Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH:12]=[N:13][CH:14]=[CH:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1.[CH3:31][C:32](OC(C)=O)=[O:33]>CC(C)=O.O1CCOCC1.[Pd]>[CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH2:12][N:13]([C:32](=[O:33])[CH3:31])[CH2:14][CH2:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CCC3)nc2C1
Temperature: 60 °C
Reaction time: 72 h
Yield: 45.7 %

Procedure:
To a solution of N-cyclobutyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine (12.0 g, 29.2 mmol) in acetone (200 mL) and dioxane (300 mL) was added Ac2O (30 mL, 318 mmol) and Pd/C (1.80 g, 16.91 mmol). The reaction was then stirred at 60° C. under H2 atmosphere (345 kPa) for 72 h. Then the mixture was filtered through a pad of Celite™, washing with EtOAc. The reaction solution was diluted with EtOAc (50 mL) and poured into saturated aqueous NaHCO3 (50 mL), then washed with brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was recrystallized with PEEtOAc, lyophilized and washed with PEEtOAc (5:1) to give pure title compound (6.1 g). 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.57-1.74 (m, 2H), 1.85-1.95 (m, 2H), 1.97-2.08 (m, 4H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.19-2.30 (m, 2H), 2.58 (t, J=5.9 Hz, 0.9H), 2.71 (t, J=5.9 Hz, 1.1H), 2.88 (t, J=10.5 Hz, 2H), 3.23-3.33 (m, 2H), 3.70 (dt, J=11.7, 5.9 Hz, 2H), 4.32-4.47 (m, 3H), 4.52 (tt, J=8.1, 3.8 Hz, 1H), 6.05 (d, J=7.8 Hz, 0.4H), 6.08 (d, J=8.3 Hz, 0.6H 6.96-7.07 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]+ 458.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=O)[CH:7]=[CH:6]2.[OH-].[Na+].O.[CH3:18][C:19]([CH3:21])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:18][C:19](=[O:20])[CH3:21])[CH:7]=[CH:6]2
Reactant: CC(C)=O
Reactant: COc1ccc2cc(C=O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2cc(C=CC(C)=O)ccc2c1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
6-Methoxy-2-naphthaldehyde (1 g, 5.4 mmol) in acetone (5.0 g), with aqueous NaOH (0.25 g of 2.8% NaOH; 3.3 mol %) was stirred for 1 hour at 20° C. followed by 1 hour at reflux. Water (10 g) was added to precipitate the product which was filtered and dried to give 1.2 g (98% of theory) of 4-(6-methoxy-2-naphthyl)-3-buten-2-one. GC showed 99% conversion and 4% of a heavy co-product (95% of butenone).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].CN(C)C=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1c(CBr)cccc1C(F)(F)C(F)(F)c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1c(CN2C(=O)c3ccccc3C2=O)cccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 8.02 g. (0.022 mole) of 2-methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl bromide, 4.10 g. (0.022 mole) of potassium phthalimide, and 40 ml. of dimethylformamide is stirred 30 minutes at room temperature, 4 hours at 95° C., and 3 hours at reflux. The cooled mixture is diluted with 100 ml of chloroform and washed with 150 ml. of water. After re-extraction of the aqueous layer with chloroform, the combined organic extracts are washed with 0.1 N. sodium hydroxide, water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. Recrystallization of the residual solid from isopropyl alcohol affords the white crystalline product, m.p. 135°-137° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:17]=1[CH:18]=O>>[F:14][C:15]([F:28])([F:29])[C:16]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][C:17]=1[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(C(F)(F)F)ccc3C(F)(F)F)CC2)nc[nH]1

Procedure:
6-[4-(2,5-Bis-trifluoromethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,5-bis(trifluoromethyl)benzaldehyde. Mass spectrum (ES) MH+=407.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:48])([F:47])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:46]=[CH:45][C:28]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:17][CH2:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[N:32]1([CH2:31][CH2:30][O:29][C:28]2[CH:45]=[CH:46][C:25]([CH:22]3[CH2:23][CH2:24][N:19]([C:16]4[CH2:17][CH2:18][C:13]5[N:14]([C:10]([C:9]([F:47])([F:48])[F:8])=[N:11][N:12]=5)[N:15]=4)[CH2:20][CH2:21]3)=[CH:26][CH:27]=2)[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCN4CCNCC4)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
TFA (10 mL) was added to tert-butyl 4-[2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]piperazine-1-carboxylate (2.02 g, 3.50 mmol) in DCM (10 mL). The resulting solution was stirred at ambient temperature for 1 hour then added to an SCX column. The desired product was eluted from the column using 2M ammonia/MeOH and the solvents were evaporated to afford 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (1.660 g, 99%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:41][CH:42]([F:44])[F:43])(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:41][CH:42]([F:44])[F:43])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(CC(F)F)C3)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (81.9 mg, 0.251 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (53.8 mg, 0.251 mmol) in acetonitrile (0.6 ml) was stirred at room temperature for 20 h. The reaction mixture was partitioned between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (24 mg, 37%) as off-white solid. MS m/e: 462 ([M+H]+)
Reaction SMILES: [CH:1]([N:4]=[C:5]=[S:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:29][O:30][CH2:31][CH3:32])[N:20]([CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])=[CH:11][C:10]=2[N:9]=1>ClCCl>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:29][O:30][CH2:31][CH3:32])[N:20]([CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[S:6])=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(C)=O
Reactant: CC(C)N=C=S
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=S)NC(C)C)ccc3c2n1CC(C)(C)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
Isopropyl isothiocyanate (255 μL, 2.38 mmol) was added to a stirred suspension of N-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide (prepared as described in Part I of Example 49, 1.02 g, 2.17 mmol) in dichloromethane (100 mL) at 0° C. The mixture was stirred for 30 minutes at 0° C., then was allowed to warm to room temperature and was stirred over the weekend. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 7.5-10% methanol in dichloromethane) followed by recrystallization from acetonitrile. The crystals were dissolved in 1:1 dichloromethane/methanol and the resulting solution was concentrated under reduced pressure to afford a white powder that was dried under vacuum at 60° C. to yield 0.43 g of N-(2-{4-amino-2-(ethoxymethyl)-7-[(6{[(isopropylamino)carbonothioyl]amino}hexyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamide as a white powder, mp 110-120° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:16][CH2:15][CH2:14][O:8]2)[CH:9]=1
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1cc(OC)c(C2OCCO2)cc1Br
Reaction time: 6 h
Yield: 91.5 %

Procedure:
Ex-46A: 5-Bromo-2,4-dimethoxybenzaldehyde (4.92 g, 20.1 mmol) was dissolved in benzene (41 mL). Ethylene glycol (3 mL, 54 mmol) and p-toluenesulfonic acid (25 mg, 0.13 mmol) were added and the solution was refluxed with a Dean-Stark trap attached. After 6 h, the reaction was cooled and washed with water (1×20 mL), saturated, aqueous NaHCO3 (1×20 mL), and water (1×20 mL). The organic phase was dried over sodium sulfate, filtered, concentrated, and dried to provide 5.32 g of 2-(5-bromo-2,4-dimethoxy-phenyl)-[1,3]dioxolane as a faint yellow oil which solidified upon standing (92% yield). 1H-NMR (CDCl3) δ 7.67 (s, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 4.11–4.13 (m, 2H), 3.98–4.03 (m, 2H), 3.91 (s, 3H), 3.87 (s, 3H). HRMS (ES+) Calcd. for C11H13BrO4: 289.0075. Found: 289.0077.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CC)c1=O
Reactant: CCNCC
Solvent: CCO
Product: CCOC(=O)c1c(N(CC)CC)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
Two grams (0.0056 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared by the method of Example 3, first paragraph) and 0.82 g. (0.011 mole) of diethylamine were added together in ethanol in an autoclave and heated on a steam bath for 2 hours. The reaction mixture was then filtered and the filtrate chilled in ice. The precipitate which formed was collected on a suction filter. Recrystallization from ethyl acetate gave 0.8 g. of product m.p. 110°-115° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]=1>>[C:19]1([S:16]([NH:15][C:10]2[CH:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([Cl:25])=[N:27][CH:28]=4)=[N:6][C:5]=3[CH3:7])[CH:13]=[N:12][C:11]=2[Cl:14])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1nc(NC(=O)c2ccc(Cl)nc2)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
Using an analogous method to that described in Example 51, N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]benzenesulfonamide was reacted with 6-chloronicotinoyl chloride. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 8.5 minutes); 1H NMR Spectrum: (DMSO-d6+D2O) 8.58 (2H, dd); 8.44 (1H, d); 8.02 (3H, d); 7.86 (1H, t); 7.71 (2H, t); 7.51 (2H, d); 2.28 (3H, s); Mass Spectrum: M+H+ 520.
Reaction SMILES: [CH3:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[CH:18]1(CN)[CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:18]1([CH2:1][N:2]=[C:3]2[C:4]3[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=3[CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH2:20][CH2:19]1
Reactant: NCC1CC1
Reactant: CN=C1c2ccccc2CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc2c(c1)CCc1ccccc1C2=NCC1CC1
Yield: 65 %

Procedure:
In a Carius tube is placed 4.52 g of N-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-imine, 9.2 g of cyclopropylmethylamine and 0.46 g of p-toluenesulfonic acid hydrate. The tube is sealed under vacuum and heated to 120° for 60 hours. The cooled tube is opened, the excess cyclopropylmethylamine is removed under vacuum, and the resiude is dissolved in ether. The solution is washed with aqueous sodium hydroxide solution and dried. The solvent is removed, and the residue is combined with the recovered cyclopropylmethylamine and 0.43 g of p-toluenesulfonic acid hydrate. The mixture is transferred to a Carius tube which is then sealed under vacuum and heated to 120° for an additional 30 hours to complete the reaction. The mixture is worked up as described above, and the crude product is crystallized from hexane to give 3.47 g (65%) of N-cyclopropylmethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-imine, mp 98°-99°. An analytical sample (hexane) had mp 99°-100°. Nmr spectrum (in CDCl3): multiplets at τ 2.1-3.0 (8H), 6.1-7.5 (6H), 8.3-9.0 (1H) and 9.1-10.0 (4H). Anal. Calcd. for C19H19N: C, 87.31; H, 7.33; N, 5.36; Found: C, 87.52; H, 7.27; N, 5.53.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH:10]=[CH2:11])([CH:8]=[CH2:9])[CH:6]=[CH2:7].[C-:12]#[N:13].[Na+]>CN(C)C=O>[C:12]([CH2:2][CH2:3][CH2:4][Si:5]([CH:10]=[CH2:11])([CH:8]=[CH2:9])[CH:6]=[CH2:7])#[N:13]
Reactant: [C-]#N
Reactant: C=C[Si](C=C)(C=C)CCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[Si](C=C)(C=C)CCCC#N
Temperature: 70 °C
Yield: 86.2 %

Procedure:
Compound 3-chloropropyltrivinylsilane (1000 mg, 5.35 mmol) and sodium cyanide (525 mg, 10.70 mmol) were dissolved in 18 ml of dimethylformamide, and the mixture was heated at 70° C. for 4 hours. After the reaction, the organic layer was extracted after addition of distilled water and ether, and then purified by column chromatography (n-Hex:EA=10:1, Rf=0.42), to give 818 mg (86% yield) of pure 3-cyanopropyltrivinylsilane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.[CH:11]12[O:16][CH:12]1[CH2:13][CH2:14][CH2:15]2>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][C@@H:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[OH:16]
Reactant: C1CC2OC2C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O[C@@H]1CCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Yield: 49 %

Procedure:
A solution of 3,4-dichloroaniline (200 g., 1.23 mole), cyclopentene oxide (400 ml.), and concentrated HCl (2 ml.) is heated at reflux temperature for seven (7) days. The unreacted epoxide is evaporated at 60° C. and the residue is treated with excess ethereal HCl, and a syrup results. This is washed with 1000 ml. of ether. The residue is crystallized and recrystallized from methanol/ether (1/5.5, v/v) to give 170.0 g. (49% yield) of trans-3,4-dichloro-N-(2-hydroxycyclopentyl)aniline, hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][C:12]([CH3:14])=[N:13][N:6]1[C:5]2([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15].[CH2:22]1N2CN3CN(C2)CN1C3.Cl>COCCOC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7]3=[N:11][C:12]([CH3:14])=[N:13][N:6]3[CH2:22][N:15]=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: COCCOC
Product: Cc1nc2n(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a stirring solution of 3.1 g (10.4 mmol) of 7-chloro-2-methyl-5-phenyl-5H-[1,2,4]triazolo[5,1-a]-isoindol-5-amine and 3.1 g (22 mmol) of hexamethylenetetramine (hexamine) in 75 ml of DME is added 1.5 ml of 4 N HCl (dioxane). A precipitate forms immediately and the two phase mixture is refluxed. After 5 hours another 1.0 g of hexamine is added and reflux is continued overnight. An additional 1.5 ml of the HCl solution is added after 12 hours and again after an additional 24 hours. After another 24 hours, thin layer chromatography (TLC) shows the disappearance of starting material. The mixture is filtered and the solvent is removed from the filtrate under vacuum. The residue is taken up in CHCl3 and applied to a 5×10 cm silica gel column (Baker 60-200 mesh). The column is eluted with CHC13 until all of the high Rf material (followed by TLC) is recovered. The solvent is removed in vacuo and the residue recrystallized from 20 ml of acetonitrile to yield 1.3 g of pure product: m.p. 150.5°-152° [concentration of the mother liquor gives an additional 0.2 g for a total yield of 1.5 g (46.6%)].
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:27][NH:28][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: Cc1ccc2nc(Nc3nc4cc(C(=O)O)ccc4n3C)sc2c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C)cc3s1)n2C
Yield: 73.8 %

Procedure:
2-(6-Methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methylamide (26 mg) was prepared by following General Procedure F using 2-(6-methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 353. 1H NMR (DMSO-d6, 400 MHz): δ 8.32 (m, 1H), 8.00 (br, 1H), 7.66 (d, 1H), 7.55 (s, 2H), 7.38 (m, 2H), 7.14 (d, 1H), 3.63 (s, 3H), 2.87 (d, 3H), and 2.35 (s, 3H).
Reaction SMILES: C(O[C:4]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[N:5]=1)C.CO.O.[NH2:27][NH2:28]>O>[NH:27]([C:4]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[N:5]=1)[NH2:28]
Reactant: NN
Reactant: CCOC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Solvent: O
Solvent: CO
Product: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reaction time: 2.5 h

Procedure:
To a solution of 0.25 part of 2-ethoxy-7-nitro-5-phenyl-3H-1,4-benzodiazepine in 8 parts by volume of methanol is added 0.2 part by volume of hydrazine hydrate (100%) with stirring and the stirring is continued at room temperature for further 2.5 hours. To the reaction mixture is added water, followed by extraction with chloroform. Chloroform layer is washed with water and dried over anhydrous sodium sulfate, followed by distillation of the solvent. Treatment of the residue with n-hexane gives 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine as orange crystalline powder. The product is treated with acetone, whereupon 2-(2-isopropylidenehydrazino)-7-nitro-5-phenyl-3H-1,4-benzodiazepine is obtained as pale yellow crystals melting at 203°-205° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([NH:13][C:14](=[O:36])[N:15]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][C:24]=2[OH:35])[CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:6]([NH:13][C:14](=[O:36])[N:15]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][C:24]=2[O:35][CH2:2][CH2:3][CH2:4][OH:5])[CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCCCI
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCO)c1
Yield: 79.6 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (5.2 mmol, 7.4 eq) of 3-iodo-1-propanol and 300 mg (0.7 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.1 eq) of potassium carbonate at 80° C. for 15 hours, 270 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3-hydroxypropoxy)biphenyl-4-yl]propanoate are obtained in oil form. Yield=79%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][NH:10][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1cccc(F)c1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 2-(3-fluorophenyl)ethanamine (1.3 mL, 9.6 mmol) and diisopropylethylamine (1.7 mL, 9.6 mmol) in dichloromethane (32 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (2.0 mL, 9.6 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel and extracted with water (35 mL). The dichloromethane layer was separated and formation of precipitate was observed which was collected by filtration. The filtrate was concentrated to yield more solid and the combined solids were dried under vacuum to yield N-(3-fluorophenethyl)-4-(trifluoromethyl)benzamide as a white solid. MS (ESI pos. ion) m/z: 312 (M+H).