Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:13]3[CH2:14][CH2:15][N:16]([C:18]([C:20]4[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)=[O:19])[CH2:17][C@@H:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([CH3:30])[C:3]=1[CH3:31].[OH-].[K+].Br[CH2:35][CH2:36][CH3:37]>CC#N>[CH3:30][C:4]1[C:3]([CH3:31])=[C:2]([O:1][CH2:35][CH2:36][CH3:37])[CH:7]=[CH:6][C:5]=1[C@@H:8]1[N:13]2[CH2:14][CH2:15][N:16]([C:18]([C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[O:19])[CH2:17][C@@H:12]2[CH2:11][CH2:10][CH2:9]1
Reactant: CCCBr
Reactant: Cc1c(O)ccc([C@H]2CCC[C@H]3CN(C(=O)c4ccc(C(F)(F)F)nc4)CCN32)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCOc1ccc([C@H]2CCC[C@H]3CN(C(=O)c4ccc(C(F)(F)F)nc4)CCN32)c(C)c1C
Temperature: 60 °C
Reaction time: 20.5 h

Procedure:
A solution of [(6R,9aS)-6-(4-hydroxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-methanone (1.54 g, 3.55 mmol) in CH3CN is treated with powdered KOH (400 mg, 7.10 mmol, 1.5 eq) and 1-bromopropane (5.33 mmol, 2.0 eq) and heated in a sealed tube reactor with stirring in a 60° C. oil bath for 20.5 h. After cooling, the mixture is filtered through a CELITE pad. The pad is washed with CH2Cl2 and the solution is concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluting with 50%-40% hexanes/EtOAc to yield {(6R,9aS)-6-(2,3-dimethyl-4-propoxyphenyl)-hexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl}-(6-(trifluoromethyl)pyridin-3-yl)methanone. LC/MS: 476 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([O:43][C:44](Cl)=[O:45])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:44]([O:43][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:45])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)cc1OCCCOC
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)C)C2CC2)C(C)C)cc1OCCCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-cyclopropylaminomethyl-4-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.470 mmol) in CH2Cl2 (3 mL) are added isobutylchloroformate (84 mg, 0.611 mmol) and triethylamine (85 μL, 0.611 mmol) under a N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 90:10) to give the title compound. MS (LC-MS): 532 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 8.22 min.
Reaction SMILES: [I-].Br[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]([CH:11]([NH:16][C:17](=[O:34])[C@H:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[O:10].Cl>C1COCC1.C1C=CC=CC=1.[Zn]>[OH:10][CH:9]([CH:11]([NH:16][C:17](=[O:34])[C@H:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [I-]
Agent: [Zn]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(O)CC(=O)OCC

Procedure:
To 10 ml of anhydrous THF were added 360 mg of zinc powder and a small amount of iodide, and the mixture was heated at reflux. A solution of 0.54 ml of ethyl bromoacetate in 6.0 ml of anhydrous THF was added thereto dropwise, followed by heating at reflux for 5 minutes. A solution of 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide prepared in the same manner as in Example 4-(b) in 14 ml of anhydrous benzene was then added thereto dropwise, followed by heating at reflux for 30 minutes. After allowing the mixture to cool, 1N hydrochloric acid was added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 410 mg of the titled compound as an oily substance.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C(O)(=O)C>[CH2:21]([O:12][CH:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: c1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
To a solution of 1-diphenylmethylazetidin-3-ol (300 mg, 1.3 mmol) in DMF (2.6 mL) at 0° C. under nitrogen was added NaH (60% in oil, 56 mg, 1.4 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with benzyl bromide (236 μL, 2.0 mmol). The mixture was allowed to warm to room temperature then heated to 80° C. overnight. The reaction mixture was cooled, acetic acid (20 drops) was added and the mixture concentrated under reduced pressure. The crude material was purified on column chromatography (eluent: Pentane/EtOAc, 95/5 to 70/30) to give the product (104 mg, 24%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)cc1OC
Yield: 50 %

Procedure:
A mixture of 15.2 g of 3,4-dimethoxytoluene, 17.8 g of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide in 100 ml of CCl4 is heated at reflux for hours, under illumination from a UV lamp. The precipitate is drained off and the filtrate is evaporated under vacuum. The residue is taken up in ether, washed with water, dried over Na2SO4 and evaporated under vacuum. An oil is obtained which contains a mixture of 50% of the expected product and 50% of the starting material, which mixture is used without further purification in the subsequent synthesis.
Reaction SMILES: Br[C:2]1C=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1C=CC(C(=O)C)=CC=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][N:37]=[CH:4][CH:5]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccncc4)ccc3c1)n2C1CCCCC1
Yield: 62 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-pyridin-4-yl-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (68 mg, 62% yield). MS: 449.19 (M+H+); HPLC Procedure A, retention time=7.98 min.
Reaction SMILES: [CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3C1.[CH3:13]C12CC3CC(CC(C)(C3)C1)C2>>[CH2:4]([C:5]12[CH2:6][CH:7]3[CH2:8][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:1]1)[CH2:13]2)[CH3:3]
Reactant: CC12CC3CC(C1)CC(C)(C3)C2
Reactant: C1CC2CCCC3CCC(C1)C23
Product: CCC12CC3CC(CC(C3)C1)C2

Procedure:
The same experiment as described in 2th line from the bottom in Table 5 of Example 5 was carried out except that perhydroacenaphthene prepared by hydrogenation of acenaphthene was used in place of TMN. Conversion rate of perhydroacenaphthene was 75.4%, and 1,3-dimethyladamantane and 1-ethyladamantane were obtained at 33.0% and 47.1% of selectivity and at 24.9% and 35.0% of yield respectively. Moreover, when amounts of catalyst was increased from 2 g to 4 g, conversion rate of perhydroacenaphthene was 85.6%, and 1,3-dimethyladamantane and 1-ethyladamantane were obtained at 45.2% and 6.6% of selectivity and at 38.7% and 5.7% of yield respectively.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14].[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:28])[CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O>>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:11][CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[O:24])=[C:21]([F:28])[CH:20]=1
Reactant: COC(=O)C(C)N
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)NC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
N,N-Diisopropylethylamine (2.0 mL, 0.011 mol) was added to a mixture of methyl 2-aminopropanoate hydrochloride (0.64 g, 0.0046 mol), 4-bromo-2-fluorobenzoic acid (1.0 g, 0.0046 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.12 g, 0.00479 mol) in N,N-dimethylformamide (10.0 mL, 0.129 mol). The reaction mixture was stirred overnight at RT, quenched with saturated sodium bicarbonate (25 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with 60% EtOAc in hexanes to afford the desired product (1.33 g, 96%). LCMS: (M+H)=303.9/305.9.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH3:12][NH:13][C:14](=[O:17])[NH:15][NH2:16].Cl>O.C(O)C>[CH3:12][NH:13][C:14](=[O:17])[NH:15][N:16]=[CH:10][C:3]1[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: CNC(=O)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC(=O)NN=Cc1ncc([N+](=O)[O-])n1C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 8.5 grams (0.055 mole) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde in 50 ml. of ethanol is added a solution of 5.0 grams (0.056 mole) of 4-methylsemicarbazide in 25 ml. of ethanol and 10 ml. of water containing 2-4 drops of concentrated hydrochloric acid. The resulting solution is heated at 60°-70° C. until a yellow solid starts to separate and then stored at 0° C. for 1 hour; 12.2 grams (98%) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde-4-methylsemicarbazone is obtained melting at 221°-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 99.1 %

Procedure:
To a solution of 15.2 g (0.105 moles) of 4-chlorothiophenol dissolved in 150 ml of DMSO was added 4.2 g (0.105 moles) of NaOH. The mixture was heated to 60° C. and 18.3 g (0.100 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 60° C. for 21/2 hrs. The mixture was cooled and poured into a solution of 100 ml of 2 N aqueous NaOH and 600 ml of water. The product was collected by filtration, washed well with water and dried to obtain 28.8 g of product (99% yield). Recrystallization from ethanol afforded purified 2-((4-chlorophenyl)thio)-5-nitrobenzonitrile, mp 162°-164.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>>[C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])[CH3:14]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
2-Aminobiphenyl a (21.9289 g, 130 mmol) was dissolved in Ac2O (30 mL, 318 mmol) and stirred 10 minutes. An additional portion of Ac2O (10 mL, 106 mmol) was added then stirred for 10 more minutes. The sample was poured onto ice. The resulting solid was vacuum filtered and washed with H2O to give N-acetyl-2-aminobiphenyl b (26.955 g, 128 mmol, 98%).
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=O>O>[C:2]1([C:1]2[N:8]=[C:36]([C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of benzamide oxime (24.92%) in 2-methyl THF (67.53 g, 124 mmoles) was charged to a 500 mL flask, followed by DI water (20.0 g), 55% aqueous tetrabutylammonium hydroxide (0.94 g), and 50% sodium hydroxide (0.96 g, 12 mmoles). To this mixture was added 2-thiophenecarbonyl chloride (17.77 g, 120 mmoles) and 50% sodium hydroxide (9.60 g, 120 mmoles) simultaneously over 30 minutes while heating to about 70° C. The reaction was complete is less than one hour. The temperature was reduced to 60° C., and the pH of the aqueous phase was neutralized to 7.61, and was drained off to waste. A hot solution of 1.25 g of Morwet D-425 in 100 ml DI water was added to the mixture, and the 2-phase mixture was heated to distill off the 2-methyltetrahydrofuran/water azeotrope (boiling point 71° C.). Additional water (150 ml) was pumped into the reactor flask over about 15 minutes, once the 2-methyltetrahydrofuran began to distill out. While maintaining good agitation, the pot temperature reached 100.5° C. (vapor temperature 97° C.). The slurry was cooled and filtered using a coarse glass frit. The scale was scraped off the agitator and combined with the wet cake; the scale was only about 3% of total product. The combined wet cake was washed with hot DI water (3×50 ml) and suction-dried for 5 minutes to give a 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole wet cake, 34.80 g. The loss on drying of the wet cake was 20.13%. The assay of the dried 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was 96.12%, and the residual chloride was <200 ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:34][C@@H:35]1[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]1>CN1CCCC1=O>[CH2:8]([C:7]1[N:6]=[C:5]([C:10]([NH2:12])=[O:11])[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[C:16]([CH3:33])[CH:15]=2)=[N:3][C:2]=1[NH:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1N[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (360 μL), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave reaction device at 190° C. for 30 minutes. The mixture was subjected to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. To the obtained residue and 1,2-dichloroethane (2.6 mL) were added trifluoroacetic acid (2.6 mL) under ice-cooling, followed by stirring at room temperature for 3 hours. The mixture was diluted with chloroform and neutralized with a 5% aqueous potassium carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-[(3R)-pyrrolidin-3-ylamino]pyrazine-2-carboxamide (109 mg) as a pale yellow solid.
Reaction SMILES: [N:1]([CH:4]([CH2:9][CH2:10][C:11]#[N:12])[C:5]([O:7]C)=[O:6])=[N+:2]=[N-:3].[OH-].[Na+]>C(O)C.O>[N:1]([CH:4]([CH2:9][CH2:10][C:11]#[N:12])[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: COC(=O)C(CCC#N)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CCCC(N=[N+]=[N-])C(=O)O
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
Methyl 2-azido-4-cyanobutyrate (1.1 g, 6.55 mmol) was dissolved into a solution of sodium hydroxide in 90% ethanol (7 ml of 1N) and the resultant solution let stand at room temperature for 45 min. Thin layer chromatography (silica, 10% ether-benzene) indicated the reaction was completed. The reaction mixture was diluted with water (7 ml) and stirred (5 min) with Dowex 50W-X8 (acidic, H30 form) resin and then filtered.The filtrate was concentrated under reduced pressure to half the volume (to remove EtOH) and the remaining solution extracted with chloroform (5×10 ml). The chloroform solution, after drying, was evaporated to give 0.89 g (89%) of the title acid as a liquid; ir (neat) νmax : 3200, 2250, 2110, 1740 cm-1 ; 1Hmr (CDCL3) δ: 2.23 (m, 2H, CH2), 2.57 (m, 2H, CH2CN) and 4.27 ppm (q, J1 =9, J2 =6 Hz, 1H, CHN3). Anal. calcd for C5H6N4O2 : C 39.62, H 3.92, N 36.36; found: C 39.00, H 3.85, N 36.10.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:42]([N:44](CC)[CH2:45][CH2:46]N)[CH3:43].NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:42]([N:44]([CH2:45][CH3:46])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:29]=[N:30]1)[CH3:43]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: CCN(CC)CCN
Solvent: NCCO
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCNCCn1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Yield: 42 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting N,N-diethyl-1,2-ethanediamine (50 mg, 0.43 mmol) for the 2-aminoethanol to afford 12 mg of the title compound (42%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([CH3:24])[C:14]([O:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=3)[O:11][CH:10]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]2[CH:18]([OH:19])[C:17]3[C:12](=[C:13]([CH3:24])[C:14]([O:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=3)[O:11][CH2:10]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1ccc(C2COc3c(ccc(OC(C)=O)c3C)C2O)cc1
Temperature: 25 °C
Reaction time: 55 h

Procedure:
Palladium-on-charcoal (5%, 0.12 g) was added to a suspension of 4′,7-diacetoxy-8-methylisoflavone (1.0 g, 2.8 mmol) in methanol (200 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 55 h. The catalyst was removed by filtration through Celite and the filtrate was evaporated in vacuo to yield 4′,7-diacetoxy-8-methylisoflavan-4-ol in quantitative yield, m.p. 135-37° C. A nuclear magnetic resonance spectrum revealed the product to be a clean 1:1 mixture of cis- and trans-4′,7-diacetoxy-8-methylisoflavan-4-ol. Mass spectrum: 356 (M, 53%); 254 (86); 253 (100); 240 (80); 196 (37).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:1](=[O:13])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)[CH3:20]
Reactant: CCO
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)c(OC)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of homovanillic acid (5 g, 27.4 mmol) and H2SO4 (96%, 1.46 mL, 27.4 mmol) in EtOH (100 mL) was stirred for 1 h at 85° C., allowed to cool to RT and concentrated. The residue was diluted in H2O and extracted with DCM. The organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated to afford 5.8 g of the title compounds as a yellow oil. LC-MS: m/z 211.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.CN(C)[CH2:15][CH2:16][CH2:17][N:18]=C=NCC.C1(N)CC1.O>CN(C)C=O>[CH:17]1([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:15][CH2:16]1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: Cl
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1I
Yield: 98 %

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.5 g, 40 mmol), 1-(3-dimethlaminopropyl) -3-ethylcarbodiimide hydrochloride (9.2 g, 48 mmol) and cyclopropylamine (2.6 g, 45.6 mmol) in N,N-dimethylformamide (70 ml) was stirred at room temperature for 4 h. Water (250 mL) was added. The solution was extracted with ethyl acetate (200mL×2), washed with saturated K2CO3 solution (200 mL) and water (200 mL). Organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the desired product (11.8 g, 98%).