Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:35]([N:34]([CH2:32][CH3:33])[C:11](=[O:13])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:21])([CH3:20])[CH3:1])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCNCC
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCN(CC)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.0 μL N-ethylbutylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 60-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.15 min. (m/Z=290.1, 374.2, 396.1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][OH:16]>>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:16][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Product: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
Into a round bottom flask, 2,5-difluoro-4-nitro-benzoic acid (5.00 g, 0.0246 mol) and methanol (20.0 mL, 0.494 mol;) was added. The reaction was heated at 45° C. for one hour. The solvent was removed under vacuum. 1N HCl was added to pH 4. The solid was filtered and washed with water to give 2-fluoro-5-methoxy-4-nitro-benzoic acid as an off white solid (2.84 g, 54%). 1H-NMR (DMSO-D6, 400 MHz): δ 13.90 (bs, 1H), 8.08 (d, 1H), 7.72 (d, 1H), 3.94 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([SH:11])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:12]1COCC1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([S:11][CH3:12])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Sc1nc2ccc(Cl)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CSc1nc2ccc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask was added 5-chloro[1,3]thiazolo[5,4-b]pyridine-2-thiol (1-1) (21.4 g, 106 mmol), anhydrous THF (400 mL), potassium carbonate (20.5 g, 148 mmol), followed by methyl iodide (16.9 g, 119 mmol). The reaction vessel was sealed and stirred at room temperature for 5 minutes. The crude reaction mixture was then suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated to give 5-chloro-2-(methylthio)[1,3]thiazolo[5,4-b]pyridine (1-2) as a pink solid. HRMS (M+H)+: observed=216.9658, calculated=216.9655.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:15][C@H:16]([OH:32])[C@@H:17]([NH:25]C(=O)C(F)(F)F)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:15][C@H:16]([OH:32])[C@@H:17]([NH2:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cnccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cnccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
11.75 g (21 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane are suspended in 500 ml of methanol and, at 60° C., 105 ml of a 1M K2CO3 solution in water are added. The mixture is stirred at 75° C. for about 3 hours; the methanol is evaporated off and the residue is extracted with ethyl acetate. The organic phase is washed once each with water and brine and concentrated. The title compound is obtained in the form of orange-brown crystals, which can be recrystallised from ethyl acetate/petroleum ether. M.p.: 146-148° C. TLC: Rf=0.08 (methylene chloride/methanol 10:1). HPLC20-100: tRet=11.23.
Reaction SMILES: [CH3:1][O:2][C:3]1C=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].COC1[N:30]=CC=CC=1C(O)=O>>[CH3:1][O:2][C:3]1[C:4]([C:5]([NH:7][C@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])=[CH:16][CH:17]=[CH:18][N:30]=1
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Reactant: COc1ncccc1C(=O)O
Product: COc1ncccc1C(=O)N[C@@H]1CN2CCC1CC2

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 2-methoxynicotinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.51 (dd, J=8 Hz 1H), 8.28 (dd, J=6 Hz 1H), 7.07 (dd, J=8 Hz 1H), 4.16 (s, 3H, m, 1H), 3.44 (dd, J=12 Hz, 1H), 2.92 (t, J=8 Hz 2H), 2.85 (m, 2H), 2.61 (ddd, J=16, 12 Hz, 1H), 2.03 (m, 1H), 1.75 (m, 3H), 1.59 (m, 1H). C14H19N3O2=261.15 LCMS (M+H): m/z 262
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>COCCOC.O>[N:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1ccc(Br)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2ccncc2)c2ccccc12
Yield: 78.6 %

Procedure:
A stirred suspension of 4-bromonaphth-1-ylamine (10 g, 45 mnmole) in 1,2-dimethoxyethane (400 ml) and water (100 ml) containing sodium carbonate (14 g) was flushed with argon for 0.3h. Tetrakis (triphenylphosphine)palladium (0) (2.75 g, 2.4 mmole) was added followed by 4-pyridylboronic acid (5.7 g, 46 mmole) and the mixture heated at reflux for 5 h. The mixture was concentrated in vacuo to a brown slurry and partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane and the combined organics dried (Na2SO4) and concentrated in vacuo to a brown solid (13.2 g). Purification of the solid by flash chromatography eluting with ethyl acetate afforded the title compound as a yellow crystalline solid (7.8 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1.O>O1CCCC1.C(=O)([O-])O.[Na+].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>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3cccc(F)c3)cc2)cs1
Yield: 64.1 %

Procedure:
Under nitrogen atmosphere, 2-({4-[2-(4-bromophenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (447 mg) synthesized in Example 67-1 and 3-fluorophenylboric acid (273 mg) were dissolved in tetrahydrofuran (10 mL) and sodium hydrogen carbonate (1 mol/l, 10 mL), tetrakis(triphenylphosphine)palladium (231 mg) was added, and the mixture was refluxed for 6.5 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1) to give the title compound (296 mg) as a pale-yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][PH:5]([O:14][C@@H:15]1[C@@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[O:18][C@@H:17]([N:45]2[CH:52]=[CH:51][C:49](=[O:50])[NH:48][C:46]2=O)[C@@H:16]1[O:53][CH2:54][O:55][CH2:56][CH:57]([C:62]([F:65])([F:64])[F:63])[C:58]([F:61])([F:60])[F:59])([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[OH:6])#[N:2].[O:66]([CH2:73][C:74]([NH:76][C:77]1[NH:78]C(=O)C2N=CN(C=2[N:129]=1)[C@@H]1O[C@H](COC(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[C@@H](O)[C@H]1OCOCC(C(F)(F)F)C(F)(F)F)=[O:75])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>>[C:1]([CH2:3][CH2:4][PH:5]([O:14][C@@H:15]1[C@@H:19]([CH2:20][O:21][C:22]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[O:18][C@@H:17]([N:45]2[C:52]3[N:129]=[C:77]([NH:76][C:74](=[O:75])[CH2:73][O:66][C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[NH:78][C:49](=[O:50])[C:51]=3[N:48]=[CH:46]2)[C@@H:16]1[O:53][CH2:54][O:55][CH2:56][CH:57]([C:62]([F:63])([F:65])[F:64])[C:58]([F:59])([F:60])[F:61])([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[OH:6])#[N:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCC(C(F)(F)F)C(F)(F)F)[C@@H]2O[PH](O)(CCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 51 %

Procedure:
This compound was synthesized in the same manner as that used for the compound 3u by using the compound 2g instead of the compound 2u. Yield was 51% (white foam).
Reaction SMILES: [F:1][C@@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:3]([NH:6][S@@](C(C)(C)C)=O)[CH:4]=[CH2:5].CO.Cl.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>C(Cl)Cl>[F:1][C@@H:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@H:3]([NH:6][C:23](=[O:22])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:4]=[CH2:5]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=C[C@@H](N[S@](=O)C(C)(C)C)[C@@H](F)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C=C[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 105.4 %

Procedure:
To a 150 mL RBF containing (R)—N-((1S,2R)-1-fluoro-1-phenylbut-3-en-2-yl)-2-methylpropane-2-sulfinamide (107.00 mg, 397 μmol) was added methanol (5 mL) and the mixture was allowed to stir at 0° C. for 10 min. At this time, HCl (4N) (993 μl, 3972 μmol) was added and the reaction was allowed to stir for 30 min. Then TEA (1384 μl, 9930 μmol) was added to the mixture followed by DCM (2 ml) and BOC2O (173 mg, 794 μmol) in one portion. The reaction was allowed to stir overnight and then the bulk of the methanol was removed by evaporation. The residue was dissolved in EtOAc and washed with HCL (0.5 N, 2×40 ml). The combined aqueous layers were back extacted with EtOAc. The combined organics were washed with sodium bicarbonate (1×50 ml, sat) and brine and then dried with sodium sulfate. The dried solution was passed though a plug of silica gel to give tert-butyl (1S,2R)-1-fluoro-1-phenylbut-3-en-2-ylcarbamate (111.0 mg). Rf=0.45 in 20% EtOAc in hexanes, UV active and stain yellow to anisaldehyde. LC/MS give an ionization for eliminated product (mass=190).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[NH:4][CH2:3]1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH2:3][C@@H:2]([NH:1][C:21]([NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])[CH2:11]2)#[N:13]
Reactant: O=C=Nc1ccccc1
Reactant: N#Cc1ccc2c(c1)C[C@H](N)CN2
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)Nc1ccccc1)CN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of (S)-3-amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile (52 mg, 0.3 mmol), prepared as described in Example 1F, in CH2Cl2 (2 mL) at RT was added phenyl isocyanate (33 μl, 0.3 mmol) dropwise. After addition, the reaction was stirred at RT for 1 h. The product was collected by filtration and washed with CH2Cl2-hexanes (1:1) to give the title compound (85 mg, 97%) as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=3[C:23]([CH:34]=O)=[N:22]2)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=3[C:23]([CH2:34][NH:3][C@@H:4]3[CH:9]4[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]4)[CH2:5]3)=[N:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc2c1c(C=O)nn2-c1ccc(F)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [H-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc2c1c(CN[C@H]1CN3CCC1CC3)nn2-c1ccc(F)cc1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a stirred suspension of (R)-(+)-3-aminoquinuclidine dihydrochloride (360 mg, 1.8 mmol) in dichloromethane (15 mL) was added sodium hydride (144 mg, 3.6 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.15 mL) was added dropwise. Then methyl 1-(4-fluorophenyl)-3-formyl-1H-indazole-4-carboxylate (454 mg, 1.5 mmol) from Step A above was added and the mixture continued to stir at room temperature for an additional 4 h. Sodium triacetoxyborohydride (1.3 g, 6.0 mmol) was added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (R)-methyl 1-(4-fluorophenyl)-3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate as a light yellow oil (492 mg, 80%): 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=7.3 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.63-7.60 (m, 2H), 7.46 (t, J=7.9 Hz, 1H), 7.27-7.24 (m, 2H), 4.37 (d, J=14.1 Hz, 1H), 4.27 (d, J=14.1 Hz, 1H), 4.00 (s, 3H), 3.39-3.34 (m, 1H), 3.22-3.01 (m, 5H), 2.81 (dd, J=13.4, 2.3 Hz, 1H), 2.30-2.25 (m, 1H), 2.20-2.17 (m, 1H), 1.92-1.86 (m, 1H), 1.75-1.69 (m, 1H) 1.63-1.59 (m, 1H); MS (ESI+) m/z 409 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].[H-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][O:19][C:20]=2[N:21]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][O:19][C:20]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: C[C@@H]1CCC[C@H]1O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CCC[C@H]1Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a solution of trans-2-methylcyclopentanol (0.18 g) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-[(trans-2-methylcyclopentyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.46 g, 75%) as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:15][C:16](=[O:18])[CH3:17])[CH2:9]2)=[O:5]>O.CO>[C:16]([NH:15][CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH:4]([OH:5])[CH3:3])[CH:7]=2)[CH2:11]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NC1Cc2ccc(C(C)=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)NC1Cc2ccc(C(C)O)cc2C1

Procedure:
A solution of 4.6 g (0.12 mol) of sodium borohydride in 25 ml of water is added to 24 g (0.11 mmol) of (2-acetamido-indan-5-yl) methyl ketone (Example G) in 200 ml of methanol at room temperature. After 21/2 hours, the mixture is evaporated in vacuo and the residue is diluted with ice-water and acidified. The reaction product is extracted with 9:1 methylene chloride/methanol, the organic phase is dried, and the solvent is removed in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:22]1([C:28]2[C:41]3[C:32](=[C:33]4[C:38](=[CH:39][CH:40]=3)[C:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][CH:35]=[N:34]4)[N:31]=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1COCC1>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[C:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]3[C:33](=[C:32]4[C:41](=[CH:40][CH:39]=3)[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:29][CH:30]=[N:31]4)[N:34]=2)=[CH:3][CH:4]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: Brc1ccc(-c2nc3ccccc3s2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)cc(-c4ccc(-c5nc6ccccc6s5)cc4)nc23)cc1
Temperature: -78 °C
Yield: 41.9 %

Procedure:
To a three-necked flask of 250 ml, 1.63 g (5.6 mmol) of 2-(4-bromophenyl)benzo[d]thiazole and 70 ml of THF were charged, then 3.5 ml (5.6 mmol) n-butyllithium (1.6M in Hexane solution) was dropped under stirring at −78° C. in a nitrogen atmosphere. The mixture was stirred for one hour at −78° C., and a solution of 1.86 g (5.6 mmol) 4,7-diphenyl-1,10-phenanthroline in 30 ml THF was dropped. Then the mixture was stirred at room temperature for overnight and was added with water. The organic layer was extracted with Dichloromethane and dried with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation. The product was purified by column chromatography on alumina using Dichloromethane/Hexane as eluent and dried in vacuo, obtaining white powder compound 1.27 g (yield of 41.91%), MS (m/z, FAB+) 541.6.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[CH:13]=[C:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])([O-:9])=[O:8].[C:23]([O:26][CH2:27][CH3:28])(=O)C>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[CH:13]=[C:14]([CH2:18][CH3:19])[C:15]([O:17][C:10]1[CH:11]=[CH:28][C:27]([O:26][CH3:23])=[CH:21][CH:22]=1)=[O:16])([O-:9])=[O:8]
Reactant: CCC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CCOC(C)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCC(=Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (22 g) was added to 22.1 g of m-nitro-α-ethylcinnamic acid suspended in 300 ml of ethyl acetate, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, upon which m-nitro-α-ethylcinnamoyl chloride precipitated. This compound was dissolved in 300 ml of ethyl acetate, and 12.4 g of p-methoxyphenol was added thereto. After the reaction at room temperature for 1 hour, the reaction mixture was washed with 10% HCl, 10% NaOH and water in this order and dried on anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain p-methoxyphenyl m-nitro-α-ethylcinnamate. Yield: 30.7 g (93.9%); melting point: 65°-66° C.; IR (cm-1): 1710, 1503, 1351.
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C[Si](Br)(C)C.[P:18]([CH2:22][CH2:23][O:24][N:25]=[C:26]([C:53]1[N:54]=[C:55]([NH:58]C=O)[S:56][CH:57]=1)[C:27]([NH:29][CH:30]1[C:51](=[O:52])[N:32]2[C:33]([C:48]([OH:50])=[O:49])=[C:34]([CH2:37][S:38][C:39]3[S:40][C:41]4[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:35][S:36][C@H:31]12)=[O:28])([OH:21])([OH:20])=[O:19]>C(Cl)Cl>[P:18]([CH2:22][CH2:23][O:24][N:25]=[C:26]([C:53]1[N:54]=[C:55]([NH2:58])[S:56][CH:57]=1)[C:27]([NH:29][CH:30]1[C:51](=[O:52])[N:32]2[C:33]([C:48]([OH:50])=[O:49])=[C:34]([CH2:37][S:38][C:39]3[S:40][C:41]4[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:35][S:36][C@H:31]12)=[O:28])([OH:21])([OH:20])=[O:19]
Reactant: O=CNc1nc(C(=NOCCP(=O)(O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nc5ccccc5s4)CS[C@H]23)cs1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: Nc1nc(C(=NOCCP(=O)(O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nc5ccccc5s4)CS[C@H]23)cs1
Reaction time: 0.5 h

Procedure:
A mixture of 7-[2-{2-(O,O-diethylphosphono)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.59 g.), methylene chloride (30 ml.) and bis(trimethylsilyl)acetamide (2.14 g.) was stirred for 30 minutes at 18° to 20° C. and thereto was added trimethylsilyl bromide (2.68 g.) followed by stirring for 5 hours and 45 minutes at 19° to 21° C. The reaction mixture containing 7-[2-(2-phosphonoethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was concentrated and to the residue were added methanol (30 ml.) and conc. hydrochloric acid (3 ml.). The mixture was stirred for 1.5 hours at room temperature and then evaporated. The residue was dissolved in an aqueous solution of sodium bicarbonate and the solution was washed with ethyl acetate and then adjusted to pH about 2 with 10% hydrochloric acid. The precipitates were collected by filtration under cooling, washing with water, dried under reduced pressure and then suspended in methanol (20 ml.). After conc. hydrochloric acid was added to the suspension to dissolve the precipitates, the resulting solution was treated with activated charcoal and then thereto was added dropwise a mixture of conc. ammonia water and methanol (1:5) whereby the pH was adjusted to 3 to 4. The precipitates were collected by filtration under cooling to give a powder of the title compound (0.85 g.), mp. 170° to 210° C.