Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C:7]([N:9]([C:11]1[C:12]([Cl:31])=[C:13]([C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)[CH3:10])=[O:8])=[O:4].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1)([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:31][C:12]1[C:11]([N:9]([CH3:10])[C:7](=[O:8])[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:44]2[CH2:45][CH2:46][N:41]([C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=3)[CH2:42][CH2:43]2)=[CH:29][CH:28]=[C:27]([Cl:30])[C:13]=1[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CBr)c3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCN(c5ccc([N+](=O)[O-])cc5)CC4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
A mixture of 8-[3-[N-(bromoacetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (90 mg), 4-nitro-1-(1-piperazinyl)benzene (48 mg) and potassium carbonate (94 mg) in dimethylformamide (2 ml) was stirred at ambient temperature for 1 hour and water added thereto. The mixture was extracted with ethyl acetate twice, and the combined organic layer was washed with water, dried and concentrated. The residue was purified by preparative thin-layer chromatography (10% methanol in dichloromethane) to give 8-[2,6-dichloro-3-[N-methyl-N-[2-[4-(4-nitrophenyl)piperazin-1-yl]acetylglycyl]amino]benzyloxy]-2-methylquinoline (44 mg).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:15])=[N:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)(=O)C.N>CO>[Cl:15][C:9]1[C:8]2[C:13](=[CH:14][C:5]([OH:4])=[CH:6][C:7]=2[O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:12]=[CH:11][N:10]=1
Reactant: CC(=O)Oc1cc(OC2CCCC2)c2c(Cl)ncnc2c1
Agent: N
Solvent: CO
Product: Oc1cc(OC2CCCC2)c2c(Cl)ncnc2c1
Yield: 77.6 %

Procedure:
A mixture of 7-acetoxy-4-chloro-5-cyclopentyloxyquinazoline (1 g), a saturated methanolic ammonia solution (10 ml) and methanol (10 ml) was stirred at ambient temperature for 30 minutes. The mixture was evaporated and the residue was triturated under water. The resultant solid was isolated, washed with water and dried under vacuum to give 4-chloro-5-cyclopentyloxy-7-hydroxyquinazoline (0.67 g); NMR Spectrum: (DMSOd6) 1.6–1.75 (m, 2H), 1.75–1.85 (m, 2H), 1.85–2.05 (m, 4H), 5.0 (m, 1H), 6.72 (d, 1H), 6.8. (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 265.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C:7]([N:9]2[C@@H:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[C:13](=[O:19])[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[H-].[Na+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.O>CN(C)C=O>[C:4]1(=[O:24])[N:5]([CH2:6][C:7]([N:9]2[C@@H:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[C:13](=[O:19])[N:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:1](=[O:29])[C:2]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:3]12
Reactant: ClCc1ccccn1
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)[C@@H]2CCC[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccn2)C(=O)[C@H]2CCC[C@H]21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
In a mixture of water (0.5 mL) and ethyl acetate (1 mL)was dissolved 2-(chloromethyl)pyridine hydrochloride (246 mg, 1.5 mmol). This solution was neutralized with the addition of sodium hydrogencarbonate. The organic layer was separated, and the remaining aqueous layer was subjected to extraction twice with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, followed by concentration under reduced pressure to give 2-(chloromethyl)pyridine. To a suspension of (3aR*,10aS*)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (389 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL), which was cooled to 0° C., was added sodium hydride (60% liquid paraffin dispersion, 44 mg, 1.1 mmol). The mixture was stirred for 3 minutes at the same temperature and for 10 minutes at room temperature. To this mixture was added a solution of the 2-(chloromethyl)pyridine, which was produce by the above-mentioned procedure, in N,N-dimethylformamide (0.5 mL). The mixture was stirred for 3 hours at room temperature. To the reaction mixture was added water, and resulting precipitate was collected by filtration, which was recrystallized from chloroform-ethanol-diisopropylether to give 232 mg (yield 48%) of the titled compound, m.p. 227°-229° C.
Reaction SMILES: [OH:1][CH:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[C:5](=[O:17])[C:4]2[S:18][CH2:19][CH2:20][S:21][C:3]1=2.[H-].[Na+].Cl[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26].C>CN(C)C=O.C(#N)C>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:17][CH:5]2[N:6]([C:7]3[CH:16]=[CH:15][C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)[C:2](=[O:1])[C:3]3[S:21][CH2:20][CH2:19][S:18][C:4]2=3)=[O:26])[CH2:28][CH2:29]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2cccnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3cccnc3n2)CC1
Temperature: 0 °C
Yield: 49.1 %

Procedure:
5-Hydroxy-6-(1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (8.45 g.) is added, at 0°C, to a suspension of sodium hydride (0.8 g.) in anhydrous dimethylformamide (125 cc.). The reaction mixture is stirred for half an hour at 0°C, and 1-chlorocarbonyl-4-methylpiperazine (8.45 g.) dissolved in anhydrous dimethylformamide (50 cc.) is then added. After stirring for two and a half hours at 5°C., the reaction mixture is diluted with ice-water (500 cc.). The precipitate which has appeared is filtered off, washed four times with distilled water (total 200 cc.) and twice with diethyl ether (total 50 cc.) and then dissolved in methylene chloride (300 cc.). The organic solution is washed four times with distilled water (total 160 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.2 g.) and evaporated. When the residual liquid reaches a volume of 50 cc., boiling acetonitrile (200 cc.) is added. After cooling for two hours at 2°C., the crystals which have appeared are filtered off, washed three times with ice-cold acetonitrile (total 15 cc.) and dried under reduced pressure (20 mm. Hg). The crystals thus isolated (8.0 g.) are dissolved in boiling acetonitrile (270 cc.), decolourising charcoal (0.2 g.) is added to the boiling solution and the whole is filtered. After twenty-four hours at 2°C., the crystals which have appeared are filtered off, washed three times with ice-cold acetronitrile (total 10 cc.) and dried under reduced presssure (20 mm. Hg). 5-(4-Methylpiperazin-1-yl)carbonyloxy-6-(1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (5.8 g.), melting at 255°C., is thus obtained.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(CC)CC>CCO>[CH3:37][C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][NH:24][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[CH2:14][C:15]([F:16])([F:18])[F:17])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22])=[O:32])([CH3:35])[CH3:36]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (130 mg, 0.373 mmol) and (S)-2-aminomethyl-1-Boc-pyrrolidine (82 mg, 0.410 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.559 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 165 mg (84%); 1H NMR (CDCl3) 1.47 (brs, 9H), 1.83 (m, 1H), 1.90 (m, 2H), 2.03 (m, 1H), 3.31 (m, 1H), 3.37 (m, 2H), 3.62 (m, 1H), 4.09 (m, 2H), 4.24 (m, 6H), 7.26 (m, 1H), 7.50 (m, 1H), 8.27 (s, 1H), 8.55 (brs, 1H); MS (ESI) 529.38 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:1]([C:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)CC(=O)OCC
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCC(=CC(=O)OCC)Nc1ccccc1

Procedure:
A solution of aniline (6 mmol), ethyl 3-oxodecanoate (6 mmol) and toluene-p-sulfonic acid (50 mg) in dry toluene (60 ml) was heated under reflux for 24 hours using Dean-Stark apparatus for the azeotropic removal of water. The solvent was removed in vacuum to afford the title product as an oil which was used without purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C@H:29]([CH3:30])[CH2:28][N:27]([C:31](=[O:34])[CH2:32]Br)[C@@H:26]([CH3:35])[CH2:25]2)=[C:20]([CH:36]=[CH:37][CH3:38])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH2:44][CH2:43][O:42][C:41]2[CH:45]=[C:46]([C:49]3([CH3:56])[NH:53][C:52](=[O:54])[NH:51][C:50]3=[O:55])[CH:47]=[CH:48][C:40]1=2>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:29]([CH3:30])[CH2:28][N:27]([C:31](=[O:34])[CH2:32][N:51]3[C:50](=[O:55])[C@@:49]([C:46]4[CH:47]=[CH:48][C:40]5[O:39][CH2:44][CH2:43][O:42][C:41]=5[CH:45]=4)([CH3:56])[NH:53][C:52]3=[O:54])[C@H:26]([CH3:35])[CH2:25]2)=[C:20](/[CH:36]=[CH:37]\[CH3:38])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@H](C)N(C(=O)CBr)C[C@H]1C
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1C[C@@H](C)N(C(=O)CN2C(=O)N[C@@](C)(c3ccc4c(c3)OCCO4)C2=O)CC1C

Procedure:
1-((2S,5R)-4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl) phenyl}-2,5-dimethylpiperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH:30]([C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[O:45][CH3:46])[CH2:35][CH2:34]1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10](S(C2C=CC=CC=2)(=O)=O)[CH:9]=1)=[O:7].[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH:30]([C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[O:45][CH3:46])[CH2:35][CH2:34]1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:7]
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)ccc1OC(CCN1CCN(c2ccccc2OC)CC1)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)c2c[nH]c3ccccc23)ccc1OC(CCN1CCN(c2ccccc2OC)CC1)c1ccc(C)cc1
Yield: 93.5 %

Procedure:
3-{3-Methoxy-4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}-1-(phenylsulfonyl)indole (0.49 g) obtained in Step 4 was dissolved in methanol (10 ml). Potassium hydroxide (0.60 g) was added to the resultant solution and refluxed for 1 hour. After cooling, the solvent was distilled off. Water was added to the residue, followed by extraction with methylene chloride. The extract was washed with brine and then dried. The solvent was distilled off, obtaining 0.37 g of 3-{3-methoxy-4-{l-(4-methylphenyl)-3-[4-(2-methoxyphenyl) piperazin-1-yl]propoxy}benzoyl}indole as a light yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:19]=[CH:20][C:21]2[N:26](O)[N:25]=[N:24][C:22]=2[CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([O:17][N:24]2[C:22]3[CH:23]=[CH:18][CH:19]=[CH:20][C:21]=3[N:26]=[N:25]2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)On1nnc2ccccc21
Reaction time: 24 h
Yield: 84.6 %

Procedure:
Boc-Py-acid, 4-[(tert-Butoxycarbonyl)amino]-1-methylpyrrole-2-carboxylic acid (31 g, 129 mmol) was dissolved in 500 mL DMF, HOBt (17.4 g, 129 mmol) was added followed by DCC (34 g, 129 mmol). The reaction was stirred for 24 h and then filtered dropwise into a well stirred solution of 5 L of ice water. The precipitate was allowed to sit for 15 min at 0° C. and then collected by filtration. The wet cake was dissolved in 500 mL DCM, and the organic layer added slowly to a stirred solution of cold petroleum ether (4° C.). The mixture was allowed to stand at −20° C. for 4 h and then collected by vacuum filtration and dried in vacuo to provide (39 g, 85% yield) of 1,2,3-Benzotriazol-1-yl 4-[(tert-butoxycarbonyl)-amino]-1-methylpyrrole-2-carboxylate as a finely divided white powder. TLC (7:2 benzene/ethyl acetate v/v) Rf 0.6, 1H NMR (DMSO-d6) δ9.43 (s, 1H) , 8.12 (d, 1H, J=8.4 Hz), 7.80 (d, 1H, J=8.2Hz), 7.64 (t, 1H, J=7.0 Hz), 7.51 (m, 2H), 7.18 (s, 1H), 3.83 (s, 3H), 1.45 (s, 9H) , 13C NMR (DMSO-d6) δ156.5, 153.3, 143.2, 129.6, 129.2, 125.7, 125.2, 124.6, 120.3, 112.8, 110.3, 109.8, 79.5, 36.8, 28.6.; IR (KBr) 3246, 3095, 2979, 1764, 1711, 1588, 1389, 1365, 1274, 1227, 1160, 1101, 999, 824, 748.; FABMS mle 358.152 (M+H 358.151 calc. for C17H20N5O4)
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[CH2:20]([S:24][CH:8]1[CH2:9][C:10](=[O:12])[CH:11]2[CH:6]([C:5]3([Cl:17])[C:14]([Cl:15])([Cl:16])[C:2]2([Cl:1])[C:3]([Cl:19])=[C:4]3[Cl:18])[C:7]1=[O:13])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCS
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: c1ccccc1
Product: CCCCSC1CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reaction time: 24 h

Procedure:
20 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 1, were dissolved in 60 ml. of benzene and then 10 g. of n-butylmercaptan and a few crystals of ferric chloride were added. This reaction mixture was shaken for 24 hours (Parr shaker). When the benzene was evaporated a white solid was obtained. One recrystallization from benzene-Skelly B mixture yielded white crystals, m.p. 97°-98° C. The infrared spectrum showed strong carbonyl at 1750 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[O:10])[CH:7]=1.[H-].[Na+].O.CN([CH:37]=[O:38])C>>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH2:20][CH2:21][C:25]([O:38][CH3:37])([CH3:26])[CH3:29])[C:12]2=[O:16])=[O:10])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCNC4=O)cc3Cl)ccn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(C)(C)CCN1CCN(C(=O)Nc2cc(Cl)c(Oc3ccnc(-c4cnn(C)c4)c3)cc2F)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A 0° C. solution of Example C9 (0.350 g, 0.812 mmol) in DMF (5 mL) was treated with NaH (60% in mineral oil, 0.100 g, 2.50 mmol), stirred at RT for 0.5 h, treated with Example C4 (0.500 g, 1.836 mmol) and stirred at RT overnight. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxy-3-methylbutyl)-2-oxoimidazolidine-1-carboxamide (128 mg, 28%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.38 (m, 2 H), 8.26 (s, 1 H), 7.97 (d, J=0.7 Hz, 1 H), 7.57 (d, J=11.3 Hz, 1 H), 7.20 (d, J=2.5 Hz, 1 H), 6.64 (dd, J=5.7, 2.5 Hz, 1 H), 3.84 (s, 3H), 3.80 (m, 2 H), 3.48 (t, J=8.2 Hz, 2 H), 3.28 (m, 2 H), 3.09 (s, 3 H), 1.70 (m, 2 H), 1.11 (s, 6H); MS (ESI) m/z: (M+H+): 531.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:14]([F:13])=[CH:15][C:16]=2[C:24]([F:27])([F:25])[F:26])[O:20][CH3:21])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(F)cc1C(F)(F)F
Product: CON(Cc1ccc(F)cc1C(F)(F)F)C(=O)C=C1OC(C)(C)OC1=O
Yield: 98 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-fluoro-2-trifluoromethyl-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (98% yield): mp 129-130° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.69 (3H, s, OCH3), 5.04 (2H, s, NCH2), 6.45 (1H, s, CH), 7.21 (1H, m, aromatic), 7.37 (1H, m, aromatic), 7.47 (1H, m, aromatic). Anal. calcd for C16H15F4NO5: C, 50.94; H, 4.01; N, 3.71. Found: C ,50.96; H, 4.07; N, 3.66.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:35]([N:17]1[CH2:18][C@@H:14]([N:12]2[N:11]=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:13]2)[CH2:15][C@H:16]1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[CH2:25][CH2:26]1)=[O:20])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccccc2)CC1
Reaction time: 0.33 h
Yield: 2069 %

Procedure:
2-(4-{4-[5-(2,4-Difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (0.136 g, 0.29 mmol), benzaldehyde (0.034 g, 0.32 mmol) and acetic acid (cat) was dissolved in DCM (20 ml) and the solution was stirred for 20 min. Then NaBH(OAc)3 (0.12 g, 0.58 mmol) was carefully added. The resulting mixture was warmed to r.t and stirred overnight. The solution was then washed with sat NaHCO3, brine, dried and concentrated to afford the title product as yellow oil (0.15 g, 6 mmol). MS m/e=555.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]([C@H:13]1[N:16]([CH:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:15](=[O:36])[C@@H:14]1[C@H:37]([O:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH3:38])=[CH2:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C.[Ni](Cl)Cl>[CH2:1]([O:8][C:9]([CH:11]([C@H:13]1[N:16]([CH:17]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:15](=[O:36])[C@@H:14]1[C@H:37]([O:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH3:38])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C(=O)OCc1ccccc1)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2C(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3S,4S)-4-(1-benzyloxycarbonylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (63 mg) in methanol (1.5 ml) was treated with sodium borohydride (7.7 mg) in the presence of nickel chloride (1.3 mg) at 0°-5° C. for 15 minutes. After stirring at room temperature for an additional 1 hour, the reaction mixture was diluted with ethyl acetate (30 ml), washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by thin-layer chromatography (SiO2) to yield (3S,4S)-4-(1-benzyloxycarbonylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[O:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43][NH:44][CH2:45][CH3:46]>CN(C=O)C>[CH2:45]([N:44]([CH2:43][CH:39]1[CH2:40][CH2:41][CH2:42][O:38]1)[C:15]1[C:16]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1)[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CCNCC1CCCO1
Solvent: CN(C)C=O
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (350 mg, 0.65 mmol, example 1b) was dissolved in DMF (2 mL). N-((tetrahydrofuran-2-yl)methyl)ethanamine (84 mg, 0.65 mmol) was added and the reaction was stirred at 80° C. overnight. The solvent was evaporated under reduced pressure and the crude was used as such in the subsequent step.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)=[N:9][CH:10]=1)=[NH:4].CN([CH:29]=[O:30])C.ClC(OC)=O>N1C=CC=CC=1>[O:30]=[C:29]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([N:11]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]4)=[N:9][CH:10]=2)[NH:4]1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(C(=N)NO)cn1
Reactant: CN(C)C=O
Agent: COC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(-c2noc(=O)[nH]2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of the compound from step c) is placed in a round-bottomed flask under a stream of nitrogen, and 10 ml of DMF and 0.3 ml of pyridine are added. 0.23 ml of methyl chloroformate is added at 0° C., and the mixture is stirred at room temperature for 3 hours. The resulting mixture is washed with water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 30 ml of toluene are added and the resulting mixture is stirred at reflux for 4 hours. The solvent is evaporated off to give 0.8 g of the title compound.