Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:31])(=[O:30])([O:3][CH2:4][C@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13](Cl)[C:12]=2[CH3:27])[C@H:7]([OH:28])[C@@H:6]1[OH:29])[NH2:2]>[Pd].O1CCCC1>[S:1](=[O:31])(=[O:30])([O:3][CH2:4][C@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:19]=[C:15]3[N:14]=[CH:13][C:12]=2[CH3:27])[C@H:7]([OH:28])[C@@H:6]1[OH:29])[NH2:2]
Reactant: Cc1c(Cl)nc2cc(-c3ccccc3)nn2c1N[C@@H]1C[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]1O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cnc2cc(-c3ccccc3)nn2c1N[C@@H]1C[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.6 %

Procedure:
A pressure bottle is charged with (rac)-{(1R,2R,3S,4R)-4-[(5-chloro-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methyl rel-sulfamate (111 mg, 0.237 mmol), tetrahydrofuran (1.4 mL) and Pd [10% on carbon/50% water wet; Degussa type) 76 mg, 0.036 mmol)]. The reaction is stirred at room temperature under an atmosphere of hydrogen (30 psi) for 18 hr. The reaction mixture is filtered through celite and concentrated in vacuo. The crude material is purified by preparative HPLC to provide (rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methyl rel-sulfamate (15 mg, yield 13%). LCMS: (FA) M+1 434; 1H NMR (400 MHz, MeOD) δ 8.05-7.98 (m, 2H), 7.94 (s, 1H), 7.43 (t, J=7.4 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 6.69 (s, 1H), 4.20 (t, J=7.8 Hz, 2H), 4.03-3.94 (m, 2H), 2.64 (s, 1H), 2.54-2.31 (m, 5H), 1.64-1.51 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].O>C1COCC1>[CH3:36][O:35][C:33]([NH:18][S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)(=[O:16])=[O:17])=[O:34]
Reactant: COC(=O)Cl
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(N)(=O)=O)c3)nc(OC)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NS(=O)(=O)c1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [100 mg, Example 3] in THF (10 mL) is treated with sodium hydride (20 mg). The mixture is stirred at 0° C. for 60 minutes, treated with methyl chloroformate (1 mL) and stirring is continued 0° C. for a further 60 minutes. The reaction mixture is poured into water and extracted twice with EtOAc (50 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered, and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc in heptanes (1:1, v/v) to give N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [41 mg, Example 4(c)] as a solid. MS: 473 (M+H), 1H NMR [(CD3)2SO]: δ 12.2 (1H, s); 8.4 (1H, s); 8.15 (1H, m); 8 (1H, d, J=3 Hz); 7.65-7.8 (1H, m); 7.2 (2H, d, J=7 Hz); 6.9 (2H, d, J=7 Hz); 6.7 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 3.6 (3H, s); 2.8 (2H, t).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][NH:5]1.Cl[CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[F:34].O>CN(C=O)C>[F:34][C:25]1[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=[CH:29][C:24]=1/[CH:23]=[CH:22]/[CH2:21][N:5]1[C:4](=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6]1
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Reactant: Fc1c(C=CCCl)cccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1nn(C/C=C/c2cccc(C(F)(F)F)c2F)c(=O)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
64.8 g (1.62 mol) of a 60% suspension of sodium hydride in oil are added portionwise under a nitrogen atmosphere to a solution of 341.9 g (1.472 mol) of ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate (prepared according to the process described in Patent EP 2895) in 5 l of anhydrous DMF, the temperature being maintained between 25° and 30° C. The addition lasts approximately one hour. The mixture is then heated for 30 minutes at 60° C. The mixture is cooled to room temperature and a mixture of 421.6 g (1.76 mol) of 1-(3-chloro-1-propenyl) -2-fluoro-3-(trifluoromethyl) benzene (prepared according to Example D1) and 98 ml of anhydrous DMF is added over 30 min. The temperature rises to 38° to 40° C. The mixture is then heated for 3 hours at 60° C. and is then allowed to return to room temperature overnight. The mixture is poured into 7 l of water and extracted with 2 times 4 l of ethyl acetate. Washing is carried out with water, the organic phase is dried over Na2SO4, filtered and evaporated under vacuum and the solid obtained is recrystallized from a hexane/ethyl acetate (4/1 ) mixture. Weight obtained: 474.7 g (Yd.=74%) M.p.=104°-106° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=O)=[N:3][CH:2]=1.O.[NH2:19][NH2:20]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[NH:20][N:19]=2)=[N:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)C1c1ccncn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(Cc2ccncn2)c2ccccc12

Procedure:
1.20 g (5.35 mmol) 2-pyrimidin-4-yl-indan-1,3-dione in 30 ml ethanol is spiked with 345 μl (6.96 mmol) hydrazine hydrate and heated for 5 h to 100° C. After cooling, the product is filtered off and washed with ethanol: m.p.: 204-206° C.; Anal. calc.(C13H10N4O.0.5 H2O) C, 63.15%; H, 4.48%; N, 22.66%. found C, 63.3%; H, 4.5%; N, 22.7%; FAB MS (M+H)+=239.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.O.O.O.O.O.O.O.S([O-])(O)(=O)=O.[Na+].CO>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)c2ccccc12
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(N=Nc2ccc(N)cc2)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 15 g of 1-(4-nitro-phenylazo)-4-(dimethylamino)naphtalene, 75 ml sodiumhydrogen sulphate nonahydrate (50% wt in water) and 80 ml of methanol was heated at reflux for 3 h. The reaction mixture was then cooled to room temperature and poured into 300 ml of water. The brownish precipitate was filtered off, washed with water (200 ml) and cold methanol-water (100 ml/100 ml) to give 12 g of nearly pure 1-(4-amino-phenylazo)-4-(dimethylamino)naphtalene as a brownish solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6]C(=C2SCCCS2)[CH2:4][CH2:3]1.[C:15]([OH:21])([C:17](F)(F)F)=[O:16].OO.[OH-].[Na+].Cl>C(#N)C.ClCCl.O>[CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH:17]([C:15]([OH:21])=[O:16])[CH2:4][CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1(C)CCC(=C2SCCCS2)CC1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C(=O)O)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
2-(4,4-Dimethyl-cyclohexylidene)-[1,3]dithiane (21.6 g, 95 mmol) and TFA (30.5 mL, 0.32 mol) were placed in acetonitrile (100 mL) and water (25 mL) and the mixture was heated at 65° C. for 3 h. 30% Aqueous hydrogen peroxide (152 mL, 1.3 mol) was added carefully and the mixture was warmed to 80° C. slowly. After 1 h, the reaction mixture was cooled to 40° C. and was added slowly to an aqueous solution of NaOH (6N, 630 mL). The resulting mixture was cooled to 0° C. and acidified with aqueous 6N HCl. Dichloromethane (500 mL) was added and the mixture was filtered. The aqueous phase was extracted with dichloromethane (100 mL×5), was dried (MgSO4) and was evaporated in vacuo to yield the title compound (12 g, 81%). MH+157.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[N:9]([CH3:14])[C:10]([SH:13])=[N:11][N:12]=2)=[C:5]([CH3:7])[N:6]=1.CO.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>C(OCC)(=O)C.CC(C)=O>[Cl:27][CH2:26][CH2:25][CH2:24][S:13][C:10]1[N:9]([CH3:14])[C:8]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])=[N:12][N:11]=1
Reactant: ClCCCBr
Reactant: Cc1nc(C)c(-c2nnc(S)n2C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(C)=O
Product: Cc1nc(C)c(-c2nnc(SCCCCl)n2C)s1
Temperature: 22 °C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
5-(2,4-dimethylthiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (Prep27, 5 g, 22 mmol) was added to a mixture of methanol (15 ml) and acetone (35 ml), followed by K2CO3 (5 g, 36 mmol) and 1-bromo-3-chloropropane (35 ml, 36 mmol). The suspension was stirred at 22° C. for 24 h. The volume of solvent was reduced, then ethyl acetate (63 ml) was added and the organic layer was washed with water, the EA was removed under vacuum and the crude purified by FC (EA/MeOH 15:1) to afford 2.5 g of pure product (y=37%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[CH2:12][C:13]#[N:14].[CH2:16]([NH:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[C:13]([NH2:14])=[CH:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCC(=O)c1ccc2ccccc2c1
Reactant: NNCc1ccccc1
Product: Nc1cc(-c2ccc3ccccc3c2)nn1Cc1ccccc1

Procedure:
900 mg of 2-benzyl-5-(2-naphthyl)-2H-pyrazol-3-ylamine obtained from 3-(naphthalen-2-yl)-3-oxopropionitrile and benzyl hydrazine in the similar method as described in Production example 30 was subjected to the similar reaction as described in Production example 31, to afford 770 mg of the title compound as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12]O.S(Cl)([Cl:24])=O>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12][Cl:24]
Reactant: O=S(Cl)Cl
Reactant: Nc1ncnc2c1nc(NCc1cccnc1)n2CCO
Product: Nc1ncnc2c1nc(NCc1cccnc1)n2CCCl
Temperature: 50 °C
Yield: 53 %

Procedure:
A mixture of 350 mg (1.22 mmol) 6-amino-9-(2-hydroxyethyl)-8-[(3-pyridinyl-methyl)amino]-9H-purine and 2 ml of thionylchloride was stirred at 50° C. After completion of the reaction (˜3h) the mixture was concentrated in vacuo and subsequently diluted with water and the pH was adjusted to pH 7 with ammonia. The precipitate was isolated, washed with water, ethyl acetate and diethylether to give 197 mg (53%) of the desired product. 1H-NMR (DMSO): 8.62 (s, 1H), 8.44 (d, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.38 (t, 1H), 7.33 (m, 1H, NH), 6.32 (s, 2H, NH2), 4.60 (d, 2H), 4.34 (t, 2H), 3.92 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@@]23C(C)(C)[C@@](C)(CC2)C(=O)O3)=[O:10])=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:26])([F:25])[F:24])[CH:3]=1.[OH-].[Na+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:10])[O:32][C@:22]([C:27]#[C:28][CH:29]3[CH2:31][CH2:30]3)([C:23]([F:24])([F:25])[F:26])[C:4]=2[CH:3]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Reaction time: 1 h
Yield: 44.8 %

Procedure:
A solution of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 5.0 g, 10.6 mmol), methyl tert-butyl ether (30 mL), 1 N NaOH aqueous (25 mL), and 4-nitrophenyl chloroformate (2.8 g, 13.8 mmol) was stirred at room temperature for 10 minutes. Then two layers were separated and NaOH (2.1 g, 52.5 mmol) was added to the organic layer. The mixture was stirred for 1 hour. The suspension was filtered and rinsed with methyl tert-butyl ether (3×10 mL), then the filtrate was washed with 1 N NaOH (25 mL), water (25 mL), and the two layers were separated. The organic layer was evaporated to about 10 mL, heptanes (25 mL) was added. Then the mixture was stirred at room temperature for an hour, the resulting suspension was filtered and washed with heptanes to give 1.5 g (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (Efavirenz, 1) as a white or off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)[CH:3]=1.C(O)(=O)CCCCCC=C.N1CCC[C@H]1C(O)=O.C(C1N=C(C2C=C(O[CH:60]3[CH2:78][CH:77]4[N:62]([C:63](=[O:83])[CH2:64][CH2:65][CH2:66][CH2:67]C[CH2:69][CH:70]=[CH:71][CH:72]5[C:74]([C:80]([OH:82])=[O:81])([NH:75][C:76]4=[O:79])[CH2:73]5)[CH2:61]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:20]([C:18]1[N:19]=[C:15]([C:4]2[CH:3]=[C:2]([O:1][CH:60]3[CH2:78][CH:77]4[N:62]([C:63](=[O:83])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:69][CH:70]=[CH:71][CH:72]5[C:74]([C:80]([OH:82])=[O:81])([NH:75][C:76]4=[O:79])[CH2:73]5)[CH2:61]3)[C:11]3[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Agent: C=CCCCCCC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinoline (28), oct-7-enoic acid and intermediate 5 following the procedure (Step D-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=633 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[C:13]#[N:14])=[CH:5][CH:4]=1.N.CO>C(O)C.[Co]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)/C(=C/C#N)CC2
Agent: [Co]
Agent: N
Solvent: CO
Solvent: CCO
Product: COc1ccc2c(c1)/C(=C/CN)CC2
Temperature: 40 °C
Reaction time: 32 h
Yield: 85.6 %

Procedure:
To a solution of (E)-(6-methoxyindan-1-ylidene)acetonitrile (1.60 g, 8.64 mmol.) in ethanol (80 ml) were added a 2M ammonia/methanol solution (40 ml) and Raney cobalt (1.6 g). The reaction mixture was stirred, under hydrogen atmosphere (4 kgf/cm2) for 32 hours at 40° C. and for further 8 hours at 70° C. The Raney cobalt was filtered off, and then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography (chloroform:methanol=9:1 to chloroform:methanol:triethylamine=90:8:2) to afford the titled compound (1.40 g, yield 86%, oily).
Reaction SMILES: [O:1]=[C:2]1[C:6]2C=CC=CC=2C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][S:15]([O:18][CH2:19][C:20]([CH3:36])([CH3:35])[C@@H:21]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:17])=[O:16].C(O)C.NN.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:2]([NH:3][CH2:12][CH2:13][CH2:14][S:15]([O:18][CH2:19][C:20]([CH3:35])([CH3:36])[C@@H:21]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:17])=[O:16])(=[O:1])[CH3:6]
Reactant: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Yield: 69 %

Procedure:
Adapting procedures or variations thereof according to Duncan et al., J. Org. Chem. 2001, 66, 5237-5240; Shue et al., Bioorg. Med. Chem. Lett. 1996, 6, 1709-1714; and Khan, J. Org. Chem. 1995, 60, 4536-4541, a 100 mL round-bottomed flask was charged with ethyl (2R)-4-{[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (22a) (1.4 g, 2.7 mmol) and 20 mL of a mixture of ethanol (EtOH)/ethyl acetate (EtOAc) (1:1 v/v). Hydrazine (N2H4) (ca. 0.17 mL, 0.17 g, 5.4 mmol) was added at room temperature. The reaction was monitored by LC/MS. Upon completion of the reaction, acetic anhydride (Ac2O) (1.02 mL, 1.1 g, 10.8 mmol) was added to the mixture. The solution was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogencarbonate (NaHCO3). The organic layer was washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and methanol (MeOH) (EtOAc/MeOH=19:1) as eluent to provide 0.8 g (69% yield) of the title compound (22b) as a colorless oil. Rf=0.50 (EtOAc/MeOH=19:1). 1H NMR (400 MHz, CDCl3): δ=1.06 (s, 3H), 1.07 (s, 3H), 1.32 (t, J=6.8 Hz, 3H), 2.00-2.06 (m, 2H), 2.05 (s, 3H), 3.08-3.12 (m, 2H), 3.35 (q, J=6.4 Hz, 2H), 3.83 (s, 1H), 3.97 (d, J=9.2 Hz, 1H), 4.17 (d, J=9.2 Hz, 1H), 4.21-4.27 (m, 2H), 4.36 (d, J=11.2 Hz, 1H), 4.62 (d, J=11.2 Hz, 1H), 5.82-5.86 (br. m, 1H), 7.26-7.35 (m, 5H), ppm. MS (ESI) m/z 430.02 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [N+](C1C=CC(C[CH:9]2[CH:14]=[C:13]([C:15]([O-:17])=[O:16])[N:12]3[C:18](=[O:35])[CH:19]([NH:20][C:21](=[O:34])[C:22]([C:26]4[N:27]=[C:28]([NH:31][CH:32]=[O:33])[S:29][CH:30]=4)=[N:23][O:24][CH3:25])[C@H:11]3[S:10]2)=CC=1)([O-])=O.C(O)(=O)C.O.[H][H]>[C].[Pd].O1CCCC1.CO>[CH:32]([NH:31][C:28]1[S:29][CH:30]=[C:26]([C:22](=[N:23][O:24][CH3:25])[C:21]([NH:20][CH:19]2[C:18](=[O:35])[N:12]3[C:13]([C:15]([OH:17])=[O:16])=[CH:14][CH2:9][S:10][C@H:11]23)=[O:34])[N:27]=1)=[O:33]
Reactant: [H][H]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CC(Cc3ccc([N+](=O)[O-])cc3)S[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 79.6 %

Procedure:
A suspension of 4-nitrobenzyl- 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (anti isomer, 4.2 g.), 10% palladium carbon (1.7 g.), acetic acid (0.63 ml.), water (6.3 ml.), methanol (42 ml.), and tetrahydrofuran (84 ml.) was subjected to catalytic reduction in a hydrogen atmosphere at room temperature for 2 hours. After removing the catalyst by filtration, the filtrate was concentrated to a volume of about 15 ml. under reduced pressure. Water (30 ml.) and ethyl acetate (50 ml.) were added to the concentrated solution, and the solution was adjusted to pH 8.0 with sodium bicarbonate under stirring. The insoluble substance was removed by filtration, and the aqueous layer was separated and washed with ethyl acetate (50 ml.). The solution was treated with activated characoal, and adjusted to pH 2.2 with 10% hydrochloric acid under ice cooling. The precipitates were collected by filtration and washed with water to give 7-[2-(2 -formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (anti isomer, 2.52 g.).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1)(=[O:31])=[O:30])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)c1ccc2ccccc2c1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-naphtalenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][O:18][C:19]3[C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][N:22]=[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:38][CH3:39])[N:10]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][O:18][C:19]3[C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=[C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:20]=3)=[CH:15][C:14]=2[O:38][CH3:39])[N:10]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(COc2nc(-c3ccccc3)ncc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carboxylate (0.47 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was poured into water, 2N hydrochloric acid was added to acidify the solution, and the precipitated crystals were collected by filtration. Recrystallized from methanol-ethyl acetate gave 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carboxylic acid as pale-yellow needle crystals (0.18 g, yield 40%). melting point: 163-164° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].Cl>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A 100 ml round-bottomed flash was charged with pyridine (30 ml) and 7.10 g (34.8 mmol) of (±)-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H)-pyridazinone from Example I, then cooled to 0° C. under an atmosphere of nitrogen. Butanoyl chloride (4.10 g, 38.3 mmol) was added dropwise to the solution via syringe. The reaction mixture was stirred for 30 min at 0° C., warmed to 23° C. over 15 min then poured into 1N aqueous hydrochloric acid (400 ml). The aqueous solution was extracted with EtOAc (2×200 ml). The combined EtOAc extracts were successively washed with 5% aqueous sodium bicarbonate solution (300 ml), saturated aqueous sodium chloride (200 ml), dried over anhydrous magnesium sulfate (5 g), filtered and concentrated in vacuo to provide 9.8 g of crude product as a solid. Recrystallization from ethyl acetate/hexanes (2:1, 35 ml) yielded 7.61 g (80%) of pure (±)-6-(4'-butanoyloxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone as colorless needles, m.p. 112°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7]([CH:9]=O)=[CH:8][C:4]=2[CH:3]=1.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7](/[CH:9]=[CH:16]/[N+:13]([O-:15])=[O:14])=[CH:8][C:4]=2[CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc2cc(F)ccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])/C=C/c1cc2cc(F)ccc2s1
Yield: 56.9 %

Procedure:
Using an analogous procedure and workup as described in example 1, for the preparation of Intermediate I-1a above, 5-fluorobenzo[b]thiophene-2-carbaldehyde (1.7 g, 9.444 mmol) was reacted with nitro methane (576.11 mg, 9.444 mmol), 10N NaOH (396.64 mg, 9.916 mmol) and ethanol (25 mL) at 0° C. for 2 hours to afford 1.2 g of the product (57.14% yield).