Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1OC[O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]([C:33](=O)[CH:34]([CH3:36])[CH3:35])[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[CH:17][CH:16]=1.C(OCC)C.[Cl-].[NH4+]>CS(C)=O.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:1]([CH2:2][CH2:3][C@H:4]3[CH2:5][C@H:6]([OH:7])[CH2:10][C:11](=[O:12])[O:13]3)[C:33]([CH:34]([CH3:36])[CH3:35])=[C:23]([C:24]([NH:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:25])[C:22]=2[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:19][CH:20]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCC[C@@H]1C[C@H](CC(=O)O)OCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@H]1C[C@H](O)CC(=O)O1
Reaction time: 18 h
Yield: 23.1 %

Procedure:
A solution of 0.26 g (1.21 mmol) of (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) of (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N, β-diphenylbenzenebutaneamide in 5 mL of dimethyl sulfoxide is heated at 105° C. for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2×50 mL) and 5% sodium hydroxide solution (2×100 mL - to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1methyl ethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.15 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two crops.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1cccc(Cl)c1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(Cl)c4)cc3)c2)o1

Procedure:
N-(3-Chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-chlorobenzylamine using method N. NMR; δH [2H6]—DMSO 9.19,(1H, t), 8.00,(2H, t), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.52,(3H, m), 7.39-7.29,(4H, m), 4.51,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.56 min, MH+ 418/420.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:33][C:31]=2[NH2:32])[CH2:26][CH2:25]1.Cl.O1CCOCC1>CO>[N:27]1([C:30]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:33][C:31]=2[NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:3]=2[CH3:23])[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1
Reactant: Cc1c(-c2ccccc2F)nc2cc(C(F)(F)F)ccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cc(C(F)(F)F)ccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-2-(2-fluorophenyl)-3-methyl-7-(trifluoromethyl)quinoline (129 mg, 0.38 mmol), 2,5-dimorpholinoaniline (100 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.095 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-2-(2-fluorophenyl)-3-methyl-7-(trifluoromethyl)-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (1H, s), 8.04 (1H, d, J=8.6 Hz), 7.58-7.72 (2H, m), 7.46-7.54 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.30-7.40 (2H, m), 7.17-7.24 (1H, m), 7.13 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.6, 2.7 Hz), 6.04 (1H, d, J=0.8 Hz), 3.92 (4H, t, J=4.7 Hz), 3.69-3.80 (4H, m), 3.06 (4H, br. s.), 2.82-3.00 (4H, m), 2.24 (3H, s). Mass Spectrum (ESI) m/e=567.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([N:17]1[CH2:22][CH2:21][C:20](OC)(OC)[CH2:19][CH2:18]1)(=[O:16])[CH3:15].C(N1CC=C(OC)CC1)(=O)C>>[CH3:13][O:12][C:9]1[C:10]2[O:11][C:20]3([O:1][C:2]=2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1)[CH2:21][CH2:22][N:17]([C:14](=[O:16])[CH3:15])[CH2:18][CH2:19]3
Reactant: COC1(OC)CCN(C(C)=O)CC1
Reactant: COc1ccc(C(=O)O)c(O)c1O
Agent: COC1=CCN(C(C)=O)CC1
Product: COc1ccc(C(=O)O)c2c1OC1(CCN(C(C)=O)CC1)O2
Temperature: 180 °C
Yield: 26.3 %

Procedure:
A mixture of 2,3-dihydroxy-4-methoxybenzoic acid (1.23 g, 6.67 mmol), 1-acetyl-4,4-dimethoxy-piperidine (1.4 g, 7.6 mmol) and 1-acetyl-1,2,3,6-tetrahydro-4-methoxy-pyridine (14.2 g, 91.5 mmol) was exposed to microwave heating (180° C., one hour) in a sealed reaction vessel. Filtration and subsequent standard HPLC purification afforded compound 508 (0.54 g, 26%). LC/MS (METHOD B): (m/z) 308.2 (MH+); RT=2.27 min; purity (UV)=95%.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[C:9]1([CH2:15][S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([NH:21][NH2:22])=[O:20])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1>[C:9]1([CH2:15][S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]2[O:20][C:2](=[O:3])[NH:22][N:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NNC(=O)c1ccccc1SCc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccccc2SCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution containing 12.2 g of trichloromethyl chloroformate in 130 ml of p-dioxane was added portionwise 16 g of 2-[(phenylmethyl)thio]benzoic acid, hydrazide [prepared by the procedure of South African Patent Application No. 838,416 (1983)] to cause a slight exotherm to 37° C. After stirring at ambient temperature for 0.5 hr., the suspension was refluxed for 6 hours, then cooled to 25° C. and poured onto excess ice/water to yield a precipitate. The mixture was filtered, washed with water and the isolated solid was recrystallized from acetonitrile to yield 14 g of the subject compound: m.p. 169°-172° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[N:15]1([CH2:14][CH2:13][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: ClCCN1CCOCC1
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of 4-cyanophenol (5.95 g, 0.05 mol) in DMF (35 ml) at 0° C. is added 60% NaOH (2.2 g, 0.055 mol). The reaction mixture is stirred at 0° C. for 15 minutes, then at room temperature for 15 minutes and then N-(2-chloroethyl)morpholine (prepared from 11.16 g, 0.06 mol of the hydrochloride salt) is added, and the reaction mixture is stirred at room temperature for about two days. There is still a small amount of starting material present so the reaction mixture is heated on a steam bath for 4 hours. The reaction mixture is cooled to room temperature and then the solvent is removed. Ice water is added to the residue, and the solid which precipitats is collected by filtration and dried to afford 11.3 g (97%) of 4-[2-(4-morpholinyl)ethoxy]benzonitrile.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:12]([CH3:14])[CH3:13])[N:8]=[C:9]([CH3:11])[N:10]=1)=O)C.[Br:15][CH2:16]Br.C[Li].C(O)(=O)C>C1COCC1.O>[Br:15][CH2:16][C:4]([C:6]1[N:7]([CH:12]([CH3:14])[CH3:13])[N:8]=[C:9]([CH3:11])[N:10]=1)=[O:3]
Reactant: CCOC(=O)c1nc(C)nn1C(C)C
Reactant: BrCBr
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(C(=O)CBr)n(C(C)C)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-isopropyl-5-methyl-2H-[1,2,4]triazole-3-carboxylic acid ethyl ester (12.09 g, 61.3 mmol) and dibromomethane (8.63 mL, 122.6 mmol) in THF (500 mL) at −78° C. was added methyllithium (40.9 mL, 122.6 mmol, 3M solution in diethoxymethane) dropwise. The reaction mixture was stirred at −78° C. for 15 min. Acetic acid (3 mL) was added and the reaction mixture allowed to warm to RT. The reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to give 2-Bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone as a colourless oil which crystallised on standing (11.26 g, 75%). 1H NMR 400 MHz (CDCl3) δ: 5.41 (1H, sept, J=6.6 Hz), 4.67 (2H, s), 2.44 (3H, s), 1.49 (6H, d, J=6.6 Hz)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[N:10][C:11]([Cl:17])=[CH:12][CH:13]=2)[N:8]=1.C(N(CC)CC)C.C(OC(C)C)(C)C>C(Cl)Cl>[Cl:17][C:11]1[N:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])=[N:8]2)=[CH:13][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc2ccc(Cl)nc2n1
Yield: 8.3 %

Procedure:
Acryloyl chloride (42 g) is added with stirring in the course of 30 minutes to a solution of 2-amino-7-chloro-1,8-naphthyridine (54 g) and triethylamine (115 g) in methylene chloride (1875 cc). The solution obtained is heated for 1 hour under reflux and then poured into isopropyl ether (5000 cc). The precipitate obtained is filtered off, washed with isopropyl ether (3×200 cc) and then water (3×200 cc) at 40° C. and dried in the air. The crude product obtained is purified by flash chromatography (under 50 kPa) on a column 60 mm in diameter containing silica (500 g; 0.04-0.06 mm), eluting with a mixture (99:1 by volume) of methylene chloride and methanol and collecting 100-cc fractions. After concentration of fractions 5 to 10 to dryness at 40° C. under reduced pressure (4 kPa), N-(7-chloro-1,8-naphthyridin-2-yl)acrylamide (5.85 g), m.p. 200° C., is obtained.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.[O:23]=[C:24]([CH3:29])[CH2:25][C:26]([NH2:28])=[O:27]>>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:28]=[C:26]([OH:27])[C:25]([C:24](=[O:23])[CH3:29])=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=2)=[CH:12][CH:11]=1
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(F)cc2)n1
Reactant: CC(=O)CC(N)=O
Product: CSc1nccc(-c2cc(C(C)=O)c(O)nc2-c2ccc(F)cc2)n1

Procedure:
Following a similar procedure to that described in reference example 10, but starting from 3-(dimethylamino)-1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one (obtained in reference example 20) and 3-oxobutyramide, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19]([Cl:26])[C:18]=1[CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([Si:44](Cl)([CH3:46])[CH3:45])([CH3:43])([CH3:42])[CH3:41].Cl>C(Cl)Cl>[Si:44]([O:30][CH2:29][CH:28]([OH:31])[CH2:27][C:18]1[C:19]([Cl:26])=[N:20][C:21]2[N:22]([N:23]=[CH:24][CH:25]=2)[C:17]=1[N:7]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)[C:6](=[O:32])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:45]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(O)CO)c(Cl)nc3ccnn23)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(O)CO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To a methylene chloride (3.6 mL) solution containing tert-butyl[5-chloro-6-(2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (500 mg, 1.08 mmol), triethylamine (300 μL, 2.16 mmol), tert-butylchlorodimethylsilane (195 mg, 1.30 mmol) and N,N-dimethylpyridine (13 mg, 0.108 mmol) were added. After the reaction mixture was stirred at room temperature for 5 hr, 1 mol/L hydrochloric acid was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography to obtain the title compound (503 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Br:10]Br>C(Cl)Cl.[Fe]>[Br:10][C:6]1[CH:5]=[CH:4][C:3]([S:8][CH3:9])=[C:2]([CH3:1])[CH:7]=1
Reactant: CSc1ccccc1C
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: CSc1ccc(Br)cc1C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a 0° C. solution of 2-methylthioanisole (0.50 g, 3.57 mmol) in methylene chloride (40 mL) was added powdered Fe (20 mg, 0.36 mmol) followed by dropwise addition of bromine (0.58 g, 3.54 mmol). After 30 minutes, the starting material had been consumed (thin layer chromatography, hexanes). The excess bromine was quenched by adding a solution of NaHSO3 and stirring for several minutes. The methylene chloride layer was separated, and the aqueous phase extracted with additional methylene chloride. The combined methylene chloride solution was dried over MgSO4, filtered, and concentrated in vacuo. The resultant oil was chromatographed (flash silica gel, ethyl acetate/hexanes 1:49) to provide the product (yield: 0.74 g, 96%). 1H NMR (300 MHz, CDCl3) δ 2.30 (s, 3H), 2.45 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.27–7.33 (m, 2H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[N:29]1([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.N1CCCCC1>CN(C)C=O>[N:29]1([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:40]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:41][CH:42]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
1.5 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 1.1 g of 4-(piperidin-1-yl-methyl)-aniline are dissolved in 15 ml of dimethylformamide and stirred for 45 minutes at 100° C. After cooling 5.0 ml of piperidine are added and the mixture is stirred for another 3 hours at room temperature. The solvent is removed and the residue purified over an aluminium oxide column (activity: 2-3) with methylene chloride/ethanol (100:3) as eluant.
Reaction SMILES: C(O[C:4](=[O:22])[C:5](=[N:12][NH:13][C:14](=[O:21])[CH2:15][C:16]([O:18]CC)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[NH:23](C(=O)CC(OCC)=O)N.[C:33]([C:41]([O:43]CC)=[O:42])(=O)C1C=CC=CC=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[OH:22][C:4]1[C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:12][NH:13][C:14](=[O:21])[C:15]=1[C:16]([NH:23][CH2:33][C:41]([OH:43])=[O:42])=[O:18]
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)NN=C(C(=O)OCC)c1ccccc1
Reactant: CCOC(=O)CC(=O)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)c(-c2ccccc2)n[nH]c1=O
Yield: 25 %

Procedure:
Ethyl 3-{2-[2-(ethyloxy)-2-oxo-1-phenylethylidene]hydrazino}-3-oxopropanoate. A mixture of ethyl 3-hydrazino-3-oxopropionate (1.46 g, 10.0 mmol), ethyl benzoylformate (2.14 g, 12.0 mmol), acetic acid (0.5 mL, 8.3 mmol) and dichloromethane (10 mL) was stirred at room temperature with excess anhydrous magnesium sulfate for 20 h, then filtered and the cake washed with ethyl acetate. The filtrate was evaporated under reduced pressure, azeotroped 3 times with toluene and chromatographed (silica gel, 10-3-% ethyl acetate/hexane) to give the title compound (0.773 g, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=7.07 Hz, 3H) 1.30 (t, J=7.07 Hz, 3H) 3.74 (s, 2H) 4.08 (q, J=7.07 Hz, 2H) 4.40 (q, J=7.18 Hz, 2H) 7.42-7.49 (m, 3H) 7.55-7.59 (m, 2H) 11.57 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]=1[CH2:21][CH3:22]>>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:10][CH:9]2[CH2:8][N:7]([CH3:11])[CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:16][C:15]=1[CH2:21][CH3:22]
Reactant: CCc1cc(O)ccc1Cl
Reactant: Cc1cc2c(o1)CN(C)CC2O
Product: CCc1cc(OC2CN(C)Cc3oc(C)cc32)ccc1Cl
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 4-chloro-3-ethylphenol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=O)=[CH:6][CH:5]=1)=O.S([CH2:23][N+:24]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[OH2:32]>COCCOCCOC.C(O)(C)(C)C>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[C:23]#[N:24])=[CH:9][CH:8]=1)([O-:12])=[O:32]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOCCOC
Product: CC(C#N)c1ccc([N+](=O)[O-])cc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A −15° C. solution of 4-nitroacetophenone (16.5 g, 100 mmol) and tosylmethyl isocyanide (29.3 g, 150 mmol) in methoxyethyl ether (400 mL) was slowly treated with a room temperature solution of the potassium t-butoxide (28 g, 250 mmol) in t-butanol (200 mL). The reaction mixture was stirred at −15° C. for 1 h and then allowed to warm to room temperature over night. Water (100 mL) was added to the mixture and organic was extracted with ether (3×200 mL). The combined organic fraction was washed with water (3×200 mL), brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (SiO2, 30% EtOAc:Hexanes) to give 13.6 g (77%) of the title compound. The NMR spectrum was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+=225.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: C=Cc1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4ccccc42)CN(C)CC3)cc1
Yield: 2.1 %

Procedure:
2,3,4,5-Tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 1.07 mmol), 4-methylstyrene (1.41 mL, 10.7 mmol) and NaH (250 mg, 60% dispersion in oil, 6.25 mmol) in DMF (6 mL) at 200° C. for 16 h to obtain 7 mg of 2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole after purification. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.45-7.40 (d, 2H), 7.25-7.16 (m, 2H), 7.1-6.9 (d, 2H), 6.8-6.7 (d, 2H), 4.7 (d, 1H), 4.4-4.3 (m, 1H), 4.20-4.03 (m, 2H), 3.55-3.40 (m, 1H), 3.22-3.10 (m, 1H), 3.09-2.90 (m, 2H), 2.83 (s, 3H), 2.65 (m, 1H), 2.35 (s, 3H), 2.2 (m, 1H).
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+].O>CO>[OH:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 8-acetoxy-5,6,7,8-tetrahydroquinoline (99.2 g) in methanol (450 mL) was added K2CO3 (144 g, 1.04 mol) and the mixture was stirred at room temperature overnight. The mixture was poured into water (500 mL) and extracted with CHCl3 (3×500 mL) and the combined organic extracts were dried (Na2SO4), and concentrated to provide 71.6 g of 8-hydroxy-5,6,7,8-tetrahydroquinoline as a brown oil. A purified sample (silica gel, 25:1 CH2Cl2-CH3OH) exhibited the following spectral properties: 1H NMR (CDCl3) δ 1.75–1.89 (m, 2H), 1.96–2.06 (m, 1H), 2.25–2.33 (m, 1H), 2.74–2.90 (m, 2H), 4.23 (br s, 1H, OH), 4.72 (dd, 1H J=7.8, 6.3 Hz), 7.12 (dd, 1H, J=7.5, 4.8 Hz), 7.41 (d, 1H, J=7.5 Hz), 8.41 (d, 1H, J=4.8 Hz); 13C NMR (CDCl3) δ 19.60, 28.84, 31.27, 68.87, 122.74, 132.19, 137.40, 147.06, 158.50. ES-MS m/z 150 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[O:15][CH3:16])[N:4]=1.[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[C:3]([CH2:2][O:27][C:26]3[C:18]([F:17])=[C:19]([C:23]([F:28])=[CH:24][CH:25]=3)[C:20]([NH2:22])=[O:21])[S:7][N:6]=2)=[C:9]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cc(Cl)ccc1-c1nsc(CBr)n1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1-c1nsc(COc2ccc(F)c(C(N)=O)c2F)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.6 %

Procedure:
To a solution of 5-(bromomethyl)-3-(4-chloro-2-methoxyphenyl)-1,2,4-thiadiazole (0.06 g, 0.19 mmol) in DMF (4 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.029 g, 0.17 mmol) and potassium carbonate (0.091 g, 0.66 mmol). The reaction mixture was stirred at room temperature for 90 min under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 25 ml water and extracted with ethyl acetate (3×25 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 100% EtOAc) to get the desired product (0.02 g, 26%).