Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCOCC1)C.[NH:9]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:10]([C:18]([O:20]N1C(=O)CCC1=O)=O)[C@@H:11]([CH3:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[NH2:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[NH:9]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@H:10]([C:18]([NH:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:20])[C@@H:11]([CH3:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC[C@H](N)C(=O)O
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
12.8 ml (0.1 mole) of N-ethylmorpholine and 40.6 g (0.1 mole) of Z-Thr(But)-OSu (Hoppe Seyler's Z. Physiol. Chem. 346, 60 (1966)) are added at 0° C. to a suspension of 16.1 g (0.1 mole) of H-Ser(But)-OH (Chem. Ber. 97, 2490 (1964)) in 100 ml of dimethylformamide. The mixture is then stirred for 5 hours at room temperature and is left to stand overnight at room temperature. The product is checked for the presence of H-Ser(But)-OH by thin layer chromatography. If no H-Ser(But)-OH is detectable by this method, any undissolved matter is filtered off. The filtrate is concentrated and the residue is partitioned between ether and 110 ml of 1 N citric acid. The ether phase is washed once more with 100 ml of 0.5 N citric acid and then with water or NaCl solution until neutral. The ether phase is then dried over Na2SO4 and is concentrated, and the product is dried in a high vacuum. Yield 32.5 g of an amorphous product (72%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:14]1[CH:19]=[CH:18][C:17]([C@H:20]([NH2:23])[CH2:21][OH:22])=[CH:16][CH:15]=1.Cl.[NH+]1C=CC=CC=1>COCCO.C(OCC)(=O)C>[OH:22][CH2:21][C@@H:20]([NH:23][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: N#Cc1cccc2c(Cl)ccnc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: COCCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc2c(N[C@H](CO)c3ccccc3)ccnc12
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A solution of 4-Chloro-quinoline-8-carbonitrile (200 mg, 1.1 mmol), (S)-Phenylglycinol (160 mg, 1.2 mmol), pyridinium hydrochloride (138 mg, 1.2 mmol) in 2-methoxyethanol (3.5 mL) was placed in a microwave 150° C., 50 Watts for 2 h. The solution was diluted with ethyl acetate and washed with brine solution. Purification by silica gel (20-80% ethyl acetate/heptane) afforded 4-((S)-2-Hydroxy-1-phenyl ethylamino)-quinoline-8-carbonitrile (320 mg, 33%) as a white solid. LCMS (ESI) 290 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27]([CH3:29])([CH3:28])[CH2:26][N:25](CC5C=CC(OC)=CC=5)[C:24]4=[O:39])=[CH:19][C:18]=3[CH3:40])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27]([CH3:28])([CH3:29])[CH2:26][NH:25][C:24]4=[O:39])=[CH:19][C:18]=3[CH3:40])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1ccc(CN2CC(C)(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(C)c3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4(C)C)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (155 mg) described in Preparation Example 118, 1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (112 mg) described in Preparation Example 54, cesium carbonate (261 mg) and copper(I) iodide (76 mg) were added toluene (10 mL) and N,N′-dimethylethylenediamine (86 μL), and the mixture was stirred with heating under reflux for 19 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one. The obtained 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one was dissolved in trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 22 hr. The solvent was evaporated from the reaction mixture, and 5% aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform/methanol (10:1). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (74 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:5]4[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc(C(F)(F)F)cc3[N+](=O)[O-])ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C(F)(F)F)cc4[N+](=O)[O-])cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-nitro-4-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide (0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 38 mg (76%) of the title compound as an off-white solid. mp 55°-57°. FDMS: m/e =418. α[D]589 =+60.50 (c=0.16, methanol).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17].[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:7]=2[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17]
Reactant: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN1C(=O)C2CCCN2C(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 2 h

Procedure:
To 10-methyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazapine-5,11(10H, 11aH)-dione (5.7 g, 24.7 mmol) in concentrated sulfuric acid (60 ml) at 0° C. was added potassium nitrate (2.62 g, 25.9 mmol). After stirring for 2 h the mixture was dumped onto ice (500 g) and extracted with ethyl acetate (5×75 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to a solid which was recrystallized from ethyl acetate-hexane (5.2 g, 77%), m.p. 160-162° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9])([CH3:4])[CH3:3].O.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Methyl 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoate (3.0 g, 6.98 mmol) was dissolved in THF (50 mL) and water (10 mL) and lithium hydroxide monohydrate (586 mg, 13.95 mmol) added. The resultant mixture was heated with stirring at 45° C. for 2 hours, then at ambient temperature for 16 hours, and at 45° C. for a further 4 hours. Water (40 mL) was added and the solvent removed in vacuo. The resultant solution was acidified carefully with 1M citric acid (2 equivalents), washed with water and brine then dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a colourless gum (2.58 g).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].Cl>N1C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][CH:2]=[C:3]([CH:8]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Cl)ccc1N
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A suspension of (E)-3,4-bis(difluoromethoxy)phenyl-2-propenoic acid (0.10 g, 0.42 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.14 mL, 1.7 mmol) and catalytic DMF (1 drop). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. A solution of the acid chloride (0.42 mmol) in pyridine (2.0 mL) was added to a cooled solution of 2-amino-5-chloro-N-methylbenzamide (0.12 g, 0.63 mmol) in pyridine (2.0 mL) at 0° C. The suspension was stirred at 0° C. for 1 h, warmed to rt and stirred for 16 h and then acidified with 1 M HCl. The precipitate was collected by filtration and recrystallised from EtOH/water providing (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-chloro-N-methylbenzamide (80 mg, 43%) as a pale brown crystalline solid; mp 185.5-187.5° C.; δH (500 MHz, DMSO-d6) 2.81 (d, J=4.5 Hz, 3H, NHCH3), 6.93 (d, J=15.6 Hz, 1H, CH═CHCO), 7.26 (t, J=73 Hz, 1H, OCHF2), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.37 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.57 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.59 (d, J=15.6 Hz, 1H, CH═CHCO), 7.66 (dd, J3,4=8.5, J4,6=2.0 Hz, 1H, H4), 7.80 (m, 2H, H2′, H6), 8.56 (d, J3,4=8.5 Hz, 1H, H3), 8.85 (m, 1H, NHCH3), 11.54 (s, 1H, NH); δC (125 MHz, DMSO-d6) 26.3, 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 119.9, 120.7, 122.5, 122.6, 123.5, 126.6, 126.7, 127.7, 131.4, 132.8, 137.7, 139.4, 141.9, 142.7, 163.3, 167.3; HRMS (ESI+) calculated for C19H15ClF4N2O4 [M+Na]+ 469.0549, found 469.0549; νmax 1052, 1267, 1508, 1633, 1684, 3303 cm−1.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH2:29])=[N:20][N:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[N:23][C:22]=23)=[CH:14][C:13]=1[CH3:30]>N1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH:29][C:8](=[O:9])[CH2:7][O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:20][N:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[N:23][C:22]=23)=[CH:14][C:13]=1[CH3:30]
Reactant: Cc1cc(C)n2nc(N)c(-c3ccc(Cl)c(C)c3)c2n1
Reactant: O=C(Cl)COC1CCCC1
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(NC(=O)COC3CCCC3)c(-c3ccc(Cl)c(C)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 133C (1.0 mL of solution in CH2Cl2) was added to a stirring solution of the product from Example 47C (51 mg, 0.178 mmol) in pyridine (1.4 mL). The reaction mixture was stirred at room temperature for 2 hours, and then quenched by addition of MeOH (0.5 mL). After 30 min, concentrated NH4OH (0.2 mL) was added, and the mixture was stirred at room temperature for 12 hours, and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 70:30-0:100) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.52-1.81 (m, 8H) 2.42 (s, 3H) 2.56 (s, 3H) 2.73 (d, J=1.0 Hz, 3H) 4.05-4.12 (m, 1H) 4.09 (s, 2H) 6.86-6.89 (q, J=1.0 Hz, 1H) 7.40 (d, J=8.5 Hz, 1H) 7.54 (dd, J=8.4, 1.9 Hz, 1H) 7.65 (d, J=1.9 Hz, 1H); MS (DCI/NH3) m/z 413/415 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5](COC)=[CH:4][N:3]=1.ClC1C(Cl)=CC([C:20]([O:22][CH3:23])=[O:21])=CN=1>>[Cl:8][C:7]1[C:2]([C:20]([O:22][CH3:23])=[O:21])=[N:3][C:4]([C:20]([O:22][CH3:23])=[O:21])=[CH:5][CH:6]=1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: COCc1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(Cl)c(C(=O)OC)n1
Yield: 73 %

Procedure:
Example 2 was repeated, except that the 2,3-dichloro-5-(methoxymethyl)pyridine was replaced by the same molar amount of methyl 2,3-dichloro-5-pyridinecarboxylate. After a reaction time of 6 hours at a bath temperature of 160° C., 1.20 g (73 percent) of a yellow product was obtained. Other data concerning the product was:
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13]1[CH:46]=[CH:45][C:16]([CH2:17][S:18][C@@H:19]2[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[C@H:21]([C:37]([NH:39][C@H:40]3[CH2:44][CH2:43][NH:42][CH2:41]3)=[O:38])[CH2:20]2)=[CH:15][CH:14]=1.Cl[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18][C@@H:19]2[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[C@H:21]([C:37]([NH:39][C@H:40]3[CH2:44][CH2:43][N:42]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[CH2:41]3)=[O:38])[CH2:20]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
230 mg of diisopropylethylamine were added to a suspension of 1.0 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (ii) above] and 240 mg of 4-dimethylaminopyridine in 10 ml of dry acetonitrile, and the resulting mixture was cooled to 0° C. A solution of 430 mg of 4-nitrobenzyl chloroformate in 4 ml of dry acetonitrile was then added to the mixture. The mixture was then stirred at room temperature for 3 hours, after which a solution of 117 mg of 4-nitrobenzyl chloroformate in 2 ml of dry acetonitrile was added and the mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with 50 ml of methylene chloride. The diluted solution was washed with a saturated aqueous solution of sodium chloride. The aqueous washings were extracted with methylene chloride. The organic extract and the methylene chloride solution were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of methylene chloride and acetonitrile as the eluent, to give 862 mg of the title compound as a powder.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][C:11]2([C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][CH:15]([CH3:24])[CH2:14]2)[C:10]1=[O:25])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[CH2:13][CH2:12][C:11]2([C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][CH:15]([CH3:24])[CH2:14]2)[C:10]1=[O:25]
Reactant: CC1CC2(CCN(OCc3ccccc3)C2=O)c2cc(F)ccc2O1
Agent: [Pd]
Solvent: CO
Product: CC1CC2(CCN(O)C2=O)c2cc(F)ccc2O1
Reaction time: 0.25 h

Procedure:
A solution of the more polar diastereomer of 1'-benzyloxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one (1.7 g) in methanol (75 mL) containing 10% palladium on carbon (350 mg) was stirred vigorously under hydrogen gas (1 atm). After 15 minutes, the mixture was filtered, and the filtrate was concentrated in vacuo. The title compound was obtained as needles following recrystallization from ethyl acetate hexanes (m.p. 205°-207° C., 840 mg).
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9]N=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[C:15]([O:24][CH3:25])[N:14]=1.C1C2C(=CC=CC=2)CCN1>CN(C=O)C>[CH3:25][O:24][C:15]1[C:16]([N+:21]([O-:23])=[O:22])=[C:17]([O:19][CH3:20])[N:18]=[C:13]([N:1]2[CH2:11][CH2:10][C:9]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:7]2)[N:14]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1nc(Cl)nc(OC)c1[N+](=O)[O-]
Agent: c1ccc2c(c1)CCNC2
Solvent: CN(C)C=O
Product: COc1nc(N2CCc3ccccc3C2)nc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.304 g, 2 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.293 g, 2.2 mmol) in DMF (3 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 4b (0.592 g, 1.87 mmol, 94%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH2:31]1[O:39][C:38]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=2[O:32]1>>[O:32]1[C:33]2[CH:34]=[CH:35][C:36]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)[NH:20][C:19]4=[O:29])=[CH:37][C:38]=2[O:39][CH2:31]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccc5c(c4)OCO5)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3,4-methylenedioxyphenylboronic acid in step C. (ESI): mass calcd. for C19H12N4O5, 376.1; m/z found, 377.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.96 (br s, 2H), 8.97 (s, 1H), 8.29-8.25 (m, 2H), 8.11 (dd, J=8.5, 2.2 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.38 (d, J=1.7 Hz, 1H), 7.27 (dd, J=8.1, 1.8 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.10 (s, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH2:28]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:29]1[O:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O.C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:37]5[CH2:38][CH2:39][N:34]([CH2:28][C:29]6[O:33][CH:32]=[CH:31][CH:30]=6)[CH2:35][CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1coc(CN2CCNCC2)c1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCN(Cc5ccco5)CC4)c(F)cc3cc2c1=O
Yield: 59.4 %

Procedure:
Ethyl 1-cyclopropyl-7,9-difluoro-8-(4-furfurylpiperazin-1-yl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared under the conditions of Example 3, but from 1.8 g of ethyl 1-cyclopropyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylate and 4.8 g of 4-furfurylpiperazine hydrochloride in 30 cm3 of dimethyl sulphoxide and 5.2 cm3 of triethylamine. 1.5 g of ethyl 1-cyclopropyl-7,9-difluoro-8-(4-furfurylpiperazin-1-yl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow-brown solid melting at about 125-128° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](O)=[O:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.S(Cl)([Cl:28])=O>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]([Cl:28])=[O:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)O)cccc2c1=O
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)Cl)cccc2c1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of thionyl chloride (10 mL) and 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazoline-8-carboxylic acid 33 (1.00 g, 2.87 mmol) was heated at reflux for 1 h. Upon cooling to room temperature, all volatiles were removed under vacuum, to give 34 (1.05 g, 100% yield) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]O)[CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:24]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:81]/[O:82][C:83]([C:96]2[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=2)([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)/[C:50]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[S:64])=[C:57](C(=O)C)[CH2:58][S:59][C@H:54]23)=[O:51])[N:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1CCOCC1.[F:108][C:109]([F:122])([F:121])[S:110]([O:113][CH2:114][CH:115]1[CH2:120][CH2:119][O:118][CH2:117][CH2:116]1)(=[O:112])=[O:111]>C(N(CC)CC)C.N1C=CC=CC=1>[F:121][C:109]([F:108])([F:122])[S:110]([O:113][CH2:114][CH:115]1[CH2:116][CH2:117][O:118][CH2:119][CH2:120]1)(=[O:111])=[O:112].[C:24]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:81]/[O:82][C:83]([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)([C:96]2[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=2)[C:90]2[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=2)/[C:50]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)=[S:64])=[C:57]([CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:58][S:59][C@H:54]23)=[O:51])[N:48]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCC1CCOCC1
Reactant: CC(=O)C1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=S(=O)(OCC1CCOCC1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCN1
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCOCC3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 98 %

Procedure:
Tetrahydropyran-4-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27 (a) from tetrahydropyran-4-yl-methanol (223 mg), pyridine (0.17 ml) and trifluoromethanesulfonic acid anhydride (596 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4 -yl) -2 -trityloxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (700 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27(b), followed by reacting the resulting reaction product with the tetrahydropyran-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27 (b).The reaction solution so obtained was post-treated in the same manner as in Example 27 (b) and the produced compound was recovered and purified similarly to Example 27 (b) to afford the titled compound (722 mg; 98%).