Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1=[O:13].C(=O)([O-])O.[Na+].[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34](ON3C(=O)CCC3=O)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.CCOCC>O.O1CCCC1>[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([NH:1][CH:2]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]3=[O:13])=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: NC1CCCCN(CC(=O)O)C1=O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CN1CCCCC(NC(=O)OCC2c3ccccc3-c3ccccc32)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3-Aminohexahydro-2-oxo-1H-azepine-1-acetic acid (which can be prepared by the procedure of Thorsett, E. D. et al. J. Med. Chem. 1986, 29, 251–260; 9.3 g, 50 mmol) was added to a solution of sodium hydrogen carbonate (5 g, 60 mmol) in water (100 mL). A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-Osu; 18.6 g, 55 mmol) in tetrahydrofuran (110 mL) was added. The solution was stirred at room temperature overnight and then ether (200 mL) was added. The layers were separated and the organic layer was back-extracted with saturated sodium hydrogen carbonate:water (1:1; 60 mL). The combined aqueous layers were acidified with 1 M HCl (110 mL). The solid was filtered off, washed with water (4×20 mL), and dried in vacuo to give 3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid (20.1 g, 98%) as a white solid, mp 118° C. (dec.)
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:19])[CH:9]=[CH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CO.C(Cl)Cl.CN(C=O)C.CO.[Pd]>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:19])[CH2:9][CH2:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:26]3[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]3)=[CH:13][CH:12]=2)=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCc1sc(C(=O)C=Cc2ccc(C=O)cc2)cc1-c1ccccc1
Reactant: O=C(O)C1CNC1
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCc1sc(C(=O)CCc2ccc(CN3CC(C(=O)O)C3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.5 %

Procedure:
A solution of 4-[(5-ethyl-4-phenyl-thiophen-2-yl)-3-oxo-propenyl]-benzaldehyde (140 mg, 0.405 mmol) and azetidine-3-carboxylic acid (51 mg, 0.506 mmol) and NaBH(OAc)3 (257 mg, 1.21 mmol) in THF (6 mL) is stirred at rt for 6 h. The reaction mixture is diluted with a small amount of methanol and DCM (150 mL) and washed with water. The organic phase is separated and the aqueous phase again extracted with DCM. The combined organic extracts are dried over MgSO4 and evaporated. The residue is suspended in methanol, filtered and dried. The solid material obtained is suspended in DMF/methanol and treated with Pd/C (20 mg, 10% Pd). The slurry is stirred under 1.5 bar of H2 at rt for 16 h. The mixture is filtered and the filtrate is evaporated and dried to give 1-{4-[3(5-ethyl-4-phenyl-thiophen-2-yl)-3-oxo-propyl]benzyl}azetidine-3-carboxylic acid (15 mg) as a colourless solid; LC-MS: tR=0.89 min, [M+1]+=434.17.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([NH:17][C:18](=[O:20])[CH3:19])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:23][C:24]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>>[Cl:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:33]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Yield: 59 %

Procedure:
The title compound was prepared from N-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide; Preparation 36 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1) according to Method B (tan solid, 159 mg, 0.37 mmol, 59% yield). The title compound was largely present as (O)—N-((3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazol-7-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.59 (m, 7H), 1.65-1.87 (m, 2H), 1.98-2.05 (m, 1H), 2.06 (s, 3H), 2.13-2.24 (m, 1H), 2.78-2.97 (m, 2H), 3.51 (ddd, J=13.56, 9.26, 4.83 Hz, 1H), 4.86 (dd, J=9.26, 5.50 Hz, 1H), 7.11 (dd, J=9.26, 1.48 Hz, 1H), 7.32 (d, J=1.88 Hz, 1H), 7.46 (dd, J=8.59, 1.88 Hz, 1H), 7.60 (s, 1H), 7.64 (d, J=8.86 Hz, 1H), 7.93 (d, J=8.59 Hz, 1H), 10.11 (s, 1H). ES-MS m/z 433 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[CH:11][CH:10]=2)O1.[Cl:32][C:33]1[CH:38]=[CH:37][N:36]2[C:39](I)=[CH:40][N:41]=[C:35]2[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][N:36]2[C:39]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)=[O:19])=[CH:13][CH:14]=3)=[CH:40][N:41]=[C:35]2[CH:34]=1
Reactant: Clc1ccn2c(I)cnc2c1
Reactant: CC1(C)OB(c2ccc(CCCC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=C(CCCc1ccc(-c2cnc3cc(Cl)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Yield: 62.6 %

Procedure:
Suspend 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-butyramide (0.47 g, 1.15 mmol), 7-chloro-3-iodo-imidazo[1,2-a]pyridine (0.29 g, 1.05 mmol) and solid potassium carbonate (0.48 g, 3.45 mmol) in dioxane (4 mL) and water (2 mL). Deoxygenate the reaction contents with nitrogen for 10 minutes at room temperature. Add trans-dichlorobis(triphenylphosphine)palladium (II) (22 mg, 0.03 mmol) to the reaction. Fit a reflux condenser and heat the reaction to 105° C. over the weekend. Cool the reaction, dilute with dichloromethane and filter through Celite®. Concentrate the filtrate and then chromatograph on silica, using 0-3% methanol/ethyl acetate, to yield the product (301 mg, 57%). MS(ES), m/z 458 (M+1).
Reaction SMILES: C1(C2N=CN(C3CCNCC3)C=2C2C=CN=C(N)N=2)C=CC=CC=1.C(C1N(C2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1C1C=CC=CC=1)(=O)C.CNC1N=C(C2N(C3CCNCC3)C=NC=2C2C=CC=CC=2)C=CN=1.Cl.NC(N)=N.O1C=CC(C=O)=N1.F[C:90]1[CH:95]=[CH:94][C:93]([C:96]2[N:97]=[CH:98][N:99]([CH:109]3[CH2:114][CH2:113][N:112]([CH2:115][C:116]4[CH:120]=[CH:119][O:118][N:117]=4)[CH2:111][CH2:110]3)[C:100]=2[C:101]2[CH:106]=[CH:105][N:104]=[C:103]([NH:107]C)[N:102]=2)=[CH:92][CH:91]=1>>[O:118]1[CH:119]=[CH:120][C:116]([CH2:115][N:112]2[CH2:113][CH2:114][CH:109]([N:99]3[C:100]([C:101]4[CH:106]=[CH:105][N:104]=[C:103]([NH2:107])[N:102]=4)=[C:96]([C:93]4[CH:94]=[CH:95][CH:90]=[CH:91][CH:92]=4)[N:97]=[CH:98]3)[CH2:110][CH2:111]2)=[N:117]1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)CC2)n1
Agent: CC(=O)c1c(-c2ccccc2)ncn1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CNc1nccc(-c2c(-c3ccccc3)ncn2C2CCNCC2)n1
Agent: Cl
Product: Nc1nccc(-c2c(-c3ccccc3)ncn2C2CCN(Cc3ccon3)CC2)n1

Procedure:
4-(4-Phenyl-1-piperidin-4-yl-1H-imidazol-5-yl)pyrimidin-2-amine [C27, prepared from tert-butyl 4-(5-acetyl-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (C24) in a manner similar to the synthesis of N-methyl-4-(4-phenyl-1-piperidin-4-yl-1H-imidazol-5-yl)pyrimidin-2-amine (C26) described in Example 12, but using guanidine hydrochloride in place of N-methylguanidine hydrochloride] was reacted with isoxazole-3-carbaldehyde according to the general procedure for the synthesis of 4-{4-(4-fluorophenyl)-1-[1-(isoxazol-3-ylmethyl)piperidin-4-yl]-1H-imidazol-5-yl}-N-methylpyrimidin-2-amine (5) in Example 5. 4-{1-[1-(Isoxazol-3-ylmethyl)piperidin-4-yl]-4-phenyl-1H-imidazol-5-yl}pyrimidin-2-amine (free base of 13) was obtained as a yellow solid. Yield: 101 mg, 0.252 mmol, 29%. 1H NMR (400 MHz, CDCl3) δ 1.97-2.08 (m, 2H), 2.12-2.24 (m, 4H), 3.03 (br d, J=12 Hz, 2H), 3.69 (s, 2H), 4.59 (tt, J=11.8, 4.0 Hz, 1H), 5.07 (br s, 2H), 6.41 (d, J=1.7 Hz, 1H), 6.54 (d, J=5.2 Hz, 1H), 7.27-7.34 (m, 3H), 7.46-7.50 (m, 2H), 7.78 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.40 (br d, J=1.5 Hz, 1H). This solid was dissolved in ethyl acetate, treated with a solution of hydrogen chloride in diethyl ether (2 N, 1 equivalent) and allowed to stir for 18 hours. The resulting solid was collected by filtration to provide the title product as a light yellow solid. Yield: 70 mg, 0.16 mmol, 19%.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](OC=C)=[O:22]>COCCOC>[C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([O:17][C:21](=[O:22])[CH2:20][Cl:19])[C@H:12]1[OH:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@H]1O)c1ccccc1
Reactant: C=COC(=O)CCl
Solvent: COCCOC
Product: O=C(CCl)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@@H]1O
Reaction time: 6 h
Yield: 80 %

Procedure:
1.0 g (4 mmol) of 6-O-benzoylgalactal is taken up in about 20-25 ml of DME and 10-15 ml of vinyl chloroacetate and stirred with 1 g of lipase from Pseudomonas spec. (lipase P, Amano) at room temperature for about 5-7 h. Filtering off the reusable enzyme, concentration of the solution in vacuo and chromatography on silica gel (ether/hexane 1:1) or crystallization result in 6-O-benzoyl-3-O-chloroacetyl-galactal in 80% yield (1050 mg).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10]([C:12]2([NH2:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)CCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2([NH2:18])[CH2:13][CH2:14][N:15]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(C(=O)NCc2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1(C(=O)NCc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A degassed mixture of 4-amino-piperidine-4-carboxylic acid 4-chloro-benzylamide dihydrochloride (48 mg, 0.13 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (21 mg, 0.12 mmol), triethylamine (126 uL, 0.9 mmol) and n-butanol (1.2 mL) was stirred at 100° C. for 18 h. The solvents were removed by evaporation and the crude mixture was first purified on a SCX-II acid resin, eluting with methanol then 2M ammonia/methanol, and then by preparative TLC, eluting with 10% methanol in dichloromethane, to give 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid 4-chloro-benzylamide (37 mg, 0.096 mmol, 80%). LC-MS (LCT2) m/z 385 [M+H+], Rt 2.84 min.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1(/[CH:17]=[C:18](\[C:27]2[CH:28]=[N:29][C:30]([S:33][CH3:34])=[CH:31][CH:32]=2)/[C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.CCOC(C)=O>[CH:12]1(/[CH:17]=[C:18](\[C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:34])=[O:9])=[CH:31][CH:32]=2)/[C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Reaction time: 4.5 h

Procedure:
A solution of mCPBA (85% pure, 64 mg, 318 μmol) in CH2Cl2 (1 mL) was added over 5 min to a stirred solution of (E)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 5, 110 mg, 318 μmol) in CH2Cl2 (5 mL) at 0° C. After 4.5 h at 0° C., the reaction mixture was diluted with EtOAc (40 mL). The resulting solution was washed with H2O-saturated aqueous NaHCO3 (1:1, 2×20 mL) and brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc then THF) provided the title compound: RTA=3.32 min; m/z (ES+)=362.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A solution of 9.0 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in 25 ml of dimethylformamide is added with stirring to a suspension of 1.93 g of sodium hydride (50% suspension in oil) in 25 ml dimethylformamide. To the mixture is added 5.5 ml of ethyl 2-bromo-2-methylpropionate. The reaction mixture is stirred 24 hr at 80° C., poured onto ice/water and extracted with ether. The ether extracts are combined and washed with dil sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent is removed in vacuo to give a yellow oil which crystallizes on standing. Recrystallization from ether affords ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-2-methylpropionate, mp 70° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:21][CH2:20][O:19]1>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:21][CH2:20][OH:19]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccccc1C(F)(F)F
Temperature: 150 °C
Yield: 19.7 %

Procedure:
A mixture of 2-trifluoromethylphenol (2.00 g, 12.3 mmol), K2CO3 (1.71 g, 12.3 mmol) and ethylene carbonate (1.20 g, 13.6 mmol) in dry DMF (30 mL) was heated at 150° C. for 1 h. After cooling, the reaction was quenched by addition of water (10 mL). The mixture was concentrated in vacuo and the residue partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with additional portions of EtOAc (3×30 mL). The combined organic layers were treated with charcoal, dried over MgSO4, and filtered through Celite. The filtrate was concentrated in vacuo and the remaining oil was purified by chromatography on silica gel using n-hexane/EtOAc (80:20) as eluent to give 0.50 g (20%) of the title product as white crystals: mp 74-77° C. Anal. (C9H9F3O2) C, H.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][CH:28]=[O:29])[C:25](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH3:31][C:32]([SH:34])=[O:33].C(N(CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[C:32]([S:34][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][CH:28]=[O:29])[C:25](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=[O:33])[CH3:31]
Reactant: CC(=O)S
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 1.6 h

Procedure:
A solution of diphenylmethyl 3-bromomethyl-7β-formamidoceph-3-em-4-carboxylate, 1β-oxide (5.0 g) in N,N-dimethylformamide (30 ml.) was treated with ethanethiolic acid (4.0 ml) and triethylamine (1.4 ml.) and the reaction stirred for 1.6 hr. at +19°. The yellow solution was poured into water (100 ml.) and ethyl acetate (100 ml.) and the resulting insoluble solid was collected, washed with ethyl acetate and dried in vacuo over phosphorus pentoxide, to give diphenylmethyl 3-acetylthiomethyl-7β-formamidoceph-3-em-4-carboxylate, 1β-oxide (2.422 g, 49%), mp 198°-199° (dec.), [α]D -60° (c 1.0, DMSO), λmax. (EtOH) 273 nm (ε 10,300), νmax. (CHBr3) 3430 (NH), 1803 (β-lactam) 1725 (CO2R), 1695, 1505 (CONH), 1042 cm.-1 (S→O) τ (DMSO-d6), 1.66 (d, J 9; NH), 1.78 (s; CHO), 2.59 (m, phenyl), 3.01 (s, CHPh2), 7.68 (s; SCH3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C:10]([CH3:29])([CH3:28])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH:40][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][C:10]4([CH3:29])[CH3:28])[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C)(C)C1
Product: CC1(C)CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 141 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H3O+of 456. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.76 (s, 1H) 8.36 (d, 1H) 8.33 (d, 1H) 7.97 (d, 1H) 7.70 (t, 2H) 7.03 (d, 2H) 6.76 (m, 1H) 4.54 (s, 2H) 3.98 (t, 2H) 3.72 (s, 2H) 3.35 (m, 4H) 3.10 (t, 2H) 1.74 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:20])[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])[CH3:4].N1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>ClCCl>[N+:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:20])[CH:7]=2)[CH3:5])(=[O:38])=[O:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(COS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(NC(=O)Oc2ccccc2)no1
Temperature: 35 °C
Reaction time: 15 h
Yield: 59.5 %

Procedure:
To a stirred solution of phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared as described in Example 131A steps 1 through 4) (250 mg, 0.91 mmol) and pyridine (0.15 mL, 1.81 mmol) in dichloromethane (5 mL) at 0° C., was added dropwise, 4-nitrophenylsulfonyl chloride (245 mg, 1.08 mmol) in dichloromethane (3 mL). The reaction mixture was warmed to 35° C. and stirred for a further 15 h. Concentration under reduced pressure gave the crude product which was purified via silica gel column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 2-methyl-2-(3-(phenoxycarbonylamino)isoxazol-5-yl)propyl 4-nitrobenzenesulfonate (250 mg, 60%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.36-8.39 (m, 2H), 8.01-8.03 (m, 2H), 7.88 (m, 1H), 7.43-7.45 (m, 2H), 7.21-7.31 (m, 3H), 6.54 (s, 1H), 4.19 (s, 2H), 1.38 (s, 6H).
Reaction SMILES: C(C(C)[C:11]([OH:13])=S)C=CC1C=CC=CC=1.C(Br)C=CC1C=CC=CC=1.C(C(O)=O)CS.[CH2:31]([S:40]([CH:43]([CH3:47])C(O)=O)(=[O:42])=[O:41])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)(=O)C>[OH:13][CH2:11][CH2:47][CH2:43][S:40]([CH2:31][CH:32]=[CH:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:41])=[O:42]
Reactant: CC(C(=O)O)S(=O)(=O)CC=Cc1ccccc1
Reactant: CC(CC=Cc1ccccc1)C(O)=S
Agent: BrCC=Cc1ccccc1
Agent: O=C(O)CCS
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(CC=Cc1ccccc1)CCCO

Procedure:
Cinnamylthiopropionic acid, m.p. 87° C., was prepared from cinnamyl bromide and mercaptopropionic acid and oxidised by the method described in Example 23(a) to cinnamylsulphonylpropionic acid, m.p. 160° C. This acid was reduced by addition to a stirred suspension of lithium aluminium hydride (2 equivalents) in tetrahydrofuran at -20° to -25° C. and the product formed isolated by ethyl acetate extraction to give cinnamyl 3-hydroxypropyl sulphone, m.p. 86° C. A solution of cinnamyl 3-hydroxylpropyl sulphone, para-toluene sulphonic acid (catalytic) and dihydropyran (2 equivalents) in dichloromethane was allowed to stand at room temperature for 24 hours, evaporated, and recrystallised from diethyl ether to give the title compound, m.p. about 45° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Cl:10][C:11]1[S:15][C:14]([C:16](OCC)=[O:17])=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[Cl:10][C:11]1[S:15][C:14]([C:16](=[O:17])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: CSc1nccc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2ccc(Cl)s2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
To a solution of 4-methyl-2-(methylsulfanyl)pyrimidine (1 eq, 235 mmol) and ethyl 5-chlorothiophene-2-carboxylate (1.11 eq, 261 mmol) in anhydrous THF (400 mL) at 0° C., under N2 was added dropwise a solution of lithium bis(trimethylsilyl)amide (1M solution in hexanes, 1.6 eq, 376 mmol). The resulting mixture was stirred for 3 h at 0° C. and then stirred at room temperature overnight. A solution of HCl 1M (750 mL) was then added till pH=1. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was diluted with diisopropylether and the resulting precipitate was filtered and to afford 29.5 g (43% yield) of 1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])=[CH:9][C:8]=1F)(=O)[CH3:5].CO>C(Cl)(Cl)Cl>[CH3:5][C:4]1[C:7]2[C:8](=[CH:9][C:10]([N:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:14]3=[O:25])=[CH:11][CH:12]=2)[NH:3][N:2]=1
Reactant: CC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Reactant: NN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3c(C)n[nH]c3c2)C1=O
Temperature: 120 °C
Reaction time: 12 h
Yield: 64.5 %

Procedure:
Hydrazine hydrate (10 mL) was added to 1-(4-acetyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (380 mg, 1.2128 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 120° C. for 12 hours, cooled to room temperature and continued stirring for the next 12 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and ice water. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% MeOH in CHCl3) afforded 240 mg of the product (64.5% yield).