Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)=O.[CH3:18][Mg]Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[CH2:18])[CH:16]=1
Reactant: C[Mg]Cl
Reactant: Cc1cccc(C(=O)c2cc(Br)ccc2O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(c1cccc(C)c1)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution (-78° C.) of 99 mg (0.3 mmol) of 5-bromo-2-hydroxy-3'-methylbenzophenone (Compound L) in 5 mL of tetrahydrofuran (under a blanket of argon) was added 1.0 mL (3.0 mmol) of methyl magnesium chloride (3M in tetrahydrofuran). With the addition, the solution turned yellowish-orange in color. The -78° C. bath was removed and the solution was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, extracted between ethyl acetate and sat. NH4Cl (aq.) solution and the layers were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give crude 4-bromo-2-[(1-m-tolyl-1-hydroxy)ethyl]phenol as a yellow oil. The crude alcohol was dissolved in 2 mL of toluene, placed under a blanket of argon and 5.9 mg of p-toluene sulfonic acid monohydrate was added. The resultant mixture was heated at 70° C. for 45 minutes, cooled to ambient temperature and purified by flash chromatography (silica, 5% ethyl acetate in hexane) to give the title compound as a clear, colorless oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1([SH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.O1CCOCC1.Cl[CH2:17][CH2:18][C:19]([C-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1)=[O:20].[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]>O>[CH:3]1([S:9][CH2:17][CH2:18][C:19]([C-:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]
Reactant: SC1CCCCC1
Reactant: O=C(CCCl)[c-]1cccc1
Agent: [Fe+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(CCSC1CCCCC1)[c-]1cccc1
Reaction time: 3 h
Yield: 20 %

Procedure:
Sodium hydroxide (0.25 mole) dissolved in minium water was treated with cyclohexylmercaptan (0.25 mole) and 700 ml dioxan. Chloropropionylferrocene (0.25 mole) was then added and the resulting mixture stirred on a steam bath for 3 hours. The mixture was diluted with water and extracted with chloroform. The organic liquors were washed successively with aqueous sodium hydroxide and water, dried and concentrated affording crude product. This was chromatographed through a silica gel column (20:1 ratio of silica to substrate) using initially 1% ethyl acetate/petroleum ether (60°-80°) then 3% ethyl acetate/petroleum ether as eluent. This afforded an oil which crystallised on cooling and trituration with petroleum ether. The solid was filtered off and washed with petroleum ether affording 3-(cyclohexylthio)propionyl ferrocene, mp 46.5°-48.5°, in 20% yield. Concentration of the petroleum ether liquors afforded a further 3% yield of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14])=[O:23]
Reactant: Cc1ccccc1N=C=O
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Br)c1
Reaction time: 21 h
Yield: 71.8 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-methylphenyl isocyanate (0.287 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-methylphenyl)ureido]phenylacetate (650 mg, 72%) as a pale brown powder. 1H-NMR (CDCl3) δ2.34 (s, 3H), 3.53 (s, 2H), 3.68 (s, 3H), 6.18 (br, 1H), 6.96 br, 1H), 7.18-7.33 (m, 4H), 7.29 (d, J=4.4 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H); MS (ESI) m/z 377 (M+), 379 (M++2).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:31])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)[C:18]([F:21])([F:20])[F:19]>>[Cl:9][C:10]1[CH:11]=[C:12]([O:31][CH2:2][C:3]2[S:7][N:6]=[C:5]([CH3:8])[N:4]=2)[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)([OH:29])[C:18]([F:19])([F:21])[F:20]
Reactant: Cc1nsc(CCl)n1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3nc(C)ns3)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 5-chloromethyl-3-methyl-[1,2,4]thiadiazole [163009-79-8] and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=459.5 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([S:10][CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][C:6]=1[CH3:25])[CH3:3].O.NN>O1CCCC1>[NH2:14][CH2:13][CH2:12][CH2:11][S:10][C:8]1[S:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[C:6]([CH3:25])[CH:7]=1
Reactant: Cc1cc(SCCCN2C(=O)c3ccccc3C2=O)sc1CN(C)C
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(SCCCN)sc1CN(C)C
Yield: 69.6 %

Procedure:
N-[3-[[5-(Dimethylamino)methyl-4-methyl-2-thienyl]thio]propyl]isoindole-1,3(2H)-dione (15.2 g) and hydrazine hydrate (8 ml) were stirred at room temperature in tetrahydrofuran (150 ml) for 48 h. The mixture was filtered and the filtrate was distilled to give the title compound as an orange oil (6.9 g) b.p. 160°-170°/0.04 mm.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:3]1=2.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][C:34]([NH:1][CH:2]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[CH2:6][S:5][C:4]4[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:3]3=4)=[O:35])[CH2:29][CH2:30]2)=[CH:23][CH:24]=1
Reactant: O=C(O)CCCN1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1ccc2c(c1)C(N)c1ccccc1CS2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(NC(=O)CCCN1CCN(c3ccc(F)cc3)CC1)c1ccccc1CS2
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
A mixture of 2.4 g of 11-amino-2-methyl-6,11-dihydrodibenzo[b,e]thiepin, 2.9 g of 4-[4-(4-fluorophenyl)-1-piperazinyl]butyric acid, 2.3 g of dicyclohexylcarbodiimide and 50 ml of methylene chloride is stirred at room temperature for 15 hours. After removal of the precipitated crystals by filtration, the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give 2.0 g of the title compound, m.p. 205°-207° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([C:18]2[CH2:19][C@@H:20]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:23]([CH:24]=2)[CH2:22][CH2:21]3)[CH:9]=1.[C:43]1([C:49]2[CH:54]=[CH:53][C:52](B3OC(C)(C)C(C)(C)O3)=[CH:51][N:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:52]3[CH:51]=[N:50][C:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:54][CH:53]=3)=[C:12]2[N:11]=[C:10]([C:18]2[CH2:19][C@@H:20]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:23]([CH:24]=2)[CH2:22][CH2:21]3)[CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1C=C(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1C=C(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2

Procedure:
This compound was prepared from (1R,5S)-tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate and 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, following essentially the similar procedures given in Preparative Example 1-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]Cl)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>CS(C)=O.ClCCl>[C:9]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])[CH2:13][CH2:12]1)#[N:10]
Reactant: N#CCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(F)c2)CC1
Temperature: 18 °C
Reaction time: 2 h

Procedure:
A mixture of 3-fluorophenylacetonitrile (200 mg, 1.48 mmol) and tert-butyl bis(2-chloroethyl)carbamate (358 mg, 1.48 mmol) was dissolved in 14.8 mL of anhydrous DMSO. The reaction was purged with a stream of nitrogen and cooled to 18° C. To this reaction was added sodium hydride (358 mg, 1.48 mmol), which was then warmed to ambient temperature and stirred for 2 hours. The reaction was warmed to 50° C. and stirred for 17 hours. The mixture was diluted with dichloromethane (40 mL), washed with water (3×40 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 0-20% EtOAc in hexanes. Collection of product containing fractions and removal of solvent yielded tert-butyl 4-cyano-4-(3-fluorophenyl)piperidine-1-carboxylate.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C[O-].[Na+].CO.[F:29][C:30]1[C:31]([O:38][CH3:39])=[N:32][CH:33]=[C:34]([CH:37]=1)[CH:35]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[F:29][C:30]1[CH:37]=[C:34]([CH2:35][NH:2][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:7][CH2:8]2)[CH:33]=[N:32][C:31]=1[O:38][CH3:39]
Reactant: COc1ncc(C=O)cc1F
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cnc(OC)c(F)c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 0.28 g of a 28% sodium methoxide/methanol solution and 28 μL of acetic acid were added. Thereto was added 75 mg of 5-fluoro-6-methoxynicotinaldehyde, then, 61 mg of sodium cyanoborohydride was added thereto, and the mixture was stirred at room temperature for 1 hour 20 minutes. Thereto was further added 62 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 1 hour 30 minutes, and then stirred at 30 to 35° C. for 1 hour. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=19:1 to 9:1, diethyl ether was added to the resultant light yellow oily substance, and the solid was filtered off to obtain 97 mg of 1-(2-(4-(((5-fluoro-6-methoxypyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a slightly yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][NH:5][C:4]1=[O:14].[CH3:15]I>CN(C=O)C>[CH3:15][N:5]1[C:4](=[O:14])[CH2:3][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1
Reactant: CI
Reactant: O=C1Cc2ccccc2CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2ccccc2CC1=O

Procedure:
To a slurry of sodium hydride (1.1 eq) in 15 mL of dry DMF was added 2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (0.0042 moles) as a solution in 10 mL of DMF. Methyl iodide (about 2 eq.) was then added. When complete by TLC, the reaction mixture was poured over ice and extracted into ethyl acetate. The organic layer was washed with water, followed by brine. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system to give 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one.
Reaction SMILES: [F:1][C:2]([F:26])([C:22]([F:25])([F:24])[F:23])[C:3]([F:21])([F:20])[C:4]([F:19])([F:18])[S:5]([O:8][CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:7])=[O:6].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)(=O)=O>>[F:26][C:2]([F:1])([C:22]([F:23])([F:24])[F:25])[C:3]([F:21])([F:20])[C:4]([F:19])([F:18])[S:5]([O:8][C@@H:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:7])=[O:6]
Reactant: CC(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OC(C)(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: C[C@H](OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OC(C)(C)C
Yield: 82 %

Procedure:
The production of tert-butyl nonafluorobutanesulphonyloxypropionate was effected with nonafluorobutanesulphonic anhydride as in example 1 with a yield of 82% (ee>99%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[CH:11][CH:10]=2)O1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[C:35]([C:49]([OH:51])=[O:50])[C:36]3[C:41](I)=[N:40][N:39]([CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)[C:37]=3[N:38]=2)=[CH:29][C:28]=1[C:52]([O:54][CH3:55])=[O:53]>>[CH2:16]([O:15][C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:41]2[C:36]3[C:35]([C:49]([OH:51])=[O:50])=[CH:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[C:28]([C:52]([O:54][CH3:55])=[O:53])[CH:29]=4)=[N:38][C:37]=3[N:39]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[N:40]=2)=[CH:24][CH:23]=1)=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(C(=O)OCc3ccccc3)cc2)OC1(C)C
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(I)nn(C4CCCCO4)c3n2)ccc1F
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4ccc(C(=O)OCc5ccccc5)cc4)nn(C4CCCCO4)c3n2)ccc1F
Yield: 66 %

Procedure:
Obtained according to the process described in Step 3.1, using benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid [described in Step 1.7], in the form of a yellow solid (yield: 66%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15]Br)=[CH:11][CH:10]=[C:9]([Cl:18])[CH:8]=2)=[O:4].[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][N:31]1[CH:32]=[CH:33][C:28]([C:27]([O:26][CH3:25])=[O:35])=[CH:29][C:30]1=[O:34])=[CH:11][CH:10]=[C:9]([Cl:18])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1ccnc(O)c1
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(Cc2c(C(=O)OC)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)c(=O)c1
Yield: 46.4 %

Procedure:
A solution of 3-bromomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (550 mg, 1.35 mmol), methyl-2-hydroxyisonicotinate (290 mg, 1.89 mmol) and potassium carbonate (280 mg, 2.03 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. Flash chromatography (ISCO column, 40% ethyl acetate/hexanes) afforded 7-chloro-3-(4-methoxycarbonyl-2-oxo-2H-pyridin-1-ylmethyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (300 mg, 46%) as a white solid. MS m/e calcd for C25H19ClN2O6 [(M+H)+] 479.0. Found 479.0.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Br:9][C:10]1[C:11]([NH:22][NH2:23])=[N:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>C1COCC1.CCOC(C)=O>[Br:9][C:10]1[C:11]2[N:12]([C:29](=[O:30])[NH:23][N:22]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1ncc(-c2ccccc2)nc1Br
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Br)nc(-c3ccccc3)cn12
Reaction time: 1.5 h

Procedure:
A mixture of 15.3 g of NaH (60% suspension in mineral oil) and 80.0 g of 3-bromo-5-phenyl-pyrazin-2-ol (J Het. Chem., 665 (1978)) was stirred together for 15 min. After gas evolution ceased, 90.0 g of trifluoromethanesulfonic anhydride was added dropwise over one h. The mixture was stirred an additional 30 min. and was filtered through a pad of silica gel and the solids were washed with methylene chloride. Concentration of the filtrate provided 3-bromo-5-phenyl-pyrazin-2-trifluoromethansulfonate that was dissolved in IPA (200 mL) and stirred as 4.48 g of hydrazine was added. The mixture was stirred at ambient temperature for 16 h. The resulting solid was collected, washed with methylene chloride, and dried under reduced pressure. The filtrate was re-subjected to the above reaction conditions a second and third time to provide (3-bromo-5-phenyl-pyrazin-2-yl)-hydrazine as the trifluoromethane sulfonate salt. A solution of 265 mg of (3-bromo-5-phenyl-pyrazin-2-yl)-hydrazine trifluoromethane sulfonate in THF (5.0 mL) was stirred as 243 mg of CDI was added in portions over 15 min. The resulting solution was stirred for 1.5 h and was diluted with EtOAc and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated to provide 8-bromo-6-phenyl-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a tan solid. MS (M+H−)=290.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][Br:18])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: COc1c(C)cccc1Oc1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1c(CBr)cccc1Oc1cccc(Cl)c1
Yield: 104 %

Procedure:
A mixture of 3-chlorophenyl 2-methoxy-3-methylphenyl ether (14.6 g), N-bromosuccinimide (11.3 g) and 2,2'-azobisisobutyronitrile (1.1 g) in benzene (100 ml) was treated in a similar manner to that of Example 6-(3) to give oily 3-chlorophenyl 2-methoxy-3-bromomethylphenyl ether (20 g).
Reaction SMILES: [OH-].[K+].[C:3]([NH:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4].[CH2:11]([O:14][CH2:15][CH2:16]Cl)[CH2:12]Cl>CS(C)=O>[C:3]([N:6]1[N:7]([C:8](=[O:10])[CH3:9])[CH:16]=[CH:15][O:14][CH:11]=[CH:12]1)(=[O:5])[CH3:4]
Reactant: ClCCOCCCl
Reactant: CC(=O)NNC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)n1ccoccn1C(C)=O
Temperature: 82.5 °C
Yield: 78.1 %

Procedure:
10.6 g of finely pulverised 85% potassium hydroxide are introduced into a solution of 9.3 g of N,N′-diacetylhydrazine and 141 g of dimethyl sulfoxide in such a manner that a temperature of 33° C. is not exceeded. After heating to 80 to 85° C., 23 g of 2,2′-dichlorodiethyl ether are added dropwise to the reaction mixture over the course of 50 minutes. The resulting highly fluid suspension is maintained at 80 to 85° C. for 3 hours, then cooled to 20 to 25° C. and filtered, and the filtration residue is washed with dimethyl sulfoxide. 11.4 g (76.0%) of 4,5-diacetyl-[1,4,5]-oxadiazepine are obtained from the combined filtrates by concentration by evaporation.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[O:22][C:21]([CH2:23]O)=[CH:20][CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:50]1[CH2:53][CH:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:51]1.C(N(CC)C(C)C)(C)C>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[O:22][C:21]([CH2:23][N:50]5[CH2:53][CH:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:51]5)=[CH:20][CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)cc3)n2)o1
Reactant: CCOC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(C5CCCCC5)cc4)n3)o2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {5-[5-(4-cyclohexylphenyl)-1,2,4-oxadiazol-3-yl]-2-furyl}methanol (0.18 g, 0.55 mmol) that was obtained in Example 2 (2c), carbon tetrabromide (0.22 g, 0.67 mmol), triphenylphosphine (0.18 g, 0.67 mmol), ethyl 3-azetidinecarboxylate hydrochloride (0.14 g, 0.83 mmol) and N,N-diisopropylethylamine (0.30 ml, 1.7 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1) as the eluent to afford the title compound (0.23 g) in a yield of 96% as a white crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](C2OC(C3N=C4C=CC(C#N)=CN4C=3)=CC=2)=[CH:5][CH:4]=1)#[N:2].Br[C:26]1[CH:27]=[C:28]([CH3:43])[C:29]2[N:30]([CH:32]=[C:33]([C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1>>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([C:33]2[N:34]=[C:29]3[C:28]([CH3:43])=[CH:27][C:26]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)=[CH:31][N:30]3[CH:32]=2)=[CH:36][CH:37]=1)#[N:40]
Reactant: Cc1cc(Br)cn2cc(-c3ccc(C#N)cc3)nc12
Reactant: N#Cc1ccc(-c2ccc(-c3cn4cc(C#N)ccc4n3)o2)cc1
Product: Cc1cc(-c2ccc(C#N)cc2)cn2cc(-c3ccc(C#N)cc3)nc12
Yield: 73 %

Procedure:
The same procedure described for 4a was used starting with 20. Yield 73%, mp 283-285° C. 1H NMR (DMSO-d6); δ 2.60 (s, 3H), 7.53 (s, 1H), 7.85-7.93 (m, 6H), 8.17 (d, J=8.4 Hz, 2H), 8.53 (s, 1H), 8.87 (s, 1H). 13C NMR; δ 144.9, 142.5, 141.1, 138.1, 132.6, 132.4, 127.0, 126.6, 126.0, 123.6, 123.3, 122.9, 118.6, 118.4, 111.9, 110.0, 109.7, 16.3. MS (m/z, rel.int.); 335 (M++1, 100), 310 (30), 279 (20), 234 (40).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:17]1[CH:25]=CC(S(O)=O)=C[C:18]=1C(O)=O.N1CCCC1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:12]2[CH2:25][CH2:17][CH2:18][CH2:13]2)(=[O:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Solvent: C1CCNC1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC2)ccc1Cl
Yield: 91 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and pyrrolidine and obtained in 91% yield. MS (m/e): 288.0 (MH−, 100%).