Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([C:15](=[O:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[O:25])=[C:19]([O:34][CH3:35])[CH:18]=2)[C@H:13]([CH2:37][O:38][C:39]2[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=2)[C:42]([O:44]C)=[O:43])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([C:15](=[O:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[O:25])=[C:19]([O:34][CH3:35])[CH:18]=2)[C@H:13]([CH2:37][O:38][C:39]2[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=2)[C:42]([OH:44])=[O:43])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OC[C@@H]2CC[C@H](COCc3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)N2[C@@H](COCc3ccccc3)CC[C@H]2COc2cccc(C(=O)O)c2)ccc1NC(=O)Nc1ccccc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-[5-(R)-benzyloxymethyl-1-[4-[N′-(2-methylphenyl) ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (185 mg, 0.28 mmol) in MeOH-THF (2:5, 7 ml) was added 1.0 M-NaOH (860 ml, 0.86 mmol) at rt, and the resulting mixture was heated at 60° C. with stirring for 1 h. The reaction mixture was poured into 1N-HCl, then extracted with CHCl3. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (5:1) as eluent to give129 (171 mg, 94%) as a colorless amorphous solid. MW 637.72 1H-NMR (CD3OD), mixture of rotamars δ 1.89–2.37 (series of m, 4 H), 2,29 (s, 3 H), 3.52–4.53 (series of m, 8 H), 3.66 and 3.74 (s, total 3 H), 4.85 (s, 2 H), 6.66–7.98 (series of m, 16 H); MS (ESI) m/z, 638 (M++H), 660 (M++Na+); Anal. Calcd for C37H39N3O7.H2O: C, 67.77; H, 6.30; N, 6.41. Found: C, 67.40; H, 5.95: N, 6.14.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[CH:29]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30]1.C(N(CC)CC)C.ClC(Cl)C.C(COC)OC>>[CH2:22]([NH:21][C:19]([C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[N:18][C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][S:32]([CH:29]4[CH2:31][CH2:30]4)(=[O:34])=[O:33])[CH2:7][CH2:6]3)=[N:10]2)=[CH:15][CH:14]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)NCc4ccccc4)cc3n2)CC1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: COCCOC
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1ccc2cnc(N[C@H]3CC[C@H](NS(=O)(=O)C4CC4)CC3)nc2c1

Procedure:
A solution of 2-[(trans-4-aminocyclohexyl)amino]-N-benzylquinazoline-7-carboxamide (200.0 mg, 0.53 mmol), cyclopropanesulfonyl chloride (37.4 mg, 0.53 mmol) and triethylamine (162.0 mg, 1.6 mmol) in 7 ml of a mixed solvents of dichloroethane:dimethoxyethane (1:2) was stirred at room temperature for 16 hours. The crude material was purified by prepHPLC to give 13.0 mg of the product (yield 10.2%). 1H NMR (400 MHz, DMSO-d6) ppm 0.78-1.06 (m, 6H), 1.39 (t, J=9.82 Hz, 4H), 1.99 (d, J=4.28 Hz, 3H), 2.37-2.48 (m, 1H), 2.54-2.64 (m, 1H), 3.13 (s, 1H), 3.78 (s, 1H), 4.18 (d, J=6.55 Hz, 1H), 4.50 (d, J=6.04 Hz, 1H), 7.08 (d, J=7.81 Hz, 1H), 7.22-7.30 (m, 1H), 7.31-7.37 (m, 6H), 7.43-7.50 (m, 1H), 7.64 (d, J=6.80 Hz, 1H), 7.85 (d, J=8.31 Hz, 1H), 8.00 (s, 1H), 9.14 (s, 1H), 9.29 (t, J=5.92 Hz, 1H). HRMS: m/z 480.20484 [M+H]+), calc. 480.20638. MS m/z, (APCI); 480.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([NH:7][NH2:8])=[O:6].FC(F)(F)[C:15](O)=[O:16].[CH2:20](Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:15](=[O:16])[N:8]([CH3:20])[N:7]=2)[CH:9]=[C:10]([CH3:12])[N:11]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C(=O)NN)cc(Cl)n1
Reactant: ClCCl
Product: Cc1cc(-c2nn(C)c(=O)o2)cc(Cl)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
Step-2: 2-Chloro-6-methylisonicotinohydrazide: To a (0° C.) cooled solution of step-1 intermediate (3.0 g, 10.5 mmol) in DCM (15 mL) was added trifluoroacetic acid (15 mL). After stirring for 2 hat RT, solvent was evaporated under vacuum. Water (20 mL) was added to the resulting residue followed by ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography to afford 1.80 g (92%) of the title compound as white solid.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>CN(C=O)C>[CH3:5][C:4]([CH3:6])=[CH:3][CH2:2][N:11]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)=CCBr
Solvent: CN(C)C=O
Product: CC(C)=CCN1C(=O)c2ccccc2C1=O
Yield: 63.4 %

Procedure:
20 g of 1-bromo-3-methylbut-2-ene and 26.1 g of phthalimide are suspended in anhydrous DMF, and then the mixture is refluxed for 12 h with heating. After returning to RT, the reaction medium is filtered and then taken up with an aqueous solution saturated with NH4Cl. The aqueous phase is extracted with AcOEt, washed with a solution of NaCl, and then dried on magnesium sulfate and dry evaporated. The obtained solid is suspended in 100 mL of water and stirred. The precipitated product is filtered, rinsed with ether and then dried in the oven in vacuo at 65° C. 18.3 g (yield=63%) of 2-(3-methylbut-2-en-1-yl)-1H-isoindole-1,3-dione are obtained as a white powder used as such.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.C(N(C(C)C)C(C)C)C.O>O1CCCC1>[CH:31]1([C:34]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=4)[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=4)=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[4-(trifluoromethyl)phenyl]benzamide (215 mg, 0.50 mmol) produced in Example A25(v), cyclopropanecarbonyl chloride (210 mg, 2.00 mmol) and N-ethyl-N-isopropylpropane-2-amine (518 mg, 4.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (220 mg, 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[O:10]([C:12](C)(C)C)[Li].[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.CC(=O)OCC>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[O:25][C:12](=[O:10])[N:5]([C:4]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([F:1])[CH:3]=2)[CH2:26]1)([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1ccc(N)cc1F
Reactant: [Li]OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N2C[C@@H](CNC(=O)OC(C)(C)C)OC2=O)cc1F
Temperature: 25 °C
Yield: 81 %

Procedure:
According to procedure C and starting from 3-fluoro-4-methylaniline (commercial) the corresponding Cbz-protected intermediate was obtained in quantitative yields. LiOtBu (2.2M in THF, 6.8 mL, 3 eq) was added to a solution of the latter (1.3 g, 5.0 mmol) and (R)-oxiranylmethyl-carbamic acid tert-butyl ester (commercial, 0.87 g, 5.0 mmol) in DMF (10 mL). The mixture was stirred at rt over the weekend after which the solution was diluted with EA, washed with water and concentrated. The residue was purified by CC (Hept-EA 2:1) to afford the title intermediate as a colorless oil (1.32 g, 81%).
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:18])[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH2:10][CH2:9]2)=O.[NH2:19][NH:20][C:21]([NH2:23])=[S:22].CO.O>C(O)(=O)C>[OH:1][N:2]=[C:3]([CH3:18])[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH2:10][CH2:9]2)=[N:19][NH:20][C:21]([NH2:23])=[S:22]
Reactant: NNC(N)=S
Reactant: CC(=NO)C(=O)c1ccc2c(c1)CCC(=O)N2C
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(=NO)C(=NNC(N)=S)c1ccc2c(c1)CCC(=O)N2C
Yield: 26.2 %

Procedure:
A mixture of 6-(2-hydroxyiminopropionyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline (1 g), thiosemicarbazide (0.48 g), methanol (10 ml), water (5 ml) and acetic acid (0.1 ml) was refluxed for 13 hours with stirring. After cooling, the resulting precipitates were collected by filtration, washed successively with ethanol, water and ethanol, and then dried to give 0.34 g of 6-(2-hydroxyimino-1-thiosemicarbazonopropyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[N:12]=[C:11]([Cl:16])[N:10]=[C:9](Cl)[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].CC(O)C.[OH-].[NH4+:23]>O>[NH2:23][C:9]1[C:8]2[CH2:7][CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]([Cl:16])[N:10]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C1CCc2nc(Cl)nc(Cl)c2C1
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)C1CCc2nc(Cl)nc(N)c2C1
Temperature: 130 °C

Procedure:
A mixture of 6-Carboethoxy-2,4-dichloro-5,6,7,8-tetrahydroquinazoline (7.68 g), 2-propanol (7 mL) and 30% ammonium hydroxide (12 mL) was heated in a sealed tube at 130° C. for 20 min. The tube was cooled and 20 mL of H2O was added to the mixture. The solid which precipitated was collected and dried to yield 4-Amino-6-carboethoxy-2-chloro-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:27](O)=O.[NH2:37][NH2:38]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:38][N:37]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(Cl)cc1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: NN
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(Cl)cc3)n2)ccc1-n1cnc(Cl)c1
Yield: 21.1 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (500 mg, 1.69 mmol, from preparation B) and 6-chloro-2-(4-chlorophenyl)hexanoic acid (440 mg, 1.685 mmol, from preparation AH) were coupled and then reacted with hydrazine (0.212 mL, 6.74 mmol) using a procedure analogous to Step A of Example 13. The crude products were purified using silica gel chromatography (40-100% ethyl acetate/chloroform) to afford 5-(5-chloro-1-(4-chlorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (180 mg, 0.356 mmol, 21% yield) as a colorless residue. LC-MS (M+H)+ 505.1.
Reaction SMILES: C([O:5][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:19]([O:21]C(C)(C)C)=[O:20])([CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:10]([NH:9][CH2:8][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:19]([OH:21])=[O:20])([OH:7])=[O:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CCC(CP(=O)(CNCc1ccccc1)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(CP(=O)(O)CNCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a solution of di-tert-butyl 2-[((tert-butoxy)-{[benzylamino]methyl}phosphoryl)methyl]pentane-1,5-dioate (0.498 g, 1.0 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) at 0° C., and the mixture was stirred at room temperature for eighteen hours. The solvent was removed under reduced pressure. The residual oil was taken up with dichloromethane (10 mL) and concentrated. This process was repeated three times to remove trifluoroacetic acid completely. The resulting oil was crystallized from methanol to give 0.174 g of white solid (53% yield) 1H NMR (D2O) δ 1.40-1.48 (m, 27H), 1.7-2.1 (m, 4H), 2.2-2.4 (m, 3H), 2.6-3.0 (m, 3H), 3.8-4.0 (m, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][N:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1
Reactant: N#CC1CNC1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-Benzhydryl-azetidine-3-carbonitrile (0.25 g, 1.0 mmol) in dichloromethane (2 ml) is treated with 1-chloroethylchloroformate (0.12 ml, 1.1 mmol). The reaction mixture is stirred at room temperature for 3 hours, the solvent evaporated and the residue taken-up in methanol and refluxed for 1 hour. The reaction mixture is cooled to room temperature and stirred for a further 18 hours. The solvent is evaporated to afford crude azetidine-3-carbonitrile hydrochloride. The crude azetidine-3-carbonitrile is dissolved in dichloromethane (3 ml) and treated with triethylamine (0.25 ml, 2.0 mmol) and 3,4-dichlorobenzylbromide (0.24 g, 1.0 mmol). The reaction mixture is stirred at ambient temperature for 2 hours, then washed with water, the organic phase dried over magnesium sulphate and evaporated. The crude product is purified by chromatography over flash silica using hexane:ethylacetate 2:1 as eluent to afford 1-(3,4-Dichloro-benzyl)-azetidine-3-carbonitrile. [MH]+ 240.97
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:23])[CH2:14][CH2:13]1)[NH:6][C:5]2=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.[NH2:63][C@H:64]1[C@H:68]([F:69])[CH2:67][N:66]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:65]1>CN(C)C=O.O>[F:69][C@H:68]1[C@H:64]([NH:63][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[N:8]=[C:7]([N:12]3[CH2:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[S:15](=[O:23])[CH2:14][CH2:13]3)[N:6]=2)[CH2:65][N:66]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:67]1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(N[C@@H]3CN(C(=O)OCc4ccccc4)C[C@H]3F)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
A suspension of 6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinazolin-4(3H)-one (600 mg, 1.77 mmol, prepared in analogy to the one in Example 91), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.02 g, 2.3 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (400 mg, 2.6 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 minutes. Then a solution of benzyl trans-3-amino-4-fluoropyrrolidine-1-carboxylate (500 mg, 2.1 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After being heated at 60° C. overnight, the mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient eluting with 10% to 25% ethyl acetate in dichloromethane) to afford 415 mg of the desired product as a yellow solid (yield was 41.8%).
Reaction SMILES: O1CCCC1.O.O.[NH2:8][CH:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]([NH:12][CH:13]1[C:28](=[O:29])[N:15]2[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:18][S:19][C@H:14]12)=[O:11].[CH3:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]([C:46](Cl)=[O:47])[C:38]1=[O:49]>CO>[CH3:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]([C:46]([NH:8][CH:9]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:18][S:19][C@H:14]23)=[O:11])=[O:47])[C:38]1=[O:49]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Reactant: Cn1c(=O)n(C(=O)Cl)c2ccccc21
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)n3c(=O)n(C)c4ccccc43)c3ccccc3)[C@H]2SC1

Procedure:
To 30 ml. of dry tetrahydrofuran (THF) were added 441 mg. (1 mmole) of 7-(α-aminophenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid dihydrate and 0.97 ml. (4 mmoles) of N,O-bis-trimethylsilylacetamide. The mixture was stirred until solution was complete, and then a solution of 210 mg. (1 mmole) of 3-methyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-ylcarbonyl chloride in 5 ml. of THF was added at room temperature. The reaction mixture was stirred for 50 minutes. Methanol (5 ml.) was added to the mixture; however, no precipitation occurred. The mixture then was evaporated to a volume of about 10 ml., and the resulting precipitate was filtered. A mixture of 50 ml. of ethyl acetate and 50 ml. of water was added to the filtrate, and the pH of the mixture was adjusted to 7.5 by addition of sodium bicarbonate. The layers were separated, and the aqueous layer was acidified to pH 2.0 by addition of 1N hydrochloric acid. The acidic mixture then was extracted twice with 50 ml. of a 6:1 mixture of ethyl acetate and tetrahydrofuran. The organic extract was dried over magnesium sulfate, filtered, and evaporated slowly to a volume of about 10 ml. The concentrate was cooled overnight, and the resulting crystalline precipitate was filtered and dried to obtain 275 mg. of the title compound.
Reaction SMILES: N[C@H](C(NC(C([O-])=O)C([O-])=O)=O)CO.CCOC(/N=N/C(OCC)=O)=O.[CH2:27]([O:29][C:30]([CH:32]([NH-:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:31])[CH3:28].[C:39]([N:49]1[CH2:51][CH:50]1[C:52](O)=[O:53])([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C1COCC1>[CH2:27]([O:29][C:30]([CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:38]1[CH2:51][CH:50]([NH:49][C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[C:52]1=[O:53])=[O:31])[CH3:28]
Reactant: CCOC(=O)C([NH-])C(=O)OCC
Reactant: O=C(O)C1CN1C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N[C@@H](CO)C(=O)NC(C(=O)[O-])C(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)N1CC(NC(=O)OCc2ccccc2)C1=O

Procedure:
The Cbz protected serylaminomalonate (0.5 g, 1.2 mmoles) and 0.33 g (1.2 mmoles) of TPP in 30 mL of THF were treated with 0.2 mL (1.29 mmoles) of DEAD for 1 hour at R.T. The mixture was chromatographed as above, yielding 0.29 g (63% mass recovery) of the mixture of the title compound and 1-Cbz-2-carboxyaziridine diethoxycarbonylmethylamide. 105 mg of the mixture was prep TLC'd (silica, 2 mm, ether/hexanes, 4 times). The title compound eluted first, and after evaporation, 64.1 mg (0.18 mmoles, 15%) was isolated as an oil. IR (neat) 1770, 1750, 1715. NMR 1.13-1.33 (6H, m), 3.56-3.7 (2H, m), 4.0-4.4 (4H, m), 4.6-4.8 (1H, m), 5.1 (3H, 2 overlapping singlets), 5.8-6 (1H, m), 7.4 (5H, s). The aziridine side product: 39.5 mg (0.1 mmoles, 8.7%) IR (neat) 1760, 1730. NMR 1.16-1.33 (6H, t), 2.4-2.6 (2H, dd), 3.06-3.16 (1H, dd), 4.1-4.4 (4H, dq), 4.5-4.8 (1H, b), 5.06-5.1 (1H, d), 5.13 (2H, s), 7.4 (5H, s).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH3:3].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16].C(N(CC)C1C=CC=CC=1)C.[H-].[Na+].[CH:35]([O:38][C:39]([C:41]1[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[N+:55]([O-:57])=[O:56])=[N:43][CH:44]([CH3:48])[NH:45][C:46]=1[CH3:47])=[O:40])([CH3:37])[CH3:36]>C1COCC1.CCCCCC>[CH:35]([O:38][C:39]([C:41]1[CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[N+:55]([O-:57])=[O:56])[N:43]([C:15]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([O:4][CH2:1][CH2:2][CH3:3])=[O:13])=[CH:7][CH:8]=2)=[O:16])[C:44]([CH3:48])=[N:45][C:46]=1[CH3:47])=[O:40])([CH3:36])[CH3:37]
Reactant: CC1=C(C(=O)OC(C)C)C(c2ccccc2[N+](=O)[O-])=NC(C)N1
Reactant: CCCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC(=O)c1ccc(OC(=O)N2C(C)=NC(C)=C(C(=O)OC(C)C)C2c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.5 %

Procedure:
A solution of 250 mg (1.35 millimole) of n-propyl-p-hydroxybenzoate in 7 ml of THF was added to a solution of 0.12 ml (1.00 millimole) of trichloromethyl chloroformate in 2 ml of THF and then a solution of 0.25 ml (1.57 millimole) of N,N-diethylaniline in 6 ml of THF was added dropwise. The reaction mixture was stirred for 1.5 hrs at room temperature. Independently, 0.30 g (6.25 millimole) of sodium hydride washed with hexane was suspended in 5 ml of THF and a solution of 200 mg (0.63 millimole) of 5-isopropyloxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-dihydropyrimidine in 5 ml os THF was added dropwise and stirred for 40 minutes at room temperature. And to this mixture the above reaction mixture was added and stirred for 30 minutes. Ice water was added and the mixture was extracted three times with ether. The organic layer was washed twice with water, dried over magnesium sulfate (dehydrating agent) and concentrated under reduced pressure. The residue was purified on silica gel by column chromatography (silica gel 30 g, eluant:benzene/ethyl acetate 9:1) to obtain 117 mg (35% yield) of tilte compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([O:25]C)=[O:24])=[N:21][CH:22]=3)[N:13]=2)[CH:9]=[CH:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33].C(Cl)[Cl:35]>CO>[ClH:35].[CH3:3][O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[N:21][CH:22]=3)[N:13]=2)[CH:9]=[CH:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)OC)nc3)no2)ccc1-c1ccccc1C
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1cc(-c2nc(-c3ccc(C(=O)O)nc3)no2)ccc1-c1ccccc1C
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A 5N aqueous solution of NaOH (0.77 mL, 3.9 mmol) was added into a solution of methyl 5-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}pyridine-2-carboxylate (400 mg, 0.96 mmol) in MeOH (6 mL). The resulting mixture was stirred at RT for 1.5 hours. The reaction mixture was diluted with DCM and washed with a 1N aqueous solution of HCl (3×). The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure. The residue was taken up with Et2O and an excess of a 1N solution of HCl in Et2O was added. The precipitate was filtered off and dried under reduced pressure to give the title compound as a white powder (370 mg, 88%). HPLC (Method A), Rt: 5.0 min (purity: 94.7%). UPLC/MS, M+(ESI): 402.4. 1H NMR (DMSO-d6, 300 MHz) δ 9.38 (d, J=2.1 Hz, 1H), 8.66 (dd, J=8.2, 2.1 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.27 (d, J=8.2 Hz, 1H), 8.19 (dd, J=7.9, 1.8 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.36 (m, 2H), 7.29 (m, 1H), 7.15 (d, J=7.0 Hz, 1H), 4.23 (d, J=12.7 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.25 (s, 3H), 2.04 (s, 3H).