Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-:16].[Na+].CCCC[O:22][C:23]([CH:25]=[CH2:26])=[O:24]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:26][CH2:25][C:23]([OH:22])=[O:24])([CH2:26][CH2:25][C:23]([OH:22])=[O:16])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: C=CC(=O)OCCCC
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)CCC1(CCC(=O)O)c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 0.25 h
Yield: 55 %

Procedure:
After 2,7-dibromofluorene (8.02 g) and benzyltriethylammonium chloride (0.56 g) were dissolved in 30 mL of benzene, 8 mL of an aqueous 50% sodium hydroxide solution was added dropwise under a nitrogen atmosphere, followed by stirring for 15 minutes. N-butyl acrylate (12.65 g) was added dropwise and the mixture was reacted at room temperature for 5 hours. The reaction solution was diluted with 200 mL of ethyl acetate, washed three times with water, washed once with brine, and then the organic layer was dried over magnesium sulfate. The solution was filtered and the solvent was distilled off. The solution was purified by silica gel column chromatography using dichloromethane as an eluent and then recrystallized from hexane to obtain (2,7-dibromo)-9H-fluorene-9,9-dipropionic acid (F2COOBuBr2) (7.87 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](OC)=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH:26](O)[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(C1C=C(C)C(S(F)(F)[F:45])=C(C)C=1)(C)(C)C.[C:49](=[O:52])([O-])O.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:52][CH3:49])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH:26]([F:45])[CH2:27][C:28]([CH3:30])([CH3:31])[CH3:29]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)CC(C)(C)C)c2)cc1
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(F)(F)F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(F)CC(C)(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)-3,3-dimethylbutan-1-ol (220 mg) in toluene (5 mL) was added 4-(tert-butyl)-2,6-dimethylphenylsulfur trifluoride (188 mg) at 0° C., and the mixture was stirred at 0° C. for 20 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (180 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH2:21][CH3:22].[CH3:23][CH2:24][O:25][C:26]([CH:28](P(OCC)(OCC)=O)[F:29])=[O:27].C([Li])CCC>C1COCC1>[Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:28](/[F:29])\[C:26]([O:25][CH2:24][CH3:23])=[O:27])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1c(C(C)=O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Cl)c1OCC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-ethanone (Compound A-121, 0.23 g, 0.72 mmol) and triethyl 2-fluoro-2-phosphonoacetate (566 mg, 2.3 μmmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.46 mL, 2.3 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% to 4% ethyl acetate in hexane).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:73][C:74]([F:79])([F:78])[C:75]([O-:77])=[O:76].[CH3:80][N+:81]1[C:82]([SH:91])=[N:83][C:84]2[C:89]=1[CH:88]=[CH:87][N:86]([CH3:90])[CH:85]=2>>[F:73][C:74]([F:79])([F:78])[C:75]([O-:77])=[O:76].[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:91][C:82]4[N+:81]([CH3:80])=[C:89]5[CH:88]=[CH:87][N:86]([CH3:90])[CH:85]=[C:84]5[N:83]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc2[n+](C)c(S)nc-2c1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(COC(=O)C2=C(CSc3nc4cn(C)ccc-4[n+]3C)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 87.2 %

Procedure:
Using 306 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-chloromethyl-3-cephem-4-carboxylate and 153 mg of 1,5-dimethyl-2-mercaptoimidazolo[4,5-c]pyridinium trifluoroacetate in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercapto-4-methylthiazolo[5,4-b]pyridinium trifluoroacetate, respectively, the reaction and purification were carried out in the same manner as in Example 15(a) to obtain 334 mg of the title compound in a yield of 88%.
Reaction SMILES: [F:1][C:2]([S:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([F:4])[F:3].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23]>>[O-:24][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21].[F:3][C:2]([F:1])([F:4])[S+:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=1[F:20]
Reactant: Fc1cccc(F)c1
Reactant: O=S(c1ccccc1)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: Fc1ccc([S+](c2ccccc2)C(F)(F)F)c(F)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Synthetic details: To a solution of phenyl trifluoromethyl sulfoxide (5) (485 mg, 2.5 mmol) in dry 1,3-difluorobenzene (7.4 mL, 75 mmol) was added (CF3SO2)2O (2.10 mL, 12.5 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C., and then at rt for another 20 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using CH3CN—CH2Cl2 (1:4) as eluent. The product was obtained as a white crystal (770 mg, 70%), m. p. 78-9° C. (recrystallized from ethyl acetate/hexanes). IR (nujol): 3099 (s), 1600 (s), 1479 (s), 1450 (s), 1200 (s) (cm−1); 1H NMR (CDCl3): 8.26 (d, J2′3′=8.1 Hz, J4′3′=8.1 Hz, 3H), 7.90 (bd, J657.5 Hz, 1H), 7.75 (dd, J3′2′=7.8 Hz, J3′4′=7.8 Hz, 2H), 7.45 (dd, J56=8.1 Hz, J54F=7.8 Hz, 1H), 7.25 (dd, J32F=9.0 Hz, J34F=9.0 Hz, 1H); 19F NMR (CDCl3): −47.6 (s, 3F), −78.3 (s, 3F), −91.7 (s, 1F), −98.2 (s, 1F); 13C NMR (CDCl3): 168 (d, J=261 Hz), 163 (d, J=262), 138, 137, 133, 132, 126 (q, J=262), 123 (q, J=262 Hz), 120, 117, 115, 108 ppm; FAB+-MS [m/e (species, intensity)]: 291 ((C13H8F5S)+, 100), 222 ((C13H8F5S)+-CF3, 80.6), 145 ((C13H8F5S)+-C6H5-CF3, 15.0) ); Chemical analysis: Calculated for C14H8F8O3S2: C, 38.18; H, 1.83; F, 34.52. Found: C, 37.97; H, 1.88; F, 34.90.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (620 mg, 1.60 mmol) is coupled to 4′-bromo-2,2,2-trifluoroacetophenone (400 mg, 1.60 mmol) using Method B to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[O:23]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[O:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:30]1[CH2:31][CH2:32][C:27]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:28][CH2:29]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
To a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassium carbonate (5.35 g) and DMF (30 mL), 1,4-dioxa-8-azaspiro[4.5]decane (4.15 g) was added and stirred at 80° C. for 20 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 100:1) to give 8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (5.13 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]([C:18]2[S:22][C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:20][CH:19]=2)=[O:17])=[C:13]([F:30])[CH:12]=1)(=[NH:10])[NH2:9]>S(Cl)(Cl)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]([C:18]2[S:22][C:21]([CH2:23][CH2:24][C:25]([N:9]([CH2:8][CH:11]=[CH2:12])[CH2:2][C:3]([OH:5])=[O:4])=[O:27])=[CH:20][CH:19]=2)=[O:17])=[C:13]([F:30])[CH:12]=1)(=[NH:10])[NH2:9]
Reactant: N=C(N)c1ccc(OC(=O)c2ccc(CCC(=O)O)s2)c(F)c1
Solvent: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(CC(=O)O)C(=O)CCc1ccc(C(=O)Oc2ccc(C(=N)N)cc2F)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 167.9 %

Procedure:
3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]propanoic acid trifluoroacetic acid salt (38 mg, 0.084 mmol) was dissolved in thionyl chloride (500 μL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, M-21 (18.8 mg, 0.11 mmol), dichloromethane (200 μL) and pyridine (300 μL) were added to the obtained residue, and the mixture was stirred for 90 minutes. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (500 μL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (acetonitrile-water, each containing 0.1% trifluoroacetic acid, 5-35%) to give the title compound (25.5 mg, 0.047 mmol, 55%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[F:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1c(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and 4-fluorobenzene-1-sulfonyl chloride to give 5,7-difluoro-2-(4-(4-fluorophenylsulfonyl)-piperazin-1-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.97 (br s, 3H), 3.04 (t, J=4.8 Hz, 4H), 3.11 (br s, 4H), 3.33-3.37 (m, 4H), 3.69 (t, J=4.4 Hz, 4H), 6.48 (s, 1H), 7.13-7.19 (m, 1H), 7.25-7.28 (m, 1H), 7.49-7.54 (m, 3H), 7.77 (d, J=2.0 Hz, 1H), 7.84-7.88 (m, 2H,), 8.34 (s, 1H). Mass Spectrum (ESI) m/e=599.4 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[N+:2]=[N-:3].C([O-])([O-])=[O:15].[K+].[K+].OO>CO.O>[N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[O:15])=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1ccc(CCN=[N+]=[N-])cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCc1ccc(C(N)=O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of 4-(2-azidoethyl)benzonitrile (1.0 g, 5.81 mmol) in a 5:1 mixture of MeOH/H2O (100 mL), K2CO3 (4.41 g. 31.94 mmol) was added and the resulting solution cooled to 0° C. Then 15.4 mL of a 30% H2O2 solution was added and the reaction was allowed to warm to room temperature. After stirring at room temperature for approximately three hours, the crude reaction mixture was concentrated under reduced pressure to remove MeOH and then extracted with EtOAc (3×100 mL). Combined organics were dried over sodium sulfate, filtered, and concentrated in vacua. Crude product was subjected to silica gel purification eluting with 1% MeOH in CH2Cl2 to give 1.06 g (96%) of 4-(2-azidoethyl)benzamide.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7]1.[CH2:13]=O.[P:15]([OH:18])([OH:17])[OH:16]>O>[OH:2][CH2:3][CH2:4][N:5]([CH2:13][P:15]([OH:18])([OH:17])=[O:16])[CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7]1
Reactant: OP(O)O
Reactant: C=O
Reactant: O=S1(=O)CCC(NCCO)C1
Agent: Cl
Solvent: O
Product: O=P(O)(O)CN(CCO)C1CCS(=O)(=O)C1
Yield: 61.9 %

Procedure:
A solution of tetrahydro-N-hydroxymethyl-3-thiophenamine 1,1-dioxide hydrochloride of Example 3 (21.5 parts, 0.1 mole); 90 percent paraformaldehyde (3.7 parts, 0.11 mole); 70 percent aqueous orthophosphorous acid (12.9 parts, 0.11 mole); and water (6.0 parts) was heated at its reflux temperature for 3 hours. The product could not be isolated as a filterable solid due to its hygroscopic nature. The solution containing 61.9 percent of the title compound was used for testing without any further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:12][O:13][CH3:14])=[CH:7]2.[OH-:15].[Na+]>O.[Ta]>[OH:15][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:12][O:13][CH3:14])=[CH:7]2
Reactant: [OH-]
Reactant: COCc1cnc2c(Cl)cccc2c1
Agent: [Ta]
Agent: [Na+]
Solvent: O
Product: COCc1cnc2c(O)cccc2c1
Reaction time: 21.5 h
Yield: 63.2 %

Procedure:
Into a tantalum liner in a 600 ml stirred Parr pressure reactor is placed 4.15 g 8-chloro-3-methoxymethylquinoline (20 mmol), 8.0 g 50% aqueous sodium hydroxide (100 mmol) and a solution of 250 mg cupric sulfate pentahydrate (1.0 mmol, 5 mole percent) in 95 ml of water. Sodium hydroxide concentration is 4%. The system is sealed, brought to 160 degrees C and held for 21.5 hours. The cooled solution is filtered through Celite, extracted with two 20 ml portions of toluene, then the aqueous layer is adjusted to pH 3-4 with sulfuric acid and finally to pH 7 with ammonium hydroxide. The mixture is extracted with two 50 ml portions of ethyl acetate. Rotary evaporation of the organic layer gives 2.39 g (63% yield) of crude 8-hydroxy-3-methoxymethylquinoline as a yellow green solid. The crude material is treated with two 500 ml portions of boiling water, leaving behind some insolubles. Long silky yellow needles of pure 8-hydroxy-3-methoxymethylquinoline separate. After filtering and drying, 1.83 g (48% yield) is obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>C1COCC1>[Cl:14][C:15]1[N:20]=[C:19]([N:11]2[CH:10]=[CH:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccc(-n2ccnc2-c2ccccc2)n1
Temperature: 50 °C

Procedure:
To a solution of 2-phenylimidazole (1-2, 484 mg, 3.36 mmol) in dry THF (15 mL) was added NaH (130 mg, 60% dispersion in mineral oil, 3.36 mmol) at room temperature. After gas evolution had ceased, 2,4-dichloropyrimidine (3-1, 0.5 g, 3.36 mmol) was added. The mixture was heated to 50° C. After 18 hours the mixture was cooled to room temperature, quenched with saturated NH4Cl, and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (50% EtOAc/hexanes) gave 2-chloro-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine as a gum. 1H-NMR (300 MHz, CDCl3) δ 8.40 (d, J=5.38 Hz, 1H), 7.80 (s, 1H), 7.45 (m, 5H), 7.25 (s, 1H), 6.68 (d, J=5.38 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[OH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26](=N)OC)=[CH:24][CH:23]=1>CO>[CH:14]1([N:13]2[C:12]3[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=3[N:1]=[C:26]2[C:25]2[CH:30]=[CH:31][C:22]([OH:21])=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Reactant: COC(=N)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Yield: 72.5 %

Procedure:
Ethyl 3-amino-4-cyclohexylaminobenzoate (130 g) obtained in Example 1, Step 3, and methyl 4-hydroxybenzimidate hydrochloride (139 g) were added to methyl alcohol (1500 ml), and the mixture was refluxed under heating for 4 hr. The reaction mixture was allowed to cool and the precipitated crystals were collected by filtration to give the title compound (131 g, yield 72%).
Reaction SMILES: O[CH2:2][C@H:3]([C@@H:5]([C@H:7]([C@H](CO)O)O)O)O.[CH2:13](O)[C@H]1O[C@H](O[C@:21]2([CH2:30]O)O[C@H:24]([CH2:26]O)[C@@H:23](O)[C@@H:22]2O)[C@H](O)[C@@H](O)[C@@H]1O.C(O)[C@H]1[O:43][C:41](=[O:42])[C@H:40](O)[C@@H:39](O)[C@@H]1O>>[CH:5]([C:3]1[CH:2]=[CH:26][CH:24]=[CH:23][C:22]=1[CH:21]=[CH2:30])=[CH2:7].[C:41]([OH:43])(=[O:42])[C:40]([CH3:13])=[CH2:39]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: C=C(C)C(=O)O
Product: C=Cc1ccccc1C=C
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
Ingredients. (1) Diglycerol 10.0 (2) Sucrose 74.0 (3) Gluconolactone (10% solution in water) 10.0 (4) Preservative 1.0 (5) Divinylbenzene/methacrylic acid copolymer 1.0 (6) Zeolite 4.0. Procedure. Mix (2) to (5) and heat at 90 to 120 C. for 30 to 45 minutes to a clear liquid. Add (1) and (6) and mix. Cool to room temperature. An opaque mobile sticky liquid is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([I:24])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cccnc1Cl
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cccnc1Oc1cccc(I)c1

Procedure:
A solution 2-Chloro-nicotinic acid benzyl ester (1.7 grams, 6.86 mmole), cesium carbonate (4.5 grams, 13.7 mmole) and 3-iodophenol (1.7 grams, 7.54 mmole) in dimethylformamide (20 ml) was stirred for 2 hours at 70-80° C. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent (2.32 g). MW 431.24; MS (m/e) 432 (M++1).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1C.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][OH:32])[CH:27]=[CH:28][C:29]=1[F:30]>>[F:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:31][O:32][C:2]1[CH:12]=[C:6]2[N:7]([CH2:11][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:15])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: Cc1ccccc1CBr
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: Cc1ccccc1CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and 1-(bromomethyl)-2-methylbenzene and (3,4-difluorophenyl)methanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(Cl)(Cl)Cl>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1]
Reactant: Oc1ccc2ccccc2n1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccccc2n1CCCCBr
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 6424.9 %

Procedure:
2-hydroxyquinoline (0.29 g, 2.0 mmoles) was dissolved in 4 ml of dimethylformamide, 60% sodium hydride (80 mg, 2.0 mmoles) was added to the solution, and the mixture was stirred at 60° C. for 30 minutes and then cooled to room temperature. 1,4-dibromobutane (2.16 g, 10 mmoles) was further added, and the resulting mixture was stirred at 60° C. for 4 hours. After chloroform was added to the reaction mixture, insolubles were removed by filtration, the filtrate was washed with water, and the solvent was evaporated. The residue thus obtained was purified by chromatography on a silica gel column to give 36 g (yield 64%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].[C:23](#[N:27])[CH2:24][C:25]#[N:26]>>[NH2:27][C:23]1[O:1][C:2]2[C:10]([CH:18]([C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=3)[C:24]=1[C:25]#[N:26])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH:5]=[CH:4][C:3]=21
Reactant: N#CCC#N
Reactant: Cn1ccc2c(O)cccc21
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: Cn1ccc2c3c(ccc21)C(c1cccc([N+](=O)[O-])c1)C(C#N)=C(N)O3

Procedure:
The title compound was prepared from 4-hydroxy-1-methylindole (40 mg, 0.27 mmol), 3-nitrobenzaldehyde (41 mg, 0.27 mmol) and malononitrile (18 mg, 0.27 mmol) similar to Example 24 to yield 61 mg (65%) of white solids. 1H NMR (CDCl3): 8.10 (d, J=7.8 Hz, 1H), 8.05-8.04 (m, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.08-7.02 (m, 2H), 6.69 (d, J=8.7 Hz, 1H), 6.59 (d, J=3.0 Hz, 1H), 5.00 (s, 1H), 4.76 (s, 2H), 3.78 (s, 3H).