Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(O)c2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(OCc3ccccc3)c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 5,6-dihydro-4-(3-hydroxyphenyl)pyridine-1(2H)-carboxylate (crude, 100 mg) and potassium carbonate (300 mg) in DMF was added benzyl bromide (60 μL) at room temperature. The resulting mixture was stirred at 80° C. for 16 h. The mixture was cooled down, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The product (60 mg) was purified by combiflash using hexane/ethyl acetate (max. EtOAc 10%) to afford tert-butyl 4-(3-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate which was then converted to the final compound using procedures analogous to those for example 1. MS(ESI): (M+H)+=462.2
Reaction SMILES: [CH2:1]([C:15]1([CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])SCCCS1)[CH2:2][C:3]1([CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])SCCCS1.[OH2:27].[OH2:28].O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CO.O1CCCC1>[CH3:13][N:12]([CH3:14])[CH2:11][CH2:10][CH2:9][C:3](=[O:28])[CH2:2][CH2:1][C:15](=[O:27])[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]
Reactant: CN(C)CCCC1(CCC2(CCCN(C)C)SCCCS2)SCCCS1
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCCC(=O)CCC(=O)CCCN(C)C
Temperature: 25 °C
Yield: 43.6 %

Procedure:
First, 695 mg of 2,2'-ethylenebis[2-(3-dimethylaminopropyl)-m-dithian] was dissolved in 24 ml of absolute methanol and 6 ml of absolute tetrahydrofuran, and after adding dropwise a solution of 3.12 g of thallium (III) nitrate trihydrate in 18 ml of absolute methanol over 2 minutes while stirring at a room temperature, the mixture was stirred for 30 minutes, filtered to remove insoluble matter, and evaporated under a reduced pressure to remove the solvent. After adding 30 ml of water, the mixture was extracted with 100 ml and 50 ml of chloroform. The extracts were combined, washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/methanol/triethylamine (80:20:1) to obtain 178 mg of the title compound as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].N[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH2:20][CH2:19]1>>[CH2:6]([OH:7])[CH2:5][CH2:4][CH2:3][CH3:2].[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[N:8]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)[CH2:22][CH2:23]3)[C:9]2=[O:10])=[CH:11][C:12]=1[S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Product: CCCCCO
Product: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3cccc(C(F)(F)F)c3)CC1)C2=O

Procedure:
Reaction of 4-chloro-5-sulfamoylphthalimide (10.1 g., 0.0386 mole) and 4-amino-1-(3-trifluoromethylbenzyl)piperidine (10.0 g., 0.0386 mole) in 200 ml. of n-pentanol according to the procedure of Example 1(a) afforded the crude 1,3-dioxoisoindole product purified by chromatography to yield 8.1 g. (42% yield) of 6-chloro-2,3-dihydro-1,3-dioxo-2-[1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-1H-isoindole-5-sulfonamide. The NMR spectral data was consistent for the compound used without further purification below.
Reaction SMILES: CC1(C)CCN(C2C=CC(SC(F)(F)F)=CC=2)C(=O)N1CC1C2C(=NC=CC=2)NC=1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34].[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[O:48])=[CH:42][CH:41]=1>>[OH:34][CH2:33][C:32]([NH:31][C:47]([NH:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][C:38]([F:37])([F:49])[F:50])=[CH:41][CH:42]=1)=[O:48])([CH3:36])[CH3:35]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(N)CO
Agent: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1c[nH]c2ncccc12
Product: CC(C)(CO)NC(=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
1-(1-hydroxy-2-methylpropan-2-yl)-3-[4-(trifluoromethoxy)phenyl]urea was prepared similar to compound 5, but the following reagents were used: 2-amino-2-methyl-1-propanol and 4-(trifluoromethoxy)phenylisocyanate. LCMS [M+H]+=293.1.
Reaction SMILES: C1CCCCCCC=1.ON1[C:14](=O)[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].O=O>C(#N)C>[C:11]1(=[O:20])[CH2:14][CH2:13][CH2:16][CH2:17][CH2:18][CH:19]=[CH:12]1.[CH:11]1([OH:20])[CH2:14][CH2:13][CH2:16][CH2:17][CH2:18][CH:19]=[CH:12]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C1=CCCCCCC1
Agent: O=O
Solvent: CC#N
Product: O=C1C=CCCCCC1
Product: OC1C=CCCCCC1
Yield: 78 %
Yield: 15 %

Procedure:
A mixture of 1.10 grams (10 millimoles) of cyclooctene, 0.13 gram (0.8 millimole) of N-hydroxyphthalimide, 0.021 gram (0.06 millimole) of acetylacetonatocobalt Co(AA)2 and 25 milliliters of acetonitrile was stirred in an oxygen atmosphere at a temperature of 100° C. for 6 hours. The product in the reaction mixture was analyzed with gas chromatography. Cyclooctene was transformed, with a transformation rate of 95%, into 2-cycloocten-1-one (cyclooctene-based selectivity 82%, yield 78%) and 2-cycloocten-1-ol (cyclooctene-based selectivity 16%, yield 15%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([OH:26])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][C:17]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[CH:28](N(CC)C(C)C)(C)[CH3:29].ClCCl.F[B-](F)(F)F.C([O+](CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([O:26][CH2:28][CH3:29])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][C:17]3([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:16]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(O)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CC(OCC)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of 3-hydroxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid ethyl ester (4.98 g) obtained in Step 7 and N,N-diisopropylethylamine (6.97 mL) in chloroform (100 mL) was added dropwise a 1M dichloromethane solution of triethyloxonium tetrafluoroborate (20 mL) under ice-cooling over 5 minutes, followed by stirring the reaction mixture under ice-cooling for 10 minutes and then at room temperature for 2.5 hours. Then, the reaction mixture was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio) 1:5) to give 3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-pr opionic acid ethyl ester (2.175 g).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:17]2[C:18](=[O:38])[C:19]([O:36]C)=[C:20]3[C:25]([CH2:24][CH2:23][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=4)[C:21]3=[O:35])=[C:16]2[C:15](=[O:39])[N:14]([CH3:40])[CH2:13][CH2:12][CH2:11]1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[CH2:26][N:22]1[CH2:23][CH2:24][C:25]2[C:20](=[C:19]([OH:36])[C:18](=[O:38])[N:17]3[C@@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][CH2:13][N:14]([CH3:40])[C:15](=[O:39])[C:16]3=2)[C:21]1=[O:35]
Reactant: COc1c2c(c3n(c1=O)[C@@H](COCc1ccccc1)CCCN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCC[C@H](CO)n2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (6R)-6-[(benzyloxy)methyl]-11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-napthyridine-1,8,10(11H)-trione (167 mg, 0.29 mmol) in dichloromethane (2.9 mL) was cooled to 0° C. and treated with boron tribromide (295 mg, 1.18 mmol). The cooling bath was removed and the mixture stirred at room temperature for 30 minutes. The reaction was quenched by the addition of MeOH followed by 1N aqueous HCl. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: O[C:2]1[S:3][C:4](I)=[CH:5][C:6]=1C.CN(C)[CH:11]=[O:12]>>[OH:12][CH2:11][C:2]1[S:3][C:4]([C:4]2[S:3][C:2]([CH2:11][OH:12])=[CH:6][CH:5]=2)=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(I)sc1O
Product: OCc1ccc(-c2ccc(CO)s2)s1

Procedure:
5,5'-Dihydroxymethyl-2,2'-bithiophene was also obtained by refluxing 2-hydroxy-methyl-5-iodo-thiophene with Cu powder in dimethyl formamide. The Ullmann condensation yielded a very poor amount of 5,5'-dihydroxymethyl-2,2'-bithiophene.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[N+:18]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[NH:1][CH2:2][C:3]([CH3:5])([NH2:6])[CH3:4])=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CC(C)(N)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 8 h
Yield: 97.4 %

Procedure:
1,2-Diamino-2-methylpropane (8.4 mL, 80.0 mmol) was added to a chilled (0° C.), solution of 4-chloro-3-nitro[1,5]naphthyridine (15.2 g, 72.7 mmol) and triethylamine (20.2 mL, 145 mmol) in dichloromethane (350 mL). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was combined with water (300 mL) and heated at reflux with stirring for 1 hour. The reaction mixture was cooled and filtered. The isolated solid was washed with water and then dried under high vacuum to provide 18.5 g of N1-(3-nitro[1,5]naphthyridin-4-yl)-2-methylpropane-1,2-diamine as a bright yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9](Br)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1Br.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:24]1[S:23][CH:22]=[CH:26][CH:25]=1
Reactant: COc1c(Br)ccc2c(OC)c(Br)ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1c(-c2cccs2)ccc2c(OC)c(-c3cccs3)ccc12
Yield: 95 %

Procedure:
1,5-Dimethoxy-2,6-dibromonaphthalene (1.00 g., 0.0029 mol.) and 2-(tributylstannyl)thiophene (4.314 g., 0.0116 mol.) were dissolved in 100 mL dry toluene in argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlenk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 300 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2:petroleum ether (1:5), the desired product was obtained as a light yellow solid. Yield: 95%. M.p. 225-228° C. Anal. Calcd. for C20H16O2S2: C, 68.15%; H, 4.58%; S, 18.19%. Found: C, 67.98%; H, 4.53%; S, 18.03%. Mass spectrum: 351.84 (M+). 1H-NMR (CDCl3; □ in ppm): 3.88 (s, 3H), 7.16 (dd, 2H), 7.43 (dd, 2H), 7.63 (dd, 2H), 7.83 (d, 2H, 9 Hz), 7.96 (d, 2H, 9 Hz). 13C-NMR (CDCl3; □ in ppm): 61.3, 119.0, 123.2, 125.7, 126.5, 126.6, 126.9, 129.2, 138.9, 152.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11]Br.O.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:11][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([F:1])=[CH:3][C:4]=1[OH:10]
Reactant: COc1ccc(O)cc1F
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(Br)c(O)cc1F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
3-Fluoro-4-methoxy-phenol (21.32 g; 0.15 mol) prepared according to literature [Freedman, J.; Stewart, K. T.; J. Heterocycl. Chem. 1989, 26, 1547-1554] is dissolved in dry dichloromethane (300 mL). The well stirred reaction mixture is cooled to −15° C. (ice/salt). A solution of bromine (23.97 g; 0.15 mol) in dry dichloromethane (75 mL) is slowly dropped into the reaction mixture. After complete addition stirring is continued for one hour. Water (150 mL) containing sodium sulfite (3.0 g) is added to the reaction mixture. Stirring is continued at ambient temperature for 30 min. The organic layer is separated, washed with water (100 mL) and dried over MgSO4 in the presence of decolorizing charcoal. After filtration the solvent is completely removed under reduced pressure. The residue is crystallized from tert-butylmethylether/hexane to give the title compound as a colorless solid. Yield: 30.74 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([CH3:23])=[N:9]2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:41]=[CH:40][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]3[NH:36][C:37](=[O:39])[NH:38][C:31]=23)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([O:29][C:30]4[CH:35]=[CH:34][N:33]=[C:32]5[NH:36][C:37](=[O:39])[NH:38][C:31]=45)=[CH:40][CH:41]=3)=[O:22])=[CH:11][C:10]([CH3:23])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(=O)Oc2ccccc2)n(-c2ccc(Cl)cc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Product: Cc1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)[nH]c34)cc2)n(-c2ccc(Cl)cc2)n1
Yield: 81.4 %

Procedure:
Method F was used with phenyl 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl-carbamate (41 mg, 0.12 mmol) and 7-(4-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (20 mg, 0.08 mmol). The solid residue obtained after evaporation of the solvents was washed only with Et2O to afford the title compound (31 mg, 79%) as a pale pink solid. 1H-NMR (6, ppm, DMSO-d6): 2.19 (s, 3H, CH3), 6.28 (s, 1H, HPyz,4), 6.31 (d, 1H, HPy,5, J=5.8 Hz), 7.10 (d, 2H, Harom,Ph,3+5, J=8.9 Hz), 7.47 (d, 2H, Harom,Ph,2+6, J=8.9 Hz), 7.57 (m, 4H, Harom,4—Cl—Ph), 7.74 (d, 1H, HPy,6, J=5.8 Hz), 8.47 (bs, 1H, NHurea), 9.05 (bs, 1H, NHurea), 11.19 (bs, 1H, NHPy3), 11.37 (bs, 1H, NHPy2). 13C-NMR (6, ppm, DMSO-d6): 13.7, 99.3, 105.1, 112.8, 119.8, 120.5, 125.7, 129.2, 131.5, 136.3, 137.2, 137.5, 141.2, 145.8, 146.8, 148.2, 148.5, 151.6, 154.1. LC-MS (m/z): 476 (M+H, 100). HRMS (EI): m/z [M+H]+ calcd. for C23H19N7O3Cl: 476.1238; found: 476.1213.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][CH2:3]1.[C:14](=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>C(#N)C>[CH3:14][N:4]1[CH2:3][N:2]([CH3:1])[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=2[S:5]1(=[O:13])=[O:12]
Reactant: CN1CNS(=O)(=O)c2cnccc21
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CC#N
Product: CN1CN(C)S(=O)(=O)c2cnccc21

Procedure:
A solution of 0.25 g of 4-methyl-2,3-dihydro-4H- pyrido[4,3e][1,2,4]thiadiazine 1,1-dioxide (Example 5) in 8 cm3 of acetonitrile is treated with 0.5 g of potassium carbonate (±3 eq.) and then with 0.26 g of methyl p-toluenesulfonate (1.1 eq.). The suspension obtained is brought to reflux for 2 hours. The solvent is then removed by evaporation under reduced pressure and the residue is distributed between 10 cm3 of water and 100 ml of chloroform. The aqueous phase is then extracted twice with 50 cm3 of chloroform. The combined organic fractions are dried over MgSO4, filtered and then concentrated to dryness. The residue is dissolved in the minimum amount of chloroform. The addition of an excess of petroleum ether (40°-60° C.) causes precipitation of the crystals of the title product. They are collected on the filter, washed with petroleum ether (40°-60° C.) and dried. Yd. : 60-65%
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1.[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:41][C:38]4[CH:39]=[CH:40][O:36][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.070 g, 1.857 mmol), isoxazol-3-amine (0.158 ml, 2.135 mmol) and THF (12.38 ml) to give a clear solution. The flask was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.90 ml, 3.90 mmol) was added dropwise. After 10 min, the mixture was diluted with EtOAc and washed with 1N aq. HCl. The aq. layer was washed with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered; and concentrated. The residue was purified by chromatography (50-g SNAP Ultra column, 25-g silica gel loading column, 0-5% MeOH/DCM) to give 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.867 g) as a tan foam that was ca. 90% pure. m/z (ESI) 476.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].[CH2:26]=[O:27].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[O:27])[CH3:19]
Reactant: C=O
Reactant: CCc1ccccc1
Agent: O=C(O)c1cc(Cc2ccccc2)ccc1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1ccccc1C=O

Procedure:
To a mixture of 22.8 parts of 5-benzylsalicylic acid, 21.2 parts of ethylbenzene, 3.8 parts of 87% paraformaldehyde and 25 parts of acetic acid was added 1.0 part of 95% sulfuric acid (catalyst). After being heated under reflux for 4 hours, the reaction mixture was washed with water, and unreacted ethylbenzene and water were removed by vacuum distillation to give 33 parts of 5-benzylsalicylic acid-ethylbenzene-formaldehyde co-condensation product. 10 parts of the co-condensation product was converted into its zinc salt in a similar manner as in Synthesis Example 1. There was obtained 11 parts of zinc salt of 5-benzylsalicylic acid-ethylbenzene-formaldehyde co-condensation product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.F[C:16]1[CH:32]=[CH:31][C:19]([O:20][CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:18][C:17]=1[N+:33]([O-])=O.[CH2:36]([C:38]1([CH2:45][CH3:46])[CH2:42][C:41](=O)[O:40][C:39]1=[O:44])[CH3:37]>>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:20][C:19]1[CH:31]=[CH:32][C:16]2[N:14]([CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][CH:9]=3)[C:37]([CH2:36][C:38]([CH2:45][CH3:46])([CH2:42][CH3:41])[C:39]([OH:44])=[O:40])=[N:33][C:17]=2[CH:18]=1
Reactant: NCc1ccc(-c2ncccn2)cc1
Reactant: O=[N+]([O-])c1cc(OCc2nc3ccccc3s2)ccc1F
Reactant: CCC1(CC)CC(=O)OC1=O
Product: CCC(CC)(Cc1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2ncccn2)cc1)C(=O)O

Procedure:
The title compound was prepared using analogous conditions described in Example 208 using (4-(pyrimidin-2-yl)phenyl)methanamine and 2-((4-fluoro-3-nitrophenoxy)methyl)benzo[d]thiazole in step B and 3,3-diethyldihydrofuran-2,5-dione in step D using conventional heating. MS (ESI): mass calcd. for C33H31N5O3S, 577.71; m/z found, 578.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.87-8.78 (d, J=4.9, 2H), 8.43-8.36 (d, J=8.5, 2H), 8.05-7.96 (m, 2H), 7.61-7.57 (d, J=9.1, 1H), 7.57-7.51 (ddd, J=8.4, 7.2, 1.2, 1H), 7.48-7.42 (m, 2H), 7.39-7.35 (m, 1H), 7.35-7.32 (d, J=8.3, 2H), 7.30-7.24 (dd, J=9.1, 2.4, 1H), 5.89-5.76 (s, 2H), 5.70-5.61 (s, 2H), 3.40-3.37 (s, 2H), 1.92-1.71 (m, 4H), 0.93-0.82 (t, J=7.4, 6H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([I:11])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=O)C.C(Cl)(=O)C.O>CO>[NH2:4][C:5]1[CH:10]=[C:9]([I:11])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16]
Reactant: COC(=O)c1nc(I)cc(NC(C)=O)c1Cl
Solvent: CC(=O)Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(I)cc(N)c1Cl
Yield: 78.6 %

Procedure:
To solution of 4-acetylamino-3-chloro-6-iodopyridine-2-carboxylic acid, methyl ester (5.0 g, 14 mmol) in methanol (25 mL) was added acetyl chloride (1 mL) and the solution heated under reflux for 1 hour. The solution was cooled and water (25 mL) added and the precipitate was collected. Recrystallization from methanol gave 4-amino-3-chloro-6-iodopyridine-2-carboxylic acid, methyl ester (3.5 g, 11 mmol) mp 152-153° C.
Reaction SMILES: FC1C=CC(OC2C=C[C:10]([C:13]3[N:18]=C(C)C=CN=3)=[CH:9][CH:8]=2)=CC=1.CC(C)([O-:25])C.[K+].C1COCC1.C(O)(=O)C.[F:37][C:38]1[CH:53]=[CH:52][C:41]([O:42][C:43]2[CH:51]=[CH:50][C:46]([C:47]([NH2:49])=[NH:48])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1.COC(OC)CC(=O)C>CN(C=O)C>[F:37][C:38]1[CH:39]=[CH:40][C:41]([O:42][C:43]2[CH:51]=[CH:50][C:46]([C:47]3[N:49]=[C:10]([C:13]([NH2:18])=[O:25])[CH:9]=[CH:8][N:48]=3)=[CH:45][CH:44]=2)=[CH:52][CH:53]=1
Reactant: N=C(N)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccnc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: COC(CC(C)=O)OC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 100 °C

Procedure:
2-[4-(4-Fluorophenoxy)phenyl]-4-methylpyrimidine: A 1M solution of potassium tert-butoxide in THF (11 mL, 11 mmol) was added via syringe to a solution of 4-(4-fluorophenoxy)benzamidine acetate (2.92 g, 10.2 mmol) in DMF. The resulting mixture was heated at 100° C. for 2 hours. Acetylacetaldehyde dimethyl acetal (2 mL, 13.6 mmol) was added via syringe. The reaction was maintained between 100°-110° C. overnight when TLC indicated complete reaction. The reaction was allowed to cool to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water (3 times), dried over MgSO4, filtered, and evaporated under reduced pressure to give the desired product as a yellow oil. 1H NMR (CDCl3): δ8.60 (d, J=5.1, 1H), 8.40 (d, J=9.0, 2H), 7.05-7.00 (m, 7H), 2.57 (s, 3H). This material was carried on without further purification.