Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@H:10]1[O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[F:39])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[F:39][C:30]1[CH:31]=[C:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=[CH:34][C:29]=1[O:28][C@H:10]1[C@@H:9]([OH:8])[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11]1=[O:27]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2C[C@H](O)[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Yield: 59.5 %

Procedure:
Tert-butyl 4-((3S,4S)-4-(benzyloxy)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (160 mg, 0.284 mmol) was dissolved in EtOH (3 mL) and 100 mg 10% Pd/C was added and stirred under balloon pressure of hydrogen overnight. The reaction was filtered and concentrated to afford tert-butyl 4-((3S,4S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (80 mg, 0.169 mmol, 59.5% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C(Cl)Cl>[OH:20][C:17](=[C:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])[CH2:18][CH3:19]
Reactant: CCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Meldrum's acid (10 g, 69.4 mmol) in CH2Cl2 (170 mL) was cooled to 0° C. Pyridine (11.2 ml, 138.8 mmol) and propanoyl chloride (10.1 mL, 76.3 mmol) were added via syringe. The resulting solution was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred for 1 hour. The reaction was diluted with CH2Cl2 and washed with aq HCl (15 mL conc HCl in 200 mL water, 1×) and water (1×). The organic solution was dried over Na2SO4 and concentrated to give a dark red solid.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].[H][H]>FC(F)(F)C(O)=O.O=[Pt]=O>[CH3:3][C:2]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:1]=1
Reactant: [H][H]
Reactant: Cc1ccc2ccccc2n1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(n1)CCCC2

Procedure:
A solution of quinaldine (available from Aldrich) (25 mL, 176 mmol) in trifluoroacetic acid (140 mL) was hydrogenated at 50 psi hydrogen in the presence of PtO2 (2.62 g, 11.5 mmol) for 1.5 h at rt. (This method was conducted in accordance with Bell, T. W. et. al. J. Am. Chem. Soc. 2002 124, 14092 incorporated herein by reference). The mixture was filtered through filter paper, diluted with water and crushed ice, and made basic by the addition of solid NaOH until the mixture was pH>10. The aqueous layer was extracted with hexane. The pooled organic layers were washed with water and dried over MgSO4. The mixture was filtered and evaporated to give 2-methyl-5,6,7,8-tetrahydro-quinoline (Intermediate 200A1) as a clear, yellow oil ˜25 g (98%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(N(CC)CC)C.[C:31]1([CH:37]([CH3:40])[CH:38]=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([CH:37]([C:40]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CC(C=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(c1ccccc1)c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Yield: 9.5 %

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (0.5 g, 1.7 mmol) in ethanol (20 mL) was added triethylamine (1 mL) and 2-phenylpropanal (0.25 g, 1.9 mmol). The reaction mixture was heated at reflux for 12 h. The mixture was then concentrated under reduced pressure, diluted with ice cold water and extracted with ethyl acetate. The organic layers were dried, filtered and concentrated, and the resulting residue was purified by preparative TLC to afford the title compound (65 mg, 9%). MS (ES+APCI) (M+H) 404.2; LCMS retention time 2.206 min (Method Y).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:14])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[O-:23][C:24]#[N:25].[K+].Cl>O>[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:25][C:24](=[O:23])[N:15]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13]=2[CH3:14])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: N#C[O-]
Reactant: CCCCc1ccc(C(=O)C(C)NC2CCCCC2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCc1ccc(-c2[nH]c(=O)n(C3CCCCC3)c2C)cc1

Procedure:
4'-n-Butyl-2-cyclohexylaminopropiophenone hydrochloride (1768 mg, 5.5 mmol) was suspended in water (30 ml), and potassium cyanate (914 mg, 11.3 mmol) in water (10 ml) was added thereto. The aqueous mixture was heated under reflux for one hour under nitrogen atomosphere, added with conc. hydrochloride (2 ml), and heated under reflux an additional one hour. The reaction mixture was extracted with dichloromethane, and the extract was washed with 10% hydrochloride, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under vacuum and recrystalization from ethyl acetate gave the title compound. Yield: 155 mg (9%), m.p. 236° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:8][CH:7]=1.[OH-].[K+].Cl>O.C(O)C>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)O)cc1
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A mixture of 24.5 g of 4-Hexadecyloxyphenoxyacetic acid methyl ester 10.14 g of potassium hydroxide in 10 ml of water and 250 ml ethyl alcohol is refluxed for 3 hours then allowed to stand at 50° for 18 hours. The mixture is poured into dilute hydrochloric acid and extracted with chloroform. The organic layer is evaporated to a residue which is crystallized from hexane:carbon tetrachloride to give 13.7 g of the desired product as a white solid, m.p. 125°-127° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([O:1][C@@H:2]([CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CON(C)C(=O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2c(OC[C@H](CN3CCC(c4ccc5ccccc5c4)CC3)OC(C)=O)cccc2o1
Reaction time: 24 h

Procedure:
(S)-4-(2-Hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N-methoxy-N-methylbenzo(b)furan-2-carboxamide (0.40 g) obtained in Example 6 was dissolved in pyridine (20 ml) and acetic anhydride (10 ml) was added at room temperature. The mixture was stood for one day. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (S)-4-(2-acetoxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N-methoxy-N-methylbenzo(b)furan-2-carboxamide (0.34 g) as a brown oil. This was dissolved in ethanol and maleic acid (0.10 g) was added. The precipitated crystals were collected by filtration and dried to give the title compound (0.25 g) as pale-yellow crystals, melting point 125–127° C.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]\1.[NH2:11][NH2:12]>CO>[NH:11]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:3]=2[CH:2]=[N:12]1
Reactant: O=C1CCCCC/C1=C/O
Reactant: NN
Solvent: CO
Product: c1n[nH]c2c1CCCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 2-[1-hydroxy-meth-(Z)-ylidene]-cycloheptanone (1.35 g, 9.63 mmol) in MeOH (10 mL) at 0° C. was added hydrazine (0.30 mL, 9.63 mmol) dropwise. The yellow reaction mixture was stirred at room temperature for 30 min then concentrated. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated to provide 1.24 g (95%) of 1,4,5,6,7,8-hexahydrocycloheptapyrazole as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.28 (s, 1H), 2.75-2.82 (m, 2H), 2.54-2.62 (m, 2H), 1.80-1.91 (m, 2H), 1.60-1.75 (m, 4H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: CS
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 50 °C
Yield: 68.2 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of methyl mercaptan sodium salt and 2 ml of DMF was stirred while heating at 50° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to give 0.21 g of 2-[3-(methylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 40”).
Reaction SMILES: [CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][C:18]#N)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]([CH2:29]CCl)[CH3:28]>>[CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][CH2:18][CH2:26][N:27]([CH3:29])[CH3:28])=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Reactant: CN(C)CCCl
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCN(C)C

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea and dimethylaminoethylchloride.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][C:16]4=[O:20])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: O=C1CCCN1CCCNc1ccc2ncc(Br)n2n1
Product: NCc1ccc(-c2cnc3ccc(NCCCN4CCCC4=O)nn23)cc1
Yield: 64 %

Procedure:
The 1-(3-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)propyl)pyrrolidin-2-one was also coupled to (4-(aminomethyl)phenyl)boronic acid using the Suzuki coupling conditions described in example 5.6.19 to obtain the titled product in 64% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.94-2.09 (m, 4H) 2.33-2.43 (m, 2H) 3.36-3.53 (m, 6H) 4.16 (s, 2H) 6.74 (d, J=9.60 Hz, 1H) 7.57 (m, J=8.34 Hz, 2H) 7.65 (d, J=9.60 Hz, 1H) 7.81 (s, 1H) 8.25 (m, J=8.34 Hz, 2H); LRMS (ESI) m/e 365.0 [(M+H)+, calcd for C20H24N6O 364.0].
Reaction SMILES: [N:1](OC(C)(C)C)=O.[NH2:8][C:9]1[C:10]2[C:36]([CH3:41])([C:37]([NH:39][NH2:40])=[O:38])[C:35](=[O:42])[NH:34][C:11]=2[N:12]=[C:13]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[N:16]=2)[N:14]=1.C(O)(C(F)(F)F)=O>C1COCC1>[NH2:8][C:9]1[C:10]2[C:36]([CH3:41])([C:37]([N:39]=[N+:40]=[N-:1])=[O:38])[C:35](=[O:42])[NH:34][C:11]=2[N:12]=[C:13]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:30])([F:29])[F:31])[N:16]=2)[N:14]=1
Reactant: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Reactant: CC(C)(C)ON=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C(=O)N=[N+]=[N-])C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Temperature: 0 °C

Procedure:
t-Butyl nitrite (0.34 mL, 2.89 mmol) was added dropwise to a THF (3.5 mL) solution containing the intermediate from Step A above (300 mg, 0.578 mmol) and TFA (50 μL, 0.636 mmol) cooled to 0° C. After 50 min. the solution was carefully concentrated in vacuo (temperature <30° C.) to give the title compound as a solid which was used without further purification. m/z 502.0 (M−N2+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH2:33]([O:35][C:36](=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH3:34].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[C:36]([O:35][CH2:33][CH3:34])(=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:42]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CCOC(=O)CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), adipic acid monoethyl ester (0.25 g, 1.44 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified by chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white powder (0.275 g), melting point: 88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:16])[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:15][CH:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[OH:16])[C:11]([O:13][CH3:14])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(C(=O)OC)C(O)c1ccc(F)c(Cl)c1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-[(3-chloro-4-fluorophenyl)(hydroxy)methyl]prop-2-enoate (11.5 g) and triethylamine (6.85 mL) in methanol (100 mL) was added benzylamine (5.38 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.0 g).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O-:35][N+:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[N:1]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:2]=[N:3][C:4]=2[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCOCCn1cnc2cnc3ccccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCn1cnc2c[n+]([O-])c3ccccc3c21
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of tert-butyl 2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7 mmol) in 200 mL of CH2Cl2 was treated with MCPBA (77% , 3.63 g, 16.3 mmol). After stirring overnight, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed with H2O and brine then dried over Na2SO4 and concentrated to give 4.60 g of tert-butyl 2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6]/[C:5](=[C:7]2/[C:8](=[O:27])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])[CH:11]=3)/[CH:4]=[C:3]1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[OH-].[Na+].O>CO>[CH3:1][C:2]1([CH3:34])[O:6]/[C:5](=[C:7]2/[C:8](=[O:27])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])[CH:11]=3)/[CH:4]=[C:3]1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1ccccc1Sc1ccc2c(c1)NC(=O)/C2=C1\C=C(N2CCOCC2)C(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(Sc4ccccc4C(=O)O)ccc32)C=C1N1CCOCC1
Temperature: 66 °C

Procedure:
A mixture of methyl 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate (50 mg) and 1M NaOH (3 mL) in 20 mL of MeOH was heated in 66° C. bath for 2 hours. The mixture was cooled to room temp, poured into 100 mL of water, and acidified to about pH 3. The precipitates were filtered, washed with water and dried in vacuo to give 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoic acid as a brown solid. Yield: 50 mg, 97%.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:32]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)O)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:31])[CH3:30])[CH:21]=[N:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])(C(C)(C)C)(C)C.[CH:43](O)=[O:44]>[Zn]>[CH:43]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:32][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:30])[CH3:31])[CH:21]=[N:22][C:15]=2[N:14]([CH3:41])[C:13]1=[O:42])=[O:44]
Reactant: O=CO
Reactant: CC(C)c1ccccc1-c1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: [Zn]
Product: CC(C)c1ccccc1-c1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 100 °C
Yield: 48 %

Procedure:
To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-((4-chlorophenyl) (hydroxy)methyl)-6-(2-isopropylphenyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 6, 50 mg, 0.086 mmol) in HCOOH (5 mL) was added Zn dust (56.6 mg, 0.86 mmol). The reaction was heated at 100° C. for 3 h, cooled to RT and filtered. The filtrate was concentrated and dried to give 3-(5-(4-chlorobenzyl)-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (20 mg, 48.0% yield) as a brown oil. LCMS: [MH+—OH] 506 and TR=2.062 min. Used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1)=[N+:25]=[N-:26]
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OCCCCCCBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
10 g of [4-(6-bromo-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone are dissolved in 200 ml of DMF and, after the addition of 14.7 g of sodium azide, the mixture is stirred at 90° C. for 24 hours, filtered and the filtrates are concentrated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution. The organic phase is dried and concentrated. There are obtained 9.2 g of [4-(6-azido-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone, MS: m/e 401 (M+H+, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:7]([CH:8]=O)=[C:6]([O:17][CH3:18])[CH:5]=1)[CH3:2].[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH2:1]([O:3][C:4]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:7](/[CH:8]=[CH:20]/[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:21])=[C:6]([O:17][CH3:18])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(OC)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: CCOc1cc(OC)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 76 %

Procedure:
The title compound was prepared by condensing 4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-53A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 210–212° C., 76% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.23 (d, 2H, J=9.0 Hz), 8.06–8.11 (m, 3H), 7.92 (d, 1H, J=16.2 Hz), 7.71 (d, 1H, J=3.9 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.9 Hz), 6.82 (s, 1H), 4.33 (q, 2H, J=6.1 Hz), 3.99 (s, 3H), 1.48 (t, 3H, J=6.1 Hz). MS (ESI) m/z=409 ([M+H]+, 100%). Anal. Calcd. for C23H20O5S.½H2O: C, 66.17; H, 5.07; S, 7.68. Found: C, 65.88; H, 5.24; S, 7.36.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[CH3:11].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:8][C:7]1[C:2]([F:1])=[C:3]([CH3:11])[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([F:10])[C:6]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(F)c(C)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)c(F)c(C)c([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
To 2,3,5-trifluoro-4-methyltoluene (1.9 g) is added conc. sulfuric acid (19 ml) and the mixture is cooled to 0° C., to which a solution of potassium nitrate (1.71 g) in conc. sulfuric acid (4.6 ml) is added dropwise below 10° C. and the mixture is stirred for 15 minutes. The mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane: n-hexane =1 : 6) to give 2,3,6-trifluoro-4-methyl-5-nitrotoluene (1.9 g).