Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([N:38]=[C:39]=[S:40])(=O)C1C=CC=CC=1.O>CC(C)=O>[NH2:38][C:39]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1)=[S:40]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(N)=S)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a ice-cold solution of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (247.6 mg) in acetone (4.8 ml) was added benzoyl isothiocyanate (94.1 mg), and the mixture was stirred at r.t. for 1 hour. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual amorphous substance was dissolved in EtOH (5 ml), and 6N—NaOH (0.288 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 2 hours, and neutralized with 1N—HCl at 0° C. The mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was solidified with ethyl ether to give N-{4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (290.7 mg) as an off-white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[N:33]([CH2:36][CH3:37])=[C:34]=[O:35]>O1CCCC1>[CH2:36]([NH:33][C:34]([NH:24][CH2:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:18]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:25])[N:7]=4)[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)=[O:35])[CH3:37]
Reactant: CCN=C=O
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)NCc1ccc2c(c1)OCCc1sc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 (0.050 g, 0.00014 mol) in tetrahydrofuran (1.0 mL) was added triethylamine (0.0588 mL, 0.000422 mol) then isocyanatoethane (0.110 mL, 0.00141 mol). The reaction was stirred at room temperature overnight, quenched with a small amount of methanol and concentrated in vacuo. The crude was precipitated from MeOH/H2O to give 525. MS(ESI+) 427.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].[CH3:14][C:15](C)([O-:17])C.[K+].C(OC(=O)C)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:15](=[O:17])[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(O)c(OC(C)=O)c1
Reaction time: 0.17 h

Procedure:
3,4-Dihydroxy-benzoic acid ethyl ester (550 mg, 3.02 mmol) was dissolved in DMF (5 ml), potassium tert-butoxide (210 mg, 2.87 mmol) was added and the mixture stirred for 10 min. Acetic anhydride (339 mg, 3.32 mmol) was added and stirring continued for 10 min. The mixture was partitioned between EA and 2 N hydrochloric acid, and the aqueous phase extracted with EA. The combined organic phases were dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:17]([CH3:19])[CH3:18])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C@H:34]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[CH2:33][CH2:32][C@H:31]2[C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:39][C:38]1[CH:37]=[CH:36][C:35]([C@@H:34]2[CH2:33][CH2:32][C@@H:31]([C:42]3[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=3)[N:30]2[C:27]2[CH:26]=[CH:25][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:29][CH:28]=2)=[CH:41][CH:40]=1)=[O:16])=[O:8])[CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: CC(C)(C)c1ccc(N2[C@H](c3ccc(N)cc3)CC[C@H]2c2ccc(N)cc2)cc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc([C@@H]2CC[C@@H](c3ccc(N)cc3)N2c2ccc(C(C)(C)C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of the product from Example 37B (17.7 mg, 0.065 mmol) and the product from Example 37E (50 mg, 0.130 mmol) in anhydrous DMSO (1.3 mL) was added HATU (27.1 mg, 0.071 mmol) and Hunig's Base (0.015 mL, 0.084 mmol). The resulting mixture was stirred at rt for 30 min, and was then partitioned between H2O (5 mL) and EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4. The drying agent was filtered off, and solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% MeOH in CH2Cl2 to give the title compound (20 mg, 24%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, J=6.72 Hz, 3 H), 0.93 (d, J=6.72 Hz, 3 H), 1.11 (s, 9 H), 1.52-1.66 (m, 2 H), 1.79-2.06 (m, 4 H), 2.06-2.20 (m, 1 H), 2.34-2.47 (m, 2 H), 3.52 (s, 3 H), 3.56-3.67 (m, 1 H), 3.74-3.87 (m, 1 H), 4.02 (t, J=8.51 Hz, 1 H), 4.42 (dd, J=8.08, 4.83 Hz, 1 H), 4.83-4.94 (m, 2 H), 5.02 (d, J=7.16 Hz, 0.5 H), 5.08 (d, J=7.59 Hz, 0.5 H), 6.18 (d, J=8.78 Hz, 2 H), 6.48 (d, J=8.35 Hz, 2 H), 6.84 (d, J=8.35 Hz, 2 H), 6.93 (d, J=8.89 Hz, 2 H), 7.11 (d, J=8.57 Hz, 2 H), 7.31 (d, J=8.35 Hz, 1 H), 7.48 (d, J=8.57 Hz, 2 H), 9.97 (s, 1 H); MS (ESI) m/z 640.3 (M+H)+.
Reaction SMILES: [ClH:1].C(N(CC(O)CNC([C:13]1[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)CC)C.C(N(CC)CC)C.[Cl-].[CH3:38][O:39][C:40](=[O:46])[CH2:41][CH2:42][C:43](O)=[O:44]>C(Cl)Cl>[ClH:1].[CH3:38][O:39][C:40]([CH2:41][CH2:42][C:43]([O:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:13]=1)=[O:44])=[O:46]
Reactant: COC(=O)CCC(=O)O
Reactant: CCN(CC)CC(O)CNC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Oc1cn(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g of 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-hydroxy-1-phenylindole hydrochloride (0.005 mole) are mixed in 25 ml of methylene chloride with 0.7 ml triethylamine (0.005 mole) and 0.6 ml of succinic acid methylester chloride and the reaction mixture agitated for 1 h at room temperature. The solution is then washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated. The residue is purified by low pressure chromatography using methylene chloride as the elution agent, as described in Example 3. 2-[3-N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-methoxycarbonylethylcarbonyloxy-1-phenylindole hydrochloride is obtained as an oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH2:23])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1)OCc1ccccc1

Procedure:
Benzyl (1R,2R)-2-((S)-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (from intermediate C, Example 2) (30 mg, 0.094 mmol) and benzyl carbonochloridate (16.07 mg, 0.094 mmol) according to General Procedure G to give 5 mg (12% yield) of the product as a yellow solid. Anal. Calcd. for C25H32N4O4 m/z 452.5, found: 453.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.08 (d, J=9.3 Hz, 2H), 7.36-7.29 (m, 5H), 6.77 (d, J=9.3 Hz, 2H), 5.05 (br. s., 2H), 4.91 (br. s., 1H), 3.75 (d, J=10.4 Hz, 1H), 3.66 (d, J=12.6 Hz, 1H), 3.31 (d, J=7.7 Hz, 1H), 3.04 (t, J=10.7 Hz, 1H), 2.83 (br. s., 2H), 2.54 (br. s., 1H), 2.15-2.03 (m, 2H), 1.99-1.91 (m, 1H), 1.83 (dd, J=9.1, 4.7 Hz, 2H), 1.79-1.69 (m, 3H), 1.32 (d, J=8.8 Hz, 2H), 1.48 (br. s., 1H), 1.62 (ddd, J=13.9, 10.4, 10.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 156.63, 154.71, 136.37, 128.52, 128.14, 126.12, 112.77, 66.77, 59.06, 50.93, 47.94, 32.19, 29.68, 24.53, 23.07.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: O=Cc1cc(O)ccc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(OC2CCCCO2)ccc1O

Procedure:
A solution of 2,5-dihydroxy-benzaldehyde (152 mmol), 3,4-dihydro-2H-pyran (167 mmol) and a catalytic amount of pyridinium p-toluenesulfonate in CH2Cl2 (480 mL) was left overnight at room temperature. The organic phase was washed with 1 N Na7CO3 (aq) (3×100 mL) and dried (Na2SO4). Evaporation in vacuo gave the desired product as brown crystals that was used without further purification. 1H-NMR (CDCl3) δ 10.72 (s, 1H), 9.88 (s, 1H), 7.32-7.29 (m, 2H), 6.96 (d, 1H), 5.38 (bs, 1H), 3.99-3.91 (m, 1H), 3.69-3.64 (m, 1H), 2.06-1.63 (m, 6H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])C=CC=CC=1>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH:12]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)N1CCC(C=O)C1
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC(C=C(C)C(C)=O)C1
Yield: 94.8 %

Procedure:
A solution of 1-allyloxycarbonyl-3-formylpyrrolidine (13.45 g) and 3-triphenylphosphoranylidenebutan-2-one (25.60 g) in dichloromethane (15 ml) was refluxed for 20 hours. The mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (200 g) and eluted with a mixture of ethyl acetate and hexane (4:6 V/V) to give 1-allyloxycarbonyl-3-(2-methyl-3-oxo-1-butenyl)pyrrolidine (16.52 g).
Reaction SMILES: [C:1]([CH:5]1[C:9](=[O:10])[CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[C:18]1([O:24][P:25](Cl)([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:4][O:3][C:1]([C:5]1[CH2:6][S:7][CH2:8][C:9]=1[O:10][P:25]([O:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:26])=[O:2]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)C1CSCC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)CSC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 108.1 %

Procedure:
To a solution of 3-carbomethoxytetrahydrothiophene-4-one (Gianturco M. A., Friedel P., Giammarino A. S., Tetrahedron, 20:1772 (1964)) (4.0 g, 25 mmol) and triethylamine (6.6 g, 65 mmol) in 50 mL dry THF at 0° was added, over a 15 minute period, diphenylchlorophosphate (17.5 g, 65 mmol). The reaction mixture was stirred at room temperature for 2 days, then treated with ice-cold water and extracted with diethyl ether. The extracts were washed with saturated NaHCO3, brine, dried with Na2SO4, and evaporated to yield an oil (10.6 g).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:23][O:24][C:25]([C:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26]>CO>[CH3:23][O:24][C:25]([C:27]1([CH2:33][NH:34][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: COC(=O)C1(CN)CCOCC1
Solvent: CO
Product: COC(=O)C1(CNC(=O)c2ncc3cc(Oc4ccccc4)ccc3c2O)CCOCC1

Procedure:
After a mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (121 mg), 4-aminomethyl-tetrahydro-pyran-4-carboxylic acid methyl ester (177 mg; commercially available) in MeOH (3 mL) was microwaved at 150° C. for 650 min; cooled, concentrated, the residue was partitioned between EtOAc and diluted HCl solution, EtOAc phase was washed with water and diluted NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated and column purified to give product (48 mg). LC MS ESI+: 437 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([NH2:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[C:26]12([CH2:36][C:37](Cl)=[O:38])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>O1CCOCC1>[C:26]12([CH2:36][C:37]([NH:18][C:12]3[C:11]4[CH2:10][CH2:9][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[O:38])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: Nc1ccnc2c1CCN(Cc1ccccc1)C2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccnc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 3.9 %

Procedure:
7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-4-ylamine (48 mg, 0.202 mmol) in 6 ml of dioxane was treated with NMM (22 μl, 0.202 mmol) followed by adamantan-1-yl-acetyl chloride (0.043 g, 0.202 mmol) and stirred at rt under argon. The reaction was monitored by TLC and LCMS. Excess acid chloride was added and the reaction was stirred. The contents were concentrated and purified by HPLC to afford the desired product (3.3 mg, 4%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(#N)C>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:21])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:10][N:9]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 39c (1.44 g; 4.32 mmol) is dissolved in acetonitrile (10 ml) under addition of N,N-diisopropyl ethyl amine (2200 μl; 12.96 mmol). Methanesulfonylchloride (990 mg; 8.64 mmol) is added and the mixture is stirred for 18 h at 25° C. The reaction mixture is evaporated to dryness and purified with silica gel chromatography. Yield: 0.895 g (55.3%), ESI-MS: m/z=375 [M+H]+, Cl-pattern
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](=[O:47])([O:44][CH2:45][CH3:46])[O:40][CH:41](Cl)[CH3:42].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[CH2:41]([O:40][C:39]([O:44][CH2:45][CH2:46][O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])=[O:47])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CCOC(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)OCCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 78 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were added into the reaction tube, and then 1-chloroethyl ethyl carbonate (0.092 g, 0.6 mmol), potassium iodide (0.0415 g, 0.25 mmol) and potassium carbonate (0.083 g, 0.6 mmol) were added successively under stirring. Then the reaction tube was sealed up. The reaction mixture was reacted at 65° C. in an oil bath for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. After cooling to room temperature, 40 mL of water was added to the reaction tube. The reaction mixture was extracted with ethyl acetate (25 mL×3), and the combined organic phase was washed with water (20 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound, (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-ethoxycarbonyloxy)-ethyl ester 34a (0.26 g, yield 78.1%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[NH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:43]=2)=[CH:40][N:41]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>COCCOC.O>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[NH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:21]3[CH:22]=[CH:23][C:18]([C:15]4[NH:14][C:13]([CH:10]5[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]5)=[N:17][CH:16]=4)=[CH:19][CH:20]=3)=[CH:44][CH:43]=2)=[CH:40][N:41]=1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)C1
Temperature: 80 °C
Yield: 63.7 %

Procedure:
Pd(Ph3)4 (54 mg, 0.046 mmol) was added to a mixture 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (378 mg, 0.97 mmol), 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (408 mg, 0.93 mmol), NaHCO3 (273 mg, 3.26 mmol) in 1,2-dimethoxyethane (8 mL) and water (2 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 6 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (370 mg, 64%). m/z 625.1 (M+H)+.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:39])[CH:21]([NH:22][C:23](=[O:38])[CH:24]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:39])[CH:21]([NH:22][C:23](=[O:38])[CH:24]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3cccs3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3cccs3)[C@H]2S1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Acetic acid (1.6 ml) and zinc powder (1.2 g) were added under and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[N-tert.-butoxycarbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylate (1.52 g) in anhydrous dimethylformamide (10 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was poured into an ice-cooled mixture of 2 to 3% hydrochloric acid and ethyl acetate and then extracted. The extract was washed with water, extracted with a sodium bicarbonate aqueous solution, after which the aqueous layer was acidified by adding 5% sulfuric acid and ethyl acetate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was pulverized by adding isopropyl ether, collected by filtration and dried to give amorphous 2-methyl-7-[N-tert.-butoxycarbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid (0.7 g).
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[C:14]1(=[CH:5][C:6]#[N:7])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
Sodium hydride (60% in oil, 0.80 g, 20 mmol) was suspended in 50 mL tetrahydrofuran and chilled in ice under nitrogen. Diethylcyanomethyl phosphonate (3.85 g, 22 mmol) was added dropwise in 10 mL tetrahydrofuran and stirring continued for 15 minutes to give a clear solution. Cyclohexanone (1.90 g, 19 mmol) was added in 5 mL tetrahydrofuran and the reaction mixture allowed to warm up to room temperature. The liquor was decanted and the residue washed three times with ether. The liquor and washings were combined, washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 4:1 to give the required product as a colorless oil (1.5 g, 67%).