Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]12[CH2:11][C:6]3([OH:12])[CH2:7][CH:8]([CH2:10][C:4]([OH:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.CN(C)C.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>C(Cl)Cl>[OH:1][C:2]12[CH2:11][C:6]3([O:12][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH2:7][CH:8]([CH2:10][C:4]([OH:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC12CC3CC(O)(CC(O)(C3)C1)C2

Procedure:
This 1,3,5-trihydroxyadamantane was dissolved in methylene chloride. To this solution were added a small amount of trimethylamine, and then an equimolar amount of trimethylsilyl chloride. Reaction was carried out at room temperature. The reaction product was partitioned by high performance liquid chromatography to obtain 1,3-dihydroxy-5-trimethylsiloxyadamantane.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(Cl)[Cl:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>CCCCCCC>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([Cl:19])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: ClCCl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
A solution of 374 g (1.48 mol) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.61 CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3-5° C. and treated in 10 min with 1.24l (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction temperature was raised to 35° C. over a period of 2 h. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4l of n-heptane, the reaction was evaporated to 2.9l, cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2 of CH2Cl2. The solvents were evaporated and filtered through silicagel with hexane/tert.-buthyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:16]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:17])[C:6]1=[O:26])([CH3:4])[CH3:3].Br[CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:2]([N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:16]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22][CH2:21]2)=[O:17])[C:6]1=[O:26])([CH3:4])[CH3:3]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCNCC1)c(=O)n2C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(C(C)C(=O)OC(C)(C)C)CC1)c(=O)n2C(C)C
Temperature: 70 °C
Reaction time: 23 h
Yield: 65 %

Procedure:
A mixture of 1-isopropyl-5-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydroquinoline-3-carboxamide hydrochloride (467 mg, 0.98 mmol, step 4 in preparation 3), tert-butyl 2-bromopropanoate (0.24 mL, 1.47 mmol), and triethylamine (0.41 mL, 2.93 mmol) in tetrahydrofuran (30 mL) was stirred at 70° C. for 23 h. After cooling to room temperature, the mixture was poured onto saturated aqueous sodium hydrogen carbonate (100 mL), and the aqueous layer was extracted with dichloromethane (100 mL×2). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ammonia/methanol/dichloromethane (0.1:1:30) to give 299 mg (65%) of the title compound as a yellow amorphous.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:19]I>CN(C)C=O>[CH:3]1([N:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)[CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(NC2CCCCC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc([N+](=O)[O-])cn1)C1CCCCC1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.38 g, 9.48 mmol) was washed 3× with hexanes then a solution of 2-cyclohexylamino-5-nitropyridine (1.88 g, 8.5 mmol) dissolved in dimethylformamide (20 mL) was added. After stirring for 30 minutes at 22° C., the reaction mixture was cooled to 0° C. and methyl iodide (0.55 mL, 8.9 mmol) was added. The solution was stirred for 1.5 hours at 0° C. followed by quenching with saturated aqueous NH4Cl. The reaction mixture was diluted with ethyl acetate and extracted 5× with water (200 mL), saturated NaCl, dried over Na2SO4 and concentrated in vacuo oil was chromatographed on SiO2 using 2:1 hexanes/ethyl acetate as eluent.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu](C#N)[C:14]#[N:15].O>CN1CCCC1=O>[F:10][C:5]1[C:6]([CH:7]=[O:8])=[CH:9][C:2]([C:14]#[N:15])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: COc1cc(F)c(C=O)cc1Br
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(F)c(C=O)cc1C#N
Temperature: 180 °C
Reaction time: 5.5 h
Yield: 25.8 %

Procedure:
5.33 g of 5-bromo-2-fluoro-4-methoxy-benzaldehyde was dissolved in 73 ml of 1-methyl-2-pyrrolidone, 2.46 g of copper cyanide was added under stirring at 180° C. for 5.5 hours. After cooling to room temperature, water was added to the reaction mixture. The mixture was extracted with ethyl acetate and filtered through Celite. Then, the resulting organic layer was washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography, to give 0.983 g of the title compound as pale yellow crystals.
Reaction SMILES: O(C)[Na].[C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:5].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH3:26])[C:21]([CH3:25])=[CH:22][C:23]=1N.O>CO>[CH3:26][C:20]1[C:21]([CH3:25])=[CH:22][C:23]2[NH:5][C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:17][C:18]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)NCC#N
Reactant: Cc1cc(N)c(N)cc1C
Agent: CO[Na]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc2nc(CNC(=O)OC(C)(C)C)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.3 g of a 30% NaOCH3 solution were added to tert-butyl cyanomethylcarbamate (0.4 g; 25.6 mmol) in 10 ml of CH3OH, and the mixture was stirred at room temperature for 1 h. After addition of 5.15 g of 4,5-diamino-ortho-xylene bishydrochloride, the reaction mixture was stirred overnight and then added to 100 ml of H2O, and the solid obtained by filtration was dried at 30° C. in vacuo. 0.5 g; ESI-MS [M+H+]=276
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:30]=[CH:29][N:15]4[C:16](=[O:28])[C:17]([CH:26]=O)=[C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:31]([CH2:36][CH:37]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1>[CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:30]=[CH:29][N:15]4[C:16](=[O:28])[C:17](/[CH:26]=[C:36](\[CH3:37])/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=Cc1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Temperature: 130 °C
Reaction time: 96 h
Yield: 369.1 %

Procedure:
8-[2-(4-Cyclobutyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carbaldehyde (100 mg, 0.236 mmol) dissolved in toluene (2 ml) was added with (carbethoxyethylidene)triphenylphosphorane (102 mg, 0.283 mmol) and refluxed by heating at 130° C. Then the regent was added until the reaction was completed, and 7 equivalents of the regent was finally added. After the reaction mixture was stirred for 4 days, the solvent was evaporated under reduced pressure, and the resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=40:1) to obtain 443 mg of yellow crystals in a mixture with triphenylphosphine oxide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].O>CN(C)C=O>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]=[CH:14][N:15]([CH3:17])[CH3:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1F
Reaction time: 1.5 h
Yield: 85 %

Procedure:
5 g of 2-fluoro-4-nitroaniline were dissolved in 35 ml of dry dimethylformamide, admixed at room temperature with 19.90 g of dimethylformamide dimethyl acetal and stirred for 90 min. For workup, 250 ml of water were added to the reaction mixture, and the precipitate was filtered off with suction, washed with water and dried. N′-(2-Fluoro-4-nitrophenyl)-N,N-dimethylformamidine was obtained in a yield of 85%. Molecular weight 211.07 (C9H10FN3O2); retention time Rt=0.49 min. [B]; MS (ESI):
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16].C(N(CC)CC)C>C(O)CCC>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1cccc(CNc2ncnc3nc[nH]c23)c1
Temperature: 90 °C
Yield: 95 %

Procedure:
3 mmol of 6-chloropurine were dissolved in 15 ml of butanol. Subsequently, 4 mmol of 3-chlorobenzylamine and 5 mmol triethylamine were added and the mixture was heated at 90° C. for 4 hours. After cooling, the precipitated product was filtered off, washed with cold water and n-butanol and crystallised from ethanol or dimethylformamide. M.p.=252° C., TLC(CHCl3:MeOH:conc. NH4OH (8:2:0.2, v/v/v)): single spot; HPLC: purity>98%. Yield 95%.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4]([N:7]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]2[S:19][C:20]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](S(C)(=O)=O)[N:25]=3)=[C:21]([CH3:23])[N:22]=2)=[O:16])[N:9]=[CH:8]1)([CH3:6])[CH3:5]>CS(C)=O>[C:1]([C:26]1[N:25]=[C:24]([C:20]2[S:19][C:18]([NH:17][C:15]([NH:14][CH2:13][CH2:12][C:10]3[N:9]=[CH:8][N:7]([CH:4]([CH3:6])[CH3:5])[CH:11]=3)=[O:16])=[N:22][C:21]=2[CH3:23])[CH:29]=[C:28]([CH3:30])[N:27]=1)#[N:2]
Reactant: Cc1cc(-c2sc(NC(=O)NCCc3cn(C(C)C)cn3)nc2C)nc(S(C)(=O)=O)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(-c2sc(NC(=O)NCCc3cn(C(C)C)cn3)nc2C)nc(C#N)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium cyanide (0.069 g, 1.4 mmol) is added to a stirred solution of 1-[2-(1-isopropyl-1H-imidazol-4-yl)-ethyl]-3-[5-(2-methanesulfonyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (0.21 g, 0.47 mmol) in dry DMSO (10 ml). The reaction is stirred at 50° C. under argon for 3 hours then the solvent is removed. The residue is dissolved in DCM and washed with water. The organic extract is dried (MgSO4) and the solvent removed to give the titled compound.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[CH:20]([CH3:22])[CH3:21])(=[O:3])[CH3:2].[CH:24]([NH2:28])([CH2:26][CH3:27])[CH3:25]>>[C:1]([C:4]1[C:5](=[O:23])[NH:6][C:7]2[C:12]([C:13]=1[NH:28][CH:24]([CH2:26][CH3:27])[CH3:25])=[CH:11][CH:10]=[CH:9][C:8]=2[CH:20]([CH3:21])[CH3:22])(=[O:3])[CH3:2]
Reactant: CCC(C)N
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)ccc(C(C)C)c2[nH]c1=O
Product: CCC(C)Nc1c(C(C)=O)c(=O)[nH]c2c(C(C)C)cccc12
Yield: 89.9 %

Procedure:
3-Acetyl-4-methylsulfoxy-8-isopropyl-2-quinolinone (2.91g, 0.01 mol) and sec-butylamine (0.73g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.7g, yield: 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: ClCCOCCCl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(N2CCOCC2)c1
Yield: 77.1 %

Procedure:
A solution of m-anisidine (11.2 mL, 0.1 mol), chloroethyl ether (11.7 mL, 0.1 mol), and diisopropylethylamine (35 mL, 0.2 mol) in toluene (100 mL) was stirred at reflux for 72 h. The precipitate was removed by filtration and washed with toluene (100 mL). The combined toluene solutions were concentrated in vacuo and purified by distillation (120-130° C., 0.2 Torr) to afford the intermediate 4-(3-methoxyphenyl)-morpholine (14.9 g, 77%).
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:25][C:26]([O:35][CH2:36][CH3:37])=[C:27]([CH2:29][C:30]([O:32]CC)=[O:31])[N:28]=2)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>CO.O>[CH2:1]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:25][C:26]([O:35][CH2:36][CH3:37])=[C:27]([CH2:29][C:30]([OH:32])=[O:31])[N:28]=2)=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(-c2nc(CC(=O)OCC)c(OCC)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccc(-c2nc(CC(=O)O)c(OCC)o2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a solution of 20 g of ethyl 2-(4-hexadecyloxyphenyl)-5-ethoxy-4-oxazoleacetate in 200 ml of methanol was added a solution of 7.6 g of sodium hydroxide in 20 ml of water under stirring at room temperature and stirred for about 3.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and the solution was acidified with hydrochloric acid to pH 1 under cooling. The precipitate was filtered off, dried and recrystallized from methanol to give 11.7 g of the title compound of white powder, m.p. 89°-91° C.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:38][OH:39])[CH2:29][CH2:30][C:31]3[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[N:16][CH:17]=1>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:38]([OH:39])[CH:5]=[O:7])[CH2:29][CH2:30][C:31]3[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)(=[O:25])=[O:26])[CH2:22][CH2:23]2)=[N:16][CH:17]=1
Reactant: O=S(=O)(CC(CCc1ncc(F)cn1)NO)N1CCN(c2ccc(Cl)cn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CCc1ncc(F)cn1)CS(=O)(=O)N1CCN(c2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (0.51 ml) was added directly to formic acid (2.0 ml) which had been cooled to 0° C. and then added a solution of 2-[4-[4-(5-chloropyridin-2-yl)piperazino]sulfonyl-3-(hydroxyamino)butyl]-5-fluoropyrimidine (0.485 g) in tetrahydrofuran (11 ml). The solution was stirred at room temperature for 3 hours and then evaporated in vacuo, the resulting residue was azeotroped with toluene and then it was dissolved in methanol and heated to 40° C. for 30 minutes. The solution was evaporated to dryness and then added diethylether and stirred at room temperature for 10 minutes, solid filtered, dried in vacuo to give N-[1-([4-(5-chloropyridin-2-yl)piperazino]sulfonylmethyl)-3-(5-fluoropyrimidin-2-yl)propyl]-N-hydroxyformamide, (0218 g), mp 154-155° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O.O.NN>C(O)COCCO>[CH:8]1([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(c1ccc[nH]1)C1CCCCC1
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: c1c[nH]c(CC2CCCCC2)c1
Yield: 69.3 %

Procedure:
A mixture of cyclohexyl pyrrol-2-yl ketone (17.7 g.) and 99% hydrazine hydrate (6.0 ml.) was heated under reflux in diethylene glycol (70 ml.) for 1.5 hours. The excess hydrazine hydrate and water were distilled off and the mixture was cooled. Potassium hydroxide (12.0 g.) was added portionwise and the mixture was then heated under reflux for 4 hours, cooled and poured into water (500 ml.). The mixture was extracted with ether (3×100 ml.) and the combined etheral extracts were washed with water (3×100 ml.) and dried over sodium sulphate. Evaporation of the ether gave an oil which was distilled to give 2-cyclohexylmethylpyrrole (11.3 g.), B.P. 137°-140° at 15 mm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])[C:28](Cl)=[O:29])([CH3:26])[CH3:25]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28](=[O:29])[N:27]([CH:31]([CH3:33])[CH3:32])[CH:24]([CH3:26])[CH3:25])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(C)N(C(=O)Cl)C(C)C
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N(C(C)C)C(C)C)nc3cc21

Procedure:
3-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-1,1-diisopropyl-urea was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.97 mmol) and diisopropyl carbamyl chloride (158 mg, 0.97 mmol). The title compound was obtained as yellow powder (55 mg, 12%).
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[N:7]1)C.CO.[OH-].[Li+].Cl>O1CCCC1>[CH3:11][C:9]1[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:12])=[O:3])[CH:10]=1
Reactant: CCOC(=O)Cn1cc(C)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(CC(=O)O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 0.51 g (3.0 mmol) of ethyl [4-methyl-1H-1,2,3-triazole-1-yl]acetate from step B above in tetrahydrofuran (10 ml), methanol (6 ml) was added 6 mL (6 mmol) of an aqueous 1.0 M lithium hydroxide solution. The resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was neutralized with 8 mL of a 2 N hydrochloric acid solution which was then evaporated to remove all volatiles. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound as a white solid (0.40 g, 95%). LC/MS 142 (M+1).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[CH2:22]([OH:25])[CH2:23][CH3:24].[OH-].[Na+]>O>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:21])[CH2:20][O:25][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCO
Reactant: CCOC(=O)CCCCCCC(CCCC1CO1)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCOCC(O)CCCC(CCCCCCC(=O)O)C(C)=O
Reaction time: 4 h

Procedure:
A mixture of ethyl 8-acetyl-12,13-epoxytridecanoate (14.9 g., 0.05 mole), propanol (60 ml.), sodium hydroxide (6.0 g., 0.15 mole) and water (15 ml.) is stirred 4 hours at 40°-45° and then heated 1 hour on the steam bath. The mixture is cooled, treated with water (250 ml.) and extracted with ether. The aqueous solution is acidified with hydrochloric acid. The oily product is taken up in ether, washed with water, and dried over sodium sulfate. Evaporation of the ether leaves the title compound as a pale yellow oil. Purification is effected by column chromatography on silica gel with 2% methanol in chloroform as the eluant.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]=1[C:7]#[N:8].[C:18](OC)(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:6]2[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)=[C:4]([CH3:17])[S:3][C:2]=2[NH:1][C:18](=[O:24])[C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1cccc(-c2c(C)sc(N)c2C#N)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1c(N)c2c(-c3cccc(OC)c3)c(C)sc2[nH]c1=O
Temperature: 25 °C
Yield: 41 %

Procedure:
To a solution of 2-amino-5-methyl-4-[3-(methyloxy)phenyl]-3-thiophene carbonitrile (Description 3) (2.80 g, 11.46 mmol) in toluene (75 mL) was added dimethyl malonate (1.31 mL, 11.46 mmol) and SnCl4 (2.68 mL, 22.92 mmol). The reaction mixture was then refluxed under nitrogen for ca. 2 h. The reaction mixture was then cooled to RT and concentrated in vacuo. The residue was partitioned between water and ethyl acetate (ca. 150 mL each) and the organic layer separated and washed with water (ca. 100 mL). The combined aqueous layer was re-extracted with ethyl acetate (ca. 100 mL). All organic layers were combined and passed through a phase separator and the mixture concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-60% ethyl acetate in DCM followed by 0-20% MeOH in DCM, to afford the title compound (1.62 g). LCMS (A) m/z: 343 [M−1]−, Rt 1.18 min (acidic).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:8]2[C:9]([Cl:11])=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][N:7]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1

Procedure:
Heat a solution of 5,6-dichloro-nicotinic acid ethyl ester (TCI America) (4.43 g, 0.02 mol), piperazine-1-carboxylic acid tert-butyl ester (4.13 g, 0.022 mol) and DIEA (5.2 mL, 0.03 mol) in DMA at 110° C. for 5 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the title compound as an orange oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:15]=O)[S:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12].C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8](/[CH:15]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[S:9][C:10]=1[Si:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: C[Si](C)(C)c1sc(C=O)cc1C1OCCO1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1cc(C2OCCO2)c([Si](C)(C)C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 4-(1,3-dioxolan-2-yl)-5-(trimethylsilyl)thiophene-2-carbaldehyde (12.82 g, 50.00 mmol) in chloroform (128 ml) was added methyl (triphenyl phosphanylidene)acetate (17.55 g, 52.50 mmol) at 0° C. by small portions. After stirring at 0° C. for 1 hr, the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, diethyl ether (200 ml) was added to the residue, and the mixture was stirred. The insoluble material (mainly triphenylphosphineoxide) was filtered, and washed 4 times with diethyl ether (50 ml). The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 450 g, ethyl acetate:hexane=1:6) to give methyl (2E)-3-[4-(1,3-dioxolan-2-yl)-5-(trimethylsilyl)thiophen-2-yl]acrylate (13.76 g, 44.04 mmol, yield 88.1%) as a pale-yellow oil.