Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18].Cl[CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH2:17]([O:19][C:20]([C:22]1([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCOCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a pre-cooled THF solution under an argon atmosphere was added at −5° C. LDA (2 M, in THF/hepatane/ethylbenzene, 17.5 ml) and then dropwise a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (5 g) in THF, keeping the temperature at about −7° C. The mixture was stirred 2 hours between −10 and −5° C. then treated slowly and dropwise with benzyl chlormethyl ether (5.47 g) at −5° C. The mixture was stirred 1 hour at 0° C. and 48 h at RT. The solvent was evaporated off, the residue partitioned between AcOEt and water. The layers were separated, the organic layer washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 5%) to give the desired 4-Benzyloxymethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (5.79 g) as a light brown oil. MS (ESI): 378.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:30])[CH2:15][C:16]3[C:24]4[C:19](=[C:20]([C:25]([O:27]CC)=[O:26])[CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:30])[CH2:15][C:16]3[C:24]4[C:19](=[C:20]([C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Yield: 85.5 %

Procedure:
A solution of ethyl 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxo-1,3-oxazolidin-3-yl]propyl}-1H-indole-7-carboxylate (55 mg, 0.129 mmol) and potassium hydroxide (70 mg, 1.3 mmol) in water (1 mL) and ethanol (2 mL) is stirred at room temperature for 3 days. The reaction mixture is neutralized with 1N hydrochloric acid, and the precipitated crystals are collected by filtration to give the title compound (44 mg, yield: 86%).
Reaction SMILES: C(=O)(O)O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][CH2:17][C:18]([CH2:20][C:21](=O)[CH3:22])=O.C(=O)=O>C(OCC)C>[C:5]1([NH:11][C:12]2[N:14]=[C:21]([CH3:22])[CH:20]=[C:18]([CH2:17][O:16][CH3:15])[N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: COCC(=O)CC(C)=O
Agent: O=C(O)O
Agent: O=C=O
Solvent: CCOCC
Product: COCc1cc(C)nc(Nc2ccccc2)n1
Temperature: 100 °C
Yield: 92 %

Procedure:
A mixture of 7.5 g of phenylguanidine hydrogen carbonate and 7.4 g of methoxyacetylacetone is heated at 100° C. for four hours with stirring, the evolution of carbon dioxide which occurs subsiding as the reaction progresses. After the brown emulsion has been cooled to room temperature, 60 ml of diethyl ether are added and the whole is then washed three times with 20 ml of water each time, dried over sodium sulphate and filtered, and the solvent is evaporated. The 10.5 g of oily residue are dissolved in 140 ml of diethyl ether, and then 4.4 g of 65% nitric acid are added thereto with stirring. The suspension of the resulting nitrate salt is stirred for a further 20 minutes and is then filtered and washed with 100 ml of diethyl ether. 6 g of 30% sodium hydroxide solutions are added with stirring to a mixture consisting of 11 g of the nitrate sale, 80 ml of diethyl ether and 60 ml of water, the organic phase is separated off, washed twice with 40 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated. The 8.7 g of light-brown oily residue are crystallised with 100 ml of petroleum ether (b.p. 50°-70° C.), filtered and dried. The 8 g of pale, beige-coloured crystalline powder melt at 59°-60° C.; yield: 92% of the theoretical yield, relative to phenylguanidine hydrogen carbonate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([N+:21]([O-])=O)[C:16]([CH3:20])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]=1[CH2:24][N:25]([CH3:27])[CH3:26]>[Fe].C(O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[C:15]([NH2:21])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]=1[CH2:24][N:25]([CH3:26])[CH3:27]
Reactant: Cc1ccc2c(Nc3ccc(Cl)c(CN(C)C)c3)nccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(Nc3ccc(Cl)c(CN(C)C)c3)nccc2c1N
Yield: 59.1 %

Procedure:
Iron (202 mg, 3.25 mmol) and concentrated hydrochloric acid (0.02 mL) were added to ethanol/water (6.5 mL/6.5 mL), followed by refluxing for 1 hour. The mixed reaction solution was added with N-(4-chloro-3-((dimethylamino)methyl)phenyl)-6-methyl-5-nitroisoquinolin-1-amine (241.5 mg, 0.65 mmol) obtained in <Step 3> above, followed by refluxing for 1 hour. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with ethanol and chloroform/2-propanol=3/1 (v/v). The resulting filtrate was distilled under reduced pressure, and dissolved in chloroform/2-propanol=3/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (dichloromethane:methanol=9:1 (v/v)) to obtain the title compound (130.9 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a suspension of crude 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (846 mg, 3 mmol) in N,N-dimethylformamide (7.5 L) is added 4-(4-methyl-piperazin-1-yl)-phenylamine (573 mg, 3 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours, then evaporated to dryness and triturated with ether. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 1.23 g of 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7](Cl)[N:6]=1>CO>[Cl:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OC)nc(Cl)n1
Reaction time: 0.25 h

Procedure:
A 0.5 M solution of sodium methoxide in MeOH was added slowly to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (0.30 g, 1.45 mmol) in MeOH (2 ml). A white precipitate formed which was stirred for further 15 minutes. The product was collected by filtration (0.20 g).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[O:13]([C:15]#[N:16])[K]>O>[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:15]([NH2:16])=[O:13])[CH2:5][CH2:4]1
Reactant: NC1CCC(=O)c2sccc21
Reactant: N#CO[K]
Agent: Cl
Solvent: O
Product: NC(=O)NC1CCC(=O)c2sccc21
Temperature: 70 °C

Procedure:
The aqueous solution (280 ml.) of (+)-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride from Example 53 is stirred while 40 grams of KOCN in 95 ml. of water is added dropwise. The mixture is warmed to 70° C. for 1.5 hour and cooled to 10° C. The light brown solid is collected and washed well with 700 ml. of water. The product is then stirred with 110 ml. of cold methanol, collected, and washed with 50 ml. of cold methanol to afford 48 grams of the title compound, m.p. 247°-249.5° C. (dec.), [α]D24 =-97.16° (c, 0.14 in methanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([CH2:17][O:18][C:19](=[O:33])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N+]([O-])=O)=[CH:22]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C.O.[Cl-].[NH4+:40]>O1CCCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:17][O:18][C:19](=[O:33])[CH2:20][N:21]1[C:29]2[C:24](=[C:25]([NH2:40])[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:34])[CH3:10]
Reactant: [NH4+]
Reactant: CCOC(=O)C(COC(=O)Cn1cc([N+](=O)[O-])c2ccccc21)(C(=O)OCC)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(COC(=O)Cn1ccc2c(N)cccc21)(C(=O)OCC)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
The 2-[2-(3-Nitroindol-1-yl)acetoxymethyl]-2-phenylmalonic acid diethyl ester (100 mg) obtained in Example 9c) was dissolved in tetrahydrofuran (2 mL), ethanol (4 mL) and water (1 mL), and to the solution were added ammonium chloride (57 mg) and reduced iron (60 mg). The mixture was stirred at 100° C. for 2 hours, cooled, and filtered through a Celite pad. The filtrate was concentrated and diluted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, and concentrated to give the title compound (93 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[CH2:11]([Li])[CH2:12]CC.ICC.Cl>C(OCC)(=O)C.C1COCC1>[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7](=[O:8])[CH2:9][CH2:11][CH3:12]
Reactant: [Li]CCCC
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCI
Solvent: C1CCOC1
Product: CCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
44.4 g of sodium hydride suspension (60% in paraffin oil) is introduced into 1500 ml of THF, and 107.5 ml of acetoacetic acid methyl ester 3 is added under nitrogen at 0° C. After 10 minutes, 440 ml of n-butyllithium solution (2.5 M in hexane) is then added in drops, and it is stirred for another 30 minutes at 0C. Now, 88.9 ml of iodoethane is added, and it is stirred overnight at room temperature. For working-up, it is again cooled to 0° C. and neutralized with 4N hydrochloric acid. The organic phase is diluted with ethyl acetate, washed with thiosulfate solution and sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is then chromatographed on silica gel with ethyl acetate/hexane, whereby 95.13 g of title compound 13 is obtained as a colorless oil.
Reaction SMILES: [CH:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][Mg]Cl)=[CH:10][CH:9]=1.Cl>CCOCC>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][CH:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C=O
Reactant: Cl[Mg]Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)C(O)Cc1ccc(Cl)cc1
Yield: 98.7 %

Procedure:
A 10 ml quantity of ether solution of 4.3 g of (0.05 mole) of pivalaldehyde was added dropwise to a solution of p-chlorobenzylmagnesium chloride (0.055 mole) in 100 ml of ether with cooling and stirring. The mixture was thereafter stirred at room temperature for 1 hour and then placed into 5% aqueous solution of hydrochloride acid containing pieces of ice. After separating off the oily layer, the aqueous layer was subjected to extraction with ether. The ethereal extract and the oily layer were combined together, washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and distilled to remove the solvent, affording 10.5 g of the above-identified desired compound in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18]>C(Cl)(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(N)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 10.0 grams (0.071 mole) of 3-chloro-4-methylaniline in 100 ml of chloroform was added 16.7 grams (0.212 mole) of pyridine. Methyl chloroformate, 8.0 grams (0.085 mole), was then added dropwise during a 20 minute period. During the addition the reaction mixture temperature was held between 25°-30° C. with external cooling. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was washed into a separatory funnel with 50 ml of chloroform; and the solution was washed with two 100 ml portions of water and 100 ml of aqueous 5% hydrochloric acid. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a waxy solid residue. The residue was recrystallized from hexane/ethyl acetate to give 10.9 grams of methyl(3-chloro-4-methylphenyl)carbamate; m.p. 80°-81.5° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:21]=2)[NH:18][C:17]([C:29]2[S:30][CH:31]([CH2:34][C:35]([OH:37])=O)[CH2:32][N:33]=2)=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.O[N:40]1[C:44]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.CN>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH3:44][NH:40][C:35](=[O:37])[CH2:34][CH:31]1[S:30][C:29]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][C:9]2[CH:10]=[N:11][C:6]([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)=[CH:21][C:20]=3[O:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[N:33][CH2:32]1
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(CS(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of {2-[5-({6-[(methylsulfonyl)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (200 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (84 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg), methylamine hydrochloride (37 mg), and triethylamine (0.080 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) and crystallized from acetonitrile. The obtained crystals were recrystallized from ethyl acetate and diethyl ether to give the title compound (148 mg, yield 72%) as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:18]#[N:19])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: N#Cc1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-cyano-phenylboronic acid to give 3-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 312(MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)(=[O:3])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCN1CCC(CO)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)OCCCN1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.36 g (6.30 mmol) of the compound from Example 27A are dissolved in 14 ml dry dichloromethane, and 3.39 g of molecular sieve (4 Å), 1.11 g (9.44 mmol) of N-methylmorpholine N-oxide and 111 mg (0.32 mmol) of tetrapropylammonium perruthenate are added in succession. The reaction mixture is stirred at RT for 1 h and then directly purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 100:1→10:1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15](O)=[O:16])=[CH:5][C:4]=2[NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.CO>O1CCOCC1.C(Cl)Cl>[OH:16][CH2:15][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[S:14][CH:13]=[CH:12][C:11]=3[C:2](=[O:1])[NH:3][C:4]=2[CH:5]=1
Reactant: O=C(O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c2cc(CO)ccc2c2sccc12
Temperature: 100 °C
Yield: 33.5 %

Procedure:
4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylic acid (1.0 eq, 38 mg, 0.155 mmol) was suspended in dioxane (1 ml). LiAlH4 (7.0 eq, 40 mg, 1.05 mmol) was added and the mixture stirred at 100° C. for 45 nm. Water was added, then MeOH and CH2Cl2. The solid salts were filtered off and washed with MeOH and CH2Cl2. After evaporation of the volatiles in vacuo, the material was dissolved in a mixture of NMP, MeOH and water and was purified by preparative HPLC. Genevac evaporation afforded 7-(hydroxymethyl)thieno[3,2-c]quinolin-4(5H)-one as an off-white solid (12 mg, 34%). LCMS (ES): 95% pure, m/z 232 [M+1]+; 1H NMR (DMSO-d6, 400 MHz) δ 4.56 (s, 2H), 7.15 (d, J=7.6, 1H), 7.39 (br s, 1H), 7.55 (d, J=5.2, 1H), 7.73 (d, J=5.2, 1H), 7.76 (d, J=8.0, 1H), 11.73 (s, 1H) ppm.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]2[O:19][CH:7]2[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClC=CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClC=CCC1=CC2OC2C=C1
Reaction time: 72 h
Yield: 55.6 %

Procedure:
24.6 g of p-chloroallylbenzene was dissolved in 100 ml of chloroform and to the mixture was added dropwise, while maintaining the temperature at 0° - 5° C, 34.5 g of m-chloroperbenzoic acid dissolved in 1l of chloroform. The resulting mixture was allowed to stand at the same temperature for 72 hours. After the separated m-chlorobenzoic acid was filtered off, the filtrate was washed with 10% sodium hydroxide solution, then with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 15.1 g (yield 55.7%) of p-chloroallylbenzene oxide having a boiling point of 96° C/2.5 mmHg.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([NH-:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.O=S(Cl)Cl.[OH-].[K+]>O.CCOC(C)=O.CCCCCCC>[C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)#[N:12]
Reactant: [NH-]C(=O)c1cccc2c1OCC2
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: N#Cc1cccc2c1OCC2
Temperature: 70 °C
Yield: 99 %

Procedure:
To a suspension of (2) (10 g, 61.28 mmol) i dry toluene (50 ml) was added SOCl2 (12 ml, 164.92 mmol) under N2. The reaction mixture was heated to 70° C. for 1 h. and then to 90° C. until TLC (AcOEt/Heptane 1:1) indicated complete reaction Water (20 ml) was slowly added to the ice cooled reaction mixture followed by 50% KOH until pH≈8. The organic layer was separated, and the aqueous layer was extracted with toluene (3×50 ml). The combined organic layers were washed with water (2×30 ml), brine (1×30 ml), dried (Na2SO4), and evaporated in vacuo to yield (3) as a solid (8.81 g, 99%). Recrystallization from abs. EtOH gave (3) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH3:18][C:19]1C=CC=C(C)[C:20]=1CN1C2C(=CC=C(C(O)=O)C=2)C(C)=C1>>[CH2:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)[CH:19]=[CH2:18]
Reactant: Cc1cccc(C)c1Cn1cc(C)c2ccc(C(=O)O)cc21
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Product: C=CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2

Procedure:
The titled compound (5.7 g) as a colorless oil was prepared from tert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate (7.5 g) obtained with the method described in the document (WO 1998/43956 A) according to the method of the process (2) of Example 66.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]2[S:4][C:3]([CH2:2][N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]4[S:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=1
Reactant: COc1cc2nc(CCl)sc2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5s4)CC3)sc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxybenzothiazole (200 mg) and homopiperazine (37 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.