Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:37][N:5]2[C:6]3[C:11]([N:12]([C:14](=[O:36])[C:15]4[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:17][CH:16]=4)[CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:38](O)(=[O:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:38]([O:1][C@@H:2]1[CH2:37][N:5]2[C:6]3[C:11]([N:12]([C:14](=[O:36])[C:15]4[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:35])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:19][CH:20]=4)[CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:40])[CH3:39]
Reactant: CC(=O)O
Reactant: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@@H](O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3N2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of (2R,3aS)-2-hydroxy-5-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline (0.8 g) prepared in Example 3, acetic acid (0.15 g) and triphenyl phosphine (0.64 g) in anhydrous tetrahydrofuran (5 ml), there was gradually dropwise added a solution of diisopropyl azodicarboxylate (0.49 g) in anhydrous tetrahydrofuran (2 ml) under ice-cooling. After stirring the reaction solution at room temperature for 2 hours, it was concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with hexane/ethyl acetate (1/1) to give 0.66 g (yield 76.0%) of the title compound as amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:18]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:14][C@@H:13]([CH3:16])[CH2:12][N:7]2[C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(F)cc32)CC1
Yield: 58 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF04)_(0.873 g, 2.50 mmol) and 4-Butylpiperidine (0.371 g, 2.63 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF08) (0.53 g, 58%). 1H NMR (CDCl3) d 7.01 (d, J=10.0 Hz, 1H), 6.92-6.88 (m, 1H), 6.68-6.64 (m, 1H), 5.57 (q, J=32.4 Hz, J=15.2 Hz, 2H), 4.02-3.83 (m, 2H), 2.92-2.70 (m, 2H), 2.23-2.10 (m, 2H), 2.04-1.97 (m, 2H), 1.81 (t, J=10.8 Hz, 1H), 1.72-1.61 (m, 2H), 1.36-1.19 (m, 9H), 0.90-0.88 (m, 6H); 13C NMR (CDCl3) d 164.8, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.3 Hz), 130.0 (d, J=10.4 Hz), 117.6 (d, J=9.6 Hz), 109.4 (d, J=23.1 Hz), 103.5 (d, J=29.3 Hz), 67.8, 64.1, 56.0, 54.3, 45.7, 36.5, 36.0, 33.0, 32.5, 29.5, 29.2, 23.1, 17.1, 14.3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1C(=O)N([Br:22])C(=O)C1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[N:6][C:7]=1[Br:22]
Reactant: Nc1cnc(C2CCC(=O)NC2)cn1
Reactant: O=C1CCC(=O)N1Br
Product: Nc1ncc(C2CCC(=O)NC2)nc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-(5-aminopyrazin-2-yl)piperidin-2-one (25 mg, 0.13 mmol) acetonitrile (10 mL) solution at 0° C. was added NBS (23.2 mg, 0.13 mmol) and the reaction mixture was stirred at 0° C. for 30 min, then at room temperature for 4 h. The reaction mixture was concentrated, and the residue was basified by 1 N NaOH (140 ul), diluted with methanol (2 mL), concentrated. The residue was triturated with EtOAc (3×1 mL), and the EtOAc supernatants were collected, combined and concentrated and a light solid was obtained as crude 5-(5-amino-6-bromopyrazin-2-yl)piperidin-2-one which was used in next step without further purification. LCMS (m/z): 241/243 (MH+), 0.41 min.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.[C:28]1([CH2:34][C:35](Cl)=[S:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:35](=[S:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:5]2[S:4]1
Reactant: S=C(Cl)Cc1ccccc1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Temperature: -15 °C
Yield: 90.2 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.0 g) was suspended in dried dichloromethane (50 ml) and then dissolved by adding triethylamine (0.72 g) and dimethylamiline (1.9 g) under cooling at -15° C. To a mixture was dropwise added a solution of phenylthioacetyl chloride (2.2 g) in dried dichloromethane (10 ml) under stirring, and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, ether was added to the residue, after which the precipitated crystals were collected by filtration and dried to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (3.4 g), mp 140° to 142° C.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:25])[C:6]1=[O:29]
Reactant: C[C@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo -1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-1-amino-2-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.28 (1H, t, J=5 Hz), 8.50 (1H, s), 7.75 (1H, s), 7.31 (2H, m), 7.12 (2H, m), 5.12 (2H, m), 4.94 (1H, d, J=5 Hz), 4.11 (2H, s), 3.78 (1H, m), 3.40 (1H, m), 3.18 (1H, m), 3.12 (3H, s), 2.82 (3H, s), 1.07 (3H, d, J=6 Hz); HRMS calcd for C23H25FN4O5+H+: 457.18817. Found: 457.18875.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:4].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:12]=1
Reactant: OCCCCCCCl
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 90 °C
Reaction time: 32 h
Yield: 71.9 %

Procedure:
Methyl 4-hydroxy cinnamate (40 g, 225 mmol) was dissolved in 1-methyl-2-pyrrolidinone (NMP, 300 mL). 6-Chlorohexanol (269 mmol, 36.8 g), anhydrous K2CO3 (37.2 g, 269 mmol) and catalytic amount of KI were added. The batch was stirred at 90° C. for 32 hours. Water was added to the cooled solution, which was subsequently extracted with ethyl acetate (EtOAc, 3×200 mL). The combined organics were washed with 10% KOH (2×100 mL), brine solution and then dried over MgSO4. The concentrated product was then recrystallized from a 1:1 mixture of EtOAc/hexanes to give 45 g (72% yield) of an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:30])[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[CH2:13][CH2:12][CH2:11]2.[ClH:31]>CO>[ClH:31].[ClH:31].[NH:20]1[CH2:21][CH2:22][CH:18]([N:14]2[C:15]3[C:10](=[CH:9][C:8]([NH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[NH:30])=[CH:17][CH:16]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(NC(=N)c4cccs4)ccc32)C1
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)CCCN2C1CCNC1)c1cccs1
Temperature: 90 °C

Procedure:
A solution of tert-butyl 3-(6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (Isomer 1) (520 mg, 1.219 mmol) in MeOH (26 ml) was treated with 3N HCl (4.06 ml, 12.19 mmol) then heated at 90° C. for 30 minutes. After cooling, the mixture was concentrated to dryness and dried under reduced pressure overnight. The solid was triturated with 5% isopropanol/95% hexanes (50 mL), collected and dried under reduced pressure (450 mg, 92%). ESI-MS (m/z, %) 327.2 (MH+, 65%), 258.1 (100%); ESI-HRMS calculated for C18H23N4S (MH+), Calculated: 327.1637; Observed: 326.1650; Chemical purity: 97.7%; Optical Rotation: 25[α]589=−0.19°, c=1.05 in MeOH.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16](OC1C=CC=CC=1C(Cl)=O)(=[O:18])[CH3:17]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Product: CC(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1
Yield: 58 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 2-acetoxybenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (15 then 25%) as eluant to afford product as a tan colored solid (80 mg, 58%). 1H NMR (CDCl3) 2.39 (d, J=1.3, 3 H), 3.62 (s, 3 H), 7.57 (d, J=4.0, 1 H), 7.74 (d, J=4.0, 1 H). 19F NMR −63.1. LC/MS 7.82 min, [M+1]+ 276.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([O:13][CH3:14])[CH:5]=1)([O-:3])=[O:2].Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:12][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:8]([O:10][CH3:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1O
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCCN1CCCC1

Procedure:
1-[2-(4-nitro-2,6-dimethoxyphenoxy)ethyl]pyrrolidine was prepared from 4-nitro-2,6-dimethoxyphenol [R F Collins and M Davis, J. Chem. Soc. 1863, (1961)] (0.4 g, 2.39 mmol), 1-(2-chloroethyl)pyrrolidine (612 mg, 0.36 mmol) and caesium carbonate (2.3 g, 0.72 mmol) to give the desired product as a brown oil (232 mg). MS (ES+) 297 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].Cl.[CH2:31]([O:38][CH2:39][CH2:40][CH:41]([NH:43][CH:44]([CH3:46])[CH3:45])[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][CH2:39][CH2:40][CH:41]([N:43]([CH:44]([CH3:46])[CH3:45])[C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:25][CH:24]=1)[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)NC(C)CCOCc1ccccc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)Cl)cc1)=N[C@@H]1CCN(C)C[C@H]21
Agent: Cl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)CCOCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoyl chloride and rac-N-(3-benzyloxy-1-methyl-propyl)-N-isopropyl-amine hydrochloride as described for example 9.
Reaction SMILES: [CH2:1]([N:3]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([O:29][CH3:30])=[O:28])[C:18]=1[CH3:31])[CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[CH3:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[CH2:1]([N:3]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[C:17]1[C:18]([CH3:31])=[C:19]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of tert-butyl 4-{ethyl[3-(methoxycarbonyl)-2-methyl-5-(trifluoromethyl)phenyl]amino}piperidine-1-carboxylate (4.50 g, 10.1 mmol) in CH2Cl2 (50 mL) was added TFA (5 mL). The reaction mixture was stirred at rt for 18 hours. Then reaction mixture was concentrated in vacuo to give the titled compound as a crude product (7.70 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:16]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:15])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:6]=1.B1([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:34]=2)OC(C)(C)C(C)(C)O1>>[NH2:16][C:4]1[S:3][C:2]([C:37]2[CH:38]=[CH:33][CH:34]=[C:35]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:36]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:15]
Reactant: Cn1cc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)cn1
Reactant: CC1(C)OB(c2cccc(CN3CCOCC3)c2)OC1(C)C
Product: Cn1cc(NC(=O)c2nc(-c3cccc(CN4CCOCC4)c3)sc2N)cn1
Yield: 36 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and 3-(4-morpholinomethyl)phenylboronic acid pinacol ester gave 356 as an off-white solid (31 mg, 36% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.80 (s, 1H), 7.98 (s, 1H), 7.80-7.73 (m, 2H), 7.65 (s, 1H), 7.49-7.38 (m, 3H), 7.35 (d, J=7.6 Hz, 1H), 3.82 (s, 3H), 3.60 (t, J=4.5 Hz, 4H), 3.53 (s, 2H), 2.45-2.33 (m, 4H). LCMS (ES+) m/z 399 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][CH2:11][CH:12]=O.C(N(CC)CC)C.Cl.[CH3:22][O:23][NH2:24]>CO>[CH3:22][O:23][N:24]=[CH:12][CH2:11][CH2:10][C:3]1[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CON
Reactant: O=CCCc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=CCCc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Yield: 104.2 %

Procedure:
To a solution of 3-(2,4,6-trichloro-phenyl)-propionaldehyde (0.45 g, 1.8 mmol) in methanol (5 ml), triethylamine (0.4 ml, 2.8 mmol) followed by O-methylhydroxylamine-hydrochloride (0.24 g, 2.8 mmol) was added and the mixture was heated at 60° C. for 2 hours. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature and quenched with water and methanol was removed with a rotavapor. The resulting aqueous solution was extracted with ethyl acetate (3×30 ml). The combined ethyl acetate layers were washed with water and dried over sodium sulfate before complete evaporation of the solvents to give the crude mass. The resulting crude mass was purified over column chromatography (silica gel 60-120 mesh, 1% ethyl acetate in hexane) to afford 3-(2,4,6-trichloro-phenyl)-propionaldehyde O-methyl-oxime (0.5 g, 80%)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[CH3:30][CH:31]([CH3:33])[CH:32]=[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)[C:20]([OH:22])=[O:21]
Reactant: C=C(C)CBr
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)C=C(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to −78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and cooling to −78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at −78° C. for 1 h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)−.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1)[CH:11]=2.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[ClH:2].[ClH:1].[ClH:2].[CH2:26]([N:28]([CH2:29][CH3:30])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:18]([CH2:19][CH3:10])[CH2:17][CH3:16])[CH:16]=1)[CH:11]=2)[CH3:27]
Reactant: CCNCC
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Agent: Cl
Product: CCN(CC)CCCOc1ccc2cc3ccc(OCCCN(CC)CC)cc3nc2c1
Temperature: 100 °C

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and diethylamine as described in Example 15 except that the mixture is heated at 100° C. for 24 hours, giving 1.5 g. of the desired product as yellow crystals, m.p. 235°-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=O)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C([O:36][CH2:37][CH2:38][O:39][NH2:40])(=O)C.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[N:40][O:39][CH2:38][CH2:37][OH:36])[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(=O)OCCON
Reactant: CC#CC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC#CC(=NOCCO)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
4-(3-Cloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (VII-4, 10 g) was dissolved in 300 ml of 1,4-dioxane, 1.5 equivalent of 2-(acetoxy)ethoxyamine was added, and 28 ml of 2 mol/L aqueous methanesulfonic acid solution was added, followed by stirring at 60° C. for 17 hours. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate. The residue obtained by concentrating the filtrate was recrystallized from hydrous ethanol-water, filtered, and dried to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VIII-33, 7.6 g) as a colorless solid.
Reaction SMILES: F[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[NH:3]1.C(O)(=O)CCC(O)=O.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][O:25][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:8][C:4]1[N:3]=[N:2][C:7]([N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=3)[CH2:21][CH2:22]2)=[CH:6][CH:5]=1
Reactant: FC1=CC=CN(F)N1
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCC2CCN(c3ccc(F)nn3)CC2)cc1
Yield: 64.3 %

Procedure:
A mixture 1.2 parts of 2,6-difluoropyridazine, 4 parts of ethyl 4-[2-(4-piperidinyl)-ethoxy]benzoate butanedioate(1:1), 5.3 parts of sodium carbonate and 141 parts of N,N-dimethylformamide was stirred for 48 hours at 60° C. After cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.4 parts (64.3%) of ethyl 4-[2-[1-(6-fluoro-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 131.9° C. (comp. 73).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[C:13]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[C:2]([CH:11]=[O:12])[CH:3]=[CH:4]2)#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCCCCCC
Reactant: O=Cc1ccc2ccccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1ccc2nc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A solution of 6-bromo-2-(quinolinecarboxaldehyde (18.9 g), 1-decyne (12.2 g) and triethylamine (24.3 g) in dry tetrahydrofuran (300 ml) was chilled to 5° C. and degassed, under nitrogen. bis(Triphenylphosphine)palladium (II) chloride (0.56 g) and copper (I) iodide (0.08 g) were added to the reaction mixture, which was degassed and stirred under nitrogen at room temperature for 30 mins, and then heated at 40° C. for 19 hrs. The mixture was cooled to room temperature, the precipitate was filtered, and the filter cake was washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane:2% ethyl acetate. The appropriate fractions were collected and evaporated. A 2 g-portion of the residue (23.4 g) was chromatographed, eluting with hexane:dichloromethane/2:1 give 1.3 g (64.0%) of product, mp 46.5°-47.5° C.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O.C(OCC)(=O)C>[Si:20]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CO
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
To a solution of 1,2-benzenedimethanol (2 g) and imidazole (1.13 g) in N,N-dimethylformamide (30 mL) was added tert -butyldimethylchlorosilane (2.08 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/2) to give the title compound (1.46 g).