Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].Cl[CH2:25][O:26][CH3:27]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:25][O:26][CH3:27])[C:6]=2[CH:12]=1
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: COCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COCN1C(=O)COc2ccc(Br)cc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
A suspension of 6-bromo-2H-1,4-benzoxazin-3(4H)-one (13 g, 57 mmol) in 1,2-dichloroethane (350 ml) was cooled in an ice bath to which N,N-diisopropylethylamine (119 ml), sodium iodide (10.25 g, 68.4 mmol) and chloromethylmethyl ether (43.3 ml, 570 mmol) were added, and the mixture was stirred at 70° C. for 3 hours. After cooling, the reaction mixture was diluted with dichloromethane, washed with cold water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 13.6 g (88%) of the title compound in the form of a light brown solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:39][NH:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(N(CC)CC)C>[CH2:41]([N:40]([CH3:39])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Reactant: CCCCNC
Solvent: CCN(CC)CC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylbutan-1-amine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=80-82° C.; 1H NMR 400 MHz (DMSO-d6) δ 9.54 (s, 1 H); 8.38-8.35 (m, 2 H), 7.82-7.75 (m, 3 H), 7.58 (t, 1 H), 7.51-7.40 (m, 3 H), 7.27 (d, J=8.0 Hz, 1 H), 7.17 (d, J=8.4 Hz, 2 H), 6.76 (d, J=7.6 Hz, 1 H), 4.64 (t, J=8 Hz, 1 H), 3.19-3.12 (m, 2 H), 2.68-2.65 (m, 2 H), 2.55-2.51 (m, 2), 2.37-2.33 (m, 2 H), 2.21 (s, 3 H), 1.40-1.36 (m, 2 H), 1.30-1.23 (m, 2 H), 0.88 (t, J=7.2 Hz, 3 H). LCMS m/e 531 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[CH3:12][C:13]([CH3:15])=O.N1CCCC1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:13]([CH3:15])([CH3:12])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccc(F)cc2O1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
1-(4-Fluoro-2-hydroxy-phenyl)-ethanone (5.0 g, 32.44 mmol), acetone (11.92 mL, 162.2 mmol) and pyrrolidine (2.7 mL, 32.44 mmol) were dissolved in 20 mL benzene, and the reaction mixture was refluxed for four hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 N HCl. The organic layer was dried over MgSO4, and solvent was evaporated under reduced pressure. The resulting residue was chromatographed (15% ethyl acetate in hexanes eluting through silica) and solvent was removed to yield 3.33 g (17.16 mg, 53%) of 7-fluoro-2,2-dimethyl-chroman-4-one as an oil. MS: 195 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:20]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH:21]=[CH2:22]>CN(C=O)C>[NH:9]([CH2:22][CH2:21][C:20]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10]
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of glycine t-butyl ester hydrochloride (20.7 g, 123 mmol) in DMF (50 mL) was added DIEA (21.5 mL, 123 mmol) and benzyl acrylate (20 g, 123 mmol). The mixture was allowed to stir at room temperature for 4 hours. This solution was concentrated in vacuo and the residue partitioned between saturated aqueous NaHCO3 and ethyl acetate and separated. The organic layer was washed once with saturated aqueous NaHCO3 and twice with brine. The ethyl acetate layer was dried (MgSO4), filtered and concentrated in vacuo to give 30 g (83%) of a slightly amber oil.
Reaction SMILES: [Na].[CH3:2][CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1)[CH2:4][CH3:5].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=1>>[Cl:17][C:18]1[N:19]=[C:20]([O:14][CH2:13][CH2:12][O:11][C:10]2[CH:15]=[CH:16][C:7]([O:6][CH:3]([CH3:2])[CH2:4][CH3:5])=[CH:8][CH:9]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Reactant: Clc1cccc(Cl)n1
Agent: [Na]
Product: CCC(C)Oc1ccc(OCCOc2cccc(Cl)n2)cc1

Procedure:
Following the same procedures, the sodium salt of 2-[4-(1-methylpropoxy)phenoxy]ethanol is reacted with 2,6-dichloropyridine to give 6-chloro-2-{2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:19])[N:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:21]1>>[O:19]=[C:11]1[N:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:13]=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:20]3[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=4)=[O:26])[CH2:21]3)[CH2:3][CH2:4]2)[CH:9]=[CH:10]1
Reactant: O=C1CCC(c2ccc(=O)n(CC(F)(F)F)c2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(=O)n(CC(F)(F)F)c3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-(4-oxo-cyclohexyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]1=2.[H-].[Na+].[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C>[O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]([CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[CH3:17])[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]1=2
Reactant: COC(=O)c1cc2c([nH]1)CCCC2=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(n1COCC[Si](C)(C)C)CCCC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (500 mg, 2.6 mmol) in DMF (3 mL) was added to a cooled (0° C.) suspension of sodium hydride (114 mg, 60% in oil, 2.8 mmol) in DMF (2 mL). After 10 min, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (550 μl, 3.1 mmol) was added. The mixture was stirred at rt for 2 h and was then poured into ice-water and extracted with EtOAc. After concentration, methyl 4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate was obtained as a crude oil (930 mg).
Reaction SMILES: [CH3:1][C:2]([C:33]1[NH:37][N:36]=[N:35][N:34]=1)([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16]CC2C=CC=CC=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:12][C:11]=1[CH2:31][CH3:32])[CH3:3]>[Pd].C(O)C>[CH3:1][C:2]([C:33]1[NH:37][N:36]=[N:35][N:34]=1)([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:12][C:11]=1[CH2:31][CH3:32])[CH3:3]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)c1nnn[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCCC(C)(C)c1nnn[nH]1
Reaction time: 2 h

Procedure:
A mixture of 1.1 g of 2-methyl-2-(1H-tetrazol-5-yl)-7-(2-ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)heptane, 1 g of 10% palladium on carbon, and 200 mL of ethanol was hydrogenated on a Parr™ apparatus at 35-40 psi for 2 hours. The mixture was filtered and the filtrate evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol providing 750 mg (84%) of the desired title product. MS, NMR. Crystallization from diethyl ether/hexanes gave material with a melting point of 135°-137° C.; when crystallized from toluene, the melting point was 142°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([CH3:27])=[C:25]([C:28](O)=[O:29])[CH:24]=[N:23]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28]([C:25]2[CH:24]=[N:23][N:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)[C:26]=2[CH3:27])=[O:29])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Cc1c(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cnn1-c1ccc(F)cc1

Procedure:
50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide. MS (Q1) 407.0 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C@@H:25]([NH:30]C(OC(C)(C)C)=O)[C@@H:26]([CH3:29])[CH2:27][CH3:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.Cl.O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C@@H:25]([NH2:30])[C@@H:26]([CH3:29])[CH2:27][CH3:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc(OCc2cccc3ccccc23)c(OC)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](N)C(=O)NCCc1ccc(OCc2cccc3ccccc23)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
12.6 9 of (2S,3S)-2-(tert-butoxycarbonyl-amino)-3-methyl-valeric acid N-{2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]-ethyl}-amide are dissolved in 100 ml of dioxane. 200 ml of a 4M solution of hydrogen chloride in dioxane are added thereto. The reaction mixture is stirred at room temperature for 24 hours and then 300 ml of water are added thereto. Extraction is carried out twice using 300 ml of ethyl acetate each time. The organic phases are washed twice using 150 ml of 2N hydrochloric acid each time. The combined aqueous extracts are adjusted to a pH value of >8 by the addition of solid potassium carbonate. Extraction is carried out twice using 400 ml of tert-butyl methyl ether each time. The organic phases are combined, dried over potassium carbonate and concentrated, yielding (2S,3S)-2-amino-3-methyl-valeric acid N-{2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]-ethyl}-amide in the form of a yellow oil.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36]C1C=CC(S)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:36][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)=[CH:3][CH:8]=1
Reactant: Fc1ccc(S)cc1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccc(F)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 4-fluoro-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:20]([O-])=O)[C:11]2=[O:23])=[CH:5][CH:4]=1>[Pd].CO>[NH2:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][N:10]([CH2:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:4][CH:5]=1)[C:11]2=[O:23]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c(=O)n(Cc3ccc(C(F)(F)F)nc3)ccc12
Reaction time: 0.67 h
Yield: 82.5 %

Procedure:
Palladium on charcoal (10%) was added to the solution of 2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5-nitroisoquinolin-1(2H)-one (1.16 g, 0.00315 mol) in methanol (30 mL) and the mixture was stirred under an atmosphere of hydrogen for 40 min. The mixture was filtered through celite. The filterate was concentrated and the residue was purified by column to obtain the product as a beige solid (0.83 g). MS m/z=320.3 (M+H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=S)[CH2:11][N:10]=[C:9](C3C=CC=CC=3Cl)[C:8]=2[CH:22]=1)([O-])=O.CN(CC(NN)=O)C>C(O)CCC>[NH:13]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:22][C:8]=2[CH:9]=[N:10][CH:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Agent: CN(C)CC(=O)NN
Solvent: CCCCO
Product: C1=CNc2ccccc2C=N1

Procedure:
In the manner given in Example 5, a solution of 1,3-dihydro-7-nitro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with (dimethylamino)acetic acid hydrazide to give 8-nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4-benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[C:12]2[C:11]3[CH2:10][CH2:9][O:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[C:12]2[C:11]3[CH2:10][CH2:9][O:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Temperature: 70 °C
Yield: 34.9 %

Procedure:
To a solution of methyl 2-[2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]pentanoate (0.089 g; 0.21 mmol) in methanol (2.1 mL) was added a solution of sodium hydroxide 10 N (0.21 ml) and the mixture was heated at 70° C. for 4 h. After cooling, the reaction mixture was concentrated under reduced pressure and the crude solid was suspended in ethyl acetate and the mixture was acidified with 1N HCl (pH˜2). The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica using a mixture dichloromethane/methanol (98/2)+0.5% acetic acid as eluent to afford 0.029 g (35%) of the title compound as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:17]3[CH2:18][CH2:19][N:20]4[C:25]([C:16]=3[NH:15][C:12]2=[CH:13][CH:14]=1)=[C:24]([CH2:26][CH3:27])[CH2:23][CH2:22][C:21]4=[S:28].O.Cl>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:17]3[CH:18]=[CH:19][N:20]4[C:25]([C:16]=3[NH:15][C:12]2=[CH:13][CH:14]=1)=[C:24]([CH2:26][CH3:27])[CH2:23][CH2:22][C:21]4=[S:28]
Reactant: CCC1=C2c3[nH]c4ccc(OC)cc4c3CCN2C(=S)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1=C2c3[nH]c4ccc(OC)cc4c3C=CN2C(=S)CC1
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (665 mg, 5.9 mmol) is added to a solution of 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizine-4-thione (500 mg, 1.6 mmol) in DMF (42 ml). After placing the reaction assembly under vacuum, the mixture is stirred under normal oxygen pressure overnight. Water (15 ml) and concentrated hydrochloric acid (3 ml) are then successively added. The solution is stored in a refrigerator for 4 hours. After filtration, 9-methoxy-1-ethyl-2,3,4,12-tetrahydroindolo[2,3-a]quinolizine-4-thione is obtained (150 mg, Y=30%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[OH:10][C:11]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccccc2c1O

Procedure:
In step 1 of sequence A, an aniline, substituted by the appropriate R2 group or groups, is condensed with a dialkyl alkoxymethylenemalonate such as diethyl ethoxymethylenemalonate by heating at 120° to 150° C. The intermediate formed is condensed by heating at a temperature of 150° to 300° C. in a high boiling inert solvent such as diphenyl ether or mixtures of diphenyl ether and biphenyl (e.g. Dowtherm A) to give the ethyl 4-hydroxyquinoline-3-carboxylate product of step 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.O[CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[CH2:32][CH2:24][CH2:25]3)=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Reactant: OC1Cc2ccccc2C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc3c(c2)CCC3)o1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (318 mg), 2-hydroxyindane (268 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (400 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(5-indanyloxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole was obtained as an oil (418 mg, 96%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: C(O[C:4](OCC)(OCC)[CH2:5][CH3:6])C.Cl.N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[NH:31][CH2:32][C:33]1([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[CH:28][CH:27]=[CH:26][CH:25]=2>C1(C)C=CC=CC=1>[CH2:5]([C:6]1[N:31]([CH2:32][C:33]2([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:20]=1)[CH3:4]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1

Procedure:
Triethylorthopropionate (2.4 mL, 12.0 mmol) and pyridine hydrochloride (60 mg, 0.5 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) in toluene (50 mL). The reaction mixture was heated at reflux for 2.5 hours and then concentrated under reduced pressure. The residue was triturated with acetonitrile and the filtered to provide 4-[(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a tan solid.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9](OC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:10][CH2:9][C:2]1[S:1][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2ccsc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cc2ccsc2s1
Reaction time: 3 h

Procedure:
A solution of methyl thieno[2,3-b]thiophene-2-carboxylate (19.8 g, 0.1 mol) in dry ether (750 mL) was added at a rapid drip rate (1 hour, 45 minutes) to a suspension of lithium aluminum hydride (7.59 g, 0.2 mol) in ether (500 mL) cooled in an ice-water bath. During the addition, precipitated material on the inside of the flask was kept suspended in the reaction medium. After the addition was complete stirring was continued at room temperature for 3 hours. The reaction mixture was cooled in an ice-water bath and there was added in succession, slowly, dropwise with vigorous stirring: water (7.6 ml); 20% aqueous NaOH (22.8 mL); water (7.6 mL); water (4 mL); 20% sodium hydroxide (12 mL); water (4 ml). Vigorous stirring was continued until a granular precipitate was obtained. The ether was decanted and the solids were washed by decantation three times with ether. The combined ether fractions were dried (MgSO4), filtered, and evaporated in vacuo to leave 16.33 g of white, solid 2-hydroxymethylthieno[2,3-b]-thiophene, m.p. 85°-87° C. Recrystallization from hexane gave material with m.p. 86°-87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:20])[CH2:10][N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[OH:20][CH:9]([CH2:10][N:11]1[CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19]1)[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH:3]=1
Reactant: Nc1cccc(C(=O)NCC(O)CN2Cc3ccccc3C2)c1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC(O)CN1Cc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of 3-amino-N-(2-hydroxy-3-(isoindolin-2-yl)propyl)benzamide (120 mg, 0.39 mmol) in MeOH (10 mL) was added dihydro-2H-pyran-4(3H)-one (78 mg, 0.78 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (123 mg, 1.95 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated, and the residue was dissolved in water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC purification. (22 mg, yield 14%) MS (ESI+) e/z: 396.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.62-7.53 (m, 2H), 7.53-7.36 (m, 5H), 7.30-7.21 (m, 1H), 4.76-4.57 (m, 2H), 4.34-4.24 (m, 1H), 4.08-3.96 (m, 2H), 3.74-3.65 (m, 1H), 3.65-3.57 (m, 2H), 3.57-3.43 (m, 4H), 3.36-3.32 (m, 2H), 2.03-1.91 (m, 2H), 1.72-1.57 (m, 2H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: OCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(OCCCCCO)c1ccccc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of benzoic acid (1 g), 1,5-pentanediol (5 mL) and p-toluenesulfonic acid (110 mg) was heated in an oil-bath at 100° C. overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (2×25 mL), washed with sodium carbonated (5%, 20 mL) followed by brine (15 mL). The organic layer was dried over anhyd. sodium sulfate, filtered and concentrated to give almost pure product (1.15 g, 67%).