Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C].[K].[I-].[K+].[CH2:5]([O:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH3:8].[CH2:21](Cl)[C:22](=[CH2:24])[CH3:23]>CN(C)C=O>[CH2:5]([O:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:23][C:22]([CH3:24])=[CH2:21])=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH3:8]
Reactant: C=C(C)CCl
Reactant: CCCCOC(=O)C=Cc1ccc(O)cc1
Agent: [C]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C=CC(=O)OCCCC)cc1
Temperature: 70 °C

Procedure:
121 g (0.88M) of finely powdered potassium carbon are are introduced into 400 m N,N-dimethyl formamide. With stirring lg of potassium iodide, 176 g (0.8M) of p-hydroxy cinnamic acid n-butylester (see above) and 85 m (0.87M) of methallyl chloride are added. Under a blanket of nitrogen and with stirring the mixture is heated up to 70° C. and kept at that temperature until the starting material is consumed (about 21 hours). The mixture is cooled to room temperature and 500 m of water are added. The solution is extracted three times with a total of 1.2 liter of hexane and the hexane extracts are subsequently washed with a 10% solution of sodium carbonate and water. The hexane extract is evaporated at 30° C. in vacuo (about 12 mbar) to dryness. The residue is crystallised from 80 m of methanol at 0° C. The colourless crystalline product is collected by filtration and dried in high vacuo (about 0.1 mbar) at room temperature. 163.5 g (74.5% of theory) of product melting at 32°-33° C. are obtained.
Reaction SMILES: [F-].[C:2]1([N:12]([S:19]([F:22])([F:21])[F:20])[C:13]2C=CC=CC=2)[C:11]2[C:6](=CC=CC=2)[CH:5]=[CH:4][CH:3]=1>>[CH3:13][N:12]([S:19]([F:22])([F:20])[F:21])[C:2]1[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FS(F)(F)N(c1ccccc1)c1cccc2ccccc12
Agent: [F-]
Product: CN(c1ccccc1)S(F)(F)F

Procedure:
Deoxofluorination of cyclooctanol with diarylaminosulfur trifluorides proceeds rapidly at −78° C. in CH2Cl2 to produce cyclooctylfluoride and cyclooctene with the former predominating (Table 8). Differing ratios of fluoride to olefin were observed with the various aromatic substituted trifluorides. The sterically hindered N-naphthyl-N-phenylaminosulfur trifluoride reacted quite slowly affording only a 10% conversion of starting material to products after 16 h at room temperature. A rapid conversion to the monofluoride was obtained with N-methyl-N-phenylaminosulfur trifluoride. Among the alkoxyalkyl compounds 35-41 (Table 5), the phenyl substituted aminosulfur trifluoride (35) proved to be the most reactive affording fluorination at −78° C. in 1 h as compared to the methyl and bisalkoxyalkyl compounds (37, 41, respectively) which required longer reaction times (˜3 hr) at −78° C. to effect the same conversion.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[C:18](OC)([CH3:20])[CH3:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:12]([O:11][C:9]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2][O:1][C:18]([CH3:20])([CH3:19])[O:15][CH2:14]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Reactant: COC(C)(C)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Yield: 91 %

Procedure:
Diethyl 2,2-bis(hydroxymethyl)malonate (20 g, 90.82 mmol), acetone (20 ml), 2,2-dimethoxypropane (20 ml), and concentrated sulfuric acid (0.2 ml) were stirred at 25° C. for 2 days. The reaction was slowly poured into saturated aqueous sodium carbonate. The organic supernatant was separated and concentrated in vacuo. The residue was then dissolved in ether, rinsed with saturated aqueous sodium carbonate and brine, and then dried over magnesium sulfate, filtered and concentrated in vacuo to afford crude 2,2-dimethyl-[1,3]dioxane-5,5-dicarboxylic acid diethyl ester (21.4 g, 91%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.27 (t, J=7.1 Hz, 6H, 2×CH3), 1.42 (s, 6H, 2×CH3), 4.24 (q, J=7.1 Hz, 4H, 2×OCH2), 4.29 (s, 4H, 2×OCH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:20]1[CH:36]=[C:24]2[N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:37])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:17][O:18][C:20]1[CH:36]=[C:24]2[NH:25][CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:37])[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Product: O=c1nc(OCc2cc(F)c(Oc3ccc(F)cc3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (3,5-difluoro-4-(4-fluorophenoxyl)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:14]=1[CH2:15][S:16][C:17]1[CH2:21][C:20]([CH2:23][CH3:24])([CH3:22])[O:19][N:18]=1.O>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:14]=1[CH2:15][S:16]([C:17]1[CH2:21][C:20]([CH2:23][CH3:24])([CH3:22])[O:19][N:18]=1)=[O:9]
Reactant: CCC1(C)CC(SCc2c(F)cccc2F)=NO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC1(C)CC(S(=O)Cc2c(F)cccc2F)=NO1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
4.6 g of m-chloroperbenzoic acid (purity: 70%, 18.8 mmoles) was added, with ice-cooling, to a solution of 4.1 g (15.0 mmoles) of 3-(2,6-difluorobenzylthio)-5-ethyl-5-methyl-2-isoxazoline dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.5 g (yield: 34.8%) of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline as a white powder (melting point: 30° C. or less).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:23])[CH:3]=1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:3]1[C:4](=[O:23])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(c2ccccc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-phenyl-5,6-dihydro-pyran-2-one (0.2 g, 0.64 mmol) from Example TT, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.26 g, 0.71 mmol), K2CO3 (0.35 g, 2.5 mmol), and DMF (3 mL). The solution was stirred overnight at room temperature and then poured into 1N HCl and EtOAc. The organic phase was dried (MgSO4), and concentrated. Purification by silica gel chromatography, eluting with MeOH:CH2Cl2 :hexane (5:80:20 to 5:95:0) gave the title compound, m.p. 196°-199° C. 1H NMR (DMSO-d6) δ 1.44 (s, 9 H), 1.76 (s, 3 H), 2.08-2.21 (m, 3 H), 2.42 (m, 1 H), 3.41 (dd, 2 H), 4.32 (s, 2 H), 4.91 (br s, 1 H), 6.16 (s, 1 H), 6.61 (d, 2 H), 6.86 (d, 2 H), 7.21 (s, 1 H), 7.34-7.46 (m, 5 H), 9.14 (s, 1 H), 12.15 (bs, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH2:39]([OH:41])[CH3:40].C(N(CC)CC)C>ClCCl>[CH2:39]([O:41][C:21]([C@@:19]12[CH2:18][N:17]([S:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2)=[O:22])[CH3:40]
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 56 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride (0.1 g) in dry dichloromethane (5 mL) was treated with absolute ethanol (0.2 g) and triethylamine (0.1 g) for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (1:4 to 2:3 by volume) to afford the title compound as a white solid (0.057 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.77 (dd, 1H), 7.48-7.36 (m, 3H), 7.19-7.11 (m, 2H), 6.61 (d, 1H), 6.40 (d, 1H), 4.37 (d, 1H), 4.17 (qd, 2H), 3.80 (t, 5H), 3.66 (t, 4H), 3.29 (d, 1H), 2.95-2.86 (m, 1H), 2.57 (d, 1H), 2.44-2.34 (m, 3H), 1.25 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[NH3:15]>>[NH2:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: N
Product: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 120 °C

Procedure:
A suspension of 2-chloro-5-nitrobenzenesulfonamide (8 g) in concentrated aqueous ammonia (80 mL) was saturated with ammonia just before its introduction into a sealed vessel. The former was placed in an autoclave and heated at 120° C. for 5 h. The reaction mixture was then concentrated to the half volume by evaporation under reduced pressure and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (yield: 6.1 g); m.p. 202-204° C.
Reaction SMILES: NC1C(Cl)=NC=CN=1.Br.Cl[C:11]1[C:12]2[N:13]([CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=3[O:30][CH3:31])[N:19]=2)[CH:14]=[CH:15][N:16]=1.CN(C)C=O>C(N(CC)CC)C>[CH3:31][O:30][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:12]2[CH:11]=[N:16][CH:15]=[CH:14][N:13]2[CH:17]=1
Reactant: COc1cc(S(C)(=O)=O)ccc1-c1cn2ccnc(Cl)c2n1
Agent: Br
Agent: Nc1nccnc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(S(C)(=O)=O)ccc1-c1cn2ccncc2n1

Procedure:
Following the general procedure of Example 5(B), 3.88 g. of 2-amino-3-chloropyrazine and 9.21 g. of α-bromo-2-methoxy-4-methylsulfonylacetophenone were reacted to give 4.8 g. of the intermediate 8-chloro-2-(2-methoxy-4-methylsulfonylphenyl)imidazo[1,2-a]pyrazine hydrobromide. The hydrobromide salt (3.6 g.) was hydrogenated in 195 ml. of dimethylformamide and 2.7 g. of triethylamine in the presence of 1 g. of 5% palladium-on-barium sulfate. After filtration, the solution was poured into 700 ml. of ethyl acetate, washed four times with a saturated sodium chloride solution and the solvent concentrated in vacuo. At a reduced volume crystallization occurred and 540 mg. of the title product were recovered by filtration.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C@@H:8]2[O:25][C@H:24]([CH2:26][O:27]C(=O)C)[C@@H:19]([O:20]C(=O)C)[C@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[C:3]=1[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[C:39]2[CH2:41][CH2:40]2)=[CH:34][CH:33]=1.C[O-].[Na+]>CO>[C@@H:8]1([O:7][C:4]2[C:3]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([CH:38]=[C:39]4[CH2:41][CH2:40]4)=[CH:36][CH:37]=3)=[C:2]([CH3:1])[NH:6][N:5]=2)[O:25][C@H:24]([CH2:26][OH:27])[C@@H:19]([OH:20])[C@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(C=C3CC3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(C=C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A solution of 5-methyl-4-{[4-(cyclopropylidenemethyl)phenyl]methyl}-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.010 g) in methanol (2 mL) was added sodium methoxide (28% methanol solution, 0.0020 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 3-(β-D-glucopyranosyloxy)-5-methyl-4-{[4-(cyclopropylidenemethyl)phenyl]methyl}-1H-pyrazole (0.0070 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH2:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>ClCCl.[Cl-].[Na+].O>[C:29]([NH:14][CH2:13][CH2:12][S:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([NH2:1])[N:10]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: NCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To 6-amino-9-benzyl-2-(2-aminoethyl)thiopurine (50 mg, 0.17 mmol) suspended in 2 ml of dichloromethane was added triethylamine (30 ml, 0.2 mmol) and then acetic acid anhydride (20 ml, 0.2 mmol) under ice cooling. After 1 hour the mixture warmed to room temperature. Thereto was added saturated brine. The mixture was extracted with chloroform and the organic layer was dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (34 mg, yield 66%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=2)=[CH:20][C:19]=1[C:34]([F:37])([F:36])[F:35].BrCC1C=CC(Cl)=C(C(F)(F)F)C=1.OCC1C=CC(O)=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:30][CH:31]=2)=[CH:20][C:19]=1[C:34]([F:35])([F:36])[F:37]
Reactant: FC(F)(F)c1cc(COc2ccc(CCl)cc2)ccc1Cl
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: FC(F)(F)c1cc(CBr)ccc1Cl
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 1-Chloro-4-(4-chloromethyl-phenoxymethyl)-2-trifluoromethyl-benzene prepared from 1-bromomethyl-4-chloro-3-trifluoromethyl-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 299 (M−237).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=O)[CH2:12]1)=[O:10].F[B-](F)(F)F.C[O+](C)C.[CH3:27][C:28]1[S:32][CH:31]=[N:30][C:29]=1[C:33]([NH:35][NH2:36])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:33]([C:29]3[N:30]=[CH:31][S:32][C:28]=3[CH3:27])=[N:35][N:36]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2Cl)CCN1
Reactant: Cc1scnc1C(=O)NN
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1scnc1-c1nnc2n1CCN(C(=O)c1ccc(Cl)cc1Cl)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(2,4-Dichlorophenyl)carbonyl]-2-piperazinone (I6) (0.250 g, 0.915 mmol) was suspended in dry Dichloromethane (DCM) (3 mL) before treating with trimethyloxonium tetrafluoroborate (0.171 g, 1.098 mmol) and stirring for 16 hours at RT, under argon before adding 5-methyl-1,3-thiazole-4-carbohydrazide (I123)(0.216 g, 1.373 mmol) and stirring for a further 3 hours. DCM was removed by evaporation and the residue was dissolved in 1-butanol (3.00 mL) before heating at 110° C. for 19 hours. 3 Å molecular sieves were added and the reaction mixture was left heating for a further 6 hours before being cooled to RT over the weekend. The reaction was worked up by diluting with DCM (50 ml) and washing with saturated sodium bicarbonate solution (50 ml). The aqueous layer was extracted with DCM (2×30 ml), combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated to afford a brown gum. The product was purified by MDAP (formic acid method), the desired fraction isolated and the solvent evaporated to afford a colourless gum. Placed in a registration vial and dried overnight to afford an off white foam of desired product in 122 mg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N([C:10]1[N:19]=[C:18]2[C:13]([C:14](=[O:33])[C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16][N:17]2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[CH:12][C:11]=1[F:34])=[N+]=[N-].C(OCC)(=O)C.Cl>C(O)C.CN(C)C=O.C(OCC)C.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:17]1[C:18]2[C:13](=[CH:12][C:11]([F:34])=[C:10]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[N:19]=2)[C:14](=[O:33])[C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N=[N+]=[N-])c(F)cc2c1=O
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 84 %

Procedure:
In a mixture of 4.5 ml of ethanol and 4.5 ml of N,N-dimethylformamide was dissolved 400 mg of anhydrous piperazine, and 450 mg of ethyl 7-azido-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added to the resulting solution, after which the resulting mixture was subjected to reaction at 80° C. for 1 hour. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 30 ml of ethyl acetate and 30 ml of water, after which the pH thereof was adjusted to 1.0 with 2N hydrochloric acid. The aqueous layer was separated, and 15 ml of chloroform was added to the aqueous layer, after which the pH thereof was adjusted to 8.5 with 1N aqueous sodium hydroxide solution. The organic layer was separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 5 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 420 mg (yield 84.0%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCCc4ccccc43)CC2C)cc1OC
Yield: 8.5 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (280 mg, 0.82 mmol) prepared in Reference Example 1 and 2,3,4,5-tetrahydro-1H-1-benzazepine (362 mg, 2.46 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (32 mg, yield: 9%) as a colorless oil. (cis:trans=1:1.5)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.N12CCCCC1C=NCCC2>C(#N)C>[CH2:1]([NH:5][C:6]1[C:7]([S:12]([NH:15][C:27]([NH:26][C:20]2[N:19]=[C:18]([O:17][CH3:16])[CH:23]=[C:22]([O:24][CH3:25])[N:21]=2)=[O:28])(=[O:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccnc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Solvent: CC#N
Product: CCCCNc1cccnc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 0.5 h

Procedure:
The following are added in succession to a mixture of 2.75 g of 3-n-butylaminopyridin-2-ylsulfonamide in 40 ml of acetonitrile: 3.5 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate and 1.97 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene. The reaction mixture is stirred for 30 minutes and evaporated, the oily residue is triturated with 10 ml of 2N hydrochloric acid and subsequently with 10 ml of ice/water and a little diethyl ether, and the mixture is filtered. The filter residue is subsequently washed with a little water and diethyl ether and dried. 4.39 g of N-(3-n-butylaminopyridin-2-ylsulfonyl)-N'-(4,6-dimethoxypyrimidin-2-yl)urea (compound No. 1.001) of a melting point of 118°-119° C. are obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([CH:20]([NH:22][CH:23]=O)[CH3:21])[C:15]=3[CH2:25][CH2:26][CH3:27])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[CH:23]=[N:22][C:20]([CH3:21])=[C:16]4[C:15]=3[CH2:25][CH2:26][CH3:27])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1C(C)NC=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cnc(C)c12

Procedure:
A mixture of 215 (20 mg) and POCl3 (2 ml) is heated at reflux for 3 hours. The excess of POCl3 is removed. Ethyl acetate (10 mL) is added, and the mixture is washed with saturated NaHCO3 (5 mL), brine (5 mL), and dried over MgSO4. After evaporation of the solvent, the residue is purified by PTLC with 5% MeOH in dichloromethane to give the title product (213). 1H NMR δ (CDCL3) 0.99 (t, 3H, J=7.5 Hz), 1.55 (p, 2H, J=7.2 Hz), 2.62 (s, 3H), 2.92 (t, 2H, J=7.5 Hz), 5.92 (s, 2H), 6.87 (dd, 1H, J=8.1, 3 Hz), 7.15 (s, 1H), 7.22 (s, 1H), 7.85 (q, 1H, J=8.1 Hz), 8.06 (s, 1H), 8.14 (d, 1H, J=8.1 Hz), 8.57 (s, 1H). LC-MS: (M+1) 351.12.