Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH3:22])=[O:19])[N:16]=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40]Br>CC(=O)CC.C(Cl)Cl>[CH3:37][O:38][CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH3:22])=[O:19])[N:16]=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc([C@H](C)NC(=O)Nc2nc3nccc(-c4ccc(O)cc4)n3n2)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COCCOc1ccc(-c2ccnc3nc(NC(=O)N[C@@H](C)c4cccc(OC)c4)nn23)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(S)-1-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-3-[1-(3-methoxyphenyl)ethyl]urea (the compound obtained in Example 223; 20.3 mg) was suspended in 2-butanone (2 ml). Thereafter, potassium carbonate (69.4 mg) and 2-methoxyethyl bromide (47.2 μl) were added to the suspension, and the obtained mixture was stirred at 80° C. for 5 hours. Thereafter, the reaction solution was diluted with methylene chloride (5 ml), and the resultant product was then washed with 1 M hydrochloric acid (5 ml×3), saturated sodium bicarbonate (5 ml×2), and distilled water (5 ml×2). The organic layer was concentrated under a reduced pressure, and the obtained residue was purified by reverse phase liquid chromatography (Inertsil PREP-ODS; 20 Φ×250 mm; eluted with water-containing acetonitrile) to obtain the captioned compound (10.7 mg).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=O)[CH3:10]>C(O)C.C(O)(=O)C>[CH:4]1[CH:5]=[C:6]2[CH:10]=[C:9]([C:12]3[O:13][C:14]4[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:16]=3)[NH:7][C:1]2=[CH:2][CH:3]=1
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2[nH]c(-c3cc4ccccc4o3)cc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Phenylhydrazine (97%; 6.3 ml, 1 eq) is introduced into a solution of 2-acetylbenzofuran (10 g, 1 eq) in ethanol (25 ml). After adding 20 drops of glacial acetic acid, the mixture is stirred at 80° C. for 1 h. Subsequently, the solvent is distilled off. The residue is introduced gradually into polyphosphoric acid (100 g), heated to 120° C. and stirred for 1 h. The reaction output is added cautiously to ice-water and neutralized with 2M NaOH. The precipitate is filtered off and washed with distilled water. The residue is dried under reduced pressure. After recrystallization in ethyl acetate/n-hexane, 7.0 g are obtained. Yield: 48%
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Br:16][C:17]1[C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1>>[Br:16][C:17]1[C:22]2[N:23]([C:2]3[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=3)[CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Reactant: COc1cc(Br)c2c(c1)OCCN2
Product: CC[C@H](COC)n1cc(Br)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 7.14 (s, 1H), 6.75 (d, J=2.5 Hz, 1H), 6.46 (d, J=2.5 Hz, 1H), 5.08–4.86 (m, 1H), 4.50–3.88 (m, 4H), 3.77 (s, 3H), 3.70–3.52 (m, 2H), 3.36 (s, 3H), 1.92–1.70 (m, 2H), 0.93 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 501.9992 [(M+H)+, calcd for C18H22N3O4Br2 501.9977].
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[NH:8][C:7]1=[O:18]>C(#N)C>[N:1]([C:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[NH:8][C:7]1=[O:18])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1ccc2c(c1)C(Cl)(c1ccccc1Cl)C(=O)N2
Agent: [Na+]
Solvent: CC#N
Product: CCOc1ccc2c(c1)C(N=[N+]=[N-])(c1ccccc1Cl)C(=O)N2
Yield: 66 %

Procedure:
0.339 g of sodium azide is added to a solution of 0.560 g of the compound obtained in step B or B' in 20 ml of acetonitrile and the mixture is refluxed for 30 minutes. The solvent is evaporated off under vacuum and the residue is taken up with water, extracted with AcOEt, washed with a saturated solution of NaCl, with water and with a 5% aqueous solution of sodium dithionite, re-extracted with DCM, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.377 g of the expected product. Infrared spectrum in DCM: 3440 cm-1, 2100 cm-1, 1745 cm-1.
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[N:8]1([CH2:5][CH2:6][NH:7][C:3](=[O:4])[CH2:1][CH3:2])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCC1=NCCO1
Reactant: C1COCCN1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Product: CCC(=O)NCCN1CCOCC1
Yield: 83 %

Procedure:
Under the same conditions as Example 13, 2.5 gm (25 mmoles) of 2-ethyl-2-oxazoline, 2.2 gm (25 mmoles) of morpholine and 0.59 mg of zinc acetate are reacted to yield 83 percent N-(2-morpholinylethyl)propionamide.
Reaction SMILES: [CH2:1]([C@H:3]1[N:8](C(OC(C)(C)C)=O)[CH2:7][C@@H:6]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[O:5][CH2:4]1)[CH3:2].O1CCOCC1.[ClH:31]>>[ClH:31].[CH2:1]([C@H:3]1[NH:8][CH2:7][C@@H:6]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[O:5][CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl(2S,5R)-5-ethyl-2-[(phenylamino)carbonyl]-4-morpholinecarboxylate (0.269 g, 0.804 mmol) was taken up in HCl in 1,4-dioxane (4 M, 0.024 mL, 0.804 mmol) and stirred at room temperature overnight. The reaction was concentrated to yield a HCl salt of the title compound (0.198 g) as a brown oil. LC-MS (ES) m/z=235 [M+H]+.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])(=[O:27])[CH:24]([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:33])(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)NCCCC(=O)O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 39.3 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 4-isobutyrylaminobutyric acid (5.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The residue obtained is recrystallized in acetonitrile and then purified by chromatography on silica (0.063-0.2 mm; 130 g) contained in a column 3 cm in diameter [eluant: methylene chloride/methanol (98:2 by volume) mixture] collecting 25-cc fractions. Fractions 79 to 85 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized by stirring in isopropyl ether. 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-isobutyrylaminobutyrate (5.5 g), m.p. 208° C., is thereby obtained.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][CH2:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>ClCCl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[O:19][CH2:20][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23](=[O:25])[C:30]=2[CH:31]=1
Reactant: O=C(O)c1ccccc1COc1ccc(Br)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: O=C1c2ccccc2COc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Trifluoroacetic anhydride (56.0 mL, 400 mmol) was added dropwise to a dichloromethane (500 mL) solution of 2-(4-bromophenoxymethyl)benzoic acid (112 g, 364 mmol) at room temperature. The mixture was stirred at room temperature for 2 hour, BF3.OEt2 (10 mL, 169.3 mmol) was then added thereto, and the mixture was stirred at room temperature for additional 2 hours. The reaction mixture was washed with a saturated aqueous sodium bicarbonate solution, and then with a saturated sodium chloride solution, the washed mixture was then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduce pressure. The residue was purified by column chromatography (hexane-ethyl acetate=3:2), to give 96.0 g (91%) of the captioned compound in the form of crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:30][CH:31](Br)[CH3:32])(=[O:29])[CH3:28].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:31]([O:30][C:27](=[O:29])[CH3:28])[CH3:32])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reactant: CC(=O)OC(C)Br
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=CCS[C@H]12)c1csc(N)n1

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) was reacted with 1-bromoethyl acetate in the presence of sodium iodide to give 1-acetoxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 100°-103° C. (decompn.).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][C:20]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)=[N:21][C:6]1=2)[CH3:4].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C=O)C>[C:27]([N:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[CH:19]=[CH:18][C:7]2[N:8]([CH3:17])[C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[N:5]([CH2:3][CH3:4])[C:6]=2[N:21]=1)(=[O:29])[CH3:28]
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3ccc[nH]3)nc21
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cccn3C(C)=O)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
Sodium hydride (0.013 g, 60% in oil) was added to a solution of 5,11-dihydro-11-ethyl-5-methyl-2-(2-pyrrolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.100 g) in dry DMF (3 mL) and stirred for 30 min. After cooling to 0° C., acetyl chloride (0.025 g) was added and the reaction mixture was allowed to warm to room temperature overnight. Water was added and the product was extracted with CH2Cl2, dried (anhyd Na2SO4), filtered, and evaporated. The residue was purified by preparative plate chromatography (ethyl acetate/hexanes, 1:1). Crystallization from ethyl acetate/pet ether gave 0.018 g of the title compound, mp 106°-108° C.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[F:5][C:6]([F:16])([F:15])[C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.C([Li])CCC.CCCCCC>>[F:14][C:7]([F:13])([C:6]([F:5])([F:15])[F:16])[C:8]([CH:2]([CH3:3])[C:1]#[N:4])=[O:10]
Reactant: CCC#N
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C#N)C(=O)C(F)(F)C(F)(F)F

Procedure:
Propionitrile (13.2 g, 0.24 mole), ethyl pentafluoropropionate (23.05 g, 0.12 mole) and a solution of n-butyllithium in n-hexane (168 ml, 0.264 mole) were reacted according to the same procedure as described in Example 1 to give 22.72 g (crude yield 94.1%) of the crude title compound. The yield calculated as the pure product was 84.1%. When the resulting compound was dissolved in CDCl3 and its NMR was measured, the ratio of the keto form/the enol form was found to be 71/29, b.p. 63°-65° C./28 mmHg.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Br[CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32].C(N(CC)CC)C>CN(C=O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[C:6]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:7]=1)=[O:21]
Reactant: FC(F)(F)CCBr
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNCCC(F)(F)F)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 2.3 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (14.5 mg, 81.9 μmol), 3-bromo-1,1,1-trifluoropropane (30 mg, 81.9 μmol) and triethylamine (34.2 μL, 246 μmol) in DMF was heated to 150° C. for 1 hour under microwave irradiation in a heavy-walled sealed tube. The crude product was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a brown solid in 2.3% yield. LCMS m/z (%)=463 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 2.6 (m, 2H) 3.2 (dd, J=15.4, 7.8 Hz, 2H) 3.5 (m, 2H) 3.8 (s, 3H) 3.9 (s, 3H) 4.4 (m, 2H) 6.4 (d, J=2.0 Hz, 1H) 7.2 (dd, J=8.6, 3.5 Hz, 1H) 7.3 (d, J=9.1 Hz, 1H) 7.4 (t, J=8.1 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H) 7.7 (d, J=2.5 Hz, 1H) 7.9 (dd, J=9.1, 2.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[O:7]=[C:8]1[CH2:13][N:12]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10][N:9]1[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[O:7]=[C:8]1[CH2:13][N:12]([C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:11][CH2:10][N:9]1[C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: Nc1nccs1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 48.3 %

Procedure:
Synthesized according to general procedure 12, method A. The reaction was set up with 2-aminothiazole (2.4 g, 24.2 mmol), anhydrous pyridine (10 mL), and 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride (9.0 g, 24.2 mmol). The dark oil was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by a second purification on silica gel using 80% EtOAc in hexanes to obtain the desired sulfonamide as a white solid (5.1 g, 11.7 mmol, 48% yield). LC/MS (10%/99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=435.2; tR=2.35 min.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([O:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23)=[O:21]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
In 180 ml of tetrahydrofuran were dissolved 21.2 g of methyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta-[b]furan-7-carboxylate and 16.9 g of 4-chlorobutyric acid chloride. To the solution below 20° C., 9.10 g of pyridine was added dropwise. The solution was stirred at room temperature for 1 hour and combined with 40 g of a 5% aqueous solution of sodium hydrogen carbonate, followed by ordinary work-up. There was obtained 30.4 g of a crude product (crude yield 96%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[CH3:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1>CCOCC>[Cl-:1].[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([CH2:4][CH2:3][CH2:2][N+:23]2[CH:22]=[CH:21][C:20]([C:17]3[S:18][CH:19]=[C:15]([CH3:14])[N:16]=3)=[CH:25][CH:24]=2)=[O:6])=[CH:8][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Cc1csc(-c2ccncc2)n1
Solvent: CCOCC
Product: Cc1csc(-c2cc[n+](CCCC(=O)c3ccc(F)cc3)cc2)n1
Product: [Cl-]

Procedure:
A 1.0 g. portion of γ-chloro-p-fluorobutyrophenone and 0.9 g. of 4-(4-methyl-2-thiazolyl)pyridine are heated in an oil bath at 95°-100°C. overnight. Ether is added and the mixture is filtered. The solid is recrystallized from acetonitrile. This solid is recrystallized from a mixture of alcohol and ether, m.p. 226°-228°C.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1>>[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][C:3]1[N:10]=[C:16]([C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)[O:1][N:2]=1
Reactant: COC(CC(=N)NO)OC
Reactant: O=C(O)c1ccc(F)cc1
Product: COC(Cc1noc(-c2ccc(F)cc2)n1)OC

Procedure:
By using N-hydroxy-3,3-dimethoxypropanimidamide obtained in Reference Example 19 (1.0 g, 6.8 mmol) and 4-fluorobenzoic acid (0.99 g, 7.1 mmol) as the raw materials, the same procedure as in Reference Example 20 was carried out to obtain the title compound (1.4 g) (colorless oil).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C[O-].[Na+].[CH:10]1([CH2:13]Br)[CH2:12][CH2:11]1>CO>[CH:10]1([CH2:13][S:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: Sc1nc[nH]n1
Reactant: BrCC1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CC2)n[nH]1
Reaction time: 10 h
Yield: 99.1 %

Procedure:
To a solution of 3-mercapto-1,2,4-triazole (7.1 g) and sodium methoxide (3.8 g) in methanol (100 ml), there was added cyclopropylmethyl bromide (9.5 g), and the resultant mixture was allowed to stand at room temperature for 10 hours. After removal of the solvent, the residue was extracted with chloroform. Evaporation of the chloroform extract gave 10.8 g of 3-cyclopropylmethylthio-1,2,4triazole. Yield, 99 %. M.P., 69°- 70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.CC([O-])=O.[Na+].[Br:14]Br>ClCCl>[Br:14][C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccccn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a suspension of 2-methoxypyridine (1-1) (3.96 kg; 36.3 mol), NaOAc (3.57 kg; 39.9 mol), and dichloromethane (22 L) was added a solution of bromine (2.06 L; 39.9 mol) in dichloromethane (2 L), maintaining the reaction temperature below 7° C. over 2-3 hours. The mixture was aged for 1 hour at 0-7° C. and stirred at room temperature overnight. The reaction mixture was filtered and rinsed with dichloromethane (about 5 L). The filtrate and washings were combined, washed with cold 2 M NaOH (22 L; pH should be below 8) maintaining the temperature below 10° C., and with cold water (11 L). The organic layer was separated and concentrated under reduced pressure to give a crude product 1-2 (6.65 kg). The crude product was purified by vacuum distillation to give pure 1-2 (5.90 kg, 86%). Known compound: G. Butora et al., JACS, 119, 7694-7701 (1997).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH3:16])[C:7]2=[O:15].Cl.CCOC(C)=O.C(Cl)Cl>C(O)C.[Fe]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([Br:1])=[C:3]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[CH:5]=[CH:4]2
Reactant: Cn1ccc2c(Br)ccc([N+](=O)[O-])c2c1=O
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: Cn1ccc2c(Br)ccc(N)c2c1=O
Temperature: 25 °C
Yield: 39.5 %

Procedure:
To a solution of 5-bromo-8-nitro-2-methylisoquinolin-1(2H)-one (Compound 123B, 0.350 g, 1.2 mmol) in ethanol (15 mL) was added iron powder (0.5 g) and 2 N HCl (3 mL). The resulting mixture was heated at reflux for 2 h. TLC (EtOAc/CH2Cl2: 1:9) showed the reaction was complete. After cooled to room temperature, the reaction mixture was filtered, solids washed with ethanol/CH2Cl2 mixture. The combined filtrate was evaporated to dryness, neutralized with aq. Na2CO3 (20 mL), and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (20 mL), dried and evaporated to give a residue, which was purified by column chromatography on silica gel (EtOAc/CH2Cl2: 1:9)) to afford the desired product as a solid (0.120 g, 39%). 1H NMR (CDCl3, 300 MHz): δ=3.51 (s, 3 H), 6.44 (d, J=7.8 Hz, 1 H), 6.53 (br, 2 H), 6.71 (d, J=7.8 Hz, 1 H), 7.03 (d, J=7.5 Hz, 1 H), 7.49 (d, J=8.7 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:22])[C:10]3[CH:16]=[C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:23].[Na+].Cl>O.O1CCCC1.CO>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:22])[C:10]3[CH:16]=[C:15]([CH:17]([CH3:21])[C:18]([OH:23])=[O:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1c(Cl)cccc1S2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1c(Cl)cccc1S2
Yield: 47.4 %

Procedure:
A mixture of 200 mg of 2-(9-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 3 g of sodium hydroxide, 25 ml of water, 30 ml of methanol and 2 ml of tetrahydrofuran was refluxed for 14 hours. After the completion of the reaction, the solvent was removed by distillation to obtain a residue, to which was added water, and the mixture was acidified with with 10% hydrochloric acid and then extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain crystals, which were chromatographed over silica gel and eluted with chloroform. The thus obtained product was recrystallized from ethyl acetate to give 95 mg (yield: 48%) of 2-(9-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as light yellow crystals having a melting point of 163°-164° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S:19](=[O:23])(=[O:22])(N)N>COCCOCCOC>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][S:19]1(=[O:23])=[O:22]
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Reactant: NS(N)(=O)=O
Solvent: COCCOCCOC
Product: COC(=O)c1cccc2c1N(CC(OC)OC)S(=O)(=O)N2
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.5 g, 2.0 mmol) from Step C above and sulfuric diamide (0.2 g, 2.4 mmol) in diglyme (2 mL) was added to boiling diglyme (5 mL) dropwise and continued to reflux for 35 min. The flask was cooled to room temperature and the solvent was removed in vacuo. The crude reaction was purified by column chromatography (silica gel, 0% to 100% ethyl acetate in hexanes) to afford methyl 3-(2,2-dimethoxyethyl)-1,3-dihydro-2,1,3-benzothiadiazole-4-carboxylate 2,2-dioxide (0.2 g, 27%): 1H NMR (500 MHz, DMSO-d6) δ 7.08 (br s, 1H), 6.59 (dd, J=8.0, 1.5 Hz, 1H), 6.52 (t, J=8.0 Hz, 1H), 6.46 (dd, J=6.0, 1.5 Hz, 1H), 4.41 (t, J=5.0 Hz, 1H), 3.82 (d, J=5.0 Hz, 2H), 3.74 (s, 3H), 3.14 (s, 6H).