Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][NH:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C1(C)C=CC=CC=1>[CH:1](=[N:8][N:9]([CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CNN=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CN(C)N=Cc1ccccc1
Yield: 90.5 %

Procedure:
258 g (1.92 mol) of N-benzylidene-/V′-methylhydrazine and 325 g (1.92 mol) of ethyl ethoxy-methylenecyanoacetate were initially charged in 1000 ml of toluene and heated at the boil for 1 hour. After cooling, the mixture was filtered off with suction, which gave 447 g (89.5% of theory) of ethyl 3-(N′-benzylidene-N-methylhydrazino)-2-cyanoacrylate [log P (pH 2.3)=2.31]. The filtrate was allowed to stand for 16 hours and then again filtered off with suction, which gave another 7.7 g (1.5% of theory) of the desired product.
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:13][CH2:12][C@@H:11]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[CH2:10][C@H:9]2[CH2:19][CH3:20])[C:4]1=[O:21].C(N(CC)CC)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N:33]=[CH:32][N:31]=1>CCO>[CH2:19]([C@@H:9]1[CH2:10][C@H:11]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[CH2:12][CH2:13][C@@H:8]1[N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:42])([F:43])[F:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[C:4]1=[O:21])[CH3:20]
Reactant: CC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C

Procedure:
A sample of the bis-HBr salt of (S)-3-amino-1-((1S,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (147 mg) was dissolved in EtOH (5 mL) and the resulting solution was charged with triethylamine (0.55 mL) and 4-chloro-6-trifluoromethylquinazoline (183 mg) before being heated at 80° C. for 14 h. The reaction was cooled and concentrated under reduced pressure, and the residue was partitioned between diethyl ether and water. The organic phase was extracted twice with water. The combined aqueous extracts were lyophilized and the resultant powder was purified by RP-HPLC to afford (S)-1-((1S,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)-cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one. MS found: (M+H)+=478.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][CH2:9][NH2:10].[Br:16][CH2:17][C:18](Br)=[O:19]>ClCCl>[BrH:16].[Br:16][CH2:17][C:18]([NH:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:2]([Cl:1])[CH:3]=1)[CH3:11])=[O:19]
Reactant: CN(CCCN)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: Br
Product: CN(CCCNC(=O)CBr)Cc1ccc(Cl)c(Cl)c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 135.6 %

Procedure:
4.9 g (20 mmol) N-(3,4-Dichlorobenzyl)-N-(methyl)propan-1,3-diamine is dissolved in 50 ml dichloromethane. The solution is cooled to −10° C. and at that temperature 2 ml (23 mmol) bromoacetyl bromide in 12 ml dichloromethane is added to it dropwise. The reaction mixture is stirred at −10° C. for 10 minutes and at room temperature for 3 hours. Dichloromethane is poured off, the residue is stirred with 15 ml abs. ethanol, the precipitated crystals are filtered off, washed with ethanol and with ether to obtain 7 g title compound in the form of its hydrogen bromide salt. Mp.: 141° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[NH:7]1)=[O:5])C.O.[OH-].[Li+].O>O1CCCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][CH:6]([C:4]([OH:5])=[O:3])[NH:7]1
Reactant: CCOC(=O)C1CCS(=O)(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCS(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 2-{3-[((S)-4-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (310 mg, approx. 0.61 mmol) in tetrahydrofuran (3.6 mL) was added lithium hydroxide hydrate (51 mg, 1.2 mmol) followed by water (910 μL). The reaction mixture was stirred at room temperature for 2 h, and then the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The remaining solution was stirred and approximately 25 drops of 1 M hydrochloric acid were added to bring the pH to 4.5. The sample was stirred for 10 min and the aqueous solution was decanted away from the yellow gum. The gum was washed with water (2 mL). The combined aqueous layers were evaporated to dryness, and dried overnight to give 2-{3-[((S)-4-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid as a pale yellow residue (292 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:40][S:41]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)(=[O:43])=[O:42].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:50][CH:47]4[CH2:48][CH2:49][N:44]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:45][CH2:46]4)=[O:26])[CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: C=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: C=C(CC)C1N(CC(=O)NC2CCN(S(C)(=O)=O)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 43.6 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 107a was reacted with 1-methanesulfonyl-piperidin-4-ylamine trifluoroacetic acid salt (0.2 g, 0.34 mmol), N-methylmorpholine (0.2 g, 2 mmol) and 4-dimethylaminopyridine (1 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-[(1-methanesulfonyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 58 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13]I>C(Cl)(Cl)Cl.ClCCl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3](=[O:12])[N:4]([CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1cc(C(F)(F)F)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 3-bromo-2-hydroxy-5-(trifluoromethyl)pyridine (1.0097 g, 4.1724 mmol) in chloroform (20 mL) was added silver carbonate (1.1964 g, 4.3388 mmol) and methyl iodide (0.40 mL, 6.4 mmol). The reaction mixture was stirred at room temperature for two hours and then at 40° C. for 24 hours. Additional methyl iodide (0.40 mL, 6.4 mmol) was added and the reaction kept at 40° C. for an additional 15 hours. The reaction mixture was then diluted with dichloromethane, filtered through celite, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 80% ethyl acetate in heptanes) to yield 0.5297 g (50%) of 3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (d, J=0.9, 1H), 8.22 (d, J=2.5, 1H), 3.56 (s, 3H).
Reaction SMILES: [CH3:1][OH:2].F[C:4]1[C:9](F)=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1.[O:15]1[CH2:19]CCC1>>[CH3:1][O:2][C:4]1[C:9]([O:15][CH3:19])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1
Reactant: C1CCOC1
Reactant: CO
Reactant: Fc1cc(C(F)(F)F)cnc1F
Product: COc1cc(C(F)(F)F)cnc1OC
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride in an oil dispersion (8.0 g of 60 percent, 0.20 mol) was extracted with hexane to remove oil and suspended in 30 ml of tetrahydrofuran and to this 5.5 ml (0.14 mol) of anhydrous methanol was added dropwise with stirring. After about 10 min, 9.16 g (0.05 mol) of 2,3-difluoro-5-(trifluoromethyl)-pyridine was added. An exothermic reaction ensued which increased the temperature to about 60° C. The mixture was then heated at reflux for 6 hours and then a small amount of methanol was added. The mixture was allowed to cool and was thereafter poured onto ice. The resulting mixture was extracted several times with ether. The combined ether extracts were dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain 9.0 g (87 percent of theory) of the title compound as a white crystalline solid melting at 22°-23.5° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O:29][CH2:30][CH3:31])=O)=NC(OCC)=O.[Si:32]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]O)=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[S:48]1C=CC=C1CC(O)=O>C1COCC1>[C:30](=[O:29])([S:48][CH2:44][C:43]1[CH:46]=[CH:47][C:40]([O:39][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[CH:41][CH:42]=1)[CH3:31]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(O)Cc1cccs1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
To an efficiently stirred solution of triphenylphosphine (81 g, 309 mmol) in THF (200 mL) was added diethyl azodicarboxylate (62.5 g, 309 mmol) at 0° C. The mixture was stirred for 30 min, after which time a thick white precipitate was obtained. The crude 4-(tert-butydimethylsilyloxy)-benzyl alcohol (48 g) in THF (100 mL) and thiolacetic acid (36.1 g, 474 mmol) were added dropwise while the temperature was maintained below 10° C. The reaction was stirred overnight while keeping the internal temperature below 10° C. The solvent was removed in vacuo and the residue was purified by flash column chromatography [SiO2: isohexane-ethyl acetate (9:1)] to give the product as a viscous brown oil (30.7 g, 50%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC)=[N+:2]=[N-:3].[CH2:22](C1C=CC(C(Cl)=O)=CC=1)[CH2:23]CCCCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:23][CH:22]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 75 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-heptylbenzoyl chloride (0.289 g, 1.21 mmol) was reacted with 2-azidoethanamine (0.104 g, 1.21 mmol) and triethylamine (0.245 g, 2.42 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-heptylbenzamide (0.260 g, 75% yield). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=7.8 Hz, 2H), δ 7.19 (d, J=7.8 Hz, 3H), δ 3.57 (q, J=5.7, 5.4 Hz, 2H), δ 3.47 (t, J=5.7 Hz, 2H), δ 2.61 (t, J=7.5 Hz, 2H), δ 1.61 (m, 2H), δ 1.26 (m, 8H), δ 0.87 (t, J=6.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.3, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.0, 31.4, 29.4, 29.3, 22.9, 14.3 ppm; HRMS (ESI) calcd for C16H24N4O (M+) 288.1950. found 288.1943.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]([NH:11]C(S)=NCCSCC1[O:19]C(CN(C)C)=CC=1)#[N:10]>>[OH2:19].[CH2:1]([N:8]=[C:9]([NH2:11])[NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: CN(C)Cc1ccc(CSCCN=C(S)NC#N)o1
Product: CCCCCCCN=C(N)N
Product: O
Yield: 132 %

Procedure:
A mixture of heptylamine (1.15 g) and N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]carbamimidothioic acid (3.12 g) was heated on an oil bath for 12 hr at 100°. The product was chromatographed (silica/methanol) to give N-cyano-N'[2-[[[5-dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]N"-heptylguanidine hydrate (2.31 g) Rf 0.49. Analysis Found: C, 56.99; H, 8.32; N, 17.53. C19H33N5OS.H2O requires: C, 57.43; H, 8.81; N, 17.63%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CCOCC.[C:20]1([C:25](Cl)=[O:26])[S:24][CH:23]=[CH:22][CH:21]=1>O.C1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:25](=[O:26])[C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CNC(=O)c1cccs1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of glycine ethyl ester hydrochloride (22 g) and potassium carbonate (86 g) in water (600 ml) was added a mixture of benzene (600 ml) and ether (400 ml) and stirred at room temperature. 2-Thenoyl chloride (25 g) in benzene (100 ml) was added during a period of about 30 minutes under stirring and then the mixture was stirred for 2 hours at room temperature. The organic layer was separated and after dried over anhydrous sodium sulfate, concentrated under reduced pressure to give colorless crystals, which were recrystallized from ethanol to obtain the objective compound (23 g), mp 82°-83° C.
Reaction SMILES: OCC[C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[C:31]([CH3:32])[C:6]=2[N:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:32][C:31]1[C:6]2[N:5]=[CH:4][N:8]([CH2:9][C:10]3[CH:27]=[CH:26][C:13]4/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]5[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=5[CH2:17][CH2:18][C:12]=4[CH:11]=3)[C:7]=2[CH:28]=[C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=1
Reactant: Cc1cc(-c2ccccc2)cc2c1nc(CCO)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc2c1ncn2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
[step 1] (E)-{2-[2-(2-Hydroxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100 mg, 0.20 mmol) obtained in Example 59, step 1 was dissolved in acetonitrile (2 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (128 mg, 0.30 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Chloroform (20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL) were added to the mixture, and the mixture was stirred at room temperature for 30 min. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/15) to give (E)-[2-(4-methyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (14 mg, 15%).
Reaction SMILES: O=[CH:2][C:3](=C)[CH3:4].C(O)C.C(O[CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>[CH2:17]([O:16][CH:12]([O:13][CH2:14][CH3:15])[C:3](=[CH2:2])[CH3:4])[CH3:18]
Reactant: CCOC(OCC)OCC
Reactant: C=C(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: C=C(C)C(OCC)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 404.5 %

Procedure:
p-Toluenesulfonic acid (1.14 g, 0.006 mol) was added to a mixture of methacrolein (42.35 g, 0.06 mol), ethanol (141.9 mL), CH2Cl2 (120 mL) and triethylorthoformate (130.6 mL, 0.785 mol). The mixture was stirred at room temperature for 3 days and then K2CO3 (2 g) was added. The mixture was stirred for 10 minutes, filtered, and then the filtrate was concentrated in vacuo. The residue was purified by distillation through a Vigreaux column at 130° C. to afford 35 g of methacrolein diethylacetal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.BrCCBr.[Mg].[C:17]1([C:27]#N)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.Cl.[O:30]1CCCC1>CO>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:27]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:30])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: CCCCc1ccc(Br)cc1
Reactant: N#Cc1nccc2ccccc12
Agent: Cl
Agent: [Mg]
Solvent: CO
Solvent: BrCCBr
Product: CCCCc1ccc(C(=O)c2nccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Bromo-4-butylbenzene (2.29 ml, 13 mmol) and a catalytic amount of 1,2-dibromoethane as an initiator were added to a mixed solution of magnesium (338 mg, 14 mmol) and tetrahydrofuran (6.5 ml) under nitrogen atmosphere, and this mixture was stirred under reflux for 10 minutes. The mixture was cooled to 0° C., a solution of 1-isoquinolinecarbonitrile (1.0 g, 6.5 mmol) in tetrahydrofuran was added, and this mixture was stirred at room temperature for 1 hour, then at 70° C. for 3 hours. Thereafter, the mixture was cooled again to 0° C., concentrated hydrochloric acid (2.6 ml) and methanol (11 ml) were added, and this mixture was heated under reflux for 2 hours. After the mixture was concentrated, the residue was dissolved in 5 N sodium hydroxide and toluene, and was filtered through celite. The toluene layer of the filtrate was separated, washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.7 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C1CCCCC1.Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>C(O)(=O)C>[Br:16][C:17]1[CH:22]=[C:21]2[C:20](=[CH:19][CH:18]=1)[NH:23][C:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][C:4]2=1
Reactant: CC1CCC(=O)CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: CC1CCc2[nH]c3ccc(Br)cc3c2C1
Yield: 74.2 %

Procedure:
To a solution of 4-methylcyclohexanone (5.47 mL, 44.6 mmol), cyclohexane (70 mL) and glacial acetic acid (50 mL) was added 4-bromophenylhydrazine hydrochloride (10.0 g, 44.6 mmol) and the reaction mixture was refluxed for 23 h under a nitrogen atmosphere. The cooled reaction mixture was filtered and the filtrate was evaporated. Diethyl ether was added and the mixture was washed with a saturated sodium bicarbonate solution and then water; the ether solution was dried and evaporated. The crude product was recrystallised from ethanol over an ice bath, filtered, washed with cold PS and dried in vacuo to afford 6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole (8.73 g, 33.1 mmol, 74%) as an off-white solid, mp 108–110° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[C:14]([CH3:16])([CH3:15])[C:13]3([CH3:18])[CH3:17])=[O:11])[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:26][CH2:25][O:24][CH3:23])[C:7](=[N:9][C:10]([CH:12]3[C:13]([CH3:18])([CH3:17])[C:14]3([CH3:16])[CH3:15])=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: COCCBr
Reactant: CC1(C)C(C(=O)Nc2nc3ccc(F)cc3s2)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCn1c(=NC(=O)C2C(C)(C)C2(C)C)sc2cc(F)ccc21

Procedure:
To a solution of the product of Example 112A (1 equiv) in 1:1 DMF/THF (0.1 M) was added sodium hydride (60% dispersion in mineral oil, 1.2 equiv) and 2-bromoethyl methyl ether (1.2 equiv).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:18]=[C:17]5[C:12]([CH:13]=[CH:14][CH:15]=[N:16]5)=[CH:11][CH:10]=4)[CH:3]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1cc(Nc2ccc3cccnc3c2)ncn1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(c3cc(Nc4ccc5cccnc5c4)ncn3)CC2)cc1

Procedure:
This compound could be prepared from (6-chloro-pyrimidin-4-yl)-quinolin-7-yl-amine and 1-phenyl-piperazine in the presence of K2CO3 and DMF.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccccc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of benzylamine (11 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6D2O) δ ppm 1.31 (t, 3H) 4.43-4.54 (m, 4H) 7.06-7.11 (m, 1H) 7.21-7.36 (m, 5H) 9.07-9.14 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:12][CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH2:25]([I:27])[CH3:26].[CH2:28](O)[CH3:29]>>[I-:27].[I-:27].[CH2:23]([N+:20]([CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N+:3]([CH2:25][CH3:26])([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:15][CH:14]=1)([CH2:28][CH3:29])[CH2:21][CH3:22])[CH3:24]
Reactant: CCI
Reactant: CCO
Reactant: CCN(CC)CCCCc1ccc(CCCCN(CC)CC)cc1
Product: CC[N+](CC)(CC)CCCCc1ccc(CCCC[N+](CC)(CC)CC)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 0.56 g of 1,4-bis(diethylaminobutyl)benzene and 2.1 g of ethyl iodide were dissolved in 7 ml of absolute ethanol, and the mixture was refluxed for 4 hours. After removing the solvent under a reduced pressure and adding acetone and a small amount of ethanol, the mixture was stirred at a room temperature for 30 minutes. The resulting crystal was filtered, washed with acetone, and dried under a reduced pressure to obtain 0.335 g of the title compound as a pale yellow crystal.