Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1([CH3:34])[CH2:9][S:8][CH:7]2[N:4]([C:5](=[O:20])[CH:6]2[NH:10]C(=O)CC2C=CC=CC=2)[CH:3]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22].P(Cl)(Cl)(Cl)(Cl)Cl.CN(C)C1C=CC=CC=1.CO>ClCCl>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:21]([CH:3]2[C:2]([Cl:1])([CH3:34])[CH2:9][S:8][CH:7]3[N:4]2[C:5](=[O:20])[CH:6]3[NH2:10])=[O:22])=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: CC1(Cl)CSC2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)c1ccccc1
Product: CC1(Cl)CSC2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice cold solution of 3-chloro-3-methyl-8-oxo-7-(2-phenylacetamido)-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylic acid, p-nitrobenzyl ester (5.04 g, 10 mmoles) in 100 ml of dichloromethane, are added in rapid succession phosphorus pentachloride (3.1 g, 15 mmoles) and N,N-dimethylaniline (1.8 g, 15 mmoles). The mixture is stirred at 0°C. for 15 minutes and at 25°C. for 3 hours, then 30 ml. of absolute methyl alcohol is added and the solution is further stirred for 1 hour. The solvent is flash evaporated. To the residue are added 25 ml. of ethyl acetate and 30 ml. of water and the mixture is stirred thoroughly. The crystalline solid thus obtained is filtered and air dried to give 2.75 g (65.2 per cent yield) of product, which decomposes above 160°C. NMR (DMSO-D6) ppm (δ), 1.74 (s, 3,3-CH3), 3.38 (ABq, δ 0.45 ppm, J 9 cps, 2--CH2), 4.92 (s, 1, 4H), 5.0 (d, 1, 6H), 5.34 (d, 1, 7H), 5.51 (s, 2, CO2CH2 ), 8.05 (ABq, δ 0.525 ppm, J 5 cps, p-NO2 --C6H4).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[C:23]([O:28]C)=[N:24][CH:25]=[CH:26][CH:27]=5)[C:19]([CH3:30])=[C:18]([CH3:31])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:31])[C:19]([CH3:30])=[C:20]([C:22]5[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)cc(C)c1C
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2ccc[nH]c2=O)c1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (105 mg, 0.25 mmol) in CH3CN (5.0 mL) was added TMSI (71.7 μL, 0.50 mmol) drop wise. The reaction was stirred at 55° C. for 1 hour. Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (82 mg, 81%). ESI-MS m/z calc. 401.5. found 402.5 (M+1)+. Retention time 1.18 minutes.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.N#N.FC(F)(F)C(O)=O.[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([N:24]1[CH2:30][CH:2]2[C:1](=[O:7])[NH:5][C:4](=[O:6])[CH:3]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the maleimide (80.4 g, 0.83 mol) in 1.5 L of CH2Cl2 in a 3-neck, 3-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at 0° C. was added trifluoroacetic acid (TFA) (6.4 mL, 83 mmol). Benzyl(methoxymethyl)trimethylsilylmethylamine (261 g, 1.1 mol) in 500 mL CH2Cl2 was added dropwise via addition funnel over 3 hours with the reaction temperature being maintained below 5° C. After the addition was complete, the mixture was allowed to warm slowly to ambient temperature and then was stirred for 16 h. The mixture was concentrated and the residue was dissolved in 500 mL CH2Cl2 and was washed with 2×50 mL saturated NaHCO3. The layers were separated and the aqueous layer was extracted 2×25 mL CH2Cl2. The combined organics were washed with 25 mL brine, dried over saturated, aqueous Na2SO3, and concentrated under reduced pressure to give the title compound which was carried on to the next step without further purification. MS (DCl/NH3) m/z 231 (M+H)+.
Reaction SMILES: N1(C2C[CH2:9][N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)CC2)CCC1.[CH:28]1([N:31]2[CH2:36]CN[CH2:33][CH2:32]2)[CH2:30][CH2:29]1>>[Cl:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:19]2[N:20]=[C:12]([CH2:11][N:8]3[CH2:33][CH2:32][N:31]([CH:28]4[CH2:30][CH2:29]4)[CH2:36][CH2:9]3)[S:13][C:14]=2[N:15]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Reactant: C1CN(C2CC2)CCN1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCN(C4CC4)CC3)sc2n1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using 1-cyclopropylpiperazine in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (117 mg, 56%).
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[Cl:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([N:57]2[N:61]=[CH:60][CH:59]=[N:58]2)[C:49]=1[C:50](O)=[O:51]>>[Cl:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([N:57]2[N:61]=[CH:60][CH:59]=[N:58]2)[C:49]=1[C:50]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:51]
Reactant: O=C(O)c1c(Cl)cccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(Cl)cccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.265 mmol) and 2-chloro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 15; 71 mg, 0.318 mmol) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2CCN(S(C)(=O)=O)CC2)c2ccccc2n1

Procedure:
2-Methyl-4-piperazin-1-yl-quinoline (227.3 mg, 1 mmol) was dissolved in anhydrous dichloromethane (7 ml), triethylamine was added (209 μl, 1.5 mmol), followed by methanesulfonyl chloride (85 μl, 1.1 mmol) which was added dropwise with ice-cooling. The mixture was diluted with dichloromethane and washed with 5% sodium bicarbonate solution. The wash solution was extracted with dichloromethane, the organic phases were combined and washed with 5% sodium bicarbonate solution, water and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure 265 mg of a white foam were obtained (0.87 mmol, 87%) which was used directly in the next step.
Reaction SMILES: [CH2:1]=O.[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([O-])=O.[K+].[CH3:13][NH:14][CH3:15]>O>[CH3:13][N:14]([CH2:5][C:4](=[CH2:1])[C:3]([O:9][CH2:10][CH3:11])=[O:8])[CH3:15]
Reactant: C=O
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CNC
Agent: [K+]
Solvent: O
Product: C=C(CN(C)C)C(=O)OCC
Reaction time: 1 h

Procedure:
Formaldehyde (60 ml of 40% solution) was added to a stirred solution of potassium ethyl malonate (34g) and dimethylamine (40 ml of 26% solution) in water (100 ml) at 15° C. The solution was stirred at laboratory temperature for one hour and then boiled under reflux for one hour. After cooling the solution was extracted with ether and the ether was evaporated to leave the product as a yellow oil. This was distilled to give a clear oil (boiling point 84° C/20 mm).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:37])[CH2:23][CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:37])[CH2:23][CH:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[CH2:17][CH2:16]1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CC1CCNCC1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
After a 4N hydrogen chloride in ethyl acetate (5 ml; 20 mmol) was added to a solution in methylene chloride (3 ml) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)-methyl]methylamine (640 mg; 1.5 mmol) synthesized by the above process under ice cooling. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from methanol-diethyl ether, thereby obtaining 412 mg (yield: 82%) of the title compound as colorless needles (melting point: 280° C. or higher).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12](C(O)=O)([CH2:13]4)[CH2:11]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].OS(O)(=O)=O.[N-:27]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12]([NH2:27])([CH2:13]4)[CH2:11]3)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)C12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Temperature: 45 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To the stirred solution of 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (3.0 g, 10.45 mmol) obtained in step II, in CHCl3 (21 mL) was added conc. H2SO4 (4.2 mL, 78.9 mmol) then solid NaN3 was added in portions, so that the temperature of the reaction did not rise above 40° C. The reaction mixture was warmed to 45° C. and after stirring for 2 h it was cooled again to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified with 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonan-3-amine as an off-white solid (2.0 g) in 74% yield. M.R: 201.0-205.9° C. m/z (M+1) 259; IR cm−1 3435, 2941, 1643, 1596, 1518, 1400, 1349, 1013, 750. 1H NMR (CDCl3) 300 MHz δ 8.14 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 3.70-3.60 (d (br), 2H), 2.62-2.50 (m, 2H), 2.38-2.23 (m, 3H), 2.15-2.0 (m, 3H), 1.95-1.60 (m, 4H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=O)[NH:9][N:10]=1.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]2[NH:21][C:11]([C:8]3[NH:9][N:10]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[N:22][C:16]=2[CH:15]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=Cc1cc(-c2cccs2)n[nH]1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2nc(-c3cc(-c4cccs4)n[nH]3)[nH]c2cc1C

Procedure:
Starting with 16.2 mg of 5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde, 12.4 mg of 4,5-dimethyl-1,2-phenylenediamine, and 17.3 mg of sodium metabisulphite, in 0.2 ml of ethanol and 0.6 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a chromatography under pressure on silica and a purification by LC-MS, 5,6-dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole is obtained in the form of a white powder.
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].C[O-].[Na+]>>[NH2:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:9][CH:10]=1)[C:7](=[NH:8])[NH:12][C:11]2=[NH:1]
Reactant: N#Cc1ccc(N)cc1C#N
Reactant: N
Agent: C[O-]
Agent: [Na+]
Product: N=C1NC(=N)c2cc(N)ccc21

Procedure:
5-Amino-1,3-diiminoisoindoline was synthesized by passing gaseous ammonia through methanolic solution of 4-aminophthalonitrile in the presence of sodium methoxide.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:15]=[C:13]([C:12]2[CH:16]=[CH:17][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[O:14][CH:5]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(CCl)co2)cc1
Temperature: 120 °C
Yield: 87.1 %

Procedure:
To a solution of 1,3 dichloroacetone (0.504 g, 3.90 mmol) in toluene (5 ml) was added 4-methoxy benzamide (0.30 g, 1.90 mmol). The reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 15% EtOAc-Hexane) to get the desired product (0.37 g, 83%).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([C:17]([CH2:19][Cl:20])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].O.Cl>CO>[Cl:20][CH2:19][CH:17]([OH:18])[C:15]1[O:16][C:12]([C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=C(CCl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2ccc(C(O)CCl)o2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.9 %

Procedure:
Sodium borohydride (1.6 g, 0.043 mole) was added in portions to a stirred mixture of 11.5 g (0.043 mole) of chloromethyl 5-(p-nitrophenyl)-2-furyl ketone in 150 ml of absolute methanol over 10 minutes at 15°-20°. The resulting solution was stirred at ambient temperature for 2.5 hours, poured into a mixture of ice and water (400 ml), and made acidic with 5% aqueous HCl. The yellow solid was collected by filtration and washed with water to give 11.5 g (100%) of title compound. Recrystallization from a MeOH--H2O mixture gave an analytical sample, m.p. 111°-113°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[NH2:23]>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Product: Cc1cc(C)cc(Nc2cc(Nc3ccc(P(C)(C)=O)cc3)ncn2)c1

Procedure:
The compound is prepared as in Example 59 by reacting 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with 3,5-dimethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH3:10].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:32]C)C=C4)N(CC2)C1.CC(O)(C)C.[OH2:74]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:32])[C@@H:9]([OH:74])[CH3:10]
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Reactant: C/C=C/c1ccccc1Cl
Solvent: CC(C)(C)O
Product: C[C@H](O)[C@@H](O)c1ccccc1Cl
Reaction time: 8 h
Yield: 90 %

Procedure:
1-(2-chlorophenyl)-trans-1-propene (1.5 g, Preparation Example 1) was dissolved in 30 mL of the mixture of t-BuOH/H2O (1:1(V/V)). At 0° C., AD-mix-α (Aldrich, U.S.A.) (13.7 g) and methane sulfone amide (CH3SO2NH2, 0.76 g, 0.0080 mol) were added thereto and stirred for overnight. When the reaction was completed, the obtained product was washed with an aqueous solution of sodium sulfite (Na2SO3) and ethylacetate (EA). Then, the organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4), filtrated, and concented under reduced pressure. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (1.65 g, yield 90%).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])([O-:3])=[O:2].C([NH:27][CH2:28][CH2:29][CH2:30][NH2:31])(=O)C1C=CC=CC=1.[C:32]([NH:34][C:35](=[N:38][CH2:39][CH2:40][S:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1)SC)#[N:33]>>[CH3:16][C:15]1[NH:14][CH:13]=[N:12][C:11]=1[CH2:10][S:9][CH2:8][CH2:7][NH:6][C:5]([NH:27][CH2:28][CH2:29][CH2:30][NH:31][C:35]([NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1)=[N:34][C:32]#[N:33])=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nc[nH]c1C
Reactant: CSC(=NCCSCc1ccccn1)NC#N
Reactant: NCCCNC(=O)c1ccccc1
Product: Cc1[nH]cnc1CSCCNC(=C[N+](=O)[O-])NCCCNC(=NC#N)NCCSCc1ccccn1

Procedure:
1-Nitro-2-methylthio-2-[2-((5-methyl-4-imidazolyl)methylthio)ethylamino]ethylene was reacted with 3-benzoylaminopropylamine and the product was hydrolysed under acidic conditions and reacted with N-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([O-])(=O)C.[Na+].C=O>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[CH2:20][CH2:19]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Product: COc1ccccc1N1CCN(Cc2c[nH]c3ncccc23)CC1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 1-(2-methoxyphenyl)piperazine (65 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.97 (m, 4H) 3.68 (m, 4H) 3.72 (s, 3H) 4.05 (s, 2H) 5.60 (m, 1H) 6.60 (m, 1H), 6.89 (m, 2H) 7.08 (ddd, J=21.36, 7.80, 4.75 Hz, 1H) 7.52 (m, 2H) 8.07 (m, 2H) (ESI) m/z 323 (M+H)+.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:22]>C(OC(=O)C)C>[Br-:15].[Br:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N+:12]1[CH:13]=[CH:14][C:9]([CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10][CH:11]=1
Reactant: C(=Cc1ccncc1)c1ccccc1
Reactant: BrCCCCCCBr
Solvent: CCOC(C)=O
Product: BrCCCCCC[n+]1ccc(C=Cc2ccccc2)cc1
Product: [Br-]
Yield: 86.2 %

Procedure:
A mixture of 0.91 g of 4-styrylpyridine and 2.44 g of 1,6-dibromohexane in 15 ml of ethylacetate was stirred and refluxed for 3 hours then filtered while hot. The crystals obtained were washed with an additional portion of ethylacetate and dried in vacuo to give 1.84 g of N(6-bromohexyl)-4-styrylpyridinium bromide. λmax 343 nm (water). NMR (CDCl3, p.p.m.): 9.4 (d.,2H), 8.2 (d.,2H), 7.2-7.8 (m.,7H), 4.9(t.,2H), 3.35(T.,2H), 1.2-2.2 (br.m., 8H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[N:13][CH:14]=2)[CH:9]=[CH:8]1.ClC[C:18]1([CH2:24][CH2:25][CH3:26])[CH2:22][NH:21][C:20](=[O:23])[CH2:19]1.O>C1COCC1>[CH2:24]([CH:18]1[CH2:22][N:21]([CH2:1][C:8]2[NH:7][C:15]3=[CH:14][N:13]=[CH:12][CH:11]=[C:10]3[CH:9]=2)[C:20](=[O:23])[CH2:19]1)[CH2:25][CH3:26]
Reactant: CC(C)(C)[O-]
Reactant: c1cc2cc[nH]c2cn1
Reactant: CCCC1(CCl)CNC(=O)C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CC(=O)N(Cc2cc3ccncc3[nH]2)C1
Temperature: 25 °C

Procedure:
Potassium terbutoxide (522 mg, 4.65 mmol, 1.1 eq) is added to a solution of 6-azaindole x269 (500 mg, 4.23 mmol) in 4 ml of THF at 0° C. After 1 hour of reaction at 0° C., a freshly prepared solution of 4-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.814 mg, 4.65 mmol, 1.1 eq, in 3 ml of THF) at 0° C. The reaction mixture is warmed to room temperature. After 3 days of agitation, water (10 ml) is added and the aqueous layer is washed with ethyl acetate (3×15 ml). The aqueous layer is then neutralized until pH 9 and extracted with dichloromethane (3×15 ml). The cumulated dichloromethane layers are dried over MgSO4, filtrated and condensed under reduced pressure. The resulting residue is purified by preparative chromatography on silicagel (CH2Cl2/MeOH/NH4OH 96/4/0.4 (v/v/v)), recrystallized in ethyl acetate, leading to 4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one 242 as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:4][CH:3]=1.[CH2:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][C@@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:19]1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:15][C:10]1[N:11]=[C:12]([N:25]2[CH2:24][CH2:23][C:22]3([CH2:18][N:19]([C:33]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[C@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21]3)[CH2:27][CH2:26]2)[CH:13]=[C:8]([CH2:7][O:6][C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Nc1nc(Cl)cc(COc2ccc(Br)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(Br)cc4)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-((4-Bromophenoxy)methyl)-6-chloropyrimidin-2-amine (454 mg, 1.4 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 1.44 mmol) and NaHCO3 (605 mg, 7 mmol) in dioxane (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.