (400 MHz, DMSO-d6-D2O): δ 8.26 (s, 1H), 4.57 (t, J=3.9 Hz, 2H), 3.47 (t, J=4.2 Hz, 2H).
Reaction SMILES: O.[Cl:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:4]=1[NH2:5].[C:14](Cl)(Cl)=[S:15].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:4]=1[N:5]=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(N=C=S)c(Cl)c1

Procedure:
A 12-L, 3-neck, round bottom flask equipped with a mechanical stirrer, a thermometer and a condenser connected to a 6-L water trap was charged sequentially with 2,6-dichloro-4-nitroaniline (500 g, 2.42 mol), toluene (5 L), thiophosgene (500 g, 4.35 mol), and dimethylformamide (5 mL, 0.065 mol). The mixture was heated to reflux over 1 hour and maintained at reflux for 4 hours. The black solution obtained was cooled over 15 hours to 23° C. The solvent was removed by rotary evaporation and the residual black oil was triturated with hexane (2 L), causing crystallization. After chilling for an hour, the rust-colored solid was collected by filtration, washed with hexane (1 L), and dried in the air at ambient temperature to a constant weight of 437 g (73%) of (1). (This material was of adequate purity to be used in the subsequent reaction; however, (1) can also be recrystallized in high yield from hexane.) The hexane filtrate was evaporated and the residue was dried under high vacuum for 15 hours, causing partial crystallization. The material was triturated with hexane (1 L) and collected by filtration. Recrystallization from hexane provided a second crop of (1) weighing 88.5 g. The total yield was 525.5 g (87%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCCCCCc1ccccc1
Reactant: BrCCCCBr
Product: BrCCCCOCCCCCc1ccccc1

Procedure:
(2.46 g), T.l.c. [K] Rf 0.58 from 1,4-dibromobutane (7.89 g) and benzenepentanol (2 g).
Reaction SMILES: Cl.[C:2](=[NH:11])(OC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C([O:15][C:16](=O)[C@H:17]([CH3:19])[NH2:18])C.C(N(CC)CC)C>O1CCCC1>[CH3:19][CH:17]1[C:16](=[O:15])[NH:11][C:2]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:18]1
Reactant: COC(=N)c1ccccc1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1N=C(c2ccccc2)NC1=O
Yield: 50.8 %

Procedure:
A mixture of methyl benzimidate monohydrochloride (5 g), alanine ethyl ester monohydrochloride (4.77 g), triethylamine (8.5 ml) and tetrahydrofuran (130 ml) was stirred and heated under reflux under nitrogen for 5.5 hours, then the solvent was removed in vacuo. The residue was triturated with a 1:1 mixture of ether and ethyl acetate, and the resulting yellow solid was collected by filtration and suspended in water (100 ml). The mixture was stirred at ambient temperature for 1 hour, then the resulting solid was collected by filtration, and dried in vacuo to give 4-methyl-2-phenyl-2-imidazolin-5-one as a yellow solid (2.58 g), m.p. 165° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH:8]([F:10])[F:9])=[C:5]([Cl:11])[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])=[N:3]1.N1C=CC=N1.[N+:25]([O-])([OH:27])=[O:26]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:6]([O:7][CH:8]([F:10])[F:9])=[C:5]([Cl:11])[C:4]([C:12]2[CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]([Cl:18])=[CH:14][C:13]=2[F:19])=[N:3]1
Reactant: Cn1nc(-c2ccc(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: c1cn[nH]c1
Product: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 0 °C
Yield: 97.3 %

Procedure:
A mixture of 18.0 grams (0.058 mole) of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chlorophenyl)pyrazole and 120 mL of concentrated sulfuric acid was stirred, and when the pyrazole was dissolved, the solution was cooled to 0° C. To this was added dropwise 5.5 mL (0.074 mole) of 70% nitric acid at a rate to maintain the reaction mixture temperature below 3° C. Upon completion of addition the reaction mixture was allowed to warm to about 10° C. where it stirred for two hours. After this time the reaction mixture was poured into ice-water and then extracted with several portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 20.1 grams of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chloro-5-nitrophenyl)pyrazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[CH3:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[NH2:30]>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[C:32]([CH3:34])[CH:33]=[C:27]([CH3:26])[CH:28]=1)=[O:15]
Reactant: Cc1cc(C)cc(N)c1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cc(C)cc(C)c2)cc1N
Yield: 69.9 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 4.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 3,5-dimethylaniline (6.4 mL, 51.33 mmol) to afford the product (4.79 g); m.p. 155-162° C.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(OC)(C)(C)C>[CH3:18][N:19]([CH3:21])[CH:20]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccccc1)c1ccccc1
Solvent: COC(C)(C)C
Product: CN(C)C=C(C(=O)c1ccccc1)c1ccccc1
Yield: 91.7 %

Procedure:
When only the 4,5-diphenyl isomer is desired the following procedure is preferred. A mixture of 778 g (3.96 mol) deoxybenzoin, 580 mL (4.38 mol) of N,N-dimethylformamide dimethyl acetal, and 775 mL of methyl tert-butyl ether was refluxed for 3 hours. The reaction mixture was cooled on ice to 0°-5° C. The precipitated solid was collected by filtration, the filter cake washed with 250 mL of cold methyl tert-butyl ether twice and dried in vacuum chamber at 65° C. to afford 913 g (92%) of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one, mp 128°-133° C. A slurry of 913 g (3.64 mol) of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one in 3.4 L of absolute ethanol was treated with 618 g (4 mol) of ethyl hydrazinoacetate hydrochloride in one portion. The mixture was stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the filtrate treated with 7 L of 50% aqueous ethanol with stirring. Cooling of the resultant solution to 0°-5° C. provided a white solid which was collected by filtration, washed with 250 mL of cold 50% ethanol twice and dried in vaccum at 40° C. to provide 970 g (87%) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate, mp 76°-80° C., containing none of the 3,4-diphenyl isomer detectable by GLC.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:13].O>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH3:13])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In THF (200 ml) was dissolved 4-bromobenzyl alcohol (19.8 g), and to the solution was added under ice-cooling 65% sodium hydride (3.6 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added dropwise under ice-cooling iodomethane (8.0 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-4-(methoxymethyl)benzene (14.8 g). In THF (10 ml) was dissolved 1-bromo-4-(methoxymethyl)benzene (12.8 g), and to the mixture was added dropwise at−78° C. 1.6M n-butyllithium/hexane (42.4 ml). The mixture was stirred for 1 hour, and to the mixture was added dropwise a solution of trimethyl borate (19.2 g) in THF (38.4 ml). The mixture was stirred for30 minutes and warmed to room temperature. To the mixture was added 5% sulfuric acid (124 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(methoxymethyl)phenyl borate (6.3 g).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.NC1C=C2C(=CC=1)[N:39]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:38](=[O:49])[CH2:37][CH2:36]2>>[CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]4[C:16](=[CH:15][CH:14]=3)[N:39]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:38](=[O:49])[CH2:37][CH2:36]4)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1C(=O)CCc2cc(N)ccc21
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Product: CCOC(=O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, ethyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate and 2-chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave Ethyl 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (MS calcd for C23H26N6O3 434.2, found [MH] 435.2; UV 209.8, 304.5 nm).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:22]([OH:24])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]([F:44])([F:43])[C:27]([NH:29][C@H:30]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:31]O)=[O:28].N[C@H](C([O-])=O)CO>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:22]([O:24][CH2:31][C@@H:30]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[NH:29][C:27](=[O:28])[C:26]([F:25])([F:43])[F:44])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@H](CO)NC(=O)C(F)(F)F
Agent: N[C@@H](CO)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@H](COCc1ccccc1)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of O-benzyl-N-benzyloxycarbonyl-L-serine (1 g) and benzyl N-trifluoroacetyl-L-serinate (873 mg) in methylene chloride (20 ml) was added N,N-diethylaminopropyl-N'-ethylcarbodiimide hydrochloride (573 mg) and -N,N-dimethylaminopyridine (37 mg) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for an hour at room temperature. The reaction mixture was diluted with ethyl acetate (200 ml) and washed successively with 0.2N hydrochloric acid, water, 10% aqueous sodium hydrogen carbonate, water and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was chromatographed on silica gel eluting successively with a 1:1 mixture of methylene chloride and hexane, methylene chloride, a 50:1 mixture of methylene chloride and acetone to give benzyl O-(O-benzyl-N-benzyloxycarbonyl-L-serinyl)-N-trifluoroacetyl-I,-serinate (1.5 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>C(O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: C=CCN1CCN(CCC(=O)OCC)CC1
Yield: 80 %

Procedure:
A mixture of 1-(2-propenyl)piperazine (6.6 g) and ethyl 2-propenoate (11.3 ml) in ethanol (100 ml) was stirred and refluxed for 1 hour 30 minutes. The solvent was evaporated, yielding 9.6 g (80%) of ethyl 4-(2-propenyl)- 1-piperazine-propanoate (interm. 1).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH:33]=O>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:33][C:32]3[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=3)[C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-allyloxy-8-acetyl -3methylflavone (2.5 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 121-23° C., 1H-NMR (CDCl3)δ: 2.20 (s, 3H); 3.87 (m, 9H); 4.73 (d, 2H, J=5,1 Hz; 5.25-5.45 (m, 2H); 5.91-6.02 (m, 1H); 6.75 (s, 2H); 6.96 (d,1H, J=16 Hz); 7.10 (d, 1H, J=8.9 Hz); 7.30 (d, 1H, J=16 Hz); 7.42-7.46 (m, 3H); 7.55-7.59 (m, 2H); 8.34 (d, 1H, J=8.9 Hz).
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C1(C)C(C)=CC=CC=1>[CH2:19]([O:14][C:13](=[O:15])[C:12]1[C:8](=[CH:7][C:3](=[C:2]([CH:16]=1)[C:1]([O:18][CH2:9][CH2:8][CH2:7][CH2:3][CH2:2][CH2:16][CH2:12][CH3:13])=[O:17])[C:4]([O:6][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:5])[C:9]([O:11][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCO
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Product: CCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCC)c(C(=O)OCCCCCCCC)cc1C(=O)OCCCCCCCC
Yield: 209 %

Procedure:
To a 2-liter four necked flask equipped with Dean Stark, 218 g of anhydrous pyromellitic acid, 650 g of n-octanol, 0.2 g of titanium tetraisopropoxide and 300 ml of xylene were added and reacted with agitation at 160 degrees C. for 4 hours under nitrogen stream while distilling water. Subsequently, washing by saturated saline and washing by 0.1 N aqueous sodium hydroxide were respectively conducted three times, followed by being dried by anhydrous magnesium sulfate. After magnesium sulfate was filtered, unreacted alcohol was distilled under diminished pressure to obtain 630 g of pyromellitic acid tetraoctyl ester as a residue. The obtained compound, regarded as Comparative 1-3, was similarly measured with respect to the properties.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])[CH3:2].ClC(OCC)=O.[BH4-].[Na+].Cl>O1CCCC1.C(N(CC)CC)C.O.C(OCC)(=O)C>[OH:12][CH2:11][C:10]1[CH:14]=[CH:15][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])=[C:8]([O:16][CH3:17])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(C(=O)O)cc1OC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCc1ccc(CO)cc1OC
Yield: 99.8 %

Procedure:
1.58 g of 4-(3-ethoxy-3-oxopropyl)-3-methoxybenzoic acid was dissolved in 16 mL of tetrahydrofuran, to which 0.96 mL of triethylamine was added dropwise at −10° C. and then 0.63 mL of ethyl chloroformate was added dropwise at −20° C., followed by addition thereto of 0.47 g of sodium borohydride in an ice bath, and this solution was stirred for 30 minutes at the same temperature. The reaction mixture, to which water was added dropwise before adding ethyl acetate and water thereto, was adjusted to pH 2 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 1.49 g of ethyl 3-[4-(hydroxymethyl)-2-methoxyphenyl]propanoate as white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C.[V]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: [V]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered vanadium carbide from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 16.3%, wherein 0.3 g of phenyl chloroformate and 25.5 g of diphenyl carbonate were formed. Selectivity for carbonates was 98.2%.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13](=O)[CH2:14]Br)[CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:12]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: O=C(O)CCNc1cccc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3cccc(NCCC(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(2-carboxyethylamino)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(2-carboxyethylamino)-2-pyridyl]thiazole.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[C:7]=1[NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.[Zn]>[NH2:12][C:10]1[CH:9]=[C:8]([C:15]([F:17])([F:18])[F:16])[C:7]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:6]([Br:5])[CH:11]=1
Reactant: O=C(CCC1CCCCC1)Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1cc(Br)c(NC(=O)CCC2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Acetic acid (3.70 mL) was added slowly to a mixture of zinc dust (7.88 g) and N-(2-bromo-4-nitro-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide (1.99 g) in tetrahydrofuran (40 mL). The reaction mixture was then stirred for 1½ hours at 25° C. The reaction mixture was filtered, diluted with saturated aqueous sodium bicarbonate (400 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated in vacuo to furnish 1.85 g (100% yield) of the title compound as a yellow solid. LC-MS (m/z) 394 (MH+); tR=3.22, (UV, ELSD) 92%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.86 (q, 2H), 1.17 (m, 3H), 1.26 (m, 1H), 1.46 (q, 2H), 1.67 (m, 5H), 2.40 (t, 2H), 5.83 (s, 2H), 6.88 (d, 1H), 7.07 (d, 1H), 9.27 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][NH:14][CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CCNC3)c1=O
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl 6-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate 120a (3.6 g, 8.3 mmol) in dioxane (10 mL) was added saturated hydrogen chloride solution in dioxane (20 mL) dropwise. The reaction mixture was stirred for 20 minutes and concentrated under reduced pressure to give 221a, which was used without further purification in the next step. LC/MS: m/z 336 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[H-].[Na+].[S:11]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>CN(C=O)C>[Br:8][C:6]1[CH:7]=[C:2]([O:27][CH2:26][C@@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:3]=[N:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CO)cc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2COc2cncc(Br)c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a suspension of 3,5-dibromopyridine (1.5 g, 6.05 mmol) and 60% NaH (307 mg, 7.7 mmol) in DMF (6 mL) was added 1-tosyl-2-(S)-pyrrolidinemethanol (1.4 g, 5.5 mmol), and the reaction mixture was stirred for 4 hours at room temperature and 1 hour at 60° C. The DMF was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with EtOAc/hexane 6:1 to afford the title compound (1.2 g).