Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][N:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH2:28][C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[CH2:48][C:44]3[N:43]([CH3:42])[CH:47]=[CH:46][N:45]=3)=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccnc1C=O
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1ccnc1CN(Cc1ccc(CNc2ccc(CN(C(=O)OCc3ccccc3)C3CCCCC3)cc2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
The compound (236 mg) obtained in Example 87-4 and 1-methyl-2-imidazole carboxaldehyde (46.5 mg) were dissolved in anhydrous methanol (7.1 ml). The solution was added with sodium cyanoborohydride (54.0 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After the reaction, the solvent was distilled off. A 1 mol/l sodium hydroxide aqueous solution was added to the residue, and chloroform extraction was then carried out. The extract was washed with saturated saline solution and then dried with magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (212 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1.S(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(Oc2ncccn2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCc1ccc(Oc2ncccn2)cc1

Procedure:
A stirred solution of 4.0 grams (0.02 mole) of (4-pyrimidin-2-yloxyphenyl)methanol (known compound) and seven drops of pyridine in 35 mL of methylene chloride was cooled in an ice-water bath and a solution of 2.0 mL (0.027 mole) of thionyl chloride was added dropwise. Upon completion of addition the reaction mixture was stirred at about 10° C. to 20° C. during a three-hour period. After this time, the reaction mixture was poured into a cold aqueous solution of sodium bicarbonate. The mixture was then stirred for 30 minutes and the organic layer was separated. The aqueous layer was extracted with one 50 mL portion of methylene chloride. The extract was combined with the organic layer, and the combination was passed through silicone-coated filter paper to remove traces of water. The filtrate was concentrated under reduced pressure, yielding grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:22])[N:5]([CH3:21])[C:6]([OH:20])=[C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[C:8]=1[CH3:9])#[N:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CC(N(C)C)=O>[C:1]([C:3]1[C:4](=[O:22])[N:5]([CH3:21])[C:6]([OH:20])=[C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])=[CH:14][CH:13]=2)[C:8]=1[CH3:9])#[N:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(N=Nc2ccc(CO)cc2)c(O)n(C)c(=O)c1C#N
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Cc1c(N=Nc2ccc(COS(=O)(=O)c3ccccc3)cc2)c(O)n(C)c(=O)c1C#N
Yield: 49.3 %

Procedure:
14.9 g of Compound [2-a] was benzenesulfonylated in the same manner as described in Step 1-h using 12 g of benzenesulfonyl chloride in 50 ml of pyridine and 20 ml of dimethylacetamide to obtain 10.8 g of Compound [2-b].
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc([N+](=O)[O-])cc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethanol (367 mg, 0.943 mmol) in DMF (3 ml) at room temperature under nitrogen was added 4-nitrophenol (144 mg, 1.037 mmol), followed by cesium carbonate (614 mg, 1.886 mmol) and the resulting mixture stirred at room temperature overnight. Ethyl acetate (50 mL) was added and washed with water followed by brine. The organic layer was then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to afford the crude product which was used for the next reaction without further purification. LCMS: retention 1.24 min/2.0 minute run: (ESI) m/z 401 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]([O-:24])=O)[CH:15]=[CH:14]1)[CH2:2]2.[Li+].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([N:9]1[CH2:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16]([CH:15]=[CH:14]3)=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]1=[O:24])[CH2:2]2
Reactant: O=C([O-])c1cccc2ccn(CCCN[C@H]3CN4CCC3CC4)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2cccc3ccn(c23)CCCN1[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
A solution of lithium (R)-1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate (574 mg, 1.7 mmol) from Step D above in DMF (8 mL) was cooled in an ice bath while N,N-diisopropylethylamine (1.3 g, 10.3 mmol) was added, followed by 1-propanephosphonic acid cyclic anhydride (T3P) (3.3 g, 10.3 mmol). The reaction mixture was stirred at room temperature for 5 h. The reaction was quenched with water and the aqueous phase was extracted with methylene chloride (3×) and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give (R)-2-(quinuclidin-3-yl)-2,3,4,5-tetrahydro-1H-[1,5]diazocino[3,2,1-hi]indol-1-one (127 mg, 24%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=6.6 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.20 (d, J=3.3 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.50 (d, J=3.0 Hz, 1H), 4.40-4.20 (m, 2H), 3.80-3.45 (m, 3H), 3.25-2.80 (m, 5H), 2.30-1.50 (m, 6H), 1.40-1.20 (m, 2H); MS (ESI+) m/z 310 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[CH2:21][C:20]([CH3:23])=[CH:19]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH3:24][N:11]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[CH2:21][C:20]([CH3:23])=[CH:19]2)[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: CC1=Cc2cccc(CCNS(=O)(=O)c3ccc(C)cc3)c2C1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC1=Cc2cccc(CCN(C)S(=O)(=O)c3ccc(C)cc3)c2C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 15.0 g (45.8 mmol) of 4-methyl-N-[2-(2-methyl-1H-inden-7-yl)ethyl]-benzenesulfonamide in 100 mL of dry DMF at room temperature, 22.4 g (68.7 mmol) of Cs2CO3 was added, followed by the dropwise addition of 10.0 g (70.4 mmol) of MeI over a 10 minute period. This mixture was stirred for 24 hours at 50° C. and then evaporated under vacuum. To the residue, 200 mL of water and 200 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was washed with 200 mL of dichloromethane. The combined organic extract was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent—dichloromethane). Yield, 14.1 g (90%) of white solid. This product was further used without an additional purification. 1H NMR (CDCl3): δ 7.50-7.55 (m, 2H, 2,6-H in p-tolyl), 7.15-7.20 (m, 2H, 3,5-H in p-tolyl), 7.04 (m, 1H, 5-H in indenyl), 7.01 (m, 1H, 6-H in indenyl), 6.78 (m, 1H, 4-H in indenyl), 6.36 (m, 1H, 3-H in indenyl), 3.08-3.18 (m, 6H, 1,1′-H in indenyl and CH2CH2), 2.69 (s, 3H, NMe), 2.67 (s, 3H, 4-Me in p-tolyl), 2.05 (s, 3H, 2-Me in indenyl). Anal. Calc. for C20H23NO2S: C, 70.35; H, 6.79; N, 4.10%. Found: C, 70.95; H, 7.13; N, 3.78%.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[N-:8]=[N+:9]=[N-:10].[Na+]>CC(C)=O.O>[N:8]([CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH:1]1[OH:7])=[N+:9]=[N-:10]
Reactant: C1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1CCCCC1O
Yield: 10.6 %

Procedure:
To a solution of 7-oxa-bicyclo[4.1.0]heptane (0.300 g, 3.06 mmol) in acetone (3 mL) was added sodium azide (0.504 g, 7.75 mmol) in water (3 mL). The reaction mixture was refluxed for 12 h. The acetone was removed in vacuo and the product was extracted with ethyl acetate (5 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (46 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[CH:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=2)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[CH2:23][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:27][CH:26]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 675.1 %

Procedure:
Dissolve the compound of Example 76 (185.2 mg, 0.33 mmol), Et3SiH (0.3 mL, 1.88 mmol) and TFA (0.3 mL, 3.8 mmol) in CH2Cl2 (30 mL). Stir at room temperature for 1 hour. Quench with saturated aqueous NaHCO3 and extract with 25% i-PrOH in CH2Cl2. Dry over Na2SO4, filter and concentrate. Purify the crude material by flash chromatography (0-5% MeOH/CH2Cl2 to afford 1.18 g of the title compound (63%). LCMS: m/z=530 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[O:27]>>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15])=[O:27]
Reactant: O=C(c1cc2ccccc2o1)C1CCCCN1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2C(=O)c2cc3ccccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared, using the method of Example 1, from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.1 g, 0.39 mmol) and (RS)-1-benzofuran-2-yl-1-piperidin-2-yl-methanone, D9 (0.1 g, 0.43 mmol) as a colourless solid (0.074 g, 43%)
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:8])[O:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>ClCCl>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3]2[O:4][C:5](=[O:8])[O:6][CH:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: O=c1occ(CBr)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1occ(CSc2ccc([N+](=O)[O-])cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 4-bromomethyl-1,3-dioxol-2-one, and 0.9 g of 4-nitrobenzenethiol was added. Then, 0.6 g of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1 [except that the column was eluted with a mixture of chloroform and n-hexane (2/1, v/v)]. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform and n-hexane to give 0.5 g of the captioned compound as yellow crystals.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:21](O)[CH3:22])[CH:20]=1>ClCCl.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:21]([F:11])[CH3:22])[CH:20]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(O)c1cc(Br)ccc1Cl
Solvent: O
Solvent: ClCCl
Product: CC(F)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (4.5 g, 20.34 mmol) was added to a stirred solution of 1-(5-bromo-2-chlorophenyl)ethanol (3.99 g, 16.95 mmol) in dichloromethane (50 mL) at 0° C. The resulting solution was stirred at 0° C. for 3 h. The reaction mixture was quenched with a 5% solution of aquous sodium bicarbonate (100 mL) and the resulting bubbling biphasic reaction mixture was vigorously stirred at 0° C. for 15 m. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane twice. The combined organic layers were washed with 1M hydrochloric acid, dried and concentrated by rotary evaporation. The product was purified by flash chromatography on silica gel (hexanes) to yield the title compound (2.65 g, 11.16 mmol, 65.8% yield) as a clear oil: 1H NMR (CDCl3): δ 7.65 (d, 1H), 7.37 (m, 1H), 7.20 (m, 1H), 5.88 (dq, 1H), 1.61 (dd, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([CH3:18])[CH2:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1.C(Cl)(Cl)Cl.[C:23]([O-])(O)=[O:24].[Na+]>CO>[OH:14][C:15]1[CH:16]=[C:7]([OH:6])[CH:8]=[CH:9][C:10]=1[CH:11]([CH3:18])[CH2:12][C:13]([O:24][CH3:23])=[O:17]
Reactant: O=C([O-])O
Reactant: CC1CC(=O)Oc2cc(O)ccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(C)c1ccc(O)cc1O
Reaction time: 16 h

Procedure:
Concentrated sulfuric acid (1.2 mL, 43 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) in methanol (1 L) at room temperature and the solution stirred for about 16 hours. At this time, TLC (8% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was neutralized with 7% NaHCO3 solution (50 ml) and the majority of the solvent (750 ml) removed under reduced pressure. The solution was diluted with ethyl acetate (1 L), washed successively with saturated NaHCO3: saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4), filtered and the solvent removed to give an orange oil. Further purification by filtering through a short pad of silica gel and eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%): 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.42 (dd, JJ=15.0, 8.9, 1H), 2.58 (dd, JJ=15.0, 5.8, 1H), 3.37 (m, 1H), 3.55 (s, 3H), 6.15 (dd, JJ=8.6, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); 13C NMR (DMSO-d6) d 20.16, 29.09, 40.77, 51.00, 102.55, 106.02, 122.09, 127.04, 155.18, 156.27, 172.55; m/z (EI; TMS derivatized; M+) 354; IR (neat; cm−1) 3384.5, 2969.3, 1708.9, 1621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4, 1166.7, 1108.1, 976.2, 839.4, 810.1.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:32])[CH:24]([NH:25][C:26](=[S:31])[CH2:27][CH2:28][C:29]#[N:30])[C@H:21]2[S:20][CH2:19][C:18]=1O)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:35]>>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:32])[CH:24]([NH:25][C:26](=[S:31])[CH2:27][CH2:28][C:29]#[N:30])[C@H:21]2[S:20][CH2:19][C:18]=1[Br:35])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reactant: BrP(Br)Br
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CS[C@H]12

Procedure:
The desired product is prepared from 7-cyanomethylthioacetamido-3-cephem-3-ol-4-carboxylic acid benzhydryl ester using the procedure described in Example 5, but replacing phosphorus trichloride with phosphorus tribromide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([C:9](=[O:11])[CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4]2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.5 g, 6.18 mmol) was taken in dry DCM (20 mL) and cooled to 0° C. To this cold mixture was added N-boc piperazine (1.15 g, 6.18 mmol) followed by addition of T3P (8 g, 12.4 mmol, 50% solution in EtOAc). The reaction was left overnight at rt. The mixture was diluted with CH2Cl2, washed with NaHCO3 soln, brine, dried (Na2SO4) and concentrated to afford the crude product that was washed thoroughly with ether-pet ether to afford 4-[2-(4-Chloro-5 methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 2.9 mmol). This was dissolved in methanol (25 mL) cooled to 0° C. and HCl saturated ether (3 mL) was added to it. The mixture was stirred at room temperature for 4 h and concentrated. Crystallization from MeOH/Petroleum ether yielded product.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:14])[O:4]1)[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28]Br)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][O:13][C:10]2[CH:11]=[CH:12][C:7]3[NH:6][C:5](=[O:14])[O:4][CH:3]([CH2:1][CH3:2])[C:8]=3[CH:9]=2)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: CCC1OC(=O)Nc2ccc(O)cc21
Product: CCC1OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 4-ethyl-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(3,4-dichlorophenylsulfinyl)butylbromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].Cl[C:20]1[S:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:20]3[S:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: CC(C)c1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)NCc1cc(-c2ccn(-c3nc(C(C)C)ns3)n2)ccc1Cl
Temperature: 165 °C

Procedure:
A mixture of methyl N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]carbamate (i.e. the product of Step B, Example 4) (0.02 g, 0.75 mmol), 5-chloro-3-(1-methylethyl)-1,2,4-thiadiazole (i.e. the product of Step A) (0.61 g, 3.75 mmol) and potassium carbonate (0.25 g, 1.5 mmol) in N-methyl-2-pyrrolidinone (2.5 mL) was heated in a Biotage Creator XM microwave apparatus at 165° C. for 15 minutes. The reaction mixture was poured into water (60 mL), and the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:42][CH2:43][CH2:44][O:45]S(C)(=O)=O)=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:52]O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:42][CH2:43][CH2:44][O:45][CH3:52])=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)C1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COCCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described in example 14(a), the crude (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium hydride/methanol to yield the (3R,4R)-3-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 651 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[OH:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=2)(=[O:31])=[O:30])=[C:3]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[OH:10])[CH:4]=1
Reactant: COc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(C(O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC)c(OC)c2)c1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To 1 g of (2-amino-5-chlorophenyl)(3-methoxyphenyl)methanol dissolved in 6 ml of pyridine are added, at room temperature, 1.08 g of 3,4-dimethoxybenzenesulfonyl chloride. After 18 hours, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 1.65 g of the expected product.