Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=N)[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.C[OH:30].O>Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])([CH3:14])[C:11](=[O:30])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=3)[C:9]2=[S:28])=[CH:6][CH:7]=1
Reactant: CC1(C)C(=N)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(O)cc1
Reactant: CO
Agent: Cl
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of 3b (0.202 g, 0.5 mmol) in HCl aq., 2N (2 ml) and methanol (5 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane/acetone, 9:1) to yield 4-[3-(4 -hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 3c, [RD8] (0.198 g, 0.49 mmol, 98%) as a white powder.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])(=O)=O.OC1C=CC(C(O)=O)=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[OH:43])[C:37]([OH:39])=[O:38].[OH-].[K+]>C(O)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[O:43][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5])[C:37]([OH:39])=[O:38]
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=C(O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
10-Undecen-1-yl Tosylate (compound I-7) was separately reacted with 4-hydroxybenzoic acid and 3-chloro-4-hydroxy-benzoic acid to synthesize the compounds I-18 and I-19. The synthesis of compound I-18 was described below as an example. 1.75 g (0.0312 mole) KOH, 0.05 g KI and 100 ml of 90% ethanol were mixed and refluxed. To the mixture 2.15 g (0.0156 mole) 4-hydroxybenzoic acid was added dropwise, and refluxed for one hour. 4.433 g (0.013 mole) compound I-7 was added slowly and refluxed for 10 hours. 10% KOH was then added and refluxed again for two hours. Ethanol was removed from the mixture which was then extracted with ethyl ether. The collected ethyl ether layer was dried over anhydrous MgSO4, filtered and concentrated to obtained solid product. The resulting solid product was recrystallized from ethanol. Yield: I-18: 40.6%; I-19: 36.4%. 1H-NMR:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[N:38]=[C:10]2[CH:11]=[C:12]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)[CH:13]=[C:14]([N:15]3[CH:19]=[CH:18][CH:17]=[N:16]3)[N:9]2[N:8]=1>O1CCOCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:38]=[C:10]2[CH:11]=[C:12]([C:20]3[CH:25]=[N:24][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]4)=[N:22][CH:21]=3)[CH:13]=[C:14]([N:15]3[CH:19]=[CH:18][CH:17]=[N:16]3)[N:9]2[N:8]=1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(-n4cccn4)n4nc(N)nc4c3)cn2)CC1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-n3cccn3)n2n1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
Ethyl isocyanate (143 mg, 2.01 mmol) was added to solution of ethyl 1-{5-[2-amino-5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]pyrimidin-2-yl}-4-methylpiperidine-4-carboxylate (180 mg, 0.40 mmol) in 1,4-dioxane (15 mL) and stirred at 80° C. for 22 h. LCMS showed desired product formation. The resultant black reaction mixture was concentrated in vacuo to give a brown tarry solid which was triturated with EtOAc (10 mL) to give the desired product as a grey solid (88 mg, 42%) MS: 519.23 [M+H]+.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH3:25]>CN(C)C=O>[CH2:24]([N:3]1[CH2:2][CH2:1][N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4]1)[CH3:25]
Reactant: CCBr
Reactant: O=C1CC2CNCCN2c2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN2c3ccccc3NC(=O)CC2C1
Temperature: 60 °C

Procedure:
To a solution of Example 1D (30 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (57 mg, 0.41 mmol) and bromoethane (10.3 μl, 0.14 mmol). The reaction was warmed to 60° C. for 14 hours. Excess potassium carbonate was filtered off. The solution was passed through a PS-isocyanate cartridge (Silicycle®, 2 g) to trap leftover starting material. The solution was concentrated and purified by preparative HPLC with a gradient of acetonitrile and 0.1% trifluoroacetic acid in water to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.19-7.24 (m, 1H), 7.14-7.18 (m, 1H), 7.09-7.13 (m, 1H), 7.01 (dd, J=7.78, 1.37 Hz, 1H), 3.52-3.64 (m, 3H), 3.32-3.39 (m, 2H), 3.19-3.27 (m, 2H), 2.97-3.10 (m, 2H), 2.66 (dd, J=13.73, 7.02 Hz, 1H), 2.09 (d, J=13.12 Hz, 1H), 1.27 (t, J=7.32 Hz, 3H); MS (ESI) m/z 246.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:20]1([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccccc4)c3c2s1
Yield: 67 %

Procedure:
Prepared from VII and aniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 67%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3395, 3057, 2228, 1731, 1644, 1608, 1577, 1491, 1459, 1378, 1352, 1301, 1255, 1214, 1147, 1128, 1106, 1071, 967, 896, 827; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.11 (s, 1H), 7.78 (d, 1H, J=9.0 Hz), 7.40 (t, 2H, J=7.5 Hz), 7.20 (m, 2H), 7.11 (t, 1H, J=7.5 Hz); HRMS calcd for C16H10N5S (M+H+): 304.0657, found 304.0657.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CN2C(=NCCC2)C1.Br.[Br-].[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[N:37]=[C:36]([CH2:38][N+]2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=1>CC#N>[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[N:37]=[C:36]([CH2:38][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: c1cc[n+](Cc2cccc(C3OCCO3)n2)cc1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Agent: Br
Agent: C1CN=C2CCCN2C1
Agent: [Br-]
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1cccc(C2OCCO2)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
To a cooled (0° C.) stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (12.2 g, 60.03 mmol, 1.0 eq.) in 250 ml of MeCN, was added dropwise DBN (12.30 g, 99.06 mmol, 1.65 eq.). The reaction was stirred for 5 mins before addition of 1-{[6-(1,3-dioxolan-2-yl)pyridin-2-yl]methyl}pyridinium bromide hydrobromide (15.7 g, 39.02 mmol, 0.65 eq.) portionwise. The mixture was stirred for further 5 mins before removal of the cooling bath and continued at ambient temperature. MeCN was evaporated and the residue dissolved in 500 ml of DCM, washed with water (×2), dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to yield N-{[6-(1,3-dioxolan-2-yl)pyridin-2-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (5 g, 22% yield) as a pale yellow oil.
Reaction SMILES: [H-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].O>C1(C)C=CC=CC=1>[ClH:18].[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1ccccc1CCc1ccccc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccccc1CCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a suspension of 1.0 g of lithium hydride in 30 ml of toluene was added dropwise a solution of 3.96 g of 2-hydroxybibenzyl in 30 ml of toluene at room temperature over 5 minutes. The mixture was heated under reflux for 30 minutes, a solution of 6.45 g of 2-chloro-N,N-dimethylethylamine in 20 ml of toluene added dropwise under reflux over 5 minutes and then reflux was continued for an additional 2 hours. The reaction mixture was cooled to room temperature, and to this was added 50 ml of water. The toluene layer was separated, washed twice with water, dried over anhydrous sodium sulfate and then the toluene distilled off in vacuo. The residue was dissolved in ethyl ether, and then 20% ethanolic hydrogen chloride solution was added. The resulting precipitate was collected by filtration and recrystallized from ethanol-ether to give 5.81 g (95% yield) of 2-(2-dimethylaminoethoxy)bibenzyl hydrochloride, m. p. 172°-173° C.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: ClCCN1CCCCC1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (II) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 1-(2-chloroethyl)-piperidine
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[F:20][C:21]1[CH:22]=[C:23]([NH2:32])[C:24]([NH:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]2[N:27]([CH2:28][CH2:29][O:30][CH3:31])[C:15]([CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[N:32][C:23]=2[CH:22]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COCCNc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COCCn1c(Cc2nc(N3CCOCC3)cc(=O)[nH]2)nc2cc(F)ccc21
Yield: 27 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 760 mg of 4-fluoro-N1-(2-methoxyethyl)benzene-1,2-diamine hydrochloride and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 5 ml of pyridine and 5 ml of dimethylformamide and then in 5 ml of acetic acid. After refluxing for one hour and purification by silica column chromatography, eluent: CH2Cl2/MeOH: 95/05, the residue obtained is purified by preparative HPLC/MS (method 1). After the acetonitrile has been evaporated off, the pH is brought to 8 using sodium bicarbonate (solid), then the aqueous phase is extracted with twice 25 ml of ethyl acetate, and the combined organic phases are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 120 mg of 2-{[5-fluoro-1-(2-methoxyethyl)-1H-benzimidazol-2-yl]methyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].Cl[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1.C1C([Cl:18])=CC=C(Cl)C=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:18][C:6]1[C:7]([Cl:11])=[C:8]([CH:2]([CH3:3])[CH3:1])[CH:9]=[CH:10][CH:5]=1
Reactant: C=CC
Reactant: Clc1cccc(Cl)c1
Reactant: Clc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)c1cccc(Cl)c1Cl
Reaction time: 8 h
Yield: 1 %

Procedure:
This experiment is carried out in the same manner as in Example 1, except that propylene is used instead of isopropyl bromide. A dry-ice condenser is used instead of coolant condenser and propylene is sparged below the liquid level through a sparger tube. Thus, 377.8 g (2.57 mole) of mixture consisting of 70% (264.6 g; 1.8 mole) m-dichlorobenzene, 30% (113.2 g; 0.77 mole) p-dichlorobenzene and 48.0 g (0.36 mole) AlCl3 are placed in a 4-neck, one-liter flask and to it 34 g (0.81 mole) propylene is sparged below the liquid level. The temperature of reaction mixture is kept below 10° C. After overnight isomerization, decomposition of the AlCl3 complex, the organic layer shows little alkylation: only 1 to 2% dichlorocumene is formed.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].BrC[C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1.[C:46]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(Cl)Cl.O>[C:42]([C:41]1[CH:44]=[CH:45][C:38]([CH2:27][N:26]([CH3:46])[S:25]([N:20]2[CH2:19][CH2:18][N:17]([C:16]3[C:11]4[CH:10]=[CH:9][NH:8][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:24][C:21]32[CH2:23][CH2:22]3)(=[O:28])=[O:29])=[CH:39][CH:40]=1)#[N:43]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(C#N)cc1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.237 mmol) was dissolved in dry DMF (2 mL) and added Cs2CO3 (0.35 mmol) and 4-bromomethyl-benzonitrile (0.35 mmol). Stirred at rt for 16 h and then added H2O (10 mL). Extracted with EtOAc (3×10 mL) and the combined organic phases were concentrated in vacuo. Purified by flash chromatography on silica using a gradient of heptane to EtOAc as eluent. The obtained compound was treated with TFA (2 mL) at rt for 2 h. The crude reaction mixture was added sat. Na2CO3 to pH=7 and the extracted with EtOAc (3×10 mL). the combined organic phases was washes with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The pure compound was obtained by trituation using CH2Cl2.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][CH:16]=[C:15]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1.[NH2:35][C:36]1[CH:37]=[N:38][N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH:40]=1>CN(C=O)C>[CH3:44][O:43][CH2:42][CH2:41][N:39]1[CH:40]=[C:36]([NH:35][C:32](=[O:34])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:15]3[C:14]4[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=4)[N:18]=[CH:17][CH:16]=3)=[CH:26][CH:27]=2)[CH:37]=[N:38]1
Reactant: COCCn1cc(N)cn1
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1cc(NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cn1
Yield: 38.9 %

Procedure:
Diisopropylethylamine (0.124 ml) and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.247 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetic acid (0.2 g), 4-amino-1-(2-methoxyethyl)pyrazole (0.092 g) and DMF (3 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The resultant mixture was evaporated and the residue was purified by column cliromatography on silica using a solvent gradient from 100:0 to 24:1 mixtures of methylene chloride and a 3.5M methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.106 g); 1H NMR: (DMSOd6) 3.21 (s, 3H), 3.62 (s, 2H), 3.63 (t, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 4.12 (t, 2H), 6.47 (d, 1H), 7.22 (d, 2H), 7.4 (s, 1H), 7.44 (s, 1H), 7.45 (d, 2H), 7.49 (s, 1H), 7.89 (s, 1H), 8.47 (d, 1H), 10.2 (s, 1H); Mass Spectrum: M+H+ 463.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:12][N:13]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (189 mg, 0.49 mmol), trimethylsilylacetylene (103 μL, 0.73 mmol), triphenylphosphine (4 mg, 0.02 mmol), and triethylamine (102 μL, 0.73 mmol) were stirred in THF (4 mL) in a flask purged with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.024 mmol) was added, and after 10 min copper iodide (2 mg) was added. The reaction stirred for 18 h at r.t. The solution was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/CHCl3) gave 168 mg (85%) of the title compound as a clear oil. MS (ES) [m+H] calc'd for C22H27N5OSi, 406; found 406.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: C1CCNC1
Product: O=Cc1ccc(C(F)(F)F)cc1N1CCCC1

Procedure:
The title compound was synthesized from 2-fluoro-4-(trifluoromethyl)benzaldehyde and pyrrolidine as described in Example 67, Step 1 (1.6 g, 63%): LCMS (ESI, m/z): 244 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH3:42])[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[S:36]1[CH:37]=[C:33]([CH2:32][N:22]([C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[O:13])[CH3:42])[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 98 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: [S:1]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][CH:9]=1)([C:4]([F:5])([F:6])[F:7])(=[O:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(c1ccc(CBr)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
A stirred solution of 22.4 g (0.1 mole) of 4-triflyltoluene, 178 g (0.1 mole) of N-bromosuccinimide, and 0.48 g (0.2 mole %) of benzoyl peroxide in carbon tetrachloride is heated at reflux for 20 hours. After cooling to room temperature, the reaction is diluted by the addition of carbon tetrachloride, and the solid byproducts are removed by filtration. The filtrate is concentrated in vacuo, and the product is purified by recrystallization from benzene.
Reaction SMILES: ClCCCS([N:8]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:9][C:10](=[O:36])[C@@H:11]([C@@H](C(=O)NOC1CCCCO1)C/C=C/C1C=CC=CC=1)[CH2:12][CH:13]([CH3:15])[CH3:14])(=O)=O.[I-].[Na+].C(NCC)C>C(C(C)=O)C.C(OCC)(=O)C>[CH2:37]([NH:8][NH:9][C:10](=[O:36])[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCCCl)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: [I-]
Agent: [Na+]
Solvent: CCNCC
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)CCC(=O)NNCC(C)C
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A solution of 0.60 g of (E)-2′-(3-chloropropylsulphonyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 10 ml of methyl ethyl ketone was treated with 0.18 g of sodium iodide and 1.04 ml of diethylamine. The mixture was heated at 80° C. for 4 hours and then at 60° C. for 48 hours. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution to give 0.16 g of (E)-2′-[3-(diethylamino)propylsulphonyl]-2(R) -[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a gum.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([OH:14])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3].[C:15]([CH2:17][NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])#N.[N+](C1C=CC=CC=1)([O-])=[O:26]>[Cl-].[Zn+2].[Cl-]>[CH2:2]([O:4][C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:15](=[O:26])[CH2:17][NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[C:7]([OH:14])[CH:6]=1)[CH3:3]
Reactant: CCCS(=O)(=O)NCC#N
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCOc1ccc(O)cc1OCC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCS(=O)(=O)NCC(=O)c1cc(OCC)c(OCC)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitrobenzene (100 ml) was cooled to zero degrees Celsius and saturated with HCl gas. To this solution was added of 3,4-diethoxy-phenol (11.64 g, 64 mmoles), propane-1-sulfonic acid cyanomethyl-amide (10.36 g, 64 mmoles) and zinc chloride (17.45 g, 128 mmoles). The reaction was stirred for 1 hour at zero degrees Celsius and then allowed to warm to room temperature. Stirring was continued for 2 hours. Thin-layer chromatography showed consumption of 3,4-diethoxy-phenol. Water (100 ml) was added cautiously and the reaction was heated to 100 degrees Celsius for 1 hour. The reaction was cooled, and extracted with methylene chloride. The extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was submitted to flash chromatography (2.5-5% ethyl acetate in methylene chloride). The purified product was triturated with ether, filtered and air dried to yield 17.3 g of propane-1-sulfonic acid [2-(4,5-diethoxy-2-hydroxy-phenyl)-2-oxo-ethyl]-amide. 1HNMR (CDCl3): 11.86 (s, 1H), 6.93 (s, 1H), 6.46 (s, 1H), 5.26 (t, 1H), 4.55 (d, 2H), 4.14 (q, 2H), 4.03 (q, 2H), 3.05 (m, 2H), 1.90 (m, 2H), 1.45 (m, 6H), 1.07 (t, 3H).