Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O.O.O.[NH2:25]N>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=3)=[N:25][NH:2][CH:3]=2)=[CH:16][CH:17]=1
Reactant: CSc1ccc(C(=O)C(=CN(C)C)c2ccc(F)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CSc1ccc(-c2n[nH]cc2-c2ccc(F)cc2)cc1
Yield: 90.1 %

Procedure:
The crude ketone from step 1 (23.9 g) was stirred in 500 mL methanol and 100 mL water with 8 mL hydrazine hydrate at reflux under nitrogen for 24 hour. The mixture was cooled, concentrated, diluted with ethyl acetate, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from ethyl acetate-hexane gave 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1H-pyrazole as a pale yellow solid (16.9 g, 90.1%). Elemental analysis Calc'd for C16H13 N2FS: C, 67.58, H, 4.61, N, 9.85, S, 11.28. Found: C, 67.44, H, 4.76, N, 9.69, S, 11.27.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[C:22]([O:24][SiH:25]([CH3:27])[CH3:26])[C:8]2[N:9]=[C:10]([C:12]3[S:13][C:14]([CH3:21])([CH3:20])[CH:15]([C:17](O)=[O:18])[N:16]=3)[S:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:31])=O.CN(C)C=O>C(Cl)Cl>[C:1]([C:5]1[CH:23]=[C:22]([O:24][SiH:25]([CH3:27])[CH3:26])[C:8]2[N:9]=[C:10]([C:12]3[S:13][C:14]([CH3:21])([CH3:20])[CH:15]([C:17]([Cl:31])=[O:18])[N:16]=3)[S:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[SiH](C)Oc1cc(C(C)(C)C)cc2sc(C3=NC(C(=O)O)C(C)(C)S3)nc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[SiH](C)Oc1cc(C(C)(C)C)cc2sc(C3=NC(C(=O)Cl)C(C)(C)S3)nc12
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
2-(6-tert.-butyldimethylsilyloxybenzothiazole-2-yl)-4,5-dihydro-5,5-dimethyl-4-thiazole carboxylic acid is dissolved under argon atmosphere in 8 ml dry methylene chloride, the clear solution is cooled to −15° C. and a mixture of 0.162 ml (1,875 mmol) oxalyl chloride and 500 μl of freshly distilled dimethyl formamide are added dropwise to the reaction under vigorous stirring. Slight gas emission can be observed during this step. The reaction mixture is stirred for additional 30 minutes at −15° C. and subsequently diluted with freshly destilled methylene chloride to a final volume of 30 ml.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(Oc3ccccc3)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(Oc3ccccc3)cc2)S(C)(=O)=O)c1

Procedure:
The title compound of Step B was prepared following the method described in Step A of Example 1 from 3-{3-[(4-phenoxy-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and methanesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamin. 1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 7.14 (m, 4H), 6.97 (m, 4H), 4.31 (s, 2H), 4.30 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.78 (s, 3H), 2.61 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[C:6]([C:22](=[O:25])[CH2:23][CH3:24])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[Sn]([N:36]=[N+:37]=[N-:38])(C)C.O.CO>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]3[NH:38][N:37]=[N:36][N:19]=3)=[CH:16][CH:15]=1)[C:6]([C:22](=[O:25])[CH2:23][CH3:24])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 110 °C
Reaction time: 96 h
Yield: 57.7 %

Procedure:
To a suspension of 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzonitrile (1.89 g) in toluene (80 ml) was added trimethyltin azide (2.47 g) and the mixture was stirred at 110° C. for 4 days. Water (50 ml) and methanol (50 ml) were added at room temperature, and the precipitated crystals were collected by filtration to give the title compound (1.19 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1c(Cl)cccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
(31) (Canadian Journal of Chemistry. 1968 46, 1952-6). To a solution of 2,6-dichlorobenzaldehyde (1.75 g, 10.0 mmol) and acetophenone (1.20 g, 10.0 mmol) in 30.0 ml of methanol was added 4.4 ml of 40% sodium hydroxide in water at 10° C. After stirring for 3 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 1.68 g (60.6%) of yellow needles: mp 84.5-85.3° C. (lit. mp 83° C. Kuck and Grutzmacher, Org. Mass. Spect. 1978, 13, 90-102). 1H NMR (250 MHz) δ 8.05-8.01 (m, 2 H), 7.90-7.84 (d, 1 H), 7.70-7.64 (d, 1 H), 7.62-7.48 (m, 3 H), 7.41-7.37 (d, 2 H), 7.24-7.18 (dd, 1 H); 13C NMR (62.7 MHz) 190.3, 139.0, 135.3, 133.3 132.8, 130.7, 130.0, 129.0, 128.9 ppm.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1csc(N)n1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1csc(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.85 mL (8.28 mmol) of cyclohexanone and 1.0 g (8.75 mmol) of 2-amino-4-methylthiazole in 10 mL of tetrahydrofuran was added 0.5 mL (8.75 mmol) of acetic acid and 4.64 g (21.8 mmol) of sodium triacetoxyborohydride. After stirring for 16 hr at rt, a further 0.45 mL (4.37 mmol) of cyclohexanone and 0.926 g (4.37 mmol) of sodium triacetoxyborohydride was added and stirring continued for 72 hr at rt. Ethyl acetate (15 mL) was added and the mixture washed with saturated sodium bicarbonate (2×15 mL) then dried (Na2SO4). Purification by chromatography on silica gave the title compound.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][N:3]=1.[CH3:12]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[N:4]([CH3:12])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Ic1n[nH]c2c1CCCCC2
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2c1CCCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of 3-iodo-1,4,5,6,7,8-hexahydrocycloheptapyrazole (600 mg, 2.29 mmol) in THF (8 ml) at 0° C. was added KOt-Bu (360 mg, 3.2 mmol). The reaction mixture was stirred at 0° C. for 30 min then iodomethane (0.20 ml, 3.2 mmol) was added. Stirring was continued at 0° C. for 30 min then at room temperature for 2 h. The reaction was quenched with water and extracted with EtOAc (2×). The organics were dried over MgSO4 and concentrated. The residue was absorbed on SiO2 and chromatographed with 10% to 20% EtOAc/hexanes to afford 387 mg (61%) of 3-iodo-1-methyl-1,4,5,6,7,8-hexahydrocycloheptapyrazole as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.77 (s, 3H), 2.65-2.76 (m, 2H), 2.43-2.54 (m, 2H), 1.77-1.88 (m, 2H), 1.59-1.76 (m, 4H). Also isolated 200 mg (32%) of the less polar 3-iodo-2-methyl-2,4,5,6,7,8-hexahydrocycloheptapyrazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.84 (s, 3H), 2.70-2.79 (m, 2H), 2.42-2.51 (m, 2H), 1.77-1.88 (m, 2H), 1.57-1.73 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][P:14]([CH2:18][C:19](O)=[O:20])([O:16][CH3:17])=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:12][O:13][P:14]([CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1)=[O:20])([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(N)ccn1
Reactant: COP(=O)(CC(=O)O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CP(=O)(OC)OC)ccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1.0 g of methyl 4-aminopicolinate, 1.0 g of α-(dimethylphosphono)-acetic acid and 1.0 g of dicyclohexylcarbodiimide in 10 ml of methylene chloride is stirred at room temperature for 6 hours. After filtration and removal of solvent the residue is chromatographed on silica gel with 5% methanol/methylene chloride as the eluent to afford methyl 4-(α-dimethylphosphonoacetamido)-picolinate as a viscous oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:45])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:28]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:27]=2)=[O:25])[CH2:21][NH2:22])[CH2:15][CH2:14]1)=[O:12])[CH3:9].Cl[C:47]([O:49][CH3:50])=[O:48]>C(Cl)Cl.C(N(CC)CC)C>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:45])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:28]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:27]=2)=[O:25])[CH2:21][NH:22][C:47]([O:49][CH3:50])=[O:48])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CN)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNC(=O)OC)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Reaction time: 4 h

Procedure:
To a solution of 100 mg of 4-((S)-3-Amino-2-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 2 ml DCM and 0.1 ml triethylamine, 20 mg methyl chloroformate was added at RT. After stirring for 4 h, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 19 mg
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16]Br)[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12
Reactant: N#CC1=C(CBr)Nc2n[nH]cc2C1c1ccccc1Cl
Reactant: C1CCNCC1
Product: Cl
Product: N#CC1=C(CN2CCCCC2)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine and piperidine in the same manner as in Example 352.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=2)[S:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])(=[O:11])=[O:10])=[CH:4][CH:3]=1.C[O:36][C:37](=[O:40])[CH:38]=[CH2:39].C(N(CC)CC)C.O>CN(C)C=O>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:8]([S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:11])=[O:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:39]=[CH:38][C:37]([OH:40])=[O:36])=[CH:7][CH:6]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(I)cc2)c(C)c1
Reactant: C=CC(=O)OC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)O)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of N-(4-iodo-phenyl)-2,4,6-trimethyl-N-[3-(tetrahydro-pyran-2yloxy)-benzyl]-benzenesulfonamide (1.06 g, 1.79 mmol) in dimethylformamide was added acrylic acid methyl ester (0.81 mL, 8.95 mmol), triethylamine (0.75 mL, 5.37 mmol), and palladium tetrakistriphenylphosphine (0.103 g, 0.09 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was allowed to cool to room temperature and was poured into water. The reaction mixture was extracted with ethyl acetate and the organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography of the residue (1:1 hexanes:methylene chloride to methylene chloride to 20% ethyl acetate/methylene chloride) afforded 0.93 g (94%) of the title compound of Step A.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:29][S:30]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])=[O:16])=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(Cl)[Cl:65]>>[ClH:65].[ClH:65].[NH2:8][C@@H:9]([CH2:29][SH:30])[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])=[O:16]
Reactant: Cc1cccc(NC(=O)c2cccc(NC[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)c2)c1C
Reactant: ClCCl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)c2cccc(NC[C@@H](N)CS)c2)c1C
Product: Cl
Reaction time: 0.75 h

Procedure:
To a solution of 3 (0.410 g ) in 10 mL of methylene chloride was added triethylsilane (0.200 g ) and 5 mL of trifluoroacetic acid. The solution was stirred for 45 min, evaporated in vacuo, and partitioned with hexane and 0.1% trifluoroacetic acid in water:methanol 2:1. The 0.1% trifluoroacetic acid/water: methanol solution was injected directly onto a Delta-Pak (C-18, 100 Å, 15 mm, 40mm×100mm) prep HPLC column. The gradient at 40 mL/min. was 100%A (0.1% trifluoroacetic acid/water) for 5 min. followed by 85% A to 50%A in 60 min. with B as 0.1% trifluoroacetic acid/acetonitrile. The pure fractions were pooled, evaporated in vacuo to near dryness, and then taken up in 5 mL of water. This water solution was passed through a 1.2 g column of Bio-Rad AG 3-X4 chloride anion exchange resin with water rinses. The resulting aqueous column eluant was lyophillized 20 h to yield the title compound as a solid. NMR (300 MHz, CD3OD)δ 7.30 (3H, m), 7.12 (3H, s), 6.97 (1H, m), 3.30 (3H, m), 2.90 (2H, m ), 2.30 (3H,s), 2.18 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:19][CH2:20][O:21][CH3:22])[C:11](=[O:18])[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:23](Cl)(=[O:27])[C:24](Cl)=O.C[C:30](=[O:38])[CH2:31][C:32](=O)[CH2:33][CH2:34][CH2:35]C.C(N(CC)CC)C.OC(C)(C)C#N>ClCCl.CN(C)C=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]([CH2:19][CH2:20][O:21][CH3:22])[C:11](=[O:18])[C:12]([C:15]([C:24]3[C:23](=[O:27])[CH:33]4[CH2:32][CH:31]([CH2:35][CH2:34]4)[C:30]=3[OH:38])=[O:17])=[CH:13][N:14]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCn1c(-c2cc(F)cc(F)c2)ncc(C(=O)O)c1=O
Reactant: CCCCC(=O)CC(C)=O
Agent: CC(C)(O)C#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCn1c(-c2cc(F)cc(F)c2)ncc(C(=O)C2=C(O)C3CCC(C3)C2=O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinecarboxylic acid (i.e. the product from Example 9, Step D) (0.25 g, 0.81 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.21 g, 1.6 mmol) and one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The remaining crude oil was re-dissolved in dichloromethane (10 mL) and then treated with bicycle[3.2.1]octane-2,4-dione (0.12 g, 0.88 mmol) (prepared according to U.S. Pat. No. 6,815,563) and triethylamine (0.16 g, 1.6 mmol). After 30 min at room temperature, a catalytic amount of 2-hydroxy-2-methyl-propanenitrile (0.0075 g, 0.088 mmol) and triethylamine (0.16 g, 1.6 mmol) were added and the reaction mixture was stirred at ambient temperature over night. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform to provide 0.180 g of the title compound (also known as 3-[[2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinyl]carbonyl]biciclo[3.2.1]octane-2,4-dione), a compound of the present invention, as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(OC)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 200 g of 4-nitro-3-(4-methoxyphenyl)-butanoic acid methyl ester, 68 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqeous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-methoxyphenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.[NH2:10]N.Cl.[I:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[NH:18].[OH-].[Na+]>O1CCCC1>[I:13][C:14]1[CH:15]=[C:16]([C:17]2[NH:19][C:3]([C:2]([F:1])([F:8])[F:9])=[N:10][N:18]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: CCOC(=O)C(F)(F)F
Reactant: N=C(N)c1cccc(I)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: FC(F)(F)c1nnc(-c2cccc(I)c2)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl trifluoroacetate (0.12 mL, 1.00 mmol) in 4.0 mL of dry tetrahydrofuran was added anhydrous hydrazine (25 mL, 0.80 mmol), and the resultant solution was heated to reflux. After one hour, the solution was cooled to room temperature and was added via syringe to a mixture of the amidine hydrochloride (283 mg, 1.00 mmol) from Step B and solid sodium hydroxide (50 mg) in 3.0 mL of dry tetrahydrofuran. The reaction mixture was warmed at reflux for 3 h, and was then allowed to cool to room temperature overnight. The precipitated solids were removed by filtration, and the filtrate was concentrated under reduced pressure to afford a yellow gum, which was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous brine, dried (magnesium sulfate) and concentrated under reduced pressure to provide the crude product, which was purified by flash chromatography (silica gel, step gradient, 0 to 20% ethyl acetate/hexanes) to afford the product as a white solid. LC/MS 339.8 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1O)([O-:3])=O.[OH-].[Na+].C1C2C(=[O:44])C3C(=CC=CC=3)C=2C=CC=1.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.C(O)CCC>[OH:44][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:24])[CH3:25])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:19])[CH3:20])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:3])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(N=Nc2ccccc2)cc1
Solvent: O
Solvent: CCCCO
Product: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
2-nitro-2'-hydroxy-3',5'-di-t-amylazobenzene 25.5 g was added to a mixture of n-butanol 80 g, water 14 g and 97% sodium hydroxide 8.2 g, and the resultant mixture was stirred while raising temperature to 65° C. Thereafter, the mixture was cooled to 50° C., and 9-fluorenone 2.0 g was added to the mixture. The reaction mixture was then heated to 90° C. in one hour, and the mixture was stirred at 90°~96° C. for four hours to effect reaction, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-3,5-di-t-amylphenyl)benzotriazole-N-oxide. Thus, the reaction of Process (b) was finished.
Reaction SMILES: [I-:1].[CH:2]1([O:7][N:8]=[C:9]([C:46]2[N:47]=[C:48]([NH:51][CH:52]=[O:53])[S:49][CH:50]=2)[C:10]([NH:12][C@@H:13]2[C:44](=[O:45])[N:15]3[C:16]([C:28]([O:30][CH:31]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])=[C:17]([CH2:21][N+:22]4[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)[CH2:18][S:19](=O)[C@H:14]23)=[O:11])[CH2:6][CH2:5][CH:4]=[CH:3]1.CN(C)C=O.P(Cl)(Cl)Cl>O>[I-:1].[CH:2]1([O:7][N:8]=[C:9]([C:46]2[N:47]=[C:48]([NH:51][CH:52]=[O:53])[S:49][CH:50]=2)[C:10]([NH:12][C@@H:13]2[C:44](=[O:45])[N:15]3[C:16]([C:28]([O:30][CH:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:29])=[C:17]([CH2:21][N+:22]4[N:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2S(=O)C1
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1
Temperature: -33 °C
Yield: 95.2 %

Procedure:
A mixture of benzhydryl 7β-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate 1-oxide iodide (syn isomer, 5.3 g) and N,N-dimethylformamide (50 ml) was stirred at -33° C. and phosphorus trichloride (1.68 g) was added thereto with stirring. The reaction mixture was stirred for 10 minutes at the same temperature, and poured into water (400 ml). Precipitates were collected by filtration and washed with water to give benzhydryl 7β-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (syn isomer, 4.95 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C:13]([O:23][Si](C)(C)C)=[CH:12][CH:11]1[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(#N)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11]([CH3:28])=[CH:12][C:13](=[O:23])[CH2:14][N:15]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1C=C(O[Si](C)(C)C)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1=CC(=O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Yield: 58.3 %

Procedure:
The crude (6S)-tert-butyl 6-((tert-butyldimethylsilyloxy)methyl)-5-methyl-3-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 77, 12.58 g, 29.27 mmol) in 8 mL ACN was stirred at rt with Pd(OAc)2 (6.57 g, 29.27 mmol) for 2 days. The mixture was diluted with 160 mL EtOAc, filtered through celite, concentrated in vacuo and subjected to flash chromatography (220 g, 0-30% EA/Hex) to obtain the desired product (6.07 g, 58.3%) (over two steps) as a beige solid.