Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23](O)=[C:22]([Cl:25])[C:21]([Cl:26])=[C:20]([Cl:27])[C:19]=1[Cl:28].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:17][C:18]1[C:23]([O:15][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[C:22]([Cl:25])[C:21]([Cl:26])=[C:20]([Cl:27])[C:19]=1[Cl:28]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Yield: 81.4 %

Procedure:
t-Butoxycarbonyl-D-methionine (20 g, 80.22 mmol) is added to a solution of pentachlorophenol (21.37 g) and dicyclohexylcarbodiimide (16.55 g, 80.3 mmol) in ethyl acetate (200 ml). After 2.5 h the solution is filtered after 2.5 h and the filtrate evaporated to dryness. The residue is recrystallised from hot methanol to give t-butoxycarbonyl-D-methionine pentachlorophenyl ester (32.5 g, 81.4%). A sample of this material (1.03 g, 2.14 mmol) is dissolved in DMF (10 ml) and to this solution is added hydroxylamine hydrochloride (0.149 g, 2.16 mmol) and diisopropylethylamine (0.91 ml, 5.2 mmol). After 16 h at room temperature the solvent is removed by evaporation and the residue partitioned between diethyl ether and 5% aqueous sodium carbonate. The aqueous phase (together with an insoluble oil which forms at the interface) is acidified by addition of citric acid to pH 6 and the product extracted twice with ethyl acetate. The combined ethyl acetate phases are washed successively with water and brine then dried over sodium sulfate. After the solvent is removed by evaporation the product is obtained as a crystalline solid by addition of a small amount of diethyl ether. A sample is recrystallised from ethyl acetate/hexane. mp 133°-134° C. 1H NMR δ (CDCl3) 8.50 (1H, broad s, --NH--), 5.58 (1H, m, urethane NH), 4.23 (1H, m, α--CH), 2.56 (H, m, γCH2), 2.09 (3H, s, S--CH3), 2.03 (1H, m, CH--CHAHB), 1.91 (1H, m, CH--CHAHB), 1.43 (9H, s, C(CH3)3); m/e (EI+) 265 (M+1), (CI-) 2.63 (M-1).
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20]>>[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([N:13]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:19](=[O:20])[CH2:18][C:17]([CH3:23])([CH3:22])[CH3:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]1)=[O:20]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: C1COCCNCCOCCOCCN1
Product: CC(C)(C)CC(=O)N1CCOCCOCCN(C(=O)CC(C)(C)C)CCOCC1

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(O)(=O)C.C(O)C.[Fe]>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a 0.2M solution of 4-bromo-2-nitrobenzaldehyde in acetic acid and ethanol (v/v 1:1) solvent system was added iron powder. The reaction mixture was stirred at ambient temperature under Argon for 1.5 h and LCMS showed the reaction was complete. Insoluble solid was filtered off and the filtrate was concentrated in vacuum. Residue was diluted with ethyl acetate and was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Crude product was purified by Biotage using 15% ethyl acetate in hexane to give desired product in 38% yield. ES/MS m/z 200/202 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH2:18]Br>CN(C=O)C>[CH3:14][O:15][N:16]=[C:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH2:18][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1]
Reactant: CON=C(CBr)c1ccc(C)cc1
Reactant: Oc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C(Cn1c(=O)ccc2ccccc21)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
To a suspension of 2-hydroxyquinoline (242 mg, 1.63 mmol) in DMF (5 mL) was added NaH (125 mg, 3.13 mmol). After 5 minutes of stirring at room temperature, 2-bromo-1-p-tolylethanone O-methyl oxime (400 mg, 1.65 mmol) was added and the mixture was stirred for 30 additional min. The mixture was poured on ice, extracted with Et2O, and dried over MgSO4. Purification by flash chromatography on silica gel (1% MeOH/CH2Cl2) gave a pure product in 28% yield: mp 129-132° C.; 1H NMR 400 MHz (DMSO-d6) δ 2.15 (s, 3H), 4.07 (s, 3H), 5.59 (s, 2H), 6.58 (d, 1H, J=9.2 Hz), 6.98 (d, 2H, J=7.0 Hz), 7.20 (m, 4H), 7.60 (s, 2H), 7.80 (d, 1H, J=8.8 Hz); Elem. anal. found: C, 74.12; H, 5.85; N, 9.00% (calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14%); MS (ESI) m/z 329.00 (MNa+).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22]>CS(C)=O.CCOC(C)=O>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C@@H:19]1[CH2:2][C@H:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)/C=C/c1ccc2ccccc2n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H]1c1ccc2ccccc2n1
Reaction time: 0.5 h

Procedure:
To a solution of tri-methylsulfoxonium iodide (495 mg, 2.25 mmol) in DMSO (4 mL) was added NaH (90 mg, 2.2 mmol) and the resulting mixture was stirred for 30 min. At this time compound 79a (400 mg, 1.87 mmol) was added in one portion and the resulting mixture was stirred overnight. The reaction mixture was then diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate (100 mL) and concentrated in vacuo to obtain a residue which was purified by flash column chromatography on silica gel (0-50% EtOAc-heptane) to afford compound 79b as a white solid. Mass spectrum (LCMS, ESI pos.) Calcd. For C14H13NO2 228.0 (M+H). found 228.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8]Cl)=[O:7])[CH3:2].[CH3:11][CH2:12][O-:13].[Na+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][O:13][CH2:12][CH3:11])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOCC(=O)CC(=O)OCC
Yield: 90.4 %

Procedure:
Using the method described in Example 1, 108.6 g of 4-chloroacetoacetic acid ethyl ester in 143 g of acetonitrile was reacted with 103.6 g of sodium ethylate. 4-ethoxyacetoacetic acid ethyl ester was obtained in a yield of 90.4 percent, related to the amount of 4-chloroacetoacetic acid ethyl ester used. The purity of the product was 98.5 percent.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:22]4[CH:21]=[N:20][C:29]5[C:24]([CH:23]=4)=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cnc2ccccc2c1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cnc5ccccc5c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoline-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoline.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]4)=[O:26])=[CH:20][C:19]=3[Cl:38])=[CH:14][CH:13]=2)[C:9]([CH3:39])=[N:8][C:7]=1[CH3:40])(=[O:5])[NH2:4]>CC(O)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]4[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]4)=[O:26])=[CH:20][C:19]=3[Cl:38])=[CH:16][CH:17]=2)[C:9]([CH3:39])=[N:8][C:7]=1[CH3:40])(=[O:5])[NH2:4]
Reactant: CCOC(=O)C1CCN(C(=O)Cc2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)N4CCC(C(=O)O)CC4)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
Potassium hydroxide (91 mg, 1.63 mmol) was added in one portion to ethyl 1-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetyl)piperidine-4-carboxylate (Intermediate 19-1; 290.7 mg, 0.54 mmol) in t-BuOH (3505 μL) at RT. The resulting solution was stirred at 45° C. for 5 hours a precipitate formed. The reaction mixture was quenched with 2M HCl (5 mL), The reaction mixture was evaporated to dryness and redissolved in water (10 mL), and filtered through nylon, washed with water and dried under vacuum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 1-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetyl)piperidine-4-carboxylic acid (59.8 mg, 21.71%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[C:27]([C:36](O)=[O:37])=[C:26]2[CH3:39])=[CH:21][CH:20]=1)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[C:27]([C:36]([N:1]3[CH2:6][CH2:5][C:4]4([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[C:8](=[O:15])[O:7]4)[CH2:3][CH2:2]3)=[O:37])=[C:26]2[CH3:39])=[CH:21][CH:20]=1)[CH3:17]
Reactant: CCOc1ccc(-n2c(C)c(C(=O)O)c3cc(OC)ccc32)cc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Product: CCOc1ccc(-n2c(C)c(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)c3cc(OC)ccc32)cc1

Procedure:
Following the general procedure I as described above, the acylation of 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one prepared as described in example 16, with commercially available 1-(4-ethoxyphenyl)-5-methoxy-2-methyl-1H-indole-3-carboxylic acid, gave the title compound. ES-MS m/e (%): 511.5 (M+H+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH:2]1[CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1.CCN(S(F)(F)[F:26])CC.O>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH:2]1[CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][F:26])[CH2:13][CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCC1CCC(C2COC3(CCCCC3)O2)CC1
Solvent: ClCCl
Solvent: O
Product: FCCC1CCC(C2COC3(CCCCC3)O2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The above 2-(4-(1,4-dioxaspiro[4.5]decyl)cyclohexyl)ethanol (20 g, 70.8 mmol) was dissolved in dichloromethane (70 ml), followed by dropwise adding to the solution, DAST (13 g, 80.7 mmol), stirring at 0° C. for one hour, adding water to the reaction solution, washing the resulting organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, distilling off the solvent, purifying the residue according to column chromatography using heptane/ethyl acetate as a developing solvent, on silica gel, to obtain 1-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)-2-fluoroethane, adding thereto formic acid (80 ml), refluxing the mixture for 2 hours, extracting the resulting product with toluene, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate, distilling off the solvent, to isolate 4-(4-(2-fluoroethyl)cyclohexyl)cyclohexanone (8.0 g, 35.3 mmol). The yield of this product from 2-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)ethanol was 49.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:57]1[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[C:59]([F:65])[CH:58]=1>C1(C)C=CC=CC=1>[F:65][C:59]1[CH:58]=[C:57]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[C:10]([F:11])([F:12])[F:13])[CH:64]=[CH:63][C:60]=1[C:61]#[N:62]
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(Br)cc1F
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ccc(C#N)c(F)c2)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
2-Amino-5-methoxy-benzotrifluoride (10.46 mmol), K3PO4 (15.7 mmol), Xphos (1.05 mmol) and Pd4(dba)3 (0.314 mmol) were added under nitrogen to a solution of 4-bromo-2-fluoro-benzonitrile (10.46 mmol) in 50 mL toluene and the mixture was stirred for 20 hours at a bath temperature of 110° C. Then the mixture was filtered through a glass fibre filter, then the filtrate was extracted with 150 mL water. The organic phase was dried on sodium sulphate and evaporated down. In this way the product was obtained in a yield of 87% of theory.
Reaction SMILES: [OH:1][C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2([CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)[O:3]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:3][C:4]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[CH:2]([OH:1])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: CN1CCC2(CC1)OC(O)(c1ccccc1)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccccc2C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.5 g. of 1,3-dihydro-3-hydroxy-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], Example 1, in 150 ml. of tetrahydrofuran is added dropwise in 30 minutes to a stirred suspension of 2.0 g. of lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes and at 50° for 1 hour, cooled, diluted cautiously with water, and extracted with chloroform. The chloroform solution is dried over potassium carbonate and concentrated to a solid. Recrystallization from benzene gives colorless crystals, m.p. 190°-191° of 4-hydroxy-4-(α-hydroxy-α-phenyl-2-tolyl)-1-methylpiperidine.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: OCCNCCO
Product: OCCN(CCO)Cc1ccc(F)cc1

Procedure:
2-[(4-Fluoro-benzyl)-(2-hydroxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (15.7 g, 150 mmol), and 4-fluoro-benzyl chloride (14.4 g, 100 mmol) 20 g of the product was isolated. Yield 20 g, (93%%); yellow oil; MS: 215 M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC(=O)CC>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:14]=1
Reactant: CCOC(=O)CCl
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3ccc(C)cc3)n2)c(O)c1
Yield: 79 %

Procedure:
55.4 g (0.15 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-(4-methylphenyl)-1,3,5-triazine are dissolved in refluxing 2-butanone (1 l) in the presence of 27.6 g (0.2 mol) of K2CO3. A catalytic amount (0.2 g) of KI is added, and 36.8 g (0.3 mol) of ethyl chloroacetate are added dropwise over 1 h 30. After refluxing for 25 h, the reaction mixture is cooled in ice, the precipitate is filtered off, washed with water to neutrality and then with methanol. Drying in the oven yields the analytically pure 2-(2-hydroxy-4-ethoxycarbonylmethoxyphenyl)-4,6-bis-(4-methylphenyl)-1,3,5-triazine (54 g, m.p. 166-167° C.) (Compound No. 47).
Reaction SMILES: O.Cl.[O-:3][CH2:4][CH3:5].[O-:6][CH2:7][CH3:8].[O-:9][CH2:10][CH3:11].[O-:12][CH2:13][CH3:14].[Si+4:15]>C(O)(C)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Si:15]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[CH:4]([OH:3])([CH3:7])[CH3:5]
Reactant: [Si+4]
Reactant: CC[O-]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)O
Solvent: O
Product: CCO[Si](OCC)(OCC)OCC

Procedure:
A silicalite-titania-silica hybrid membrane was prepared using the sol gel technique and suction method as follows. A silicalite-impregnated substrate was prepared as in Example 1. 0.4903 g H2O and 0.0789 g HCl (37% aqueous solution) were diluted in 9.000 g of anhydrous isopropanol. 2.5560 g of titanium tetraisopropoxide and 0.2080 g of silicon tetraethoxide were added to 9.0000 g of anhydrous isopropanol. The H2O--HCl--iPrOH solution was added slowly to the Ti(OiPr)4 --Si(OEt)4 -isopropanol solution with a magnetic stirrer to yield a titania-silica hybrid sol. A silicalite-titania-silica hybrid membrane was formed using the sol and the method of Example 1.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].Cl.[CH2:22](O)[CH3:23]>>[CH3:3][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:22][CH3:23])=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: CCO
Reactant: CC(C)c1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Agent: Cl
Product: CCOC(=O)c1ccc2nc3sc(C(C)C)cc3c(=O)n2c1
Temperature: 128 °C

Procedure:
A cooled suspension of 1.4 g (0.00486 mol) of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-7-carboxylic acid (Example 18) in 150 ml of ethanol is saturated with hydrogen chloride. The mixture is stirred and refluxed in a wax bath at 128° C. for eighteen hours under nitrogen. The ethanol is evaporated in vacuo to give 0.43 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, ethyl ester; mp 122°-123° C. after recrystallization from absolute ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([F:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([C:33](=[O:34])[C:32]2[CH:31]=[C:30]([F:29])[CH:38]=[C:37]([F:39])[CH:36]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3,5-difluorobenzoyl chloride gave the title compound.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[S:22]1[C:26](B(O)O)=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.C(=O)([O-])[O-].[K+].[K+].O>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>[S:22]1[C:26]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
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: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cc4ccccc4s3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), benzo[b]thien-2-ylboronic acid (103 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-(2-(benzo[b]thiophen-2-yl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.2 (d, 1H), 7.5 (d, 1H), 7.38 (s, 1H), 7.2-7.3 (m, 3H), 7.1 (d, 1H), 7.04 (d, 1H), 4.4 (m, 2H), 3.6 (m, 2H), 3.2 (m, 2H), 3.1 (s, 3H), 2.9 (m, 2H), 2.7 (m, 2H), 2.41 (s, 3H), 2.3 m, 2H).
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:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[NH2:21][C:22]1[CH:32]=[CH:31][C:25]2[NH:26][C:27](=[O:30])[CH2:28][S:29][C:24]=2[CH:23]=1>CCO>[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]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[N:21][C:22]1[CH:32]=[CH:31][C:25]2[NH:26][C:27](=[O:30])[CH2:28][S:29][C:24]=2[CH:23]=1
Reactant: Nc1ccc2c(c1)SCC(=O)N2
Reactant: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: CCO
Product: O=C1CSc2cc(N=Cc3cccc(OCc4ccc5ccccc5n4)c3)ccc2N1
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A liquid mixture of 1.316 g (5 mmol) of 3-(2-quinolinylmethoxy)benzaldehyde, 0.901 g (5 mmol) of 7-amino-3,4-dihydro-2H-1,4-benzothiazin-3-one and 70 ml of EtOH was heated under reflux and stirring for 24 hours. The mixture was then allowed to cool down. The precipitate was collected by filtration, whereby 1.969 g of the title compound were obtained as pale yellow powder (yield: 92.3%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23](OC(C)(C)C)=[O:24])=[N:21][CH:22]=3)[CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3].[CH3:30][NH2:31]>>[CH3:30][NH:31][C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:2]([CH3:3])[CH3:1])[CH2:5][CH2:6]3)[CH2:16][CH2:15]2)=[CH:22][N:21]=1)=[O:24]
Reactant: CN
Reactant: CC(C)N1CCC(CC2CCN(c3ccc(C(=O)OC(C)(C)C)nc3)CC2)CC1
Product: CNC(=O)c1ccc(N2CCC(CC3CCN(C(C)C)CC3)CC2)cn1

Procedure:
N-Methyl-5-(4-{[1-(1-methylethyl)-4-piperidinyl]methyl}-1-piperidinyl)-2-pyridinecarboxamide was prepared using an analogous process to that described in Examples 10 and 11 from 1,1-dimethylethyl 5-(4-{[1-(1-methylethyl)-4-piperidinyl]methyl}-1-piperidinyl)-2-pyridinecarboxylate (may be prepared as described in Example 4) and methylamine. The compound displayed 1H-NMR and mass spectral data that were consistent with structure. MS electrospray (+ion) 359 (MH+).