Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:39]([OH:41])=[O:40])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(CC)CC)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)C(=O)N1CC(NC(=O)Nc2cccc(C(=O)O)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 69.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-ethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (510 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxide monohydrate (175 mg) solution (12 ml) and tetrahydrofuran (12 ml) were added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, isopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 339 mg of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.Cl[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:18][CH2:17][N:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1=[O:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCNC(=O)C1
Product: CC(C)(C)OC(=O)N1CCCN(COCc2ccccc2)C(=O)C1

Procedure:
The title compound was prepared from tert-butyl hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate (Example 2, Step B) and benzyl chloromethyl ether essentially following the method described in Example 2, Step C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[Na+].[Na+].O>CC(CC(C)C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:37][C:38]#[N:39])[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: N#CCN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccccc3)C2)CC1
Yield: 53.2 %

Procedure:
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine (0.0127 mol), chloroacetonitrile (0.013 mol) and sodium carbonate (0.013 mol) in methylisobutyl keton (100 ml) was stirred and refluxed. The mixture was cooled and water was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5 and 99/1). The pure fractions were collected and the solvent was evaporated, yielding 3.64 g (53%) of (±)-cis-1-[3,5-bis (trifluoromethyl)benzoyl]-4-[4-(cyanomethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (intermediate 6).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: Cc1ccc(CC(=O)O)cn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccc(C)nc3)nc12

Procedure:
From (6-methyl-pyridin-3-yl)-acetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+22.8° (c=1.06, CHCl3), ES-MS m/e (%): 400 (M+H+, 100).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][OH:27])[CH2:23][O:22]1.O[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][O:27][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)[CH2:23][O:22]1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2ccc(C=O)cc2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
39.3 g (150 mmol) of triphenylphosphine are added to a solution of 13.2 g (100 mmol) of 1,2-O-isopropylideneglycerol in 250 ml of dry THF, and the mixture is stirred at RT for 30 min. The mixture is cooled to about 0° C., and 12.2 g (100 mmol) of 4-hydroxybenzaldehyde and 31.9 g (150 mmol) of diisopropyl azodicarboxylate (DIAD) are added. The yellow reaction solution is stirred at RT for 16 h. The mixture is then concentrated using a rotary evaporator, and the residue is added to 150 ml of sat. sodium bicarbonate solution. The mixture is extracted with ethyl acetate (three times, 150 ml each), and the combined organic phases are dried over sodium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane→cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C(O)(=O)C>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]2[O:5][C:3]([CH3:4])=[C:2]([CH3:1])[N+:6]=2[O-:7])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)C(C)=NO
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(Br)cc2)[n+]([O-])c1C
Yield: 74.1 %

Procedure:
A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and 4-bromobenzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) was cooled to 0° C. and then gaseous HCl was bubbled through the solution for 35 min while the reaction was stirred in an ice bath. Diethyl ether (500 mL) was then added to the reaction to precipitate the product and the resultant slurry stirred 45 min at 0° C. before being filtered. The solids were rinsed with Et2O (50 mL), taken up in water (1 L) and conc. NH4OH (60 mL) added to the slurry. This mixture was extracted with CHCl3, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give 97.4 g (74%) of 2-(4-bromophenyl)-4,5-dimethyloxazole-3-oxide as a white solid. The compound should be used directly with 24-48 h: 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=9.0 Hz, 2H), 7.61 (d, J=9.0 Hz, 2H), 2.35 (s, 3H), 2.20 (s, 3H); 13C (125 MHz, CDCl3) δ 142.1, 131.9, 129.5, 126.3, 124.1, 122.2, 11.1, 6.2; IR (KBr) 1685, 1529, 1418, 1377, 1233, 1165 cm−1; UV (EtOH) λmax 307 nm (ε 24371); HRMS (TOF) m/z calc'd for C11H1179BrNO2: 267.997, found 267.9951.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCOCC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and morpholine to afford a white powder. HPLC (Condition 4) tR=5.62 min, UPLC-MS (Condition 3) tR=1.03 min, m/z=450 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.14 (d, J=1.17 Hz, 4H) 3.55-3.68 (m, 4H) 6.71 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.87 (d, J=8.99 Hz, 3H) 8.34 (br. s, 1H) 8.75 (s, 1H) 10.41 (br. s, 1H) 13.04 (br. s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:24]Br.CS(C)=[O:28]>CC(=O)OCC.O>[Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:28]
Reactant: CS(C)=O
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(CBr)c(Br)sc21
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Temperature: 50 °C
Yield: 33.8 %

Procedure:
To a solution of 6-bromo-5-(bromomethyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.7 g, 3.43 mmol) in DMSO (20 mL) was added IBX (1.92 g, 6.85 mmol). The reaction was heated at 50° C. for 2 h, cooled to RT then diluted with EA (80 mL) and water (50 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1) to give 6-bromo-1-methyl-2,4-dioxo-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (500 mg, 33.8% yield) as a yellow oil. LCMS: MH+ 431 and TR=1.313 min.
Reaction SMILES: [Cl-].C([O:6][C:7](=[O:94])[CH2:8][C@@H:9]([C:77](=[O:93])[NH:78][C@@H:79]([CH2:87][O:88]C(C)(C)C)[C:80](=[O:86])[O:81]C(C)(C)C)[NH:10][C:11](=[O:76])[CH2:12][NH:13][C:14](=[O:75])[C@H:15]([CH2:51][CH2:52][CH2:53][NH:54][C:55]([NH:57]S(C1C(C)=C(C)C2OC(C)(C)CC=2C=1C)(=O)=O)=[NH:56])[NH:16][C:17](=[O:50])[CH2:18][CH2:19][C:20](=[O:49])[O:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[O+:27]=[C:26]2[C:36]([C:39]3[CH:48]=[CH:47][C:42]4[O:43][CH2:44][CH2:45][O:46][C:41]=4[CH:40]=3)=[CH:37][S:38][C:25]=12)(C)(C)C.O.C([SiH](C(C)C)C(C)C)(C)C.[F:106][C:107]([F:112])([F:111])[C:108]([OH:110])=[O:109]>C(OCC)C>[F:106][C:107]([F:112])([F:111])[C:108]([O-:110])=[O:109].[C:80]([C@H:79]([CH2:87][OH:88])[NH:78][C:77](=[O:93])[C@H:9]([CH2:8][C:7]([OH:94])=[O:6])[NH:10][C:11](=[O:76])[CH2:12][NH:13][C:14](=[O:75])[C@H:15]([CH2:51][CH2:52][CH2:53][NH:54][C:55]([NH2:57])=[NH:56])[NH:16][C:17](=[O:50])[CH2:18][CH2:19][C:20](=[O:49])[O:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[O+:27]=[C:26]2[C:36]([C:39]3[CH:48]=[CH:47][C:42]4[O:43][CH2:44][CH2:45][O:46][C:41]=4[CH:40]=3)=[CH:37][S:38][C:25]=12)([OH:86])=[O:81]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CCC(=O)OCOc2cc(N3CCOCC3)[o+]c3c(-c4ccc5c(c4)OCCO5)csc23)C(=O)NCC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)C2
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)CCC(=O)OCOc1cc(N2CCOCC2)[o+]c2c(-c3ccc4c(c3)OCCO4)csc12)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vial was charged with a magnetic stirring bar, 7-((8S,14S,17S)-14-(2-tert-butoxy-2-oxoethyl)-17-(tert-butoxymethyl)-20,20-dimethyl-3,6,9,12,15,18-hexaoxo-8-(3-(3-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonyl)guanidino)propyl)-2,19-dioxa-7,10,13,16-tetraazahenicosyloxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-morpholinothieno[3,2-b]pyran-4-ium chloride (83) (0.500 g, 0.364 mmol) and a solution of water (20 μL, 1.09 mmol) and triisopropyl silane (224 μL, 1.09 mmol) in trifluoroacetic acid (5.19 mL, 70 mmol). The reaction solution was magnetically stirred at room temperature. After 3 hours, the reaction solution was charged with ethyl ether (20 mL). The resulting precipitate was filtered, and purified by high-pressure liquid chromatography to give 7-((8S,14S,17S)-17-carboxy-14-(carboxymethyl)-8-(3-guanidinopropyl)-18-hydroxy-3,6,9,12,15-pentaoxo-2-oxa-7,10,13,16-tetraazaoctadecyloxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-morpholinothieno[3,2-b]pyran-4-ium trifluoroacetate (84) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH3:29])[CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)=[O:13])=[CH:7][C:6]=2[CH:30]=1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>C(=O)([O-])[O-].[K+].[K+].C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:30]=[CH:6][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH3:29])[CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:17][CH:16]=4)=[O:13])=[CH:7][C:4]=3[CH:3]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3CCC2)cc1)C1CCOCC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
A mixture of 2-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.95 g) and 4-methoxycarbonylphenylboronic acid (0.4 g) in 1M potassium carbonate (6 ml), ethanol (6 ml) and toluene (75 ml) was stirred for 30 minutes at room temperature under argon. Tetrakis(triphenylphosphine)palladium(0.12 g) was added to the mixture, and the mixture was refluxed for 6 hours under argon. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo. The residue was subjected to a silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give 2-(4-methoxycarbonylphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.4 g) as colorless prisms.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([CH:8]=CC)=O)[CH3:2].[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[NH2:18])[CH3:13].[CH2:25](O)[CH3:26]>>[CH2:12]([O:14][C:15]([C:16]1[CH:6]([CH3:8])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:11])[C:25]([CH3:26])=[N:18][C:17]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:24])[CH3:13]
Reactant: CCOC(=O)C=C(N)N1CCCC1
Reactant: CC=CC(=O)CC(=O)OCC
Reactant: CCO
Product: CCOC(=O)C1=C(N2CCCC2)N=C(C)C(C(=O)OCC)C1C
Yield: 42 %

Procedure:
Boiling a solution of 7.8 g of ethylideneacetoacetic acid ethyl ester and 9.2 g of 3-pyrrolidino-3-aminoacrylic acid ethyl ester in 100 ml of ethanol for 2 hours and distilling the residue yields 2-pyrrolidino-4,6-dimethyl-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of boiling point (1.5 mm. Hg: 199°-204° C.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][NH2:24]>C(Cl)Cl.CCOCC>[CH3:23][NH:24][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCc1ccccc1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 8-phenyl octanoic acid (28.6 g, 129.8 mmol, 1 eq) in CH2Cl2 (100 mL) cooled to 0° C. was added oxalyl chloride (17 mL, 195 mmol, 1.5 eq) dropwise via an addition funnel over 30 minutes. Upon the completion of the addition, the ice bath was removed and the reaction was stirred at rt for 2 h. It was then heated at reflux for 30 minutes. The reaction was cooled to rt and concentrated in vacuo to afford a yellow oil. It was added as a solution in Et2O (100 mL) to a solution of condensed methyl amine (˜20 mL) in Et2O (200 mL) at −78° C. Immediately, a white precipitate formed. The cold bath was removed and the reaction was allowed to stir overnight warming to rt under a stream of N2. The residue was washed with Et2O and concentrated to afford N-methyl-8-phenyloctanamide (25.2 g, 83%) as a yellow-white solid. 1H NMR (CDCl3) δ 7.68–7.10 (m, 5H); 5.42 (bs, 1H); 3.80 (m, 3H); 2.60 (m, 2H); 2.18 (m, 2H); 1.60 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][NH2:26]>CO>[CH3:24][O:25]/[N:26]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: CON
Solvent: CO
Product: CO/N=C(\C)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 60.8 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (60 mg, 0.198 mmol) and O-methylhydroxylamine (49.6 mg, 0.593 mmol) in MeOH (10 mL) was stirred at rt overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA and then neutralized to free base) to give 40 mg (60.8%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-4 δ ppm 8.82 (s, 1H), 8.32 (d, 1H), 8.12 (d, 1H), 7.98 (m, 3H), 7.84 (d, 1H), 7.54 (m, 1H), 4.83 (s, 2H), 4.09 (s, 3H), 2.28 (s, 3H). LC-MS (method B): [MH]+=333.1, tR=2.34 min.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1([CH3:23])[O:21][CH2:20][CH2:19][CH:18]2[N:15]1[C:16](=[O:22])[CH2:17]2.C1(C)C=CC(S([N:33]=[N+:34]=[N-:35])(=O)=O)=CC=1.C[Si](Cl)(C)C>CCCCCC.O1CCCC1>[CH3:13][C:14]1([CH3:23])[O:21][CH2:20][CH2:19][CH:18]2[N:15]1[C:16](=[O:22])[CH:17]2[N:33]=[N+:34]=[N-:35]
Reactant: CC1(C)OCCC2CC(=O)N21
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21

Procedure:
In a nitrogen stream under stirring, 50 ml of dry tetrahydrofuran is cooled to -78° C. and, then, 20 ml of a solution of 15% n-butyllithium in n-hexane is added thereto. After dropwise addition of 3.66 ml of diisopropylamine, the mixture is stirred at -78° C. for 15 minutes. A solution of 3.1 g of 2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -78° C. for one hour. Then, a solution of 4.34 g of p-toluenesulfonyl azide in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -50° C. to -60° C. for 1.5 hours. To this mixture 5.1 ml of trimethylsilyl chloride is added dropwise and the reaction mixture is heated under reflux for 5 hours. After cooling, the insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is shaken with water and ethyl acetate and the ethyl acetate layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solvent is then distilled off and the residue is purified by silica gel column chromatography to give 2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4.2.0]octan-8-one as a 1:4 mixture of cis- and trans-isomers.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[ClH:1].[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: NCC(O)CO
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Product: Cl
Product: OCC(O)CNc1cc(-c2ccc(C(F)(F)F)cc2)nc2ccccc12

Procedure:
The title compound, m.p. 243-247° C., and MS: m/e=362 (M+), was prepared from 4-chloro-2-(4-trifluoromethyl-phenyl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.O[CH2:42][C:43]1[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:44]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:42][C:43]4[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:44]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CCOC(=O)c1cc(CO)ccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)c1cc(COc2cc3ncnc(Nc4ccc(Cl)cc4F)c3cc2OC)ccn1
Temperature: 25 °C
Yield: 59 %

Procedure:
1,1'-(azodicarbonyl)dipiperidine (840 mg, 3 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (315 mg, 1 mmol), ethyl 4-hydroxymethyl-2-pyridinecarboxylate (250 mg, 1.4 mmol), (J. Het. Chem. 1993, 30, 631-635) and tributylphosphine (800 μl, 3 mmol) in methylene chloride (50 ml) at 0° C. The mixture was allowed to warm to ambient temperature over 2 hours, the insolubles were removed by filtration and the filtrate was washed with water and brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (10:0 increasing to 9:1). The purified product was recrystallised from methylene chloride/hexane to give 4-(4-chloro-2-fluoroanilino)-7-(2-ethoxycarbonylpyrid-4-yl)methoxy-6-methoxyquinazoline (285 mg, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][N:8]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(Cc2ccccc2)c2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 1-benzyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-fluorobenzoyl chloride; 1H NMR (CDCl3) δ 10.58 (1H, s), 8.07 (1H, s), 7.62-7.66 (2H, m), 7.36 (1H, d), 7.13-7.23 (9H, m), 6.99 (1H, t), 5.25 (1H, dd), 4.26 (2H, m), 3.94 (1H, d), 2.99 (1H, dd), 2.83 (1H, dd), 1.22 (3H, t); MS (ESI): 469 (MH+).