Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:57][CH2:56][N:48]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=3[CH:55]=[C:47]2[C:46]1=[O:58])(=[O:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CCN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(-c4cccc(N5CCn6c(cc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, 138c (250 mg, 0.637 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (325.5 mg, 0.701 mmol), Pd(PPh3)4 (36.8 mg, 0.0319 mmol), Na2CO3 aqueous solution (1.0 N, 2.10 mL, 2.10 mmol), DME (2.0 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:CH2Cl2=5:95) gave 2-(5-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 138d.
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[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=1.Cl[CH2:31][C:32](=O)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]2[S:21][CH:31]=[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:22]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cc1csc(C(c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)n1

Procedure:
1.5 g (0.0037 mol) of the compound from Example III and 1.5 ml=1.83 g (0.011 mol) of ethyl chloroacetoacetate were heated together with 30 ml of toluene and 10 ml of water at 100° C. for 1 hour. The mixture was neutralised with 10% strength sodium bicarbonate solution, the organic phase was separated off, dried with sodium sulphate and concentrated to a small volume in vacuo, and the residue was separated by column chromatography. A yellow oil was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:15][CH2:16][O:17][CH3:18])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+]>CO.O>[CH3:18][O:17][CH2:16][CH2:15][N:9]1[C:10]([C:11]([F:14])([F:12])[F:13])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(CCOC)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCn1ncc(C(=O)O)c1C(F)(F)F
Yield: 70.5 %

Procedure:
To a solution of 1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.291 g, 1.09 mmol) in methanol (3 mL) and water (3 mL) was added lithium hydroxide (0.072 g, 1.73 mmol). The reaction mixture was stirred at reflux for 2 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (3×25 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide 1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as a orange oil (0.183 g, 71%), which was used without further purification. Mass spectrum: m/z: 239.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.Br.[NH2:15][CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18].Cl>C(Cl)Cl.CCCCCC>[NH2:15][CH:16]([CH2:21][CH2:20][OH:19])[C:17]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1])=[O:18]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: NC1CCOC1=O
Agent: Br
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(CCO)C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.1 %

Procedure:
To a stirring solution of 2,4-dichloroaniline (4.27 g, 26.37 mmol), in anhydrous methylene chloride (100 mL) under N2 at 0° C. (ice-water bath), was added dropwise, trimethylaluminum (39.56 mL of a 2M solution in hexane, 79.11 mmol). The resultant mixture was stirred under N2 at room temperature for 24 h. The mixture was cooled and (±)-α-amino-γ-butyrolactone hydrobromide (39.56 mL, 74.11 mmol, Aldrich Chemical Co., Milwaukee, Wis.) was then added portionwise and the reaction mixture then allowed to stir at room temperature for 48 h. The reaction mixture was cooled to 0° C., treated with 6N hydrochloric acid until the pH of the mixture was 2 to 3. The resultant solid was filtered and suspended in 100 mL of water. The suspension was made basic with 50% aqueous NaOH (pH=13) and 300 mL of methylene chloride was added. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 50% ethyl acetate in hexane. The desired fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (2.3 g, 36%), mp 89°-91° C. IR (Nujol, cm-1), C=O (1658), N--H (3323.9), OH (3265.9). 1H NMR (400 MHz, CDCl3) spectrum was consistent with the title product. Analysis calculated for C10H12Cl2N2O: C, 45.65; H, 4.60; N, 10.68; Cl, 26.90; Found: C, 45.69; H, 4.60; N, 10.53; Cl, 26.70.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[SH:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9]>N1C=CC=CC=1.[OH-].[Na+]>[CH3:1][NH:2][C:3]([S:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[S:4]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CNC(=S)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
Methylisothiocyanate (4 g) is added to a solution of 3-mercaptopropanoyl-L-proline (10.1 g) in a mixture of pyridine (250 ml) and 0.5 N sodium hydroxide (100 ml). The solution is kept at 40° for two hours and concentrated to dryness in vacuo. The residue is dissolved in water (100 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is concentrated to dryness to yield 1-[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:29]1[C:30]([F:38])=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:26](=[O:28])[CH3:27])[C:30]=2[F:38])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: CC(=O)c1cccc(B(O)O)c1F
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: [Na+]
Product: CC(=O)c1cccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1F

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (3-acetyl-2-fluorophenyl)boronic acid (273 mg), sodium carbonate (254 mg), and tetrakis(triphenylphosphine)palladium (173 mg), the title compound was obtained as a pale-yellow oil (yield 443 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:23])[N:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:14])[CH:6]=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:23])[N:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH3:14])[CH:6]=2)=[C:2]([F:1])[CH:27]=1
Reactant: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ncn1
Reaction time: 8 h
Yield: 68.4 %

Procedure:
3-[6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-yl]-1-(3-diethylaminopropyl)-1-methylurea (54.0 mg) was dissolved in tetrahydrofuran (2 ml)-methanol (2 ml), and then 10% palladium carbon (27.2 mg) was added thereto, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated under a reduced pressure to provide the titled compound (34.3 mg, 68.6%) as a pale yellow solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Li]CCCC.CCCCCC.CN([CH:29]=[O:30])C1C=CC=CC=1>CCOCC>[S:9]1[C:8]([CH:29]=[O:30])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: CN(C=O)c1ccccc1
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cc2ccccc2s1
Temperature: -15 °C
Reaction time: 1.75 h
Yield: 73.1 %

Procedure:
To a solution of thianaphthene (1.45 g, 10.5 mmol (97% pure)) in anhydrous Et2O (20 mL) at -15° C. was added dropwise a 1.6M solution of n-BuLi in hexane (9.9 mL, 15.7 mmol). The mixture was stirred at -15° C. (1.75 h) and at 25° C. (15 min). After recooling to -15° C., anhydrous N-methylformanilide (1.6 mL, 12.7 mmol) (distilled from CaH2) was added dropwise and the mixture was heated at reflux (30 min). The reaction mixture was quenched by addition of a mixture of 3N HCl (9 mL) and ice chips (20 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (3×75 mL). The combined organic layers were washed with 1N HCl (3×40 mL), saturated aq. NaHCO3 (40 mL), dried (MgSO4), and evaporated to dryness. The residue was dissolved in EtOH (3 mL) and mixed with saturated aq. NaHSO3 (15 mL). The resulting mixture was allowed to stand for 30 min and the crystalline bisulfite addition product was collected by filtration, washing with Et2O (50 mL) and dried in a vacuum desicator. The yellow solid was dissolved in warm H2O (30 mL) and cooled to 0° C. Saturated aq. Na2CO3 was added and the mixture was stirred at 25° C. for 15 min. Filtration, washing with H2O and drying afforded benzo[b]thiophene-2-carboxaldehyde as an amorphous solid (1.25 g, 7.68 mmol) in 73% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][N:25]1[CH2:41][C:42](O)=[O:43].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:5]1([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[CH2:15][CH2:14][N:13]([C:42](=[O:43])[CH2:41][N:25]3[CH2:26][CH2:27][C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:24]3=[O:23])[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(=C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of bis(4-fluorophenyl)(piperidin-4-yl)methanol (0.30 g, 1.00 mmol, Example 32A) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) under nitrogen. To the mixture was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (6.1 mg, 0.005 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.49-7.57 (m, 4H), 7.17-7.35 (m, 10H), 7.06-7.13 (m, 4H), 5.49 (s, 1H), 4.36 (d, J=14.0 Hz, 1H), 4.17 (d, J=16.6 Hz, 1H), 4.10 (d, J=15.7 Hz, 1H), 3.81 (d, J=14.3 Hz, 1H), 3.34 (t, J=6.7 Hz, 2H), 2.95-2.98 (m, 1H), 2.73-2.85 (m, 1H), 2.72 (t, J=6.6 Hz, 2H), 2.50-2.62 (m, 1H), 1.20-1.39 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][NH:4][C:3]1=[S:8].C(O)(=O)C.C(O)(=O)C.[OH:17][C:18]1[C:19]([CH2:28]O)=[CH:20][C:21]2[O:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:27]=1>>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][N:4]=[C:3]1[S:8][CH2:28][C:19]1[C:18]([OH:17])=[CH:27][C:22]2[CH2:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1
Reactant: Cc1c[nH]c(=S)n1C
Reactant: OCc1cc2c(cc1O)CCCO2
Solvent: CC(=O)O
Product: Cc1cnc(SCc2cc3c(cc2O)CCCO3)n1C
Yield: 29.2 %

Procedure:
In a manner analogous to Example 1, 1,5-dimethylimidazole-2-thione (0.80 g, 6.25 mmal) was treated with 6-hydroxy-7-hydroxymethyl-1,2,3,4-tetrahydrobenzopyran diacetate (1.70 g, 6.25 mmal) to afford 7-(((1,5-dimethyl-1H-imidazole-2-yl)thio)methyl)-6-hydroxy-1,2,3,4-tetrahydrobenzopyran (480 mg, 26%) mp 139°-140° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2.[O:19]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:19][C:7]([CH3:17])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:18])[C:14]([NH2:16])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(N)=O)=C(C)C1=O
Yield: 79.2 %

Procedure:
Oxidation as described in protocol B, using 186 mg (0.747 mmol) of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 907 mg CAN (1.65 mmol) yielded 157 mg of 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: C([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:24]4[C:18]5([CH2:30][CH:21]([C:22](=[O:29])[C:23]=4[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19]5)[CH2:17][C:14]=32)=[N:9]1)C1C=CC=CC=1.Cl.[H][H]>O1CCOCC1.[Pd]>[F:27][C:25]([F:26])([F:28])[C:23]1[C:22](=[O:29])[C@H:21]2[CH2:30][C@@:18]3([C:24]=1[C:13]1[CH:12]=[CH:11][C:10]4[NH:9][N:8]=[CH:16][C:15]=4[C:14]=1[CH2:17]3)[CH2:19][CH2:20]2
Reactant: [H][H]
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4nn(Cc5ccccc5)cc4c3CC23CCC1C3
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3
Reaction time: 0.75 h

Procedure:
To a solution of 2-benzyl-6-(trifluoromethyl)-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one (0.820 g, 2.00 mmol) in 50 mL of dioxane was added 12N aqueous HCl (0.170 mL, 2.00 mmol) followed by 30% palladium on carbon (0.250 g) and the stirred mixture was hydrogenated under balloon pressure of hydrogen. After 45 minutes, additional 30% palladium on carbon (0.090 g) was added. After hydrogenating for an additional 1 hour, the mixture was filtered through a pad of silica gel, washing with EtOAc. The filtrate was washed with 5% aqueous NaHCO3 and the aqueous phase was back-extracted with EtOAc. The combined organic layers were diluted with Et2O and hexanes and washed with water and brine. The organic phase was concentrated under vacuum and the residue was chromatographed on silica gel (elution with 1:4 to 1:1 EtOAc/hexanes) to yield (rac)-(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:14]([N:21]([CH2:23][CH2:24]Cl)[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:14]([N:21]([CH2:23][CH2:24][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: COc1ccc(O)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(OCCN(C)Cc2ccccc2)c(C=O)c1
Temperature: 70 °C

Procedure:
In a similar manner to the previous example, a solution of 2-hydroxy-5-methoxybenzal dehyde (25.0 g) in DMF (50 ml) was added to a stirred suspension of sodium hydride (6.84 g of a 60% dispersion in mineral oil) in dry DMF (125 ml) at ambient temperature under nitrogen with stirring. The mixture was heated at 70° C. for 2 hours and then cooled to ambient temperature and a solution of N-benzyl-2-chloro-N-methylethylamine in toluene (75 ml) was added [prepared from 48.5 g of the hydrochloride salt]. The oil obtained after work up was distilled under vacuum to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-5-methoxybenzaldehyde as an oil. A sample of this oil which boiled at 202°-206° C. at 0.65 mbar was dissolved in ether and acidified with ethereal hydrogen chloride. The precipitate was collected by filtration, washed with ether to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-5-methoxybenzaldehyde hydrochloride, m.p. 167°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:28])[CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:30]\[OH:31])=[C:4]([F:28])[CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(CO)cc2)c2ccc(Cl)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(CO)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-fluorophenyl)-3-(4-(hydroxymethyl)-phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing 15% of the corresponding Z isomer, MS (ESI+): m/z=415.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)C(=CNc1ccc(F)c(Cl)c1)C(=O)OCC

Procedure:
3-Chloro-4-fluoroaniline (I) and diethyl ethoxymethylenemalonate were heated at 120°-130° C. to give diethyl (3-chloro-4-fluorophenyl)aminomethylenepropanedioate (II). The latter was cyclized by heating it at reflux in diphenyl ether to give the quinoline III.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][N:27]=1)[C:12]([NH:14][C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1)=[O:13].[CH3:28][C:29]([CH3:58])([O:31][C:32](=[O:57])[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH2:47][C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51](O)=[O:52])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:51]([C:50]2[CH:49]=[C:48]([CH2:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][C:32]([O:31][C:29]([CH3:58])([CH3:30])[CH3:28])=[O:57])[CH:56]=[CH:55][CH:54]=2)=[O:52])=[C:3]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[NH:14][C@@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH:25]=[CH:26][N:27]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 65 °C
Yield: 66.6 %

Procedure:
To a solution of (S)-2-(2-amino-5-chlorophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide 237b (1.02 g, 2.7 mmol), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid 251c (1.19 g, 2.7 mmol), DIPEA (1.04 g, 8.1 mmol) and DMAP (190 mg, 1.55 mmol) in DMF (20 ml) was added HATU (1.13 g, 2.97 mmol). The reaction mixture was heated at 65° C. for 24 hours, then cooled and concentrated. The residue was combined with another run (0.28 mmol scale), dissolved in DCM (150 mL), washed with water (4×50 mL), dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (10% to 30% EtOAc in DCM) gave the title compound (1.44 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:28]2=[N:29][C:30]3[C:31](=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=3)[N:27]2[CH2:26][CH2:25][CH2:24]1.[CH3:37][C:38](=O)[CH2:39][CH3:40]>CO.C(=O)([O-])O.[Na+]>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:28]2=[N:29][C:30]3[C:31](=[C:32]([NH:36][CH:38]([CH3:37])[CH2:39][CH3:40])[CH:33]=[CH:34][CH:35]=3)[N:27]2[CH2:26][CH2:25][CH2:24]1
Reactant: Nc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC(C)Nc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
Sodium triacetoxyborohydride (171 mg, 0.807 mmol) was added to a stirred solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine (183 mg, 0.549 mmol) and butan-2-one (1.0 mL) in methanol (1.0 ml) at 0° C., and the mixture was stirred at room temperature for 8 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (86.4 mg, 0.222 mmol, 40%).