Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=3[C:28]([F:31])([F:30])[F:29])[CH:13]=2)[NH:8][CH:7]=1)([CH3:5])[CH3:4]>CO>[CH:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:23]([C:24]([F:25])([F:27])[F:26])=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][C:17]=3[C:28]([F:31])([F:29])[F:30])[CH:13]=2)[NH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(C=O)cc3C(F)(F)F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CO)cc3C(F)(F)F)cc12
Reaction time: 1 h

Procedure:
0.27 g (7.22 mmol) of sodium borohydride is added to a solution of 1.0 g (2.41 mmol) of aldehyde derivative from Example V in 20 ml of methanol in 4 portions at room temperature and the mixture is stirred for 1 hour. Afterwards the reaction solution is concentrated to one half, 60 ml of water are added and the mixture is concentrated until methanol is completely evaporated in a rotary evaporator. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are washed with sodium chloride solution, dried and concentrated, and the residue is dried in a high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]3[CH2:29][CH2:28][NH:27][CH2:26][C:19]3=[N:20][C:21]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]1.[CH:31](OC1C=CC=CC=1)=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]3[CH2:29][CH2:28][N:27]([CH:31]=[O:32])[CH2:26][C:19]3=[N:20][C:21]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]1
Reactant: O=COc1ccccc1
Reactant: CC(C)Nc1nc2c(nc1N1CCC([C@H](F)c3ccc(F)cc3F)CC1)CCNC2
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC([C@H](F)c3ccc(F)cc3F)CC1)CCN(C=O)C2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of (S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (30.5 mg, 0.073 mmol) in THF (364 μL) at room temperature was treated with phenyl formate (140 μL, 1.09 mmol). The reaction mixture was stirred at 60° C. for 1 h. The reaction was purified by HPLC Method B using a 50% to 80% ACN gradient to give the title compound, as a TFA salt, as a pale yellow solid (9.4 mg, 23%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.29 (m, 6H), 1.45 (d, J=12.7 Hz, 1H), 1.66 (m, 2H), 2.00 (m, 1H), 2.10 (m, 1H), 2.77 (m, 4H), 3.49 (m, 2H), 3.76 (t, J=5.9 Hz, 1.4H), 3.82 (t, J=6.1 Hz, 0.6H), 4.12 (m, 1H), 4.48 (s, 0.6H), 4.52 (s, 1.4H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (td, J=8.3, 6.3 Hz, 1H), 8.18 (s, 0.7H), 8.24 (s, 0.3H); ESI-MS m/z [M+H]+ 447.90.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([N+:16]([O-])=O)[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl-].[Ca+2].[Cl-].C([OH:24])C>O.[Fe]>[NH2:16][C:10]1[C:11]([C:14]([NH2:15])=[O:24])=[N:12][CH:13]=[C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:9]=1
Reactant: CCO
Reactant: Cc1cccnc1-c1cnc(C#N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: Cc1cccnc1-c1cnc(C(N)=O)c(N)c1
Yield: 94 %

Procedure:
Heat a solution of 5-(3-methyl(2-pyridyl))-3-nitropyridine-2-carbonitrile (1 g, 4.1 mmol), iron (2.3 g, 40 mmol) and calcium chloride (560 mg, 5 mmol) in ethanol (15 mL) and water (4 mL) to reflux for 1 hour. Cool the mixture, filter through Celite and wash with ethyl acetate. Evaporate the filtrate and re-dissolve the residue in ethyl acetate. Wash with water and brine, dry (MgSO4) and evaporate to give the title compound as a pale yellow solid (880 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)=O)=[CH:10][C:9]=1[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19].[NH2:22][C:23](=[N:35][OH:36])[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([Cl:34])[CH:25]=1>>[Cl:34][C:26]1[CH:25]=[C:24]([C:23]2[N:22]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])=[C:9]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=3)[O:36][N:35]=2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CS(C)(=O)=O
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(CS(C)(=O)=O)c3)n2)cc1Cl

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 40 (182.62 mg; 0.60 mmol) and Intermediate 34 (114.32 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 1/1), affording the title compound. 1H NMR (CDCl3) δ 8.58 (d, J=1.7 Hz, 1H), 8.32 (d, J=1.5 Hz, 1H), 8.28 (dd, J=8.0, 1.8 Hz, 1H), 8.15 (dd, J=8.1, 1.6 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.41-7.29 (m, 3H), 7.20 (d, J=7.3 Hz, 1H), 4.33 (d, J=13.9 Hz, 1H), 4.19 (d, J=14.0 Hz, 1H), 3.98 (s, 3H), 2.64 (s, 3H), 2.09 (s, 3H). LC/MS (Method B): 495.2 (M−H)−, 497.1 (M+H)+. HPLC (Method A) Rt 5.51 min (Purity: 99.6%).
Reaction SMILES: C(O[CH2:10][CH2:11][CH2:12][CH:13]([CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:14][NH:15][S:16]([CH2:19][CH2:20][CH2:21][Cl:22])(=[O:18])=[O:17])(=O)C1C=CC=CC=1.C[O-].[Na+].ClCCCS(NCC(CC(O)C)COC(=O)NCCCCCCCCCCCCCCCCCC)(=O)=[O:49]>CO>[Cl:22][CH2:21][CH2:20][CH2:19][S:16]([NH:15][CH2:14][CH:13]([CH2:12][CH:11]([OH:49])[CH3:10])[CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:18])=[O:17]
Reactant: CCCCCCCCCCCCCCCCSCC(CCCOC(=O)c1ccccc1)CNS(=O)(=O)CCCCl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)CC(C)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)CC(C)O
Yield: 54.5 %

Procedure:
A mixture of 1.24 g (2.0 mM) of 2-(benzoyloxypropan-1-yl)-1-(3-chloropropylsulfonylamino)-3-n-hexadecylthiopropane m14 and 0.77 ml (2 mM) of 5.18 M/L sodium methoxide in methanol solution in 50 ml of methanol is allowed to react by the same procedure as described in (131) and 562 mg (54.5% yield) of the titled compound m15 is obtained.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][N:13]=2)[CH:9]=[N:8][CH:7]=1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[CH:7]1[N:8]=[CH:9][N:10]2[CH:11]([C:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][N:13]=3)[CH2:3][CH2:4][CH2:5][C:6]=12
Reactant: ClCCCc1cncn1Cc1noc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc2c(C3CCCc4cncn43)noc2c1

Procedure:
A suspension of 3-[(5-(3-chloropropyl)-1H-imidazol-1-yl)methyl]-1,2-benzisoxazole hydrochloride (1.9 g, 0.006 mole) in anhydrous tetrahydrofuran (25 mL) is stirred under an atmosphere of nitrogen and cooled in an ice bath during the portionwise addition of solid potassium t-butoxide (1.7 g, 0.015 mole). The reaction mixture is stirred at 0°-5° C. for 3 hours and then acidified by addition of glacial acetic acid (0.5 mL). The solvent is evaporated and the residue is taken up in methylene chloride (20 mL) and washed with saturated sodium bicarbonate (10 mL) and water (10 mL). The solution is dried over anhydrous sodium sulfate, filtered and evaporated to give crude 3-(5,6,7,8-tetrahydroimidazo-[1,5-a]-pyridin-5-yl)-1,2-benzisoxazole which is converted to the hydrochloride salt, m.p. 250°-252° C., when its solution in isopropanol is treated with ethereal hydrogen chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[S-:13][C:14]#[N:15].[Na+].BrBr.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:14]([NH2:15])[S:13][C:7]=2[CH:6]=1)=[O:12])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2nc(N)sc2c1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A solution of ethyl-4-aminobenzoate (35 g, 212 mmol) in glacial acetic acid (300 mL) was added to a stirred solution of sodium thiocyanate (69 g, 848 mmol) in acetic acid (150 mL). The mixture was cooled in an ice-water bath and a solution of bromine (12 mL, 233 mmol) in acetic acid (60 mL) was added dropwise via an addition funnel. The reaction mixture was stirred at 0° C. to RT for 4 h and then poured into water (1.5 L). Saturated sodium carbonate solution was added to neutralize the solution. Precipitated solid was filtered, washed with water and EtOAc, and dried in vacuo to obtain the title compound of this step (31.65 g, 67.2% yield).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2.[H-].[Na+].[CH2:22](OS([O-])(=O)=O)[CH3:23].O>C1COCC1>[CH2:22]([O:1][CH2:2][C@@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2)[CH3:23]
Reactant: CN1[C@H]2CC[C@@H]1[C@H](CO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Reactant: CCOS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@@H]1[C@@H](c2ccc(Cl)c(Cl)c2)C[C@@H]2CC[C@H]1N2C
Temperature: 35 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
(1R, 2R, 3S)-2-hydroxymethyl-3(3,4-dichlorophenyl)tropane (26.9 g, 0.09 mol) in THF (200 ml) was added sodium hydride 60% in oil (4.6 g, 0.12 mol) and ethylsulphate (15.7 ml, 0.12 mol) and heated to 30-40° C. on an oil bath for ½ hour. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture is then heated to 30-40° C. on an oil bath for 1 hour and poured into water (500 ml). The mixture was extracted twice with tert.butylmethylether, the organic phases was washed with water and dried over MgSO4 and evaporated to yield the 32.82 g of the title compound.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH:21]([N:24](CC)C(C)C)(C)C.CN>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([NH:24][CH3:21])=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: ClCCl
Product: CNc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), then N,N-diisopropylethylamine (0.15 ml, 0.88 mmol), methylamine (2 M tetrahydrofuran solution, 0.50 ml, 1.00 mmol) were added. After stirring in a sealed tube at an external temperature of about 60° C. for 3 hours, this was diluted with dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:23][C:24]2[C:25]([NH2:33])=[CH:26][C:27]3[O:31][CH2:30][O:29][C:28]=3[CH:32]=2)=CC=1>>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:9]=2[CH:10]=1)=[N:33][C:25]1[CH:26]=[C:27]2[O:31][CH2:30][O:29][C:28]2=[CH:32][C:24]=1[CH:23]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Product: COc1cc2c(cc1OC)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 80.9 %

Procedure:
Using the procedure of Example 1, 5,6-dimethoxyindan-1-one (192 mg, 1 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (255 mg, 1 mmol) to yields 7,8-dimethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (260 mg, 81 % of theory).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>CC(=O)OCC.C1COCC1>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:29][CH2:28][O:27][CH3:26])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2]
Reactant: COCCO
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCCOC)cc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (119 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 19 μL (241 μmol) 2-methoxyethanol, 66 mg (251 μmol) diphenyl-2-pyridylphosphine and 10 ml THF are placed under protective gas. At 0° C. 58 mg (252 μmol) DBAD are added and then the mixture is stirred overnight at RT. Then it is diluted with EA and extracted with 10% sodium carbonate solution. The organic phase is stirred with 20 mL of 4N HCl for 5 min and then extracted. The organic phase is washed with saturated saline solution and then the solv. is eliminated i.V. The residue is purified on silica gel. (Eluant: DCM/MeOH/ammonia) The solv. of the corresponding fractions is eliminated i.V. and the residue is crystallised with cyclohexane/EA.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([O:12]CC)=O)[CH:8]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[CH2:21]([NH:24][C:10](=[O:12])[CH:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH3:23]
Reactant: CCCN
Reactant: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Product: CCCCCCC(C(=O)NCCC)n1cnc([N+](=O)[O-])c1

Procedure:
Ethyl 2-(4-nitro-1H-imidazole-1-yl)octanoate (17 moles, 5.0 g) was reacted with propylamine as in Example 1 to yield 2.5 g of N-propyl-2-(4-nitro-1H-imidazol-1-yl)octanoamide. (MS).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][N:15]([CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([CH3:23])[CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: CN(C)c1cccc(N)c1
Product: CN(C)c1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 190 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (245 mg, 1.28 mmol) (described in a previous experimental) and N,N-dimethyl-1,3-phenylenediamine (1.60 g, 11.8 mmol) is stirred under N2 at 190° C. for 1 h, and the resulting product is chromatographed (twice) over alumina (3% EtOH/CHCl3) to give 7-amino-4-(3-dimethylaminoanilino)pyrido[4,3-d]pyrimidine (113 mg, 32%) as a pale yellow solid. 1H NMR (DMSO) δ 9.66 (1H, brs), 9.33 (1H, s), 8.36 (1H, s), 7.22 (1H, brd, J=7.8 Hz), 7.16 (2H, m), 6.57 (2H, brs), 6.51 (1H, ddd, J=8.0, 2.3, 1.2 Hz), 6.42 (1H, s), 2.91 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1.Cl[CH:24]([O:26]C)Cl.Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:22][C:18]1[CH:17]=[C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])[CH:21]=[CH:20][C:19]=1[CH:24]=[O:26]
Reactant: Cc1cccc(OCCc2nc(-c3ccccc3)oc2C)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1C=O
Reaction time: 2.5 h
Yield: 52 %

Procedure:
A solution of 6.00 g of 5-methyl-2-phenyl-4-(2-m-tolyloxy-ethyl)-oxazole and 4.70 g of dichloromethylmethylether in 30 ml of CH2Cl2 was treated at 0° C. with 11.2 ml TiCl4 over 15 min and stirring was continued at 0° C. for 2.5 h. The red solution was treated at 0° with 600 ml of 1 N aqueous HCl, the organic layer was washed with 0.1 N aqueous NaOH and twice with brine. The organic layer was dried, the solvent evaporated and the residue was chromatographed on silica (n-hexane/AcOEt, 7:1) to give 3.42 g (52%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[S:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[S:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(C3CCOC3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(C3CCOC3)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 68.4 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydrofuran-3-yl)thio-3-cephem-4-carboxylate (80 mg) (as obtained in Example 1) was dissolved in dimethylformamide (1.6 ml) and the solution was cooled to -20° C. The solution, after addition of iodomethyl pivalate (77 mg) thereto, was stirred at a temperature of -20° to -10° C. for 30 minutes (for the esterification reaciton), after which cold water (5 ml) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate, and the organic layer separated was washed with an aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to leave a yellow oil. The oily residue was purified by a column chromatography on a silica gel column (15 g) with elution using ethyl acetate as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected under reduced pressure gave the titled compound (65 mg; 68%) as white powder.
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([O:6][C:7](=[O:32])[CH2:8][CH2:9][NH:10][C:11](=[O:31])[C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]=1[N+:28]([O-])=O)[CH3:5].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(OCC)(=O)C.C(O)C.C(OCC)(=O)C>[CH2:4]([O:6][C:7](=[O:32])[CH2:8][CH2:9][NH:10][C:11](=[O:31])[C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)[CH:15]=[CH:14][C:13]=1[NH2:28])[CH3:5]
Reactant: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1N
Temperature: 70 °C
Yield: 53 %

Procedure:
Tin (II) chloride (12.2 g, 64.4 mmol) was added to a solution of 5.12 g (12.9 mmol) of N-(5-(4-cyanobenzyloxy)-2-nitrobenzoyl)-b-alanine ethyl ester in 40 mL of 1:1 ethyl acetate/ethanol and the mixture heated to 70° C. for 15 min, cooled, and poured into a mixture of ice water, 1N sodium bicarbonate, and ethyl acetate. 1N sodium hydroxide was added carefully until a clear solution resulted and the aqueous phase was separated and extracted with ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated to give a dark solid that was purified by chromatography (silica gel-60, 1:1 ethyl acetate/hexane) to give 2.51 g (53%) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyl)-b-alanine ethyl ester as a light yellow solid. 1H NMR (300 MHz, CDCl3) d 7.67 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.52 (2H, d, J=8.3 Hz, NC-Ar-H2), 6.94 (1H, d, J=2.9 Hz, O-Ar-H), 6.89 (1H, dd, J=2.9, 8.8 Hz, O-Ar-H), 6.78 (1H, b, N-H), 6.66 (1H, d, J=8.8 Hz, O-Ar-H), 5.04 (2H, s, ArCH2O), 4.16 (2H, q, J=7.3 Hz, OCH2CH3), 3.66 (2H, bq, J=5.8 Hz, NHCH2CH2), 2.62 (2H, t, J=5.8 Hz, NHCH2CH2), 1.27 (3H, t, J=7.3 Hz, OCH2CH3); Exact mass (FAB, M+H+) calcd for C20H22N3O4 : 368.1610; Found: 368.1603.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:41])[CH2:13][CH2:12][N:11]([C:14](=[O:38])[C@H:15]([NH:19][C:20]([C@@H:22]3[CH2:26][CH2:25][C:24]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH2:27][CH:28]=[O:29])[CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:40])[CH3:39])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:41])[CH2:13][CH2:12][N:11]([C:14](=[O:38])[C@H:15]([NH:19][C:20]([C@@H:22]3[CH2:26][CH2:25][C:24]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])([CH2:27][CH2:28][OH:29])[CH2:23]3)=[O:21])[CH:16]([CH3:17])[CH3:18])[CH2:10][C:9]2([CH3:39])[CH3:40])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)[C@@H]1CCC(CC=O)(NC(=O)OC(C)(C)C)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@@H](NC(=O)[C@@H]1CCC(CCO)(NC(=O)OC(C)(C)C)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of tert-butyl (3R)-3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)-1-(2-oxoethyl)cyclopentylcarbamate (from step D, 60 mg, 0.101 mmol) in MeOH (2 mL) at −78° C. was added NaBH4 (7.67 mg, 0.203 mmol). The resulting mixture was stirred at −78° C. for 1 hour. The solvent was removed under reduced pressure and to the residue was added ethyl acetate (10 mL). The resulting mixture was washed with water (2 mL), brine (2 mL), dried over Na2SO4 and concentrated to yield t-butyl (3R)-3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)-1-(2-hydroxyethyl)cyclopentylcarbamate (58 mg, 0.098 mmol, 96% yield) as a solid. MS (ESI+) m/z 594 M+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9](O)[CH2:10][CH2:11][CH3:12].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Cc1cccc(N)c1
Reactant: CCCCO
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCCCNc1cccc(C)c1
Yield: 80 %

Procedure:
214 parts of m-toluidine, 75 parts of n-butanol and 10 parts of triphenyl phosphite are heated for 10 hours at 230° C in a stirred autoclave. The autoclave is then let down and the water of reaction formed, the excess of m-toluidine and the unconverted butanol are distilled off under reduced pressure. 130 parts of N-butyl-m-toluidine, corresponding to a yield of 80% of theory, distil at a boiling point of 65° - 70° C/0.2 mm Hg.