Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:47](=[O:49])=[O:48].[CH:50]([Si:53](Cl)([CH:57]([CH3:59])[CH3:58])[CH:54]([CH3:56])[CH3:55])([CH3:52])[CH3:51]>C(Cl)Cl.O>[CH:50]([Si:53]([O:48][C:47](=[O:49])[N:13]([C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1)([CH:57]([CH3:59])[CH3:58])[CH:54]([CH3:56])[CH3:55])([CH3:52])[CH3:51]
Reactant: O=C=O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[Si](OC(=O)N(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)[C@H]1CCN(C(=O)OC(C)(C)C)C1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-1-(tert-butoxycarbonyl)-3-({2-[1-(triphenylmethyl)-1H-imidazol-4-yl]ethyl}amino)pyrrolidine, as described above in Step E, (411 mg, 0.786 mmol) in CH2Cl2 (10 mL), was added triethylamine (0.110 mL, 0.786 mmol) and the mixture was cooled to −78° C. Solid CO2 (1.73 g, 39.3 mmol) was added and after 30 min, triisopropylsilyl chloride (0.172 mL, 0.802 mmol) was added and the reaction mixture was warmed to ambient temperature. After 1 hour, the reaction was diluted with water and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 3% MeOH—0.1% to 0.3% NH4OH, to yield the above-titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.C([N:16]1[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)(=O)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([CH:19]2[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:30])=[CH:24][CH:25]=1
Reactant: Brc1ccccn1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccccn1)C1CCNCC1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 36.3 g (0.23 mole) of 2-bromopyridine in 500 ml of anhydrous tetrahydrofuran (THF) at -65° C. was added 88 ml (0.22 mole) of a commercial solution of 2.5M n-butyllithium in hexane at such a rate that the temperature did not exceed -60° C. The dark solution was stirred at -65° C. for 1 hr and then treated dropwise with a solution of 24.9 g (0.1 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 250 ml of THF at such a rate that the temperature did not exceed -60° C. The mixture was stirred for 1 hr at -65° C. and overnight at ambient temperature. The dark mixture was poured into 2 liters of a saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted once with a 500-ml portion of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 500 ml of a 4% sodium hydroxide solution, 250 ml of water, and 250 ml brine.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O>O.ClCCl>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH2:19][Cl:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: Oc1ccc(-c2ccc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(-c2ccc(OCCCl)cc2)c(F)c1

Procedure:
The compound 2',4'-difluoro-4(2-chloroethoxy)biphenyl is prepared by a process wherein to a solution of 15 g of sodium hydroxide in 30 ml of water there is added 68.2 g of 4-(2',4'-difluorophenyl)phenol and 106 g of 2-chloroethyl-p-toluene-sulfonate. The mixture is heated to about 95°-100° C. while stirring (at 96°-98° C. an exothermic reaction occurs) and maintained at this temperature for 5 hours. The resulting material is diluted with dichloromethane, washed with water, and evacuated until dry. The crude product is crystallized using isopropyl alcohol to yield 62 g (69% of theory) of the final product. If a further crop (9 g) of pure product can be obtained from the mother liquor, the total yield of the product is 80% of theory.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8]1.Cl[C:15]1[N:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][C:22]=2[OH:32])=[CH:17][CH:16]=1>C1COCC1>[N:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:18]3[N:19]=[N:20][C:15]([O:13][CH2:12][CH:9]4[CH2:10][CH2:11][NH:7][CH2:8]4)=[CH:16][CH:17]=3)=[C:22]([OH:32])[CH:23]=2)[CH:31]=[CH:30][CH:29]=[N:28]1
Reactant: OCC1CCNC1
Reactant: Oc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(OCC2CCNC2)nn1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.7 mL, 0.7 mmol) was added to pyrrolidin-3-ylmethanol (0.06 g, 0.64 mmol) in THF (1.4 mL) and the mixture was stirred for 10 min at 50° C. 2-(6-Chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2 (0.05 g, 0.18 mmol) was added to the reaction at 0° C. and the mixture was stirred for 1 h at RT. Solvent was evaporated under reduced pressure. The crude material was purified via reverse phase preparative HPLC (5 to 95% acetonitrile in water, 5 mM NH4OH as modifier). Enantiomer 1 and Enantiomer 2 were isolated via preparative SFC. Two solids (11 mg (17%), and 12 mg (20%) were afforded.
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.COC(OC)OC.[C:18]1([CH3:28])C=CC(S(O)(=O)=O)=CC=1.[CH3:29][NH:30][CH2:31]C>COC(C)(C)C>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([N:6]=[CH:29][N:30]([CH2:18][CH3:28])[CH3:31])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)c(C)cc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCNC
Solvent: COC(OC)OC
Solvent: COC(C)(C)C
Product: CCN(C)C=Nc1cc(C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To a mixture of 10.0 g (50 mmol) of 4-bromo-2,5-dimethylaniline and 126 ml (1.15 mol) of trimethoxymethane 0.86 g (5 mmol) of p-toluene sulfonic acid were added. The reaction mixture was refluxed for 16 hrs and concentrated in vacuo. The crude product was solved in 50 ml of dichloro methane and 5.9 g (100 mmol) N-methylethanamine were added. The reaction mixture was stirred for 16 hrs at room temperature. The reaction mixture was concentrated in vacuo. Column chromatographic (gradient: petroleum ether->methyl-tert.butyl ether) yielded 5.2 g (19.5 mmol) 39% of N′-(4-bromo-2,5-dimethylphenyl)-N-ethyl-N-methylimidoformamide; log P (pH 2.3)=1.36.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24].[BH4-].[Na+]>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@@H:12]([OH:13])[CH2:11][C@H:10]1[OH:24].[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@H:12]([OH:13])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@H](O)C[C@H]1O

Procedure:
Specifically to formulate the analogue of PGA1, which bears the name of Methyl 15-Hydroxy-9-oxo-16,17,18,19,20-pentanorprosta-10,13E-dien-1-oate (XVI), the depentyl PGE1 (Methyl 11α,15-Dihydroxy-9-oxo-16,17,18,19,20-pentanorprosta-13E-en-1-oate (XV) is mixed with a mild carboxylic acid at a relatively high temperature of about 50° to 70° C. Using acetic acid also gives the 15-acetate (XVII). On the other hand, mixing the same depentyl analogue of PGE1 with sodium borohydride in a dry alcohol at about -20° to +25° C. will produce the depentyl analogues of PGF1α (XVIII) and PGF1β (XIX).
Reaction SMILES: C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:11])(=O)=O)=CC=1.[H-].[Na+].[CH2:23]1[S:31](=[O:33])(=[O:32])[O:30][CH2:29][CH2:28][O:27][S:24]1(=[O:26])=[O:25].C(Cl)Cl>O1CCCC1.C(#N)C>[F:11][CH:23]1[S:24](=[O:25])(=[O:26])[O:27][CH2:28][CH2:29][O:30][S:31]1(=[O:33])=[O:32]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=S1(=O)CS(=O)(=O)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S1(=O)OCCOS(=O)(=O)C1F
Reaction time: 0.25 h

Procedure:
The fluorinating agent used was N-fluorobenzenesulfonimide obtained from PCR Chemicals (Gainesville Fla.). To a suspension of 0.34 g of NaH in 50 mL of tetrahydrofuran was added 2.45 g of ethylene methanedisulfonate followed by 3.8 g of N-fluorobenzenesulfonimide in 25 mL of acetonitrile. After about 15 min, 25 mL of CH2Cl2 was added, the solution was filtered, and the product was isolated by crystallization from CH2Cl2-cyclohexane to give 0.49 g of ethylene fluoromethanedisulfonate, m.p. 84-86° C. (93-2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=2[O:10][N:9]=1.[H-].[Na+].[H][H].Br[CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[Na+]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][C:11]=2[O:10][N:9]=1
Reactant: [H][H]
Reactant: Oc1ccc2c(-c3ccccc3F)noc2c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc2c(-c3ccccc3F)noc2c1
Temperature: 50 °C

Procedure:
3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (9.7 g) is dissolved in 80 ml of DMF and added to an ice-cooled suspension of NaH (1.4 g) in 50 ml of DMF. When hydrogen evolution stops, ethyl bromoacetate (7.5 g) in 20 ml of DMF is added and the reaction mixture is allowed to come to room temperature. After two hours 200 ml of H2O and 10 ml of 50% NaOH are added and the reaction warmed at 50° C. After an additional 30 minutes a product is collected after acidification and filtering. Recrystallization from toluene/CH3CN gives {[3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 182°-184° C.
Reaction SMILES: [OH:1][CH:2]([CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].[C:16](OC(=O)C)(=[O:18])[CH3:17].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:16]([O:1][CH:2]([CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCCC(O)C1CC2C=CC1C2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COCCCCC(OC(C)=O)C1CC2C=CC1C2
Yield: 97 %

Procedure:
In 63.3 g of pyridine, 105.2 g of 5-(1-hydroxy-5-methoxypentyl)-2-norbornene (Monomer 1) was reacted with 61.3 g of acetic anhydride in the presence of 2 g of 4-dimethylaminopyridine at room temperature for 10 hours. The reaction was stopped by adding 30 g of water. Extraction with hexane gave the organic layer, which was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The oily matter thus obtained was distilled in vacuum, obtaining 122.4 g of 5-(1-acetoxy-5-methoxypentyl)-2-norbornene. The yield was 97.0%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:13]=4[C:14](=[O:17])[C:15]=3[OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1>C(Cl)(Cl)Cl.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:13]=4[C:14](=[O:17])[C:15]=3[O:16][CH2:10][C:8]3[CH:9]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(OCc3ccccc3)c(=O)c2c1
Yield: 85 %

Procedure:
Prepared analogously to Example 5d) starting from 2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 85%; TLC (9/1 Chloroform/Methanol) Rf: 0.57.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:22]([O:8][CH:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CC=CCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](OC=C1C=CCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-cyclohexene-1-methanol (Aldrich, 13.0 mL, 0.11 mol), N,N-diisopropylethylamine (43 mL, 0.244 mol) and 4-dimethylaminopyridine (2.70 g., 0.022 mol) in 375 mL of dry CH2Cl2 under N2 at 25° C. was added tert-butyldiphenylchlorosilane (32 mL, 0.123 mol). The mixture was stirred at 25° C. for 48 hours. The reaction mixture was washed sequentially with 150 mL portions of 1N HCl, water, brine and dried over anhydrous MgSO4. The solvent was evaporated. The residue was loaded onto a 4"×4" column of silica and slowly eluted using hexanes as eluant. 3-(tert-butyldiphenylsilyloxymethylene)-1-cyclohexene, 33.6 g (86%), was obtained as a colorless oil which was homogenous by TLC (Rf=0.4, hexanes).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.[F-:14].[Cs+]>CS(C)=O.O>[F:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cnc(Cl)c2ccccc12
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cnc(F)c2ccccc12
Temperature: 145 °C
Yield: 30.6 %

Procedure:
To a solution of 1-chloro-4-methoxyisoquinolin (2.5 g, 12.91 mmol) in DMSO was added cesium fluoride (4.01 g, 25.82 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (700 mg, 62%) as a white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.10 (m, 1H), 8.08 (m, 1H), 7.78-7.75 (m, 1H), 7.69-7.65 (m, 1H), 7.49 (m, 1H), 4.04 (s, 3H); 19F NMR: δ ppm −78.66 (1F); MS: MS m/z 178.1 (M++1).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:11][C:10]2=[O:29])=[CH:6][CH:5]=1)([OH:3])=O.[NH:32]1[CH2:36][CH:35]=[CH:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[N:32]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13][N:12]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:11][C:10]3=[O:29])=[CH:30][CH:31]=2)=[O:3])[CH2:36][CH:35]=[CH:34][CH2:33]1
Reactant: C1=CCNC1
Reactant: O=C(O)c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1)N1CC=CC1
Reaction time: 8 h

Procedure:
23 mg (0.053 mmol) of 1-(4-carboxybenzyl)-4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of dichloromethane. 6 mg (0.079 mmol) of 3-pyrroline, 13 mg (0.079 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.022 ml (0.159 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1.[NH3:13].Cl>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:13])=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)cnc1O
Reactant: N
Agent: Cl
Solvent: CO
Product: NC(=O)c1nc(Br)cnc1O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In 3 mL of methanol is suspended 0.6 g of methyl 6-bromo-3-hydroxy-2-pyrazinecarboxylate obtained according to the method described in literature [J. Med. Chem., 1969, 12(2), 285-287]. Then, 6 mL of 25% aqueous ammonia is added thereto and the resulting solution is stirred at ambient temperature for 17 hours. The reaction mixture is adjusted to pH 3 by adding 6 mol/L hydrochloric acid. The solvent is distilled off under reduced pressure. Isopropyl ether and water are added to the residue and filtered to obtain 0.33 g of 6-bromo-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[N:4][C:3]=1[C:15]([NH2:17])=[O:16].[CH:18](N)=O>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]2[N:1]=[CH:18][NH:17][C:15](=[O:16])[C:3]=2[N:4]=[N:5]1
Reactant: NC(=O)c1nnn(Cc2ccccc2F)c1N
Reactant: NC=O
Product: O=c1[nH]cnc2c1nnn2Cc1ccccc1F
Temperature: 0 °C

Procedure:
70,5 g (0.3 mol) of 5-amino-1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and 339 g (300 ml; 7.53 mol) of formamide are heated at a gentle boil for 2 hours. The reaction solution is then allowed to cool to approximately 100° and poured onto 2 l of ice-water. The precipitated product is filtered off with suction and washed with water. Drying at 100° yields 3-(2-fluorobenzyl)-3H,6H,7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one having a melting point of 215°-218°.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#N)[CH:2]=1.[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[C:12]([Mg]Cl)[CH:11]=1.Cl.C1C[O:23]CC1>>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:12]2[CH:11]=[C:10]([CH3:18])[CH:15]=[CH:14][CH:13]=2)=[O:23])[CH:2]=1
Reactant: Cc1cccc(C#N)c1
Reactant: Cc1cccc([Mg]Cl)c1
Reactant: C1CCOC1
Agent: Cl
Product: Cc1cccc(C(=O)c2cccc(C)c2)c1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
An oven-dried, three-necked 1-L flask equipped with magnetic stirring bar, gas inlet, dropping funnel, and condenser was flushed with nitrogen and loaded with m-tolunitrile (49.1 g, 419 mmol) and THF (30 mL). A solution of m-tolyl magnesium chloride in THF (1 M, 440 mL) was added dropwise at such a rate that the internal temperature was kept below 50° C. The mixture was heated to reflux for 18 h, then cooled to −15° C., and hydrolyzed with ice-water (210 mL) and aqueous HCl (36.5%, 300 mL). The mixture was stirred at room temperature for 30 min and heated to 80° C. for 18 h. Most of the THF (400 mL) was removed by distillation. The solution was extracted with MTBE (250 mL, 3×200 mL). The combined organic layers were washed with saturated NaHCO3 solution (200 mL) and saturated NaCl solution (200 mL), dried over MgSO4, and concentrated under vacuum to give di-m-tolyl-methanone (99.5 g, quantitative) as a red oil, which was used without further purification for the next step. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.62 (s, 2H), 7.54 (d, 2H, J=7.0 Hz), 7.36-7.31 (m, 4H), 2.37 (s, 6H). 13C NMR (75 MHz, CDCl3=77.23 ppm): δ (ppm): 197.1, 138.1, 133.2, 130.5, 128.3, 127.4, 21.4 [lit. ref.: Coops, J.; Nauta, W. Th.; Ernsting, M. J. E.; Faber, M. A. C. Recueil 1940, 57, 1109].
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[NH3:26]>C(O)C>[O:15]=[C:10]1[C:9]2[NH:16][CH:17]=[CH:18][C:8]=2[C:7]2[CH:6]=[C:5]([S:2](=[O:4])(=[O:3])[NH2:26])[CH:14]=[CH:13][C:12]=2[NH:11]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCC(=O)[O-]
Product: NS(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 3 %

Procedure:
In a sealed tube, 490 mg (1.5 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) is dissolved in 1.5 mL of an aqueous solution of ammonia at 28%. The mixture is stirred at 100° C. for 4 hours. The solution is cooled then the solvents are evaporated. The residue is taken up in 10 mL of anhydrous ethanol. A solution of 1.1 mL (15 mmol) of thionyl chloride in 4.5 mL of anhydrous ethanol is then added slowly. The reaction mixture is stirred at 70° C. for 48 hours then cooled to room temperature. The solvents are evaporated and the residue is purified by chromatography on silica (eluent chloroform/methanol/ammonia 85/13/2) to give 18 mg (3%) of 4-oxo-8-sulfamoyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](=[O:18])[CH:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:14]1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]C>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28])=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](=[O:18])[CH:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:14]1
Reactant: COC(=O)c1cc(Cl)c(-n2[nH]c(NC(=O)c3ccccc3)cc2=O)c(Cl)c1
Reactant: CCCCCCCCCCCCCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCCCCCCCCCCCOC(=O)c1cc(Cl)c(-n2[nH]c(NC(=O)c3ccccc3)cc2=O)c(Cl)c1

Procedure:
1-(2,6 -Dichloro-4-methoxycarbonylphenyl)-3-benzamido-5-pyrazolone prepared by the method as described in step (1) was reacted with 1-tetradecanol in the presence of butyl titanate as catalyst in a manner similar to Synthesis Example 1 to obtain the desired coupler, 1-(2,6 -dichloro-4-n-tetradecyloxycarbonylphenyl)-3-benzamido-5-pyrazolone as colorless crystals. The melting point of the product as 146°-147°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:10][C:6]1[CH2:7][CH2:8][CH2:9][C:5]=1[CH2:4][CH2:3][O:2][CH3:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COCCC1CCCC1=O
Product: COCCC1=C(OC(C)=O)CCC1

Procedure:
The subject compound is prepared from 2-(2-methoxyethyl)cyclopentan-1-one (Example 895) and acetic anhydride by the procedure of Example 10. The product is an oil, b.p. 60° C. (0.2 mm.).