Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9][C:10]1[O:11][C:12]2[C:13](=[C:15]([C:23](OC)=[O:24])[CH:16]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[CH:18]=2)[CH:14]=1>>[Br:9][C:10]1[O:11][C:12]2[C:13](=[C:15]([C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:24])[CH:16]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[CH:18]=2)[CH:14]=1
Reactant: COC(=O)c1cc(OC(C)C)cc2oc(Br)cc12
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(OC(C)C)cc3oc(Br)cc23)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 2-amino-5-methyl pyridine and methyl 2-bromo-6-isopropoxybenzofuran-4-carboxylate (345a) to give an off-white solid (1.45 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1 H) 8.27 (d, J=8.31 Hz, 1 H) 8.14 (s, 1 H) 7.60 (dd, J=8.44, 1.89 Hz, 1 H) 7.30 (d, J=2.01 Hz, 1 H) 7.24 (s, 1 H) 7.16 (d, J=1.76 Hz, 1 H) 4.57-4.64 (m, 1 H) 2.34 (s, 3 H) 1.38 (d, J=6.04 Hz, 6 H); LCMS for C18H17BrN2O3 m/z 389.00 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1)=[O:30])[CH2:23]2)(=[O:19])=[O:18])C1C=CC=CC=1>C(O)C.[Pd]>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29]([N:24]2[CH2:23][C:22]3[C:26](=[CH:27][CH:28]=[C:20]([S:17](=[O:18])(=[O:19])[NH:16][C:10]4[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=4[OH:8])[CH:21]=3)[CH2:25]2)=[O:30])=[CH:37][CH:36]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(NC(=O)N2Cc3ccc(S(=O)(=O)Nc4ccc(F)cc4OCc4ccccc4)cc3C2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(NC(=O)N2Cc3ccc(S(=O)(=O)Nc4ccc(F)cc4O)cc3C2)cc1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 5-{[2-(benzyloxy)-4-fluorophenyl]sulfamoyl}-N-(4-tert-butylphenyl)-1,3-dihydro-2H-isoindole-2-carboxamide (150 mg, 0.261 mmol) in ethanol (10 mL) was added 10% palladium activated carbon (150 mg) at room temperature, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=19:1), powdered with hexane, and then collected by filtration to afford the title compound as a brownish red powder (98.4 mg).
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:26])=[C:10]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:15][C:11]2=[C:12](O)[N:13]=1)=[O:7])CCC.C([O:31][C:32]([C:34]1[N:39]=C(O)C2C=C(C3C=CC(OC)=CC=3)SC=2C=1O)=[O:33])CCC>>[OH:26][C:9]1[C:8]([C:6]([NH:39][CH2:34][C:32]([OH:33])=[O:31])=[O:7])=[N:13][CH:12]=[C:11]2[S:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[CH:17][C:10]=12
Reactant: CCCCOC(=O)c1nc(O)c2sc(-c3ccc(OC)cc3)cc2c1O
Reactant: CCCCOC(=O)c1nc(O)c2cc(-c3ccc(OC)cc3)sc2c1O
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCC(=O)O)ncc3s2)cc1

Procedure:
The title compound was prepared from a mixture of 4,7-dihydroxy-2-(4-methoxy-phenyl)-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester and 4,7-dihydroxy-2-(4-methoxy-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester, example 3-b, under conditions analogous to experimental example 1-f. MS: (+) m/z 390.24, 392.19 (M+1, 35Cl/37Cl).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[O:10][C:9]=2[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[CH:45]=1>O>[N:38]1[C:37]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[O:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[CH:6][CH:7]=2)=[CH:45][N:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=12
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(O)cc2)C1=O
Reactant: ClCc1cn2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(OCc3cn4ccccc4n3)cc2)C1=O
Temperature: 80 °C
Yield: 60.2 %

Procedure:
4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydro furan-2-yl)benzonitrile (3.15 g, 10.3 mmol) was added to a mixture of cesium carbonate (13.4 g, 41.3 mmol) and DMF (100 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)imidazo[1,2-a]pyridine (2.0 g, 12.3 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (2.7 g, 60%) as an off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H), 1.25 (s, 6H). MS: [M+H]+: m/z=436.2. HPLC: (97.3%, Condition-A).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].[Cr]([O-])([O-])(=O)=[O:13].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[C:10]([OH:13])(=[O:11])[CH2:9][CH:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])[CH3:8]
Reactant: O=[Cr](=O)([O-])[O-]
Reactant: CC(C)=CCCC(C)CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)=CCCC(C)CC(=O)O

Procedure:
Citronellol is oxidized with a chromate-type oxidizing agent (e.g., Jones reagent) to the carboxylic acid which is then esterified to give an ester of citronellic acid. The double bond is converted into an epoxide by a peroxide as described in Step 4. And then, the epoxide is oxidatively cleaved with a periodate to give an aldehyde, which is converted into the olefinic compound by convention Wittig reaction using trimethylphosphonium bromide and a base. The compound thus prepared is condensed with dimethyl methylphosphonate in the presence of base to give the desired compound. When an optically active compound such as (S)-(-)-citronellol is used as a starting material and allowed to react in the same manner, (S)-dimethyl 2-oxo-4-methyl-7-octenylphosphonate is prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([O:38]CC)=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]=2[C:9]1=[O:34].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([OH:38])=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[C:10]=2[C:9]1=[O:34]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Temperature: 25 °C

Procedure:
Ethyl (3-chloro-4-{1,3-dioxo-4,9-bis[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.375 g, 0.64 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:2N aqueous hydrochloric acid (20 ml) for 5 hours. The reaction was cooled to room temperature. On addition of water, the resulting white solid was collected by filtration and washed with water (0.315 g, 0.56 mmol). LC/MS: Rt=3.57, [MH]+ 562.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[CH:11]3[O:13][CH:12]3[C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].[NH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23].[H-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([CH3:15])([CH3:14])[C@@H:11]([OH:13])[C@H:12]([N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C1CCCN1
Reactant: COC(=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reaction time: 6 h

Procedure:
6-Carbomethoxy-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (2.42 g, the preparation of which is described in Example 4 of U.K. Pat. No. 1,511,187) and 2-pyrrolidone (0.88 g), were stirred in dimethyl sulphoxide (40 ml) under nitrogen at room temperature. Sodium hydride (0.31 g, 81% dispersion in mineral oil) was added during 5 mins. and the reaction stirred for a further 6 hours. Addition of water, extraction with ethyl acetate, drying or the organic phase with magnesium sulphate, filtration, evaporation and recrystallisation from ethyl acetate-pentane gave 6-carbomethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]-pyran-3-ol of m.p. 190°-192°.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:26])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CC(C)=O>[CH3:14][O:13][C:6]1[CH:5]=[CH:4][C:3]([C:15](=[O:26])[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:2]([O:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(CCC(=O)c2ccc(OC)c(CCC(C)C)c2O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1c(C(=O)CCc2ccc(OC)cc2)ccc(OC)c1CCC(C)C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Then, 21.5 g of 1-(2-hydroxy-4-methoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone was dissolved in 150 ml of anhydrous acetone, and 41.6 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred for 30 minutes. Then, 18.4 g of methyl α-bromoacetate was added to the reaction mixture, and the mixture was stirred at room temperature for 5 days to effect reaction After the reaction, the reaction mixture was extracted with diethyl ether and the solvent was removed from the extract, and the obtained residue was subjected to the silica gel chromatography (eluting solvent: n-hexane/ethyl acetate =8/1) to obtain 20.9 g (yield=80.9%) of 1-(4-methoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl -3-(4-methoxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][CH3:13]>C(O)C.O>[CH2:11]([NH:14][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH3:13]
Reactant: CCCN
Reactant: ClCCOc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCNCCOc1ccccc1

Procedure:
the 2-phenoxyethyl chloride is reacted with n-propyl amine in the presence of an ethanol-water solvent at a temperature of from 100° C. to 110° C. to form N-n-propyl-N-2-phenoxy-ethyl amine;
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=2[F:26])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[Cl-].[NH4+].O1CCCC1.C(O)C>[Fe].O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:3]2[C:2]([Br:1])=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:15])[N:8]3[C:12](=[O:14])[CH3:13])=[C:18]([F:26])[CH:19]=1
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccc([N+](=O)[O-])cc3F)c2CC[C@@H]1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2ccc(Br)c(Oc3ccc(N)cc3F)c2CC[C@@H]1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.7 %

Procedure:
A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, and charged with 1-[(2S)-6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (500 mg, 1.18 mmol), iron powder (331 mg, 5.91 mmol), ammonium chloride (128 mg, 2.37 mmol), tetrahydrofuran (9 mL), ethanol (3 mL), and water (9 mL). The resulting mixture stirred for 12 h at 80° C. and was then filtered. The filtrate was concentrated, and the residue was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-[(2S)-5-(4-amino-2-fluorophenoxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (370 mg, 80%) as a light brown solid. MS (ESI, pos. ion) m/z 393, 395 [M+H]+.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH:38]=[CH2:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH:20]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:21][CH2:22][OH:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:40]>>[ClH:40].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH:38]=[CH2:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH:20]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:21][CH2:22][OH:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12)c1csc(N)n1
Yield: 99.3 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 2.7 g) was treated with conc. hydrochloric acid (0.94 g) in a similar manner to that of Example 1-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 2.72 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([OH:20])=O)[CH2:8][C:9]=1[NH:10]2.ClC(OCC(C)C)=O.Cl.[CH3:30][NH:31][O:32][CH3:33]>C1COCC1.O.C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:16])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([N:31]([O:32][CH3:33])[CH3:30])=[O:20])[CH2:8][C:9]=1[NH:10]2
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(C(=O)O)CC3
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
Step 1 A solution of 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid (Intermediate 49-3, 2 g, 5.93 mmol) and TEA (2.067 mL, 14.83 mmol) in THF (20 mL) was treated with isobutyl chloroformate (0.810 g, 5.93 mmol) at 0° C. The mixture was stirred for 10 min, then was treated with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.579 g, 5.93 mmol) in THF (2 mL) and water (1 mL). The mixture was stirred at 0° C. for 1 h, then was diluted with DCM, washed with NaHCO3 (aq) and water, dried and concentrated. The residue was triturated with DCM to provide 5-bromo-N2-methoxy-N2-methyl-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide as a light yellow solid (1.73 g, 77%). Mass spectrum m/z 380, 382 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and pyridin-3-ylboronic acid. HPLC (Condition 4) tR=4.38 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=445.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.53-2.68 (m, 1H) 3.37-3.49 (m, 4H) 3.68 (t, J=8.41 Hz, 2H) 4.66 (t, J=5.28 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.49 (dd, J=7.82, 4.69 Hz, 1H) 7.84 (d, J=8.99 Hz, 3H) 7.99 (d, J=2.35 Hz, 1H) 8.54-8.60 (m, 1H) 8.64 (d, J=1.96 Hz, 1H) 8.72-8.78 (m, 1H) 10.18 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[O:16][N:15]=[CH:14][CH:13]=1)[CH:2]=[CH2:3].[O-]CC.[Na+].Cl>C(O)C>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)ccc1-c1ccno1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCOc1cc(C)ccc1C(=O)CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred suspension of 5-[2-(allyloxy)-4-methylphenyl]isoxazole (Step 3, 7.3 g, 33.8 mmol) in ethanol (40 mL) was added sodium ethoxide (21% solution in ethanol, 40 mL, 110 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was acidified to pH 2 with hydrochloric acid (2N, aqueous) and the solid was filtered off and air dried for 1 hour to give the title compound as an off-white solid, 4.8 g, in a 66% yield. LCMS (2 min acidic) 1.12 min 51-100% pure by UV, ES+/AP+ 216, ES−/AP− 214.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH2:21](Br)[CH:22]=[CH2:23]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:23][CH:22]=[CH2:21]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: C=CCBr
Product: C=CCN1C(=Nc2ccc([N+](=O)[O-])cc2C)SCC12CCCC2

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with allyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(prop-1-en-3-yl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:24](Cl)(=[O:26])=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:29]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:24](=[O:26])(=[O:25])[NH2:29])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(OCc2ccccc2)c1-c1ccccc1
Reaction time: 2.5 h

Procedure:
3-Benzyloxy-5-chlorosulfonyl-4-phenylbenzoic acid (1.0 g) is in portions added to conc. ammonium hydroxide (10 ml), while stirring at 10°-12° C. After additional stirring at room temperature for 18-20 hours, the mixture is left in a refrigerator for 2-3 hours. The separated ammonium salt is collected by filtration and washed with a small amount of icecold water. After drying, the salt is dissolved in 1 N sodium hydroxide (10 ml) and the 3-benzyloxy-4-phenyl-5-sulfamylbenzoic acid is precipitated by the dropwise addition of the solution to 1 N hydrochloric acid (12 ml). The acid is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, it is obtained with a melting point of 199°-200° C.
Reaction SMILES: C(OC([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[NH:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: c1nc(N2CCCC3(CCN3)C2)c2cc[nH]c2n1
Reaction time: 5 h
Yield: 94.3 %

Procedure:
To a solution of an optically-active compound of 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester (2.55 g) in methanol/tetrahydrofuran (51 ml/51 ml) was added 20% palladium carbon (510 mg), and the mixture was hydrogenated under 4 atmospheres for 5 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was slurry-washed with diisopropyl ether (30 ml) to give the titled compound (1.55 g).
Reaction SMILES: C([NH:3][CH:4]1[C:37](=[O:38])[N:6]2[C:7]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[N:18][CH:19]=3)[CH2:9][S:10][C@H:5]12)=O.Cl.O.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.O1CCCC1>[NH2:3][CH:4]1[C:37](=[O:38])[N:6]2[C:7]([C:21]([O:23][CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[N:18][CH:19]=3)[CH2:9][S:10][C@H:5]12
Reactant: Cc1ccc(/C=C\SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC=O)[C@H]3SC2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(/C=C\SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)cn1
Reaction time: 2.5 h
Yield: 84.9 %

Procedure:
To a suspension of benzhydryl 7-formamido-3-[(Z)-2-(2-methyl-5-pyridyl)vinylthio]-3-cephem-4-carboxylate (17.5 g) in methanol (90 ml) was added conc. hydrochloric acid (10.0 ml) at ambient temperature and the mixture was stirred at 30° to 35° C. for 2.5 hours. The reaction mixture was poured into a mixture of cold water (250 ml), tetrahydrofuran (250 ml) and ethyl acetate (500 ml). The resultant mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give benzhydryl 7-amino-3-[(Z)-2-(2-methyl-5-pyridyl)vinylthio]-3-cephem-4-carboxylate (14.1 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3[C:10](=[O:29])[N:11]([C:20]4[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=4)[CH:12]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=4)[C:8]=3[C:7]([CH3:30])=[N:6]2)[CH2:2]1.[CH2:31](Cl)Cl.CO>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]2[C:8]3[C:7]([CH3:30])=[N:6][N:5]([CH:3]4[CH2:2][N:1]([CH3:31])[CH2:4]4)[C:9]=3[C:10](=[O:29])[N:11]2[C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: Cc1nn(C2CNC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Reactant: ClCCl
Solvent: CO
Product: Cc1nn(C2CN(C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared using an analogous procedure to that described in Step 139.2 using 1-(azetidin-3-yl)-4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 138.2). tR: 0.61 min (LC-MS 2); ESI-MS: 438.1 [M+H]+ (LC-MS 2); Rf=0.29 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.96 (m, 6H) 2.33 (s, 3H) 3.35 (s, 3H) 3.45-3.59 (m, 2H) 3.66-3.78 (m, 2H) 4.97-5.10 (m, 1H) 6.07 (s, 1H) 7.26 (d, J=8.60 Hz, 2H) 7.33-7.42 (m, 3H) 7.71 (d, J=2.74 Hz, 1H).