Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]([CH2:10][C:11]1[CH:12]=[C:13]2[C:20]([CH3:21])=[N:19][N:18]([CH3:22])[C:14]2=[N:15][C:16]=1[Cl:17])[C:8]#[N:9].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(OCC)(=O)C>O.[Br-].[Zn+2].[Br-]>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:25]=1)[CH2:6][N:7]([CH2:10][C:11]1[CH:12]=[C:13]2[C:20]([CH3:21])=[N:19][N:18]([CH3:22])[C:14]2=[N:15][C:16]=1[Cl:17])[C:8]1[N:32]=[N:33][NH:34][N:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nn(C)c2nc(Cl)c(CN(C#N)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 164.4 %

Procedure:
A mixture of (3,5-bis-trifluoromethyl-benzyl)-(6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethyl)-cyanamide (8.5 g, 10 mmol), sodium azide (1.4 g, 20 mmol), and zinc bromide (4.1 g, 10 mmol) in water (300 mL) was refluxed for 3 h. The reaction mixture was cooled to RT, 5% hydrochloric acid (50 mL) and ethyl acetate (500 mL) were added, and the resulting mixture was stirred for 20 min, after which time the organic layer was separated. This process was repeated 3 more times with ethyl acetate (3×500 mL). The combined organic layers were dried and concentrated, and the residue was purified by column chromatography over 230-400 mesh silica gel. Elution of the column with 15% ethyl acetate in hexanes gave the pure product as a colorless solid (8.3 g), yield: 90%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[Cl:20]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:20][C:17]1[N:16]=[CH:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: FC(F)(F)c1cccc(-c2ccnc3cncn23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Cl)ncn23)c1
Temperature: 0 °C

Procedure:
To a solution of 0.01 mole of 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine in chloroform is added 0.011 mole of N-chlorosuccinimide. The mixture is heated on a steam bath for one hour, cooled and poured into an ice-cold solution of 2.5 N sodium hydroxide. The organic layer is separated, dried (MgSO4) and passed through a column of hydrous magnesium silicate with chloroform as eluent. The eluent is concentrated to dryness to give the product of the example.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([C:41]([CH2:48][CH3:49])([CH2:45][CH:46]=[CH2:47])[C:42](Cl)=[O:43])[CH:39]=[CH2:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[C:41]([CH2:45][CH:46]=[CH2:47])([CH2:48][CH3:49])[CH2:38][CH:39]=[CH2:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CCC(CC)(CC=C)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCC(CC)(CC=C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 77.5 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.65 g (3.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a- hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyl dimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 2.80 g (15.0 mmol) of 2-allyl-2-ethyl-4-pentenoyl chloride, to provide 1.63 g of the title compound.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]=2[CH:18]=1)(=[NH:4])[NH2:3].[C:19](Cl)(=[O:22])[O:20][CH3:21].[OH-].[Na+]>C(Cl)Cl>[CH3:21][O:20][C:19]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]=2[CH:18]=1)=[NH:3])=[O:22]
Reactant: CCOC(=O)c1cc2cc(C(=N)N)ccc2o1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(C(=N)NC(=O)OC)ccc2o1
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
Methylene chloride (2 ml) was added to ethyl 5-amidino-2-benzofurancarboxylate hydrochloride (100 mg, 0.372 mmol), and methyl chlorocarbonate (30 μl, 0.391 mmol) and then, a 0.2N aqueous sodium hydroxide solution (0.391 ml, 0.782 mmol) was added at room temperature, which was followed by vigorous stirring for 10 minutes. Methylene chloride (15 ml) was added to the reaction mixture. The mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 88.0 mg of ethyl 5-(methoxycarbonylamidino)-2-benzofurancaroxylate as a colorless solid (82%). Tetrahydrofuran (2 ml), water (2 ml) and a 1N aqueous sodium hydroxide solution (2 ml, 2 mmol) were added to the compound (73.0 mg, 0.252 mmol), and the mixture was stirred at room temperature for one hour. 1N Hydrochloric acid was added to the reaction mixture to adjust its pH to 2-3, and low boiling matters were distilled away under reduced pressure to give 183 mg of 5-(methoxycarbonylamidino)-2-benzofurancarboxylic acid as a yellow solid (inclusive of sodium chloride).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C-]#N.[Na+]>O.O1CCOCC1>[CH:1]1([O:6][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Brc1cccs1
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1csc(OC2CCCC2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 25.3 %

Procedure:
To a mixture of cyclopentanol (51.1 ml, 0.56 mol) and dioxane (50 mL) was added sodium hydride (60% in mineral oil, 4.91 g, 0.12 mol) at 0-5° C. under argon. The mixture was heated at 80° C. until an homogenous solution was observed. 2-Bromothiophene (10 g, 5.9 mL, 0.061 mol) was added at 80° C., followed by cuprous iodide (11.7 g, 0.061 mol). The mixture was heated at 120° C. for 6 hours. After cooling to 20-25° C., sodium cyanide (30 g, 0.61 mol) in water (200 mL) was added. The mixture was vigorously stirred for 20 minutes, filtered, and extracted with hexane. The hexane extract was washed with water, dried (Na2SO4), and concentrated to dryness. Filtration through a column (silica, 100% hexane) gave 2-cyclopentyloxythiophene (2.6 g, 25.2%) as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 6.7 (dd, J=5.7, 3.7 Hz, 1H), 6.54 (dd, J=5.7, 1.5 Hz, 1H), /86.18 (dd, J=3.7, 1.5 Hz, 1H), 4.66 (Sept, J=2.7 Hz, 1H), 1.5-2.0 (m, 8H).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:11]=1[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:28][N:29]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(OC)ccc1OCC(O)CNC(C)(C)C
Solvent: O
Product: COc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
Methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methoxybenzoyl]propionate was cyclised with hydrazine hydrate in a similar manner to that described in Example 2 (ii) to give 6-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methoxyphenyl]-4,5-dihydro-3(2H)-pyridazinone (m.p. 127°-128° C). The hydrochloride, crystallised from methanolether, had m.p. 227°-229° C. (Found: C, 56.24; H, 7.24; Cl, 9.06; N, 10.75; C18H27N3O4.HCl requires: C, 56.03; H, 7.31; Cl, 9.19; N, 10.88%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH:1]1[C:11](=[O:12])[CH2:10][O:8][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]1=2
Reactant: O=C(Cl)CCl
Reactant: Nc1ccncc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cnccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
4-amino-3-pyridinol (650 mg, 5.904 mmol) was dissolved in anhydrous N,N-dimethyl formamide (15 ml) under nitrogen atmosphere, and chloroacetyl chloride (0.52 ml, 6.494 mmol) solution was added thereto dropwise at room temperature and then stirred for 30 minutes. Then, potassium carbonate (2.0 g, 14.760 mmol) was added thereto dropwise at room temperature, and the reaction mixture was heated at 100□ for 18 hours. The reaction mixture was cooled to room temperature and water was added to quench the reaction. The organic layer was extracted with ethyl acetate and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain white solid. The obtained white solid was recrystallized from ethyl acetate and n-hexane to obtain white solid (520 mg, 59%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[I-].[K+].[I:13]([O-])(=O)(=O)=O.[K+].[Cl-].[Na+]>C(O)(=O)C.O>[I:13][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 100 %

Procedure:
In a round bottom flask, a mixture of o-nitro aniline (formula 4) (13.7 g, 100 mmol), and potassium iodide (16.6 g, 100 mmol), potassium periodate (21.4 g, 100 mmol), sodium chloride (11.7 g, 200 mmol) in acetic acid and water (9:1) was stirred for 8-15 hours at room temperature. The reaction mixture was then poured over chopped ice and extracted with dichloromethane. The extract was further washed twice with water, then brine solution and dried over anhydrous sodium sulfate. On removal of dichloromethane 4-iodo-2-nitro aniline (formula 3) was obtained in 100% yield (26.4 g). The product was analyzed by the analytical methods like 1H & 13C NMR and GC-MS for its purity.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:6][CH:5]=1.[CH3:28]OS(OC)(=O)=O>C1COCC1>[NH2:3][C:4]1[N:9]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([N:18]([CH3:28])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:6][CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: Nc1ccc(NS(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc(N)nc1C#Cc1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
At RT NaH (60% dispersion in mineral oil, 4.6 mg, 0.12 mmol) is added to N-[6-amino-2-(2-phenylethynyl)pyridin-3-yl]benzenesulfonamide D5a (27 mg, approx. 0.07 mmol) in THF (0.6 ml). After stirring for 10 minutes dimethylsulfate (8 μl, 0.08 mmol) is added to the mixture and stirring continued for 1 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 16 mg (57%). HPLC-MS: M+H=364; tR=1.85 min (*Method—2).
Reaction SMILES: [CH:1]1([CH2:4]Cl)[CH2:3][CH2:2]1.[Mg].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C(OCC)C>[CH2:2]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:1][CH3:4]
Reactant: C1CCOC1
Reactant: ClCC1CC1
Agent: [Mg]
Solvent: CCOCC
Product: CCCCOCCCC

Procedure:
In another method, the organosilicon compound catalyst system component is obtained by the reaction of a monocycloalkyltrialkoxysilane (i.e., mono(cyclopropyl)methylene-, mono(cyclobutyl)methylene-, mono(cyclopentyl)methylene-, mono(cyclohexyl)methylene-, mono(cycloheptyl)methylene-trialkoxysilane) with a (cycloalkyl)methylene Grignard reagent. For example, (cyclopropyl)chloromethane is first reacted with magnesium in the presence of a solvent, e.g., an ether such as tetrahydrofuran, diethyl ether, or di-n-butyl ether, to yield a (cyclopropyl)methylene Grignard reagent ((cyclopropyl)methylene magnesium chloride). This reaction may be carried out at a temperature from about room temperature to about 60° C. The (cyclopropyl)methylene Grignard reagent is then reacted with (cyclopropyl)methylene trimethoxysilane to obtain bis{(cyclopropyl)methylene} dimethoxysilane; this reaction may be conducted in the presence of an ether such as tetrahydrofuran, diethyl ether, or di-n-butyl ether, or in the presence of an aliphatic hydrocarbon solvent such as hexane or heptane or an aromatic hydrocarbon solvent such as toluene, benzene, or xylene. This reaction may be carried out at a temperature from about 50° C. to about 200° C., preferably at a temperature from about 100° C. to about 200° C. or at a temperature from about 100° C. to about 200° C. under boiling or refluxing of the solvent.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([OH:22])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[OH:22])=[CH:19][CH:18]=1
Reactant: COc1ccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc([C@@H]2CCNC[C@H]2O)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g, 30 mmol) in methanol (150 mL) was added 10% Pd/C (4.8 g) and the reaction mixture was stirred overnight under a hydrogen atmosphere. The catalyst was then removed by filtration through Celite and the solvent was evaporated under reduced pressure to give (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 24.6 mmol, 81% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.15 (m, 2H) 6.80-6.86 (m, 2H) 4.30 (d, J=5.27 Hz, 1H) 3.37-3.43 (m, 1H) 3.04 (dd, J=11.58, 4.36 Hz, 1H) 2.86 (d, J=12.17 Hz, 1H) 2.43 (td, J=12.09, 2.67 Hz, 1H) 2.22-2.35 (m, 2H) 1.57-1.63 (m, 1H) 1.43-1.54 (m, 1H).
Reaction SMILES: [CH:1]1[C:6]([NH:7][C:8]2[N:13]=[C:12]([Cl:14])[N:11]=[C:10]([Cl:15])[N:9]=2)=[CH:5][C:4]2[C:16]([O:18][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=4[O:27][C:21]4[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]3=4)[C:3]=2[CH:2]=1)=[O:17].CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.C([N:57](CC)CC)C>>[CH:1]1[C:6]([NH:7][C:8]2[N:13]=[C:12]([Cl:14])[N:11]=[C:10]([Cl:15])[N:9]=2)=[CH:5][C:4]2[C:16]([O:18][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=4[O:27][C:21]4[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]3=4)[C:3]=2[CH:2]=1)=[O:17].[NH2:57][C@H:4]([C:16]([OH:18])=[O:17])[CH2:3][CH2:2][CH2:1][CH2:6][NH2:7]
Reactant: CCN(CC)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(Nc3nc(Cl)nc(Cl)n3)cc21
Solvent: O
Solvent: CCOC(C)=O
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 1 h

Procedure:
α-t-BOC-lysine (1.39 g, 5.64 mmol) was dissolved in 50 ml of 9:1 water-triethylamine, and the solution was cooled to 0° with an ice-water bath. A single portion (1.00 g, 1.88 mmol) of DTAF was added, and the reaction mixture was allowed to stir at 0° for 1.0 hr. The solution was poured into 200 ml of EtOAc, and aqueous citric acid solution was added until the pH of the aqueous phase was approximately 4. The layers were separated, and the aqueous layer was extracted with 100 ml of EtOAc. The combined organic layers were washed with 100 ml of water, dried (MgSO4) and evaporated affording 1.22 g of the DTAF-lysine derivative as an orange foam. The crude product was dissolved in a small volume of MeOH and precipitated by the addition of ether-hexane.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH3:16])[C:6]=1[C:17]([O:19]C)=O)#[N:2].C(N(CC)CC)C.[H][H].C[O-].[Na+]>O1CCCC1.[Co]>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:16])[C:6]3[C:17](=[O:19])[NH:2][CH2:1][CH2:3][O:4][C:5]=3[C:13]=2[CH:12]=1
Reactant: [H][H]
Reactant: COC(=O)c1c(OCC#N)c2cc(OC)ccc2n1C
Agent: [Co]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)c1c(n2C)C(=O)NCCO1
Temperature: 80 °C
Yield: 33.2 %

Procedure:
A mixture of methyl 3-(cyanomethoxy)-5-methoxy-1-methyl-1H-indole-2-carboxylate (0.60 g, 2.2 mmol) and triethylamine (0.40 mL, 0.29 g, 2.9 mmol) in 35 mL of tetrahydrofuran in a pressure reaction vessel is treated with Raney cobalt catalyst (0.40 g). The reactor is pressurized with hydrogen (590 psi) and heated at 80° C. for 10 hours. The cooled reaction mixture is filtered and the filtrate evaporated. The oil residue is dissolved in 50 mL of methanol, and sodium methoxide (0.80 g, 15 mmol) is added to the solution. The mixture is heated at reflux for 3 hours, then cooled and evaporated. The residue is distributed between 75 mL of ethyl acetate and 150 mL of brine. The aqueous layer is extracted several times with fresh ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous sodium sulfate) and evaporated. The crude product residue is purified by flash chromatography (silica gel, 5% methanol in dichloromethane elution) to yield 0.18 g (33%) of product. A sample recrystallized from ethyl acetate-hexane has mp 184°-186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCc3ccccc3C2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 1,2,3,4-tetrahydroisoquinoline (6.6 mg, 0.050 mmol, 1.1 eq), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H18N2O2: 318.1368, found 318.1377.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[N:24]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1ccccc1N
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Temperature: 250 °C
Yield: 142.1 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(272 mg, 1.0 mmol) was dissolved in diethylene glycol(10 ml), and 2-methoxyaniline(281 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eleunt to obtain 298 mg of desired compound as solid in 76% of yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:38])([F:37])[CH2:19][N:20]1[C:24]([CH2:25]O)=[CH:23][C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:21]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:25][C:24]3[N:20]([CH2:19][C:18]([F:37])([F:17])[F:38])[N:21]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=4)[CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCc1cc(-c2ccc(C(F)(F)F)cc2)nn1CC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([C:9]([NH2:11])=[NH:10])[S:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:13]C(=O)C(C)(C)C>>[C:1]([C:4]1[N:5]=[C:6]([C:9]([NH2:11])=[NH:10])[S:7][CH:8]=1)([CH3:2])([CH3:3])[CH3:13]
Reactant: N=C(N)c1nc(C2CC2)cs1
Reactant: CC(C)(C)C(=O)CBr
Product: CC(C)(C)c1csc(C(=N)N)n1

Procedure:
4-tert-Butyl-thiazole-2-carboxamidine (Compound N) was prepared in analogy to Compound M with procedure shown in Example 10 by using 1-bromo-3,3-dimethyl-butan-2-one instead of 2-bromo-1-cyclopropyl-ethanone. MS: calc'd (MH+) 184, measured (MH+) 184.
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:12][CH:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][C:8]1=O)C.Cl.Cl.[NH2:24][CH2:25][C:26]1[NH:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].ClCCCl>[NH:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[CH2:25][N:24]1[CH:8]2[CH:7]([CH2:12][CH:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][C:4]1=[O:21]
Reactant: CCOC(=O)CCC1CC(Cc2ccccc2)CCC1=O
Reactant: NCc1nc2ccccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: O=C1CCC2CC(Cc3ccccc3)CCC2N1Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.7 %

Procedure:
A mixture of 0.74 g of 3-(5-benzyl-2-oxo-cyclohexyl)-propionic acid ethyl ester, 0.572 g of 2-aminomethylbenzimidazole dihydrochloride, 10 mL of 1,2-dichloroethane, 0.40 g of sodium acetate and 0.74 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 100 mL chloroform and 40 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography eluting with a gradient of ethyl acetate to 10% methanol in ethyl acetate gave 0.15 g of 1-(1H-benzimidazol-2-ylmethyl)-6-benzyl-octahydro-quinolin-2-one.