Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10].[CH3:11][O:12][CH2:13][CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.Cl>C(OCC)C.BrC1SC=CC=1C>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccsc1Br
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COCCCc1sccc1C
Temperature: 30 °C

Procedure:
Magnesium turnings (365 mg, 15.0 mmol, 1.5 equiv.) were suspended in 15 ml dry diethyl ether. A crystal of iodine and a few drops of 2-bromo-3-methylthiophene in 10 ml ether were added till the reaction started (3 min. with heating to 30° C.). The remaining solution of 2-bromo-3-methylthiophene (total 2.44 g, 10.0 mmol, 1.0 equiv.) was added dropwise to maintain the reaction at reflux. The reaction mixture was refluxed for 30 min. Toluene-4-sulfonic acid 3-methoxy-propyl ester (2.13 g, 12.0 mmol, 1.2 equiv.) dissolved in 5 ml diethyl ether was added dropwise and the yellow solution was refluxed again for 2 hours. The brown suspension was cooled, acidified with 1N HCl and extracted twice with ethyl acetate. The combined organics were washed with KHSO4/K2SO4 and brine, dried over Na2SO4, filtered, evaporated and chromatographed on a 50 g Silicagel cartridge with heptane and than MTBE-heptane 1:9 as solvent to give 2-(3-methoxy-propyl)-3-methyl-thiophene, 410 mg, m/e 170.0 (MH+) by GC/MS.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=[O:9])C=1Cl.O.[CH3:16][C:17]1[CH:33]=[CH:32][C:31]2[C:19](=[CH:20][C:21]3[S:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:22]=3[CH:30]=2)[CH:18]=1>C(Cl)(Cl)Cl>[CH:29]1[C:23]2[C:22]3[CH:30]=[C:31]4[C:19](=[CH:20][C:21]=3[S:25][C:24]=2[CH:26]=[CH:27][CH:28]=1)[CH:18]=[C:17]([CH:16]=[O:9])[CH:33]=[CH:32]4
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc2cc3c(cc2c1)sc1ccccc13
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc2cc3c(cc2c1)sc1ccccc13
Yield: 22.8 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser and N2 inlet line with bubbler was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (Aldrich, 38.6 g, 0.119 mol), H2O (100 mL) and CHCl3 (1500 mL). After refluxing the mixture for 15 min, 8-methylbenzo[b]-naphtho[2,3-d]thiophene (Cambridge Chemicials, Inc., 21.0 g, 89.6 mmol) was aded to the flask. After refluxing the mixture for 5 h an additional portion of DDQ (19.3 g, 85 mmol) was added. The mixture was then refluxed overnight, cooled and the deep red solution filtered. The solvent was then removed by rotary evaporation and the residual H2O removed by azeotropic distillation with several portions of PhCH3. The material was then dissolved in PhCH3 (500 mL) and applied to a 40×10 cm column of SiO2 and eluted with additional PhCH3 as the solvent. The appropriate fractions were combined and the solvent removed to give 7.12 g of crude material. This was crystallized (PhCH3), filtered and dried to give 5.35 g (22.7% yield) of benzo[b]naphtho[2,3-d]thiophene-8-carbaldehyde, mp 182°-185°, (C,H,S).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][C:4](OCC)=[O:5].[CH3:15][NH:16][NH2:17]>CCO>[CH3:15][N:16]1[C:4]([OH:5])=[CH:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:17]1
Reactant: CCOC(=O)CC(=O)c1ccccn1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(-c2ccccn2)cc1O
Temperature: 85 °C
Yield: 78.8 %

Procedure:
To a solution of ethyl 3-oxo-3-(pyridin-2-yl)propanoate (25.00 g, 129 mmol, Matrix Scientific) in EtOH (60 mL) was added methylhydrazine (6.81 mL, 129 mmol). The mixture was heated at about 85° C. for about 3 h then cooled to rt and concentrated at rt under reduced pressure. The material was triturated with Et2O (40 mL). The solids were collected by filtration then washed with Et2O to give 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-ol (17.80 g, 79%). The filtrate was concentrated under reduced pressure then the material was triturated with 1:1 DCM/Et2O. The solids were collected by filtration and washed with Et2O to give a second crop of 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-ol (1.20 g, 5%): LC-MS (Table 1, Method g) Rt=1.05 min, m/z 176 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 11.05 (s, 1H), 8.50-8.47 (m, 1H), 7.83-7.80 (m, 1H), 7.78-7.69 (m, 1H), 7.24-7.19 (m, 1H), 5.90 (s, 1H), 3.57 (s, 3H).
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.[CH3:8][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]=[O:11].[NH4+].[Cl-].O>C1(C)C=CC=CC=1>[C:1]([CH:10]([OH:11])[C@@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:8])#[N:2]
Reactant: [C-]#N
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Temperature: -78 °C
Reaction time: 6 h

Procedure:
Diethylaluminum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was added dropwise to a stirred solution of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene (33 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. Saturated NH4Cl (20 mL) and water (10 mL) were added then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of diastereoisomers. Rf=0.63 (50% EtOAc in hexanes). LCMS calc.=257.1; found=257.1 (M+1)+. 1H NMR (500 MHz, CDCl3) major diastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31 (m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20](O)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(Br)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)n(-c3cccc(Br)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 98A in analogy to the synthesis of the compound of Example 23. 122 mg (52% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:24])[CH2:17][C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19].[NH2:25][C:26]([CH3:40])=[CH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)=[O:29].C(O)(=O)C>CC(O)C>[CH3:24][C:16]1[NH:25][C:26]([CH3:40])=[C:27]([C:28](=[O:29])[C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:32][CH:31]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCCOC(=O)CC(C)=O
Reactant: CC(N)=CC(=O)c1ccc(C(C)(C)C)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(C(C)(C)C)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 76 mg (0.53 mmol) of n-propyl 3-oxobutanoate, 115 mg (0.53 mmol) of 3-amino-1-[4-(tert-butyl)phenyl]but-2-en-1-one and 5 μl (0.053 mmol) of acetic acid in 8 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 170 mg (62% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [H-].[Na+].[H][H].[OH:5][C:6]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH2:15]([O:5][C:6]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(O)c1O
Reactant: [H][H]
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1cccc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
For example, sodium hydride (0.52 g, 21.7 mmol) is added to DMSO (20 ml) followed by an aldehyde of formula 11 wherein R3, R4 and R5 are hydrogen, i.e., 2,3-dihydroxybenzaldehyde, (2.8 g, 20.2 mmol). After stirring the solution for 1 h at ambient temperature, benzyl bromide 12 (2.4 ml, 20.2 mmol) was added forming a red-brown reaction mixture which was further stirred 12 h at ambient temperature. The solution was then partitioned between ethyl acetate (200 ml) and 0.5 N hydrochloric acid (300 ml). The organic layer was separated and MgSO4, filtered and concentrated to afford a brown oil. The brown oil is purified by flash chromatography (15% ethyl acetate/hexane) to give 3.21 g of 2-benzyloxy-3-hydroxy-benzaldehyde 16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][NH:12]2)[CH2:10][CH2:9]1.C=O.[C:25]([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:25])[CH2:9][CH2:10]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CC1)NCC2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Reaction time: 0.25 h

Procedure:
A mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.5 g, prepared as described in Example RC10), 37-40% aqueous formaldehyde solution (2.9 ml), sodium cyanoborohydride (0.75 g) and acetonitrile (100 ml) was stirred for 15 minutes. Glacial acetic acid was added to neutralise the solution and stirring was continued for a further 45 minutes. The mixture was basified with aqueous sodium hydroxide solution, then extracted with ethyl acetate. The extracts yielded 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([C:23]1[N:24]=[N:25][C:26](Cl)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:31][CH:30]=1)[CH2:20][CH2:21][CH3:22].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][O:16][C:26]1[N:25]=[N:24][C:23]([CH2:19][CH2:20][CH2:21][CH3:22])=[C:28]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:33][CH:34]=2)[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1CCO
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nnc(OCC[C@H]2CCCCN2C(=O)OC(C)(C)C)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (R)-2-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.87 mmol, 0.20 g) in DMF (1.0 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (2.61 mmol, 0.104 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.435 mmol, 0.15 g) in DMF (1.0 mL). After completion of addition, the reaction mixture was warmed to 50° C. for 12 hour. The reaction was poured into a mixture of water (10 mL) and ethyl acetate (5 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 cartridge using ethyl acetate/hexanes gradient to give (R)-2-{2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:18])/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].N1C=CC=CC=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>O1CCCC1.O>[CH3:18][N:2]([CH:3]=[C:4]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH3:1]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCC(=O)C(=CN(C)C)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of methyl (E)-4-[2-(dimethylamino)vinyl]-3-nitrobenzoate (500 mg), which was prepared by the method of Brown et al. described in Journal of Medicinal Chemistry, vol. 35, page 2419 (1992), and pyridine (0.16 ml) in tetrahydrofuran (3 ml) was added butyryl chloride (0.21 ml) at 20° C. The reaction mixture was stirred at 40° C. for 24 hours and 50° C. for 4 hours. After cooled to 20° C., the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:1) to give methyl 4-(1-dimethylaminomethylene-2-oxopentyl)-3-nitrobenzoate (426 mg) as colorless amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[CH:36]([N:39]([CH:43]([CH3:45])[CH3:44])[CH2:40][CH2:41][NH2:42])([CH3:38])[CH3:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:42][CH2:41][CH2:40][N:39]([CH:43]([CH3:45])[CH3:44])[CH:36]([CH3:38])[CH3:37])=[S:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CC(C)N(CCN)C(C)C
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCCN(C(C)C)C(C)C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, N,N-diisopropylethylenediamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (52 mg, yield 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([F:40])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[N:19]([CH:36]4[CH2:38][CH2:37]4)[C:18]=3[CH:39]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC[C:50]([N:52]=[C:53]=[O:54])=[O:51]>C1COCC1>[CH:36]1([N:19]2[C:18]3[CH:39]=[C:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]4)[C:15]([F:40])=[CH:16][C:17]=3[N:21]3[C:50](=[O:51])[NH:52][C:53](=[O:54])[CH:22]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=4)=[O:24])[CH:20]23)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(=O)OCc2ccc([N+](=O)[O-])cc2)n3C2CC2)CC1
Reactant: O=C=NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)N2C(=O)NC(=O)C(C(=O)OCc4ccc([N+](=O)[O-])cc4)C2N3C2CC2)CC1
Reaction time: 20 h
Yield: 59.7 %

Procedure:
A solution of p-nitrobenzyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazole acetate (553 mg, 1 mmol) in THF (50 ml) is treated in succession at 0° with triethylamine (300 mg, 3 mmol) and chloroacetyl isocyanate (298 mg, 2.5 mmol). After stirring for 20 hours the solvent is distilled off and the residues is taken up in ethyl acetate and washed in succession with water (50 ml) and 10 percent sodium chloride solution (50 ml). The organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is recrystallized from ethyl acetate. There are obtained 373 mg (59%) of p-nitrobenzyl 5-cyclopropyl-8-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-7-[4-(tert-butoxycarbonyl)-1-piperazinyl]pyrimido[1,6-a]benzimidazole-4-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].[CH2:18]=O>O>[CH2:13]([N:15]([CH2:18][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]2[C:8]=1[NH:7][C:6](=[O:12])[CH2:5][CH2:4]2)[CH2:16][CH3:17])[CH3:14]
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: CCNCC
Reactant: C=O
Solvent: O
Product: CCN(CC)Cc1ccc(O)c2c1NC(=O)CC2
Reaction time: 5 h

Procedure:
To a stirred suspension of 3,4-dihydro-5-hydroxycarbostyril (30 g, 184 mM) in water (300 mL) was added diethylamine (14 g, 191 mM) followed by a 36% solution of formaldehyde in water (300 mL). The mixture was stirred for 5 hours and the resulting precipitate was filtered and washed with ice-water (50 mL) to give 8-diethylaminomethyl-3,4-dihydro-5-hydroxycarbostyril.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[CH:9]=[CH2:10].[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22]>COC1C=CC(O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:20]([O:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH2:8][CH:9]=[CH2:10])=[CH:13][CH:14]=1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=CCOc1ccc(CO)cc1
Reactant: C=C(C)C(=O)O
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(COC(=O)C(=C)C)cc1
Yield: 80.4 %

Procedure:
To a 250 ml reaction flask fitted with a Dean-Stark water trap, condenser and magnetic stirrer was added toluene (100 ml), 4allyloxybenzyl alcohol (30.0 g; 0.18 moles), methacrylic acid (15.7 g; 0.18 moles), 4-methoxyphenol (0.6 g) and p-toluene sulfonic acid (0.23 g). The stirred solution was heated under reflux until all of the water was removed (2 hours). The solution was cooled and washed with an equal volume of sodium bicarbonate solution and then with sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent removed by distillation under reduced pressure to yield 4-allyloxybenzyl methacrylate (33.6 g; 81% yield) as an orange colored viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CCN(CC)CC.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])#[N:9]
Reactant: Cc1nsc(N)c1C#N
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1snc(C)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 5-amino-3-methylisothiazole-4-carbonitrile (method 4) (5.31 g, 38.2 mmol) in DCM (200 mL) at 0° C., NEt3 (5 g, 50 mmol) was added followed by the dropwise addition of a solution of the butyryl chloride (4.88 g, 45.8 mmol) in DCM (50 mL). After the completion of the addition the reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was washed with water (100 mL), 1N HCl (100 mL), brine (200 mL) and dried over Na2SO4. Concentration of the DCM layer provided the crude product which was triturated from DCM/hexanes ( 1/10) and filtered off to isolate the pure N-(4-cyano-3-methyl-isothiazol-5-yl)-butyramide (7.57 g, 95%) as an orange solid.
Reaction SMILES: [S:1]1([CH2:7][CH:6]=[CH:5][CH2:4]1)(=[O:3])=[O:2].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.[OH-].[Na+]>C(O)C>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[C:4]1[CH:5]=[CH:6][C:7](=[CH:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[S:1]1(=[O:3])=[O:2]
Reactant: O=S1(=O)CC=CC1
Reactant: O=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S1(=O)C(=Cc2cccs2)C=CC1=Cc1cccs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
About 80 mmol (9.4 g) of 3-sulfolene (MW=118) and 170 mmol (19.04 g) (15.9 ml) of thiophene-2-aldehyde (MW=112, d=1.2 g/cm3) were added to an alkaline solution of 1 g of NaOH in 200 ml of ethanol. The mixture was stirred at room temperature for 3 days. A yellow precipitate formed which was filtered off with suction and washed thoroughly with ethanol and water.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:17])[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:17])[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2c(C)cccc2C1=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc2c1CC(CC=O)C2=O
Reaction time: 1.5 h
Yield: 94 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 12.0 g of (RS)-2-(2-buten-1-yl)-4-methyl-1-indanone in 220 ml of anhydrous dichloromethane and 45 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 6.6 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 160 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 10.6 g (94%) of (RS)-2-(2-oxoethyl)-4-methyl-1-indanone were obtained as a light yellow oil.