Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:29][CH3:30])[CH:21]=1.[C:31]([NH:35][C:36](=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:38]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:47]2[CH2:46][CH2:45][N:44]([CH2:43][C:39]3[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=3)[C:36]([NH:35][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:50])[CH2:49][CH2:48]2)=[O:26])=[C:22]([O:29][CH3:30])[CH:21]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: COc1cc(N)ccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (12.91 g, 20.2 mmol, 12.91 mL) was added dropwise to a solution of 4-amino-2-methoxybenzoic acid (1.70 g, 10.1 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (3.07 g, 11.2 mmol) and triethylamine (3.08 g. 30.3 mmol, 4.23 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.39 g). MS (ESI) m/z 425.4 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(N)CCN.O>COCC(O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: NCCCN
Solvent: COCC(C)O
Solvent: O
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 105 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Thebaine (4.0 g dry basis, 13 mmol) is placed in a mixture of 1-methoxy-2-propanol (13.0 g) and 1,3-propanediamine (1.6 g, 22 mmol, 1.66 equiv) and is heated at 105° C. A solution of p-toluenesulfonylhydrazide (4.8 g, 26 mmol, 2.0 equiv) in 1,3-propanediamine (9.6 g, 130 mmol, 9.96 equiv) is added in portions to the thebaine mixture at such a rate that the batch temperature is maintained in the range 105 to 110° C. The reaction mixture is held at 105 to 110° C. for 1 hour then cooled to room temperature and water (24 g) is added while maintaining the batch temperature at ≦30° C. The resulting slurry is stirred, further cooled to ˜2° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.80 g, 94.3% yield; 99.0 area % purity by HPLC)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=1>CO.O>[NH:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]3)[C:5]([Cl:22])=[CH:4][N:3]=2)[CH:28]=[N:27]1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Solvent: O
Solvent: CO
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cn[nH]c3)ncc2Cl)CC1
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.070 g, 0.21 mmol) and tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.11 g, 0.63 mmol) was stirred in MeOH:water (10:1 ratio, 4 mL) at 70° C. for 2 hours and then at 90° C. for 16 hours. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-15% MeOH in DCM) to give the title compound 19 as a light yellow solid (0.015 g, 19%). 1H NMR (300 MHz, d6-DMSO) δ 0.93-1.02 (m, 2H), 1.38-1.49 (m, 2H), 3.04-3.16 (m, 4H), 6.03 (brs, 1H), 6.98 (brs, 1H), 7.18-7.39 (m, 4H), 7.48-7.72 (m, 1H), 7.79-8.00 (m, 1H), 8.37 (s, 1H), 9.62 (s, 1H). LCMS-C: rt 4.92 min; m/z 383 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](=O)[CH3:30])[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH:29]([C:25]1[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][N:26]=1)[CH3:30])[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cc(C)ccn1
Reactant: Cc1cccnc1CNCCCCNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(C(C)N(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2C)c1

Procedure:
Using General Procedure B, reaction of {4-[(3-Methyl-pyridin-2-ylmethyl)-amino}-butyl}-carbamic acid tert-butyl ester, 1-(4-methylpyridin-2-yl)-ethanone and NaBH(OAc)3 in CH2Cl2 gave {4-[[1-(4-methyl-pyridin-2-yl)-ethyl]-(3-methylpyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a pale yellow oil. Conversion to the HBr salt using General Procedure D gave COMPOUND 244 as a white solid. 1H NMR (D2O) δ 1.47 (br, 4H), 1.54 (d, 3H, J=6.0 Hz), 2.45 (s, 3H), 2.60 (m, 1H), 2.63 (s, 3H), 2.71 (m, 1H), 2.85 (br, 2H), 4.27 (s, 2H), 4.49 (q, 1H, J=6.0 Hz), 7.78 (d, 1H, J=6.3 Hz), 7.83 (t, 1H, J=7.2 Hz), 7.95 (s, 1H), 8.33 (d, 1H, J=7.8 Hz), 8.56 (m, 2H). 13C NMR (D2O) δ 15.08, 17.10, 22.38, 24.01, 25.03, 39.57, 51.07, 52.81, 59.73, 125.84, 127.25, 127.40, 137.08, 138.22, 140.83, 148.27, 152.41, 154.85, 162.82. ES-MS m/z 313 (M+H). Anal. Calcd. for C19H28N4.4.3HBr.3.5H2O: C, 31.55; H, 5.48; N, 7.74; Br, 47.49. Found: C, 31.64; H, 5.63; N, 7.43; Br, 47.61.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([CH3:31])[CH2:10][C@H:11]([O:29][CH3:30])[C@@H:12]([OH:28])[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].N1C(C)=CC=CC=1C.O([Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])S(C(F)(F)F)(=O)=O>C(=O)(O)[O-].[Na+]>[C:1]([O:7][CH2:8][C@H:9]([CH3:31])[CH2:10][C@H:11]([O:29][CH3:30])[C@@H:12]([O:28][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@@H:13]([O:26][CH3:27])[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](O)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Product: CO[C@@H](C[C@@H](C)COC(=O)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C[C@@H](C)CO[Si](C)(C)C(C)(C)C)OC
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
Alcohol 24 (2.98 g, 6.48 mmol) was dissolved in 50 ml of methylene chlorideat 25° C. and 2,6-lutidine (1.51 ml, 2.0 equiv) was added. t-Butyldimethylsilyl triflate (2.23 ml, 1.5 equiv) was added and the mixture was stirred at 25° C. for 10-15 min. The solution was poured in 40 ml of saturated aqueous sodium bicarbonate solution and extracted with 2×200 ml of methylene chloride. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give4.0 g of the bis-t-butyldimethylsilyl ether 25 as an oil. This material washomogeneous by 1H and 13C NMR and was used directly in the subsequent transformation.
Reaction SMILES: O[CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:5](=[O:18])[CH:4]2[CH2:19][C:20](=[CH2:22])[CH2:21][CH:3]12.[BH3-]C#N.[Na+].O>FC(F)(F)C(O)=O>[CH2:22]=[C:20]1[CH2:19][CH:4]2[C:5](=[O:18])[N:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]([F:16])([F:15])[F:17])=[CH:11][CH:12]=3)[CH2:2][CH:3]2[CH2:21]1
Reactant: C=C1CC2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(O)C2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=C1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 3-Hydroxy-5-methylene-2-(4-trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrol-1-one (0.1 g, 0.32 mmol) in trifluoroacetic acid (20 mL) was added NaCNBH3 (0.04 g, 0.64 mmol) at −20° C., and the mixture was stirred for 1 h. Water (30 mL) was added. The mixture was extracted with dichloromethane (3×20 mL), washed with brine (50 mL), and dried over anhydrous Na2SO4. The solvent was removed by reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (10:1 to 5:1) to yield the title compound (40 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 7.69-7.64 (m, 2H), 7.25-7.19 (m, 2H), 4.91 (s, 2H), 4.07-4.01 (m, 1H), 3.54-3.49 (m, 1H), 3.19-3.12 (m, 1H), 2.96-2.71 (m, 4H), 2.25-2.18 (m, 1H); LC-MS: [M+1]+ 298.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[CH3:29][O:30][CH2:31][C:32]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:33]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) in THF (4 mL) was added triethylamine (0.12 mL, 0.85 mmol). The mixture was cooled in an ice bath and a solution of methoxyacetyl chloride (0.092 mL, 0.85 mmol) in THF (1 mL) was added dropwise. After stirring for 1 h at room temperature the precipitate was filtered and the organic phase was evaporated. The residue was dissolved in methanol (5 mL), sodium bicarbonate (1 spatula) was added and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was extracted (dichloromethane/water). Then the organic phase was dried over sodium sulfate and concentrated. Chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) afforded the title compound (180 mg, 73%) as a white solid. MS: m/e=355.3 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([N:14]1[CH2:33][CH2:32][CH2:31][C@H:15]1[C:16]([NH:18][C@H:19]([C:24]([NH:26][CH2:27][C:28]([NH2:30])=[O:29])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC([O:43][C:44](=O)[C@H:45]([CH2:57][C:58](=[O:60])[NH2:59])[NH:46]C(OCC2C=CC=CC=2)=O)=CC=1)([O-])=O.CN(C)C=O>C(OCC)(=O)C>[NH2:46][C@H:45]([C:44]([NH:11][C@H:10]([C:12]([N:14]1[CH2:33][CH2:32][CH2:31][C@H:15]1[C:16]([NH:18][C@H:19]([C:24]([NH:26][CH2:27][C:28]([NH2:30])=[O:29])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])=[O:13])[CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:43])[CH2:57][C:58](=[O:60])[NH2:59]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CSCc1ccccc1)C(=O)NCC(N)=O
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CSCc1ccccc1)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of S-benzyl-L-cysteinyl-L-prolyl-L-leucyl-glycinamide (0.502 g.) in ethyl acetate (3 ml.) benzyloxycarbonyl-L-asparagine p-nitrophenyl ester (0.387 g., 1.0 mmol) was added and the suspension stirred at room temperature for 48 hr. The precipitate which formed was collected by filtration and washed with ethyl acetate (20 ml.) and ethanol (5 ml.), and then dried. The crude benzyloxycarbonyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-L-leucyl-glycinamide was recrystallized from 40% methanol. Yield, 0.718 g. (99%); m.p. 212°- 213.5°; [α]20D -60.5° (c 1, dimethylformamide).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.Cl[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[Cl-].[Na+]>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19](=[O:20])[O:21][CH:22]([CH3:24])[CH3:23]
Reactant: NCc1cccc(Br)c1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCc1cccc(Br)c1
Yield: 90.8 %

Procedure:
3.00 g of 3-bromobenzylamine hydrochloride suspended in chloroform (20 ml) was mixed with 2.86 g of triethylamine at room temperature. The resulting solution was stirred under cooling with ice while 1.82 g of isopropyl chloroformate was added dropwise and then stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into saturated aqueous sodium chloride, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated at ordinary pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 3.33 g of isopropyl N-(3-bromobenzyl)carbamate as a colorless transparent viscous liquid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[N:38]O)[NH2:37]>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[N:38]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:27][N:37]=1
Reactant: NC(=NO)c1ccccc1Cl
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3Cl)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 46.9 (0.275 mmol) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 53.0 mg (39% of theory).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.[H-].[Na+].[CH2:16](O)[CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH:30]([N:37]([CH3:39])[CH3:38])[CH2:31][CH2:32][CH2:33]C(=O)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C)C=O.O1CCCC1.O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH:30]([N:37]([CH3:39])[CH3:38])[CH2:31][CH2:32][CH2:33][CH:16]([CH3:17])[C:10]#[N:11])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)CCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C#N)CCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of p-toluenesulphonylmethylisocyanide sold under the trade name TosMIC (5 g) in dimethylformamide (10 ml) was added at 0° C. under argon over a period of 10 minutes to a stirred suspension of sodium hydride (3.6 g of a 50% dispersion in mineral oil) in dimethylformamide (30 ml). Ethanol (3.6 ml) was then added at 0° C. After 30 minutes a solution of 6-[1-(4-chlorophenyl)cyclobutyl]-6-dimethylaminohexan-2-one (6.11 g prepared in a similar manner to that described in Example 53) in tetrahydrofuran (50 ml) was added at 0° C. and the mixture stirred at ambient temperature for 16 hours. The reaction mixture was poured into water and the aqueous mixture extracted with ether. The extracts were washed, dried and evaporated to give an oil which was distilled on a Buchi Kugelrohr apparatus (150° C./0.35 mm). The distillate was dissolved in ether and treated with maleic acid to give a gum which was washed with ether and basified to give 6-[1-(4-chlorophenyl)cyclobutyl]-6-dimethylamino-2-methylhexanenitrile (mp 54°-56° C.).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:44]1[N:45]=[C:46]([NH:49]C=O)[S:47][CH:48]=1)[C:21]([NH:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.Cl>CO>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:21]([NH:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([OH:7])=[O:5]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3ccccc3C(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3ccccc3C(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 10 °C
Yield: 45 %

Procedure:
7-[2-{N-(2-tert-Butoxycarbonylphenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g.) was added to a mixture of trifluoroacetic acid (7 ml.) and anisole (0.35 ml.) with stirring at about 10° C., followed by stirring for 1.5 hours at 5° to 10° C. and for an additional 15 minutes at room temperature. After concentration of the reaction mixture, to the residue were added methanol (30 ml.) and conc. hydrochloric acid (2.33 ml.). The resulting mixture was stirred for 1.5 hours at room temperature and concentrated and then the residue was shaken with a mixture of an aqueous solution of sodium bicarbonate and ethyl acetate. The aqueous layer (pH 7 to 8) was separated and thereto were added ethyl acetate and 10% hydrochloric acid with stirring whereby the pH was adjusted to 2 to 3. The resulting precipitates were filtered and redissolved in an aqueous solution of sodium bicarbonate. To the aqueous solution (150 ml.) was added ethyl acetate (300 ml.) and the mixture was acidified to pH 2 to 3 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried and then concentrated. The residue was washed with diethyl ether to give the title compound (0.8 g.). mp. 220° to 230° C. (dec.)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12].C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:12][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1cccc(CN)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CNS(C)(=O)=O)c1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
Methanesulfonyl chloride (4.170 g, 36.4 mmol) was added to a solution of 3-methoxybenzylamine (5.000 g, 36.4 mmol) and triethylamine (3.946 g, 39.0 mmol) in THF (100 mL) at room temperature. The mixture was stirred for 18 h and the insolubles were removed by filtration. The organic solution was concentrated to a yellow oil which was purified by flash chromatography (6:4 hexanes:EtOAc to 1:1 hexanes:EtOAc) to yield N-(3-methoxy-benzyl)-methanesulfonamide (7.431 g). 1H NMR (400 MHz, CDCl3) δ7.26 (m, 1H), 6.92-6.82 (m, 3H), 4.62 (m, 1H), 4.28 (d, 2H), 3.80 (s, 3H), 2.87 (s, 3H); MS 214 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:21][OH:22])[CH:5]=[C:6]([F:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([F:19])[CH:10]=1.[H-].[Na+].Cl[C:26]1[CH:27]=[C:28]2[N:35]([CH3:36])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[C:11]([F:19])[CH:10]=1)[CH2:21][O:22][C:26]1[CH:27]=[C:28]2[N:35]([CH3:36])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)c(F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3,5-difluoro-4-(3-fluoro-4-(trifluoromethyl)phenoxy)phenyl)methanol (122 mg, 0.377 mmol) in DMF (4 mL), sodium hydride (45.3 mg, 1.131 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (70 mg, 0.377 mmol).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(#N)C.[C:10]1([CH2:16][C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:10]1([CH2:16][C:17]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)NN
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: COC(=O)NNC(=O)Cc1ccccc1
Reaction time: 15 h
Yield: 76.1 %

Procedure:
To a solution of 90.1 g. (1.0 mole) of methyl carbazate and 500 ml. of acetonitrile 154.6 g. (1.0 mole) of phenyl acetyl chloride are added. The reaction mixture is heated to boiling for 15 hours and clarified. The residual oil is poured into 500 ml. of water, whereby the oil soon solidifies. Thus 158.4 g. of the white desired compound are obtained, yield 76.1%, M.p. 94°-95° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21](N2CCCC2)=[O:22])[CH2:17][CH2:16]1>CC(OC)(C)C>[Br:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[O:22])[N:8]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN1CCC(C(=O)N2CCCC2)CC1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
Add a solution of n-butyllithium (1.9M in n-hexane, 4 ml, 7.6 mmol) to a solution of 2,6-dibromopyridine (1.81 g, 7.64 mmol) in MTBE (20 mL) dropwise under nitrogen, over 20 min., maintaining the temperature between −72 and −67° C. Stir the yellow heterogeneous solution at −70° C. for 20 min. to provide a green homogeneous solution. Add a solution of 1-methyl-4-(pyrrolidin-1-yl-carbonyl)piperidine (1 g, 5.09 mmol) in 10 mL MTBE dropwise over 20 min., maintaining the temperature below −69° C. Stir the yellow mixture at −75° C. for 1 hr. Quench the reaction mixture with a saturated solution of ammonium chloride (5 mL) between 0 and 10° C. Acidify the mixture to pH 2 with fuming HCl (2 mL). Extract the organic layer. Wash the aqueous phase with MTBE (50 mL), make the aqueous layer basic with a solution of 30% NaOH, and extract with ethyl acetate (2×50 mL). Combine the organic layers, dry over MgSO4, and concentrate under reduced pressure at 40° C. to provide the title intermediate as an oil (1.23 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[C:4](Cl)[N:3]=1.C(O)=[O:19]>>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][O:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: O=CO
Reactant: Nc1nc(Cl)c2ncn(OCC(O)CO)c2n1
Product: Nc1nc2c(ncn2OCC(O)CO)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
2-Amino-6-chloro-9-(2,3-dihydroxyprop-1-oxy)purine (100 mg, 0.39 mmol) was dissolved in 80% formic acid solution and stirred at 100° C. for 2.5 hours. The reaction was evaporated to dryness under reduced pressure and the residue treated with methanol (5 ml) and 0.88 ammonia solution (3 ml). After stirring the reaction at 60° C. for 2 hours, the solvents were evaporated under reduced pressure and the residue recrystallised from water yielding the title compound (35 mg, 38%), m.p. 252°-3° C. Uv: λmax (H2O) 252 (ε12,600) nm; IR: υmax (KBr) 3330, 1690, 1640, 1605, 1540, 1475 cm-1 ; 1H NMR: δH [(CD3)2SO] 3.39 (2H, m, CH2OH), 3.72 (1H, m, CHOH), 4.10 (1H, dd, J=10.7, 7.6 Hz, 7.6 Hz, CH2ON), 4.33 (1H, dd, J=10.5, 3.3 Hz, CH2ON), 4.70 (1H, t, J= 5.7 Hz, OH), 5.15 (1H, d, J=5.2 Hz, OH), 6.62 (2H, br.s, NH2), 7.90 (1H, s, H-8), 10.58 (1H, br.s, NH); m/z 241 (M+, 3%), 210 (2), 167 (27), 151 (100), 109 (20), 61 (47). Found: C, 38.85; H, 4.66; N, 29.14%, M+ 241.0813. C8H11N5O4 requires C, 39.84; H, 4.60; N, 29.03%, M+ 241.0811.