Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C@H:21]([NH:26]C(OC(C)(C)C)=O)[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[N:11](C(C)(C)C)[C:10](=[O:19])[CH2:9]1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:26][C@@H:21]([CH2:20][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[S:12](=[O:13])(=[O:14])[NH:11][C:10](=[O:19])[CH2:9]2)=[C:2]([Br:1])[CH:3]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(Br)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Temperature: 130 °C

Procedure:
Methyl (2S)-3-[3-bromo-4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-2-[(tert-butoxycarbonyl)amino]propanoate (458 mg, 0.654 mmol) was dissolved in trifluoroacetic acid (10 mL) and heated at 130° C. in the microwave for 2 minutes. The solution was concentrated in vacuo to a white foam (420 mg, 99%). The product was used in subsequent steps without purification. 1H NMR (500 MHz, CDCl3): δ 7.68 (dd, J=14.2, 1.6 Hz, 1H), 7.56–7.51 (m, 1H), 7.40–7.36 (m, 1H), 5.65 (t, J=7.4 Hz, 1H), 4.39 (t, J=6.8 Hz, 1H), 3.82 (s, 3H), 3.47–3.42 (m, 1H), 3.36–3.25 (m, 2H), 2.18–3.11 (m, 1H); LCMS found for C13H16BrN2O5S (M+Na)+: m/z=391.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: COCCN
Solvent: CO
Product: COCCNC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2-methoxyethanamine (19 μl, 0.23 mmol) via procedure W to afford 50 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)carbamimidoyl)benzamide. MS (Q1) 409 (M)+.
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC.[Li+].[Cl-].[F-].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:33]([O:32][C:30]([C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:10]3)=[CH:4][N:3]=1)=[CH2:31])[CH3:34]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Cl)ncc2OCC3)n(C(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(OCC)c1cc2c(cn1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 80 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
A mixture of 13-chloro-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,12-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (1.60 g, 4.64 mmol), tributyl(1-ethoxyvinyl)stannane (1.70 g, 4.71 mmol), LiCl (585 mg, 13.9 mmol), and Pd(PPh3)4 (537 mg, 0.460 mmol) in THF (30 mL) in a sealed tube was stirred at 80° C. for 48 hrs under N2 atmosphere. After being cooled to room temperature, aq. KF (2.0 M, 50 mL) was added. The resulting mixture was stirred at room temperature for 1 h and then filtered. The filtrate was extracted with ethyl acetate (5×50 mL). The combined organic layers were washed brine and dried over MgSO4. Removal of the solvent gave the desired product (900 mg, 51% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 5.90 (m, 1H), 5.30 (s, 1H), 4.64-4.60 (m, 4H), 4.39 (s, 1H), 3.95-3.94 (m, 2H), 2.27 (s, 3H), 1.51-1.48 (m, 6H), 1.42-1.39 (m, 3H). LCMS m/z [M+H]+ 381.3
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[C:25]([Si:12]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: OC1CC=CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cyclopent-3-enol (500 mg, 6.0 mmol) in CH2Cl2 (30 mL) at 0° C. was added imidazole (1.06 g, 15.6 mmol) and TBDPS-Cl (2.1 g, 7.8 mmol). The reaction was gradually warmed to room temperature and stirred for 16 hours. The reaction was then diluted with water (40 mL) and extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 5% EtOAc/Hexanes afforded tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane, which was then dissolved in CH2Cl2 (30 mL). 70% m-CPBA (830 mg, 6.9 mmol) was added at 0° C. The reaction was gradually warmed to room temperature while stirring for 16 hours. The reaction was then diluted with a saturated aqueous solution of NaHCO3 (40 mL) and extracted using CH2Cl2 (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 20% EtOAc/Hexanes afforded (6-oxabicyclo[3.1.0]hexan-3-yloxy)(tert-butyl)diphenylsilane.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14]CC)=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1>[OH-].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2cc(F)ccc2c1O
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A suspension of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate (65 g, 0.28 mol) in 10% sodium hydroxide (250 mL) was heated at reflux for 3 hours during which time a solution was obtained. The reaction mixture was allowed to cool to ambient temperature and then it was filtered through filter paper under vacuum. The filtrate was acidified with concentrated hydrochloric acid. The resulting precipitate was collected, washed with water and then dried to provide 53.5 g of 7-fluoro-4-hydroxy-3-quinolinecarboxylic acid as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:16][C@@H:17]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[C@@H:20]([S:31][CH3:32])[O:19][C@H:18]1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][CH2:50][OH:51])=[CH:43][CH:42]=2)[CH:34]=1)(=[O:15])[CH3:14]>C(Cl)Cl>[C:13]([O:16][C@@H:17]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[C@@H:20]([S:31][CH3:32])[O:19][C@H:18]1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][CH2:49][CH2:50][O:51][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:45][CH:46]=2)[CH:34]=1)(=[O:15])[CH3:14]
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCOS(C)(=O)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Methanesulfonyl chloride (41 μL, 0.53 mmol) and triethylamine (80 μL, 0.58 mmol) were added to a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-hydroxybutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (22, 247 mg, 0.44 mmol) in 5 mL CH2Cl2 and stirred at room temperature for 2 hours. The reaction was quenched with 1N aqueous HCl. The aqueous layer was extracted two times with EtOAc. The combined organic layers were washed with H2O and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide the product 23 (279 mg, 99% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (s, 2 H), 7.02-7.11 (m, 3 H), 7.00 (d, J=7.8 Hz, 2 H), 5.33 (dd, J=9.6 Hz, 1 H), 5.21 (dd, J=9.6 Hz, 1 H), 5.12 (dd, J=9.6 Hz, 1 H), 4.48-4.56 (m, 1 H), 4.39 (d, J=9.9 Hz, 1 H), 4.24 (t, J=6.1 Hz, 1 H), 3.93 (d, J=3.8 Hz, 2 H), 2.99 (s, 3 H), 2.62 (t, J=7.2 Hz, 2H), 2.22 (s, 3 H), 2.15-2.20 (m, 3 H), 2.10 (s, 3 H), 2.01 (s, 3 H), 1.70-1.81 (m, 4 H). MS (ES+) [M+NH4]+=654.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=2[N+:23]([O-:25])=[O:24])=[C:5]([CH3:26])[CH:4]=1.Cl.[CH:28]1([CH:31]([NH2:35])[CH2:32][CH2:33][CH3:34])[CH2:30][CH2:29]1>>[CH:28]1([CH:31]([NH:35][C:11]2[C:10]([N+:23]([O-:25])=[O:24])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:26])[CH:14]=[CH:13][N:12]=2)[CH2:32][CH2:33][CH3:34])[CH2:30][CH2:29]1
Reactant: CCCC(N)C1CC1
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(C)c1
Agent: Cl
Product: CCCC(Nc1nccc(-c2ccc(OC)cc2C)c1[N+](=O)[O-])C1CC1
Yield: 33.2 %

Procedure:
Trifluoro-methanesulfonic acid 4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.764 g, 1.95 mmol), prepared substantially as described in Part C of Example 67a, and 1-cylcopropyl-butyl amine HCl (0.580 g, 3.9 mmol) were treated substantially as described in Part C of Example 67a to produce 0.230 g (50%) of (1-cyclopropyl-butyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([SH:6])[CH3:5].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH2:17][O:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=O)C>ClCCl>[CH2:4]([S:6][CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH2:17][O:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])[CH3:5]
Reactant: CCS
Reactant: CC(=O)OC1NC(=O)C1CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCSC1NC(=O)C1CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of 572 mg sodium hydroxide in 50 ml. water was added 1.32 ml. of ethanthiol. After 10 minutes a solution of 5.02 g. 4-acetoxy-3-(p-nitrobenzyloxycarbonyloxyethyl)-2-oxo-azetidine in 100 ml. dichloromethane was added and the mixture was stirred vigorously at 0° C. for 30 minutes then at 25° C. for 3 hours. The dichloromethane layer was separated and the aqueous phase was extracted with two 70 ml. portions of dichloromethane. The combined dichloromethane extracts were washed with 70 ml. water, then with 70 ml. saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. The crude product was purified by column chromatography silica gel, eluting with 5:1 chloroform ethyl acetate, to obtain 4.15 g. of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[CH2:12]Cl)([O-:3])=[O:2].[CH2:15]([NH:19][CH3:20])[CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[CH2:12][N:19]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:20])([O-:3])=[O:2]
Reactant: O=C(CCl)Nc1ccccc1[N+](=O)[O-]
Reactant: CCCCNC
Solvent: c1ccccc1
Product: CCCCN(C)CC(=O)Nc1ccccc1[N+](=O)[O-]

Procedure:
N-(2-Nitrophenyl)-2-chloroacetamide (32.2 g) was dissolved in benzene (350 ml) and N-n-butylmethylamine (26.1 g) added. The mixture was boiled under reflux for 22 hours, the benzene evaporated off, and water (300 ml) added. The mixture was extracted with diethyl ether (3 × 200 ml), the extract dried with magnesium sulphate, filtered, and the ether evaporated off to give N-(2-nitrophenyl)-2-(N-n-butyl-N-methylamino)acetamide as a yellow oil which was used in the next stage without purification.
Reaction SMILES: OC1C=CC=CC=1C1SC=C(CC(O)=O)N=1.C([O:19][C:20](=[O:35])[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=2[OH:34])[S:25][CH:26]=1)C.[Li+].[OH-]>>[OH:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:24]1[S:25][CH:26]=[C:22]([CH2:21][C:20]([OH:35])=[O:19])[N:23]=1
Reactant: CCOC(=O)Cc1csc(-c2c(O)cccc2O)n1
Agent: O=C(O)Cc1csc(-c2ccccc2O)n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1csc(-c2c(O)cccc2O)n1
Yield: 93.6 %

Procedure:
The procedure used for the preparation of 5a was repeated with 4b (805 mg, 2.89 mmol) and 2N LiOH (5.1 mL) to provide 5b (680 mg, 94%) as a yellowish solid, which was recrystallized from THF/hexane. mp 210° C. (dec); IR (KBr) 3540-2500 (br), 3256 (br), 1688, 1461, 1230 cm-1 ; 1H NMR (DMSO-d6) δ 3.78 (2H, s, CH2), 6.42 (2H, d, J=8.1 Hz, Ar), 7.08 (1H, t, J=8.1 Hz, Ar), 7.46 (1H, s), 12.21 (2H, s, OH), 12.47 (1H, br s, CO2H); FDMS m/z 251 (M+), 252 (M+ +1); Anal. Calcd for C11H9NO4S: C, 52.58; H, 3.61; N, 5.57. Found: C, 52.36; H, 3.57; N, 5.38.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]3[NH:17][C:16](=O)[CH2:15][N:14]=[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:12]=3[CH:26]=2)=[O:7])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]3[NH:17][C:16](=[S:30])[CH2:15][N:14]=[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:12]=3[CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCC(=S)N2
Temperature: 60 °C
Reaction time: 6 h
Yield: 25.9 %

Procedure:
A mixture of intermediate (6) (0.01 mol) and tetraphosphorus decasulfide (0.012 mol) in THF (100 ml) was stirred at 60° C. for 6 hours, poured out into ice water and stirred for 1 hour. DCM was added. The mixture was stirred for 30 min, filtered over celite and washed several times with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (2.85 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 100%; 35–70 μm). The pure fractions were collected and the solvent was evaporated. The residue (1.3 g, 30.5%) was crystallized from acetonitrile. The precipitate was filtered off and dried, yielding 1.1 g (26%) of (4-chlorophenyl)[5-(3-chlorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepin-7-yl]-methanone (intermediate 13), mp. 125° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH3:38])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>CO.O1CCCC1.[C].[Pd]>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH3:38])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 78.2 %

Procedure:
p-Nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylate (syn isomer, 0.8 g.) was dissolved in a mixed solution of methanol (30 ml.) and tetrahydrofuran (60 ml.). After adding 10% palladium carbon (0.4 g.) to the solution, the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Water (30 ml.) was added to the residue and the mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. After removing the insoluble substance from the mixture by filtration, the filtrate was washed with ethyl acetate (50 ml.). Ethyl acetate (70 ml.) was added to the solution, and the mixture was adjusted to pH 1.5 with 10% hydrochloric acid and then shaked sufficiently. After the ethyl acetate layer was removed, the aqueous layer was extracted with ethyl acetate (30 ml.) twice. The ethyl acetate layer and the extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to give 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylic acid (syn isomer 0.48 g.), m.p. 165° to 174° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35])=[C:26]=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:35])([F:37])[F:36]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) in pyridine (3 mL) was added 1-isocyanato-2-(trifluoromethyl)benzene (53 μL, 0.348 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (15 mL)/tetrahydrofuran (5 mL), and washed successively with aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→90/10), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate (10 mL) to give the title compound (95 mg, 61%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:16]#[N:17].[Na+]>CS(C)=O>[C:16]([CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:17]
Reactant: COC(=O)c1cc2cccc(CBr)c2o1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2cccc(CC#N)c2o1

Procedure:
A solution of 11.92 g of methyl 7-bromomethylbenzofuran-2-carboxylate and 5.57 g of sodium cyanide in 150 ml of dimethyl sulphoxide is stirred at room temperature over 1 hour. The reaction mixture is poured onto water and extracted with ethyl acetate (3×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (dichloromethane); Rt=3.86.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:7][C:4]2([O:6][CH2:5]2)[CH2:3]1.C(Cl)Cl.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O-:23].[K+]>CC#N.O.CCOC(C)=O>[F:1][C:2]1([F:8])[CH2:7][C:4]([CH2:5][O:23][C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[O:13][CH3:12])([OH:6])[CH2:3]1
Reactant: COc1cc([N+](=O)[O-])ccc1[O-]
Reactant: FC1(F)CC2(CO2)C1
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCC1(O)CC(F)(F)C1
Yield: 64.5 %

Procedure:
A mixture of 5,5-difluoro-1-oxaspiro[2.3]hexane+3 eq. CH2Cl2 (22.52 g, 0.06 mol), potassium 2-methoxy-4-nitrophenolate (12.43 g, 0.060 mol) prepared in Part E and NaH2PO4.H2O (7.45 g, 0.054 mol) in 50 mL MeCN-water (85:15) was heated at 130° C. in a steel bomb for 3.5 h. The reaction mixture was diluted with EtOAc, washed with 5% Na2CO3, dried (MgSO4) and concentrated. The crude product was recrystallized from ca. 150 mL MTBE giving 3,3-difluoro-1-((2-methoxy-4-nitrophenoxy)methyl)cyclo-butanol (11.2 g, 0.039 mol, 64.5% yield) as a light yellow solid. An additional 1.2 g of a slightly less pure desired product was obtained upon concentration of the mother liquor to ca. 50 mL. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (1 H, dd, J=8.94, 2.64 Hz), 7.76 (1 H, d, J=2.77 Hz), 6.95 (1 H, d, S=9.06 Hz), 4.16 (2 H, s), 3.94 (3 H, s), 3.36 (1 H, s), 2.73-2.92 (4 H, m).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reaction time: 72 h
Yield: 1243.2 %

Procedure:
A solution of 15.1 g (47.1 mmol) of (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid (mycophenolic acid) and 0.7 g (3.7 mmol) of p-toluenesulfonic acid in 400 ml of methanol was allowed to stand at room temperature for 3 days. The mixture was concentrated under reduced pressure to approximately 75 ml and then partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase was further washed with brine and then dried over sodium sulfate. Concentration of the organic phase under reduced pressure gave 15.4 g (46.0 mmol, 98%) of methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 104°-105° C.
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:5]1[NH:6][C:7]([C:11]([O:13]CC)=[O:12])=[C:8]([CH3:10])[N:9]=1)[CH3:4].CO>C1COCC1>[CH2:3]([C:5]1[NH:6][C:7]([C:11]([OH:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)[CH3:4]
Reactant: CCOC(=O)c1[nH]c(CC)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc(C)c(C(=O)O)[nH]1
Temperature: 70 °C
Yield: 102.5 %

Procedure:
Lithium hydroxide (2 mL, 2 mmol, 1 M in H2O) was added to a solution of ethyl 2-ethyl-4-methyl-1H-imidazole-5-carboxylate (72 mg, 0.39 mmol) in THF:MeOH (6 mL/2 mL). The reaction mixture was heated at 70° C. for 4 h. The solvent was evaporated and dried in vacuo to give the title compound (61.6 mg, >99%) as a white solid which was directly used in the next step without purification.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4](/[C:7](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8]/[CH2:9][OH:10])=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:36]([O:38][C:39](=[O:52])[C@@H:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[CH3:37]>C1C=CC=CC=1>[CH2:36]([O:38][C:39](=[O:52])[C@@H:40]([O:49][CH2:50][CH3:51])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:10][CH2:9]/[CH:8]=[C:7](/[C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:5]=2)\[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:44][CH:43]=1)[CH3:37]
Reactant: OC/C=C(\c1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(-c3ccccc3)cc2)cc1)OCC
Yield: 83.1 %

Procedure:
Reaction of (E)-3-biphenyl-4-yl-3-phenyl-prop-2-en-1-ol (1.0 g, 3.49 mmol), tributylphosphine (1.3 ml, 5.24 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (0.92 g, 3.84 mmol) and azodicarboxylic dipiperidide (1.32 g, 5.24 mmol) in benzene in an identical manner to example 3 gave the title compound (1.47 g, 83%).