Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl-].[NH2:3][C@@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([OH:20])=[O:19])=[C:8]([CH2:11][N+:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][S:10][C@H:5]12.[CH:23]1([O:26][N:27]=[C:28]([C:32]2[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=2)[C:29](O)=[O:30])[CH2:25][CH2:24]1.C(OCC)(=O)C>C[Si](C)(C)NC(=O)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.O1CCCC1>[NH2:37][C:34]1[S:35][CH:36]=[C:32]([C:28](=[N:27][O:26][CH:23]2[CH2:25][CH2:24]2)[C:29]([NH:3][C@@H:4]2[C:21](=[O:22])[N:6]3[C:7]([C:18]([O-:20])=[O:19])=[C:8]([CH2:11][N+:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:9][S:10][C@H:5]23)=[O:30])[N:33]=1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)cs1
Reaction time: 0.67 h
Yield: 56.4 %

Procedure:
1-[(7β-Amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride (960 mg) was dissolved in a solution of N-trimethylsilylacetamide (1.5 g) and bis(trimethylsilyl)acetamide (2.8 ml) in tetrahydrofuran (10 ml). To this solution was added the activated acid solution, which was prepared from 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (500 mg) according to a similar manner to that described in Example 1, at -20° C. The mixture was stirred at -20° C. to -10° C. for 40 minutes. The mixture was poured into ethyl acetate (250 ml). The precipitate was collected and suspended in methanol (20 ml). To the suspension was added concentrated hydrochloric acid (0.62 ml) and the mixture was warmed at 30° to 35° C. for 2 hours. The mixture was poured into ice-water (50 ml), adjusted to pH 2.5 with saturated aqueous solution of sodium bicarbonate, and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (30 ml). After the column was washed with water (300 ml), 1% isopropyl alcohol (60 ml), and 3% isopropyl alcohol (60 ml) successively, the elution was carried out with 5% isopropyl alcohol (250 ml) and 10% isopropyl alcohol (150 ml) successively. The fractions containing the object compound were collected, combined, concentrated in vacuo to about 100 ml and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (553 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([CH2:21][NH:20][C:19](=[O:22])[CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:31])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][CH3:36]>C1COCC1>[CH2:35]([N:20]1[C:19](=[O:22])[CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][C:14]2([CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:31])[CH:7]=3)[CH2:12][CH2:13]2)[CH2:21]1)[CH3:36]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNC(=O)C(c2ccccc2)O3)ccc1OC(C)C
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)OC(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one (65 mg, 0.15 mmol) in THF (1 mL) at 0° C. was added NaH (6 mg, 0.15 mmol) and the reaction mixture was stirred for 30 minutes. Bromoethane (34 mg, 23 μL, 0.31 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give 2-ethyl-9-(4-isopropoxy-3-methyl-benzoyl)-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.48-7.43 (m, 2H), 7.39-7.29 (m, 3H), 7.23-7.17 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 5.11 (s, 1H), 4.56 (dt, J=12.1, 6.0 Hz, 1H), 3.63 (d, J=12.4 Hz, 1H), 3.59-3.19 (m, 5H), 3.09 (d, J=12.4 Hz, 1H), 2.92 (d, J=28.7 Hz, 1H), 2.22 (s, 1H), 2.23-2.16 (m, 3H), 1.59 (s, 3H), 1.35 (d, J=6.0 Hz, 6H), 1.14 (t, J=7.2 Hz, 3H). ESI-MS m/z calc. 450.3. found 451.1 (M+1)+; Retention time: 1.76 minutes (3 min run).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][OH:10]>>[C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[O:10])[NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CO
Agent: ON=C1CCCCC1
Product: O=C1CCCCCN1
Reaction time: 20 h

Procedure:
0.375 g of a high silica MFI catalyst was packed into a fixed-bed-type reactor having an inner diameter of 10 mm. A mixture of cyclohexanone oxime and methanol (1:1.8 in ratio by weight) was vaporized and supplied to the reactor while using a nitrogen gas as a carrier, to conduct a gas phase Beckmann rearrangement reaction at 380° C. under 0.1 MPa with a space velocity (WHSV) of cyclohexanone oxime of 8 h−1. The reaction was continued for 20 hours, and the resulting reaction mixture was analyzed over time utilizing gas chromatography. The results (i.e., conversion of cyclohexanone oxime and selectivity to ε-caprolactam) are shown in the below Table 1 as the results obtained before regeneration of the catalyst.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C@H:4]([CH3:17])[C@@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([OH:8])[CH2:6][CH3:7].[P:19](=O)([OH:22])([OH:21])[OH:20]>C(O)C>[P:19]([O:8][C@@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([CH2:6][CH3:7])[C@@H:4]([CH3:17])[CH2:3][N:2]([CH3:1])[CH3:18])([OH:22])([OH:21])=[O:20]
Reactant: O=P(O)(O)O
Reactant: CC[C@@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Solvent: CCO
Product: CC[C@@](OP(=O)(O)O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Reaction time: 24 h
Yield: 16 %

Procedure:
10 g (0.04 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol were dissolved in 40 ml of ethanol and treated with stirring with 3 g of 85 wt. % ortho-phosphoric acid. After 24 h, the crystals formed were filtered off under reduced pressure and dried for 24 h in a drying cabinet at 40° C. to a final pressure of 10 mbar. 2.2 g (16% of theoretical) of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate were obtained as colourless crystals with an enantiomeric purity of 85%.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].P(=O)(O)(O)O.OC[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH2:24][OH:25])[C:18]=1[OH:26]>C(C(C)=O)C(C)C>[CH:1]([C:2]1[CH:8]=[C:7]([CH2:24][C:19]2[C:18]([OH:26])=[C:17]([CH2:23][C:21]3[CH:22]=[CH:17][C:18]([OH:26])=[C:19]([CH:20]=3)[CH:24]=[O:25])[CH:22]=[C:21]([CH3:23])[CH:20]=2)[CH:6]=[CH:5][C:3]=1[OH:4])=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: Cc1cc(CO)c(O)c(CO)c1
Agent: O=P(O)(O)O
Solvent: CC(=O)CC(C)C
Product: Cc1cc(Cc2ccc(O)c(C=O)c2)c(O)c(Cc2ccc(O)c(C=O)c2)c1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Under an atmosphere of nitrogen, 244.0 g (2.0 mol) of salicylaldehyde was weighed into a four-neck flask with a capacity of 1 liter fitted with a reflux condenser, a thermometer and a stirrer, and 244.0 g of a 75% aqueous solution of phosphoric acid was then added dropwise to the flask over a period of 30 minutes and stirred at room temperature. 84.0 g (0.5 mol) of a powdered form of 2,6-bis(hydroxymethyl)-4-methylphenol was then added to the mixed solution intermittently at 60° C. over a 6 hour period, and the resulting mixture was then stirred for a further 17 hours. 366.0 g of methyl isobutyl ketone was then added to the reaction mixture, a phase separation was performed, and the 235.0 g water layer (phase) was removed. The reaction system was then neutralized by adding 80.6 g of a 16% aqueous solution of sodium hydroxide, 150 g of water was added, water washing was conducted at 80° C., and the water phase was then separated and removed. This water washing and separation operation was repeated a further two times, the resulting residue was concentrated under reduced pressure at 160° C., and following the addition of 94.0 g of methyl isobutyl ketone to the residue at 120° C., 470.0 g of toluene was added at 110° C. to crystallize the product. The resulting crystals were isolated by filtration, yielding 160.6 g of a wet cake. This wet cake was transferred to a four-neck flask with a capacity of 1 liter, and dissolved by adding 240.0 g of methyl isobutyl ketone. Subsequently, the solution was concentrated at normal pressure by heating to 130° C., 184.0 g of toluene was added, and a further concentration was conducted at normal pressure by heating to 115° C. 240.0 g of toluene was then added to the residue to crystallize the product. The crystals were collected by filtration, yielding 89.7 g (yield: 47.7%) of the target product (the precursor compound). (Identification by LC-MS (liquid chromatography-mass spectrometry) (using APCI (Atmospheric Pressure Chemical Ionization)) revealed a Mw value of 375).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (80 mg, 90%), MS (ISP) m/z=356.3 [(M+H)+], mp 330.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([O:23][C:24]([NH:26][NH:27][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
11.2 g 4-fluoro-3-methyl-benzoyl chloride was added to 6.1 g triethylamine and 8 g hydrazinecarboxylic acid tert-butyl ester in 150 mL dichlormethane. The reaction was stirred for 1 h at RT and extracted with water. The organic layer was evaporated and the residue was crystallized from diisopropylether to yield 13 g of the desired product. Rt: 1.22 min (method B) (M+H)+: 269
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[C:44]2[N:45]([CH:49]=[N:50][CH:51]=2)[CH:46]=[CH:47][CH:48]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S1C=CC=C1C([O-])=O.[Cu+]>[CH:51]1[N:50]=[CH:49][N:45]2[CH:46]=[CH:47][CH:48]=[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:35][CH2:34][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]5)=[CH:26][C:9]=4[N:10]=3)[C:44]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Brc1cccn2cncc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cccn5cncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 72.8 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (132 mg, 0.19 mmol), 8-bromoimidazo[1,5-a]pyridine (45 mg, 0.23 mmol), Pd(PPh3)4 (22 mg, 0.02 mmol) and copper(I) thiophene-2-carboxylate (7 mg, 0.04 mmol) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 202 as a yellow solid (72 mg, 73%). LCMS (Method G): RT 5.12 min; [M+H]+ 521. 1H NMR (400 MHz, CHCl3-d): δ 8.33 (s, 1 H); 8.21 (s, 1 H); 8.04 (d, J=6.9 Hz, 1 H); 7.93 (d, J=6.9 Hz, 1 H); 7.36 (s, 1 H); 7.07 (m, 1 H); 6.74-6.69 (m, 1 H); 5.19 (s, 1 H); 4.07 (t, J=4.7 Hz, 4 H); 3.96-3.86 (m, 4 H); 3.88-3.83 (m, 2 H); 2.61 (s, 8 H); 1.25 (s, 6 H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([F:12])=[C:7]([Br:13])[CH:6]=2.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(Cl)Cl.CCOC(C)=O>[CH2:29]([O:28][C:26]([NH:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([F:12])=[C:7]([Br:13])[CH:6]=2)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1nc2cc(Br)c(F)cc2cc1N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2cc(Br)c(F)cc2cc1NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
DCM (10.0 mL) was added to a mixture of ethyl 3-amino-7-bromo-6-fluoroquinoline-2-carboxylate (882.5 mg, 2.818 mmol) and pyridine (592.1 mg, 7.485 mmol). The mixture was cooled to −10° C. A solution of benzyl chloroformate (650.6 mg, 3.623 mmol) in DCM (5.0 mL) was added slowly over a period of 5 min. The mixture was then allowed to warm to room temperature and was stirred for 2 h. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as an off-white solid (854.9, 68%). LCMS calc. for C20H17BrFN2O4 (M+H)+: m/z=447.0. found 447.0.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:16]([CH2:23][CH2:24][CH3:25])[CH2:17][C:18]([O:20]CC)=[O:19].[O-]CC.[Na+]>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:16]([CH2:23][CH2:24][CH3:25])=[C:17]([C:18]([OH:20])=[O:19])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCC)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4-azido-N-ethylbenzamide (0.73 g) obtained in Example 43a) and ethyl 3-keto-n-hexanoate (0.77 ml) in ethanol (20 ml) was added 20% sodium ethoxide in ethanol solution (1.85 ml) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white solid (1.13 g, 98%).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1.CCN(CC)CC>C(O)C>[CH3:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(NN)c1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 3-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(3-methylphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (84 mg, 21%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC(C)([O-])C.[K+].Cl[CH2:12][C:13]([N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].O>CN(C=O)C>[OH:3][CH2:2][CH2:1][O:4][CH2:12][C:13]([N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(C)CN(C(=O)CCl)c1ccccc1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN(C(=O)COCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of ethylene glycol (12.4 g, 200 mmol) in DMF (50 ml) was carefully added potassium tert-butoxide (16.8 g, 150 mmol) while the temperature was kept below 70° C. The resulting mixture was stirred at ambient temperature for 30 min, then a solution of the above acetamide (11.3 g, 50 mmol) in DMF (5 ml) was added in one portion and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into iced water (400 ml) and extracted with dichloromethane (2×50 ml). The combined organic phases were dried (MgSO4) and the solvent was evaporated in vacuo to give 12.5 g of 2-(2-hydroxyethoxy)-N-(2-methyl-1-propyl)-N-phenylacetamide.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:37]3[N:36]=[C:30]([NH:31][C:32](=[O:35])[NH:33][CH3:34])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:47]1([N:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(OCC)(=O)C>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:37]3[N:36]=[C:30]([NH:31][C:32](=[O:35])[NH:33][CH3:34])[N:29]=[C:27]([O:28][C:54](=[O:55])[N:53]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CNC(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-methylcarbamoyldeoxyguanosine (889 mg, 1.61 mmol) was azeotroped with anhydrous pyridine three times and then dissolved in anhydrous pyridine (16 mL), and diisopropylethylamine (421 μL, 2.41 mmol) and then diphenylcarbamoyl chloride (424 mg, 1.93 mmol) were added thereto. The mixture was stirred at room temperature for 0.5 hours. Then, after addition of ethyl acetate (10 mL), the reaction was terminated by adding sodium bicarbonate water (10 mL) thereto. The reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (150 mL) once and then with ethyl acetate (150 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C200) with ethyl acetate/40% to 50% hexane to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-O-diphenylcarbamoyl-2-N-methylcarbamoyldeoxyguanosine (1.13 g, 94%).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1C(O)=O.OCCS(C1C=CC(OC2C=CC(S)=CC=2)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>C1C=C(Cl)C(Cl)=CC=1>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(C(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(CCO)c1ccc(Oc2ccc(S)cc2)cc1
Agent: [K+]
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-carboxy-4-bromoanthraquinone (6.9 parts) and 4-(4'-β-hydroxyethylsulfonylphenoxy)thiophenol (6.5 parts) were allowed to react with each other at 100° to 120° C. in O-dichlorobenzene in the presence of cuprous chloride and potassium carbonate. Thereafter, methanol was added to the reaction mixture to deposit solids, which were collected on a filter, washed throughly with methanol and water and then dried at 80° C. The resulting product was subjected to sulfonation and esterification simultaneously at 20° to 40° C. in 14% oleum. Thereafter, ice was added thereto, and the solids deposited were collected on a filter, thereby obtaining an anthraquinone compound of the following formula (free acid form). ##STR383##
Reaction SMILES: [NH2:1]/[C:2](/[CH2:9][O:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:24][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[CH:27]=[C:28]([C:33]([CH3:35])=O)[C:29]([O:31][CH3:32])=[O:30]>C(O)C>[Cl:24][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[CH:27]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:33]([CH3:35])[NH:1][C:2]([CH2:9][O:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])=[C:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C=C(\N)COCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 34.9 %

Procedure:
24.0 g (75.4 mmoles) of ethyl 3-amino-4-(2-(phthalimido)ethoxy)crotonate and 18.9 g (79.2 mmoles) of methyl 2-(2-chlorobenzylidene)acetoacetate in 64 ml of ethanol were heated under reflux for 20 hours. The reaction mixture was diluted with 56 ml of ethanol and was cooled to crystallise the product. 14.2 g (yield 70%) of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine were obtained.