Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[N:29]#CBr>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16]#[N:29])[CH2:12][CH2:11]2)[CH2:9]1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To 1.0 g of 1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] of Example 17 in 16 ml of dry chloroform is added 2.4 g of anhydrous potassium carbonate and 0.73 g of cyanogen bromide. The reaction is stirred 7 hours at room temperature and then is filtered through paper. Approximately one ml of methanol is added and the solution is rotary evaporated to a glass. The glass is chromatographed on 80 cc of silica gel with 1:1, ether:dichloromethane to give a crystalline solid. The solid is recrystallized thrice from acetone-hexane to give a solid of 1-(2-chlorophenyl)-1'-cyanospiro(indoline-3,4'-piperidine), mp 157.5°-159.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)N(C)CCN2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(methyl(2-morpholinoethyl)carbamoyl)benzoate (4.4 g, 13.66 mmol, 1.00 equiv, 95%) in tetrahydrofuran/water (15/10 mL), and lithium hydroxide hydrate (1.77 g, 43.17 mmol, 3.00 equiv). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water and adjusted to pH 2-3 with hydrochloric acid. The resulting mixture was washed with 2×30 mL of ethyl acetate. The aqueous layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate:methanol (4:1). This resulted in 2.7 g (65%) of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.17 (m, 2H), 7.78 (m, 1H), 7.61 (m, 1H), 3.98 (m, 6H), 3.56 (m, 5H), 3.47 (m, 1H), 3.10 (s, 3H). MS (ES, m/z): 293 [M+H]+.
Reaction SMILES: N[CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].C[N:55](C=O)C>O>[C:50]([O:49][C:47](=[O:48])[CH2:46][NH:55][CH:3]([C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:11])[CH3:12])[CH:8]=1)[CH3:2])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(-c2nc(CCN)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(-c2nc(C(C)NCC(=O)OC(C)(C)C)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 50 %

Procedure:
A solution of 2-{1-[4-(2-Amino-ethyl)-2-p-tolyl-imidazol-1-yl]-2-methyl-propyl}-3-benzyl-7-chloro-3H-quinazolin-4-one (181 mg, 0.343 mmol), potassium carbonate (47 mg., 0.343 mmol), and tert-butyl bromoacetate (67 mg., 0.343 mmol) in DMF (2.0 mL) was stirred at room temperature for 4.5 h. The reaction was diluted with water and the resulting white precipitate was filtered and purified by flash chromatography ( silica gel, 95:5 methylene chloride: methanol) to provide the title compound as a white solid (109 mg., 50%). MS(ES+) m/e 640 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23](=[O:25])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1.[CH3:33][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23]([OH:25])([CH3:33])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-c1cnnc(C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)(C)O)n2)ccc1-c1cnnc(C)c1
Reaction time: 0.08 h

Procedure:
1-(2-(3-Methoxy-4-(6-methylpyridazin-4-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidin-4-yl)ethanone (60 mg, 0.13 mmol) was dissolved in THF (5 mL) and was added slowly to a solution of methylmagnesium bromide (3 M in THF, 0.358 mL, 1.07 mmol) in THF (5 mL). The mixture was stirred for 5 min. The mixture was cooled on an ice bath and ammonium chloride (sat, aq, 5 mL) was added. The mixture was stirred for 5 min. The mixture was extracted with EtOAc (×2). The solvents were evaporated and the residue was purified by column chromatography on silica eluting with a gradient of MeOH in DCM to give the title compound as a solid, 42 mg (68%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]([CH3:24])[N:6]=1>O1CCCC1.O>[CH3:24][C:7]1[N:6]=[C:5]([S:2][CH3:1])[CH:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=1
Reactant: C[S-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(Cl)nc(C)n1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.8 %

Procedure:
Sodium thiomethoxide (140 mg, 2 mmol) was added to 4-chloro-2-methyl-6-(tributylstannyl)pyrimidine (835 mg, 2 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude product was purified by silica gel chromatography, eluting with 5% EtOAc/hexanes to give 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (256 mg, 30% yield). 1H NMR (300 MHz, CDCl3) δ 7.07 (s, 1H); 2.62 (s, 3H); 2.51 (s, 3H); 1.44-1.70 (m, 6H); 1.21-1.42 (m, 6H); 0.98-1.21 (m, 6H); 0.91 (t, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C1C(=O)N([Br:30])C(=O)C1>C1COCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:30])=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
6-(2-Chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 7b (55 mg, 0.172 mmol) is dissolved in 1:1 THF/MeOH (2 mL) and cooled to −78° C. under an atmosphere of nitrogen. TsOR.H2O (49 mg, 0.258 mmol) is added followed by NBS (31 mg, 0.174 mmol). After 10 minutes, the reaction mixture is warmed to 0° C. and then 2 hours later warmed to room temperature. After 16 hours, the reaction mixture is quenched by the addition of 10% Na2S2O3 and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure. The crude product is triturated with methylene chloride to give 58 mg (85%) of pure desired product as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.O.[C:11](O)(=O)[CH:12]=[O:13]>O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]=[CH:11][C:12](=[O:13])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=CC(=O)O
Solvent: O
Product: O=c1cnc2ncc(Br)cc2[nH]1
Yield: 65.8 %

Procedure:
A solution of 5-bromo-2,3-pyridinediamine (465 mg, 2.473 mmol) and glyoxylic acid monohydrate (284 mg, 3.09 mmol) in water (5 ml) was stirred at rt for 3 h and the resultant precipitate was filtered and washed with water (50 ml), MeOH (20 ml) and finally diethyl ether (20 ml) before drying in vacuo gave the desired product as a light brown solid (368 mg, 66%).
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:25]([CH:27]([CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)[C:28](OC)=O)=[O:26].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:23][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:28]=[C:27]([CH2:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)[C:25](=[O:26])[N:24]=3)=[CH:11][CH:10]=2)[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cc(Cl)cc(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 14.5 %

Procedure:
To the solution of 2-(4-{[3-chloro-5-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate (230 mg, 0.488 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (131 mg, 0.585 mmol) in NMP (3 mL) was added K2CO3 (270 mg, 1.950 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (38 mg, 0.071 mmol, 14.63% yield). LCMS: rt=3.68 min, [M+H+]=533
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([Cl:25])=[O:24]>C1C=CC=CC=1>[ClH:25].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[C@H:12]([CH3:16])[C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccco1
Reactant: C[C@H]1NCCN(CCCc2ccccc2)[C@H]1C
Solvent: c1ccccc1
Product: C[C@@H]1[C@H](C)N(CCCc2ccccc2)CCN1C(=O)c1ccco1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 1 from a mixture of cis-1-(3-phenylpropyl)-2,3-dimethylpiperazine [b.p. 126° - 128°C (2 mmHg), dipicrate, m.p. 227° - 228°C], 2-furoyl chloride and benzene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[H-].[Na+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:19](=[S:20])[N:18]([CH3:22])[CH3:17])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC(=S)N(C)C)ccc2o1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (2 g, 10 mmol) in 50 mL dry DMF was treated portionwise with NaH (252 mg of a 95% dispersion in mineral oil, 10 mmol). After 30 min, dimethylthiocarbamoyl chloride (1.9 g, 15 mmol) was added and the reaction stirred at 40° C. for 1.5 hours. The reaction mixture was then concentrated in vacuo, and the residue taken up in EtOAc. The organic layer was then washed 1×water, 1×brine, dried (Na2SO4) and the solvent removed in vacuo to give 3.5 g of the crude title compound. Recrystallization from CHCl3/hexanes, gave 1.3 g (45%) of the title compound. 400 MHz 1H NMR (DMSO-d6) δ 7.72 (s, 1H), 7.68 (d, 1H, J=9.8 Hz), 7.43 (s, 1H), 7.17 (d, 1H,J=9.8 Hz), 3.85 (s, 3H), 3.32 (s, 3H), 3.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:20])[C:10]=1[CH2:11][N:12]1[CH2:16][CH2:15][C@H:14]([N:17]([CH3:19])[CH3:18])[CH2:13]1)[C:5](O)=[O:6].S(Cl)([Cl:23])=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:20])[C:10]=1[CH2:11][N:12]1[CH2:16][CH2:15][C@H:14]([N:17]([CH3:19])[CH3:18])[CH2:13]1)[C:5]([Cl:23])=[O:6]
Reactant: CN(C)[C@H]1CCN(Cc2c(Cl)cc(C(=O)O)cc2Cl)C1
Reactant: O=S(Cl)Cl
Product: CN(C)[C@H]1CCN(Cc2c(Cl)cc(C(=O)Cl)cc2Cl)C1
Product: Cl

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 7), except that 3,5-dichloro-4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]benzoic acid obtained in the step 4 was used, and that treatment after the reaction was that thionyl chloride was distilled off under reduced pressure, and then the operation of adding of toluene to the residue, followed by azeotropic removal of thionyl chloride was repeated twice.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-:8].[K+].[Br:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1>C(#N)C>[Br-:10].[C:18]([CH2:17][O:16][C:15]1[CH:21]=[CH:22][C:12]([CH2:11][N:3]2[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]([O:8][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=3)=[CH:4]2)=[CH:13][CH:14]=1)([OH:20])=[O:19]
Reactant: Clc1nc[nH]c1Cl
Reactant: O=C(O)COc1ccc(CBr)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)COc1ccc(Cn2c[n+](Cc3ccc(OCC(=O)O)cc3)c(Cl)c2Cl)cc1
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 2 equivalents of 2-(4-(bromomethyl)phenoxy)acetic acid (3.61 g, 14.72 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and neutralized with 6M HBr. Volatiles were removed in vacuo and the resulting white precipitate was collected and analyzed. 1H NMR (300 MHz, DMSO-d6): δ 4.67, 5.51, 7.12, 7.61, 9.23, 12.17.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl.N1C=CC=C[CH:26]=1>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:26])[CH:5]=[CH:4][C:3]=1[NH:9][S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Reactant: Nc1ccc(Cl)cc1Br
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Br)c1
Temperature: 60 °C

Procedure:
2-Bromo-4-chloro-phenylamine (2.06 g, 10 mmol) and 4-tert-butylbenzenesulfonyl chloride (2.55 g, 11 mmol) were suspended in anhydrous pyridine (10 mL) and heated at 60° C. for 4 h. After cooling to room temperature the reaction mixture was added to 6 M HCl (100 mL) and the product was extracted with ethyl acetate (3×50 mL). The combined organic extract was dried over MgSO4, the solvent was evaporated, and the crude product was purified by flash chromatography to afford the title compound as a white solid. MS: (M+H)/z=403.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12](OCC)(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[O-]CC.[Na+]>C(O)C>[OH:10][C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:4][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COC(=O)c1ccccc1N
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of methyl anthranilate (121 g, 0.8 mol) and diethyl malonate (128 g, 0.8 mol) in ethanol (900 mL) was added a 20% solution (274 g) of sodium ethoxide in ethanol, and the mixture was stirred at room temperature for 30 min. Ethanol was evaporated, and the mixture was stirred at 140° C. for 12 hr. After cooling, the obtained solid was washed with diethyl ether, and dissolved in water. Insoluble materials were filtered off, the filtrate was acidified with 5N hydrochloric acid, and the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried under reduced pressure to give the title compound (161 g, 86%) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[C@H:19]([CH3:20])[C@H:18]4[N:15]([C:16](=[O:24])[C@@H:17]4[C@H:21]([OH:23])[CH3:22])[C:14]=3[C:25]([O:27]CC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:9][N:8]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[N:6]=1.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[C@H:19]([CH3:20])[C@H:18]4[N:15]([C:16](=[O:24])[C@@H:17]4[C@H:21]([OH:23])[CH3:22])[C:14]=3[C:25]([OH:27])=[O:26])[CH2:9][NH:8]2)[N:6]=1
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](c4csc(N)n4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](c4csc(N)n4)C3)[C@H](C)[C@H]12
Yield: 45.7 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (900 mg), 20% palladium hydroxide on carbon (350 mg), 0.05M phosphate buffer (pH 6.5, 20 ml) and tetrahydrofuran (30 ml) was stirred at room temperature for 3 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated to remove the organic solvent. The residue was washed with ethyl acetate, adjusted to pH 6.2 with aqueous potassium carbonate and concentrated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (60 ml) eluting in turn with water (250 ml) and 5-7% aqueous acetone (200 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl) pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (233 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1)[OH:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[F:13][C:14]([F:21])([F:20])[C:15]([NH:1][CH2:2][CH2:3][CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1)=[O:16]
Reactant: NCCC(O)c1cccc(I)c1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC(O)c1cccc(I)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-amino-1-(3-iodophenyl)propan-1-ol (105) (3.9 g, 14 mmol) in DCM (50 mL) were added ethyl trifluoroacetate (2 mL, 17 mmol) and triethylamine (2.95 mL, 21 mmol). and the mixture was stirred at RT for 4 h during which the reaction was found to be complete. Concentration under reduce pressure gave (2,2,2-trifluoro-N-(3-hydroxy-3-(3-iodophenyl)propyl)acetamide) as a yellow oil. The product was pure enough to be used as such for the next transformation. Yield (4.9 g, 93%): 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 4.79-4.82 (m, 1H), 3.67-3.72 (m, 1H), 3.37-3.42 (m, 1H), 2.96 (bs, 1H), 1.87-1.99 (m, 2H).
Reaction SMILES: Br.C1(C)C=C(C)C=C(C)C=1S([N:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])(=O)=O.C1(O)C=CC=CC=1.C(Cl)[Cl:34]>>[ClH:34].[ClH:34].[ClH:34].[NH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]
Reactant: Cc1cc(C)c(S(=O)(=O)N(CCCCN)CCCCCN)c(C)c1
Reactant: ClCCl
Agent: Br
Solvent: Oc1ccccc1
Product: Cl
Product: NCCCCCNCCCCN
Yield: 50 %

Procedure:
HBr (30% in HOAC, 33 mL), 41 (2.43 g, 6.83 mmol), and phenol (6 g, 60 mmol) in CH2Cl2 were reacted, and product was isolated by the procedure of 2 to give 0.97 g (50%) of 20 as a hygroscopic solid: NMR (D2O) δ 1.47 (m, 2 H), 1.70-1.80 (m, 8 H), 3.00-3.10 (m, 8 H). Anal. (C9H26Cl3N3) C, H, N.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1.CN(C=O)C.[NH2:17][C:18]1[C:19]([F:25])=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][N:28]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][C:33]=1[O:39][CH3:40])[N:30]=[CH:29][N:28]=[C:27]2[O:24][C:20]1[C:19]([F:25])=[C:18]([CH:23]=[CH:22][CH:21]=1)[NH2:17]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a stirred slurry of cesium carbonate (10.25 g, 31.47 mmol) in a 9:1 mixture of THF/DMF (100 mL) at rt, was added 3-amino-2-fluorophenol (2.00 g, 15.74 mmol) in one portion. After stirring for 30 min at rt, 4-chloro-6,7-dimethoxyquinazoline (3.54 g, 15.74 mmol) was added and the reaction mixture was heated at 50° C. for 18 h. The reaction was cooled to rt, then diluted with dichloromethane. The solution was washed with water, then brine, and dried over MgSO4. Filtration followed by concentration under reduced pressure gave a solid that was triturated with a mixture of 10% dichloromethane in ethyl acetate. Filtration afforded 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (2.10 g, 42%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 6.93 (dd, J=8.4, 8.4 Hz, 1H), 6.71 (dd, J=8.4, 8.4 Hz, 1H), 6.53 (m, 1H), 5.37 (brs, 2H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:70]=[CH:69][N:68](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:70]=[CH:69][NH:68][N:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4nc[nH]n4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-trityl-1,2,4-triazol-3-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (1.89 g: 1.50 mMol.) in a mixture of anisole (7 ml) and nitromethane (28 ml) is added dropwise a solution of aluminum chloride (1.99 g: 15 mMol.) in anisole (7 ml) at -30°--40° C., and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (15 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvents and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (2:3) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,4-triazol-3-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (418 mg). Over-all yield: 34%.