Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([N:24]2[C:28]([C:29]3[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=3)=[CH:27][C:26]([O:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[N:25]2)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:32]1[CH:31]=[CH:30][C:29]([C:28]2[N:24]([C:21]3[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[N:25]=[C:26]([O:36][CH2:37][C:38]([F:40])([F:39])[F:41])[CH:27]=2)=[CH:34][CH:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(-n2nc(OCC(F)(F)F)cc2-c2ccc(O)cc2)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(OCC(F)(F)F)cc2-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cn1
Reaction time: 1 h

Procedure:
A solution of trifluoromethanesulfonic anhydride (207 μl) in CH2Cl2 (1 mg) was added to a solution of 4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenol (300 mg) and pyridine (199 μl) in CH2C12 (3 ml) under ice-bath cooling. The mixture was stirred at same temperature for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution (5 ml) The mixture was partitioned between AcOEt and 1M HCl. The mixture was washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 4-[l-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-yl]phenyl trifluoromethane-sulfonate (439 mg) as an oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:8]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)C.N>CN(C)C=O>[C:13]1([C:10]2[N:11]=[N:12][C:7]([C:29]#[C:28][C:30]3([OH:38])[CH:35]4[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]4)[CH2:31]3)=[C:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: O=S(=O)(Oc1nnc(-c2ccccc2)cc1Cc1ccccc1)C(F)(F)F
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2nnc(-c3ccccc3)cc2Cc2ccccc2)CN2CCC1CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of 484 mg of 3-phenyl-5-benzyl-6-pyridazyl trifluoromethane sulfonate, 223 mg of 3-ethynyl-3-quinuclidinol, 284 mg of tetrakis (triphenylphosphine)palladium(0), 47 mg of cuprous iodide, 513 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 80° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1) and then crystallized from hexane/ethyl acetate, to give 413 mg of the target compound.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH:7]([NH:12][C:13](=[O:47])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[S:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[C:32](=[O:46])[NH:33][CH:34]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:39]([CH:34]([NH:33][C:32]([C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[S:23][S:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:48])=[O:5])=[O:47])=[O:46])[CH2:35][CH:36]([CH3:38])[CH3:37])([OH:41])=[O:40]
Reactant: COc1ccc(SSc2ccc(OC)cc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(SSc2ccc(OC)cc2C(=O)NC(CC(C)C)C(=O)O)c(C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 34.7 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-4-methoxy-phenyldisulfanyl]-5-methoxybenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (2.4 g, 3.4 mmol) from Example 31, 25 mL dichloromethane, 25 mL trifluoroacetic acid and 2.5 mL anisole. The crude product was recrystallized from methanol/water to afford 0.7 g of the title compound, mp 168-169° C.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[C:19]([NH2:26])=[C:20]([NH2:25])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[Cl:17][C:18]1[C:19]2[NH:26][C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)=[N:25][C:20]=2[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: Nc1ccc(Cl)c(Cl)c1N
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccc(Cl)c(Cl)c4[nH]3)cc2)S1

Procedure:
4,5-Dichloro-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 3,4-dichloro-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[N+:5]([O-])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C(Cl)(=[O:17])C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]([CH2:7][OH:17])=[N:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1nn(-c2ccccc2)[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccccc2)nc1CO
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
7.1 g of 4,5-dimethyl-2-phenyl-1,2,3-triazol-1-oxide was dissolved in 25 ml of toluene, and heated to 80° C. 4.8 g of acetyl chloride diluted with 13 ml of toluene and 9.1 ml of triethylamine diluted with 13 ml of toluene were simultaneouly added dropwise thereto, keeping the temperature below 85° C. After stirring for 1 hour at 80° C., 2.5 ml of acetyl chloride diluted with 5 ml of toluene and 4.5 ml of triethylamine diluted with 5 ml of toluene were simultaneously added. After stirring for 1 hour at 80° C., the solution was left overnight at room temperature. 7 ml of 30% aqueous solution of sodium hydroxide was added, then toluene and triethylamine were distilled off under reduced pressure. 5 ml of ethanol and 30% aqueous solution of sodium hydroxide were added, and refluxed with heating for 1 hour. After ethanol was distilled off under reduced pressure, 50 ml of 10% saline solution was added, and left for some time at room temperature. The deposited crystals was dissolved in ethyl acetate, washed with water and a saturated salt solution, then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified through silica gel column chromatography (hexan/ethyl acetate=1/2), then washed with hexan/diisopropyl ether (=10/1) to obtain 5.7 g of the aimed compound.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.ClCCl.O>C(#N)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
Trichlorinated derivative, 2-chloro-1-(2,4-dichlorophenyl)-ethanone (5.58 g), is added to 5.10 g of imidazole (75 mmole) in 25 ml of acetonitrile, and the reaction medium is stirred at ambient temperature for 24 hours. Then 50 ml of dichloromethane and 50 ml of water are added, followed by extracting, decanting, washing then re-extracting with dichloromethane. The organic phases are dried and evaporated under reduced pressure until a dry extract is obtained, which is purified by chromatography on silica eluting with a CH2Cl2/MeOH mixture 96/4 to afford 4.76 g of the expected product.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[CH:6]=[C:7]([O:25]CC2C=CC=CC=2)[C:8]2[N:12]=[C:11]([CH3:13])[N:10]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:9]=2[CH:24]=1)=[O:4]>[Pd].O1CCCC1>[OH:25][C:7]1[C:8]2[N:12]=[C:11]([CH3:13])[N:10]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C:9]=2[CH:24]=[C:5]([C:3]([N:2]([CH3:33])[CH3:1])=[O:4])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OCc4ccccc4)cc(C(=O)N(C)C)cc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O)cc(C(=O)N(C)C)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
A mixture of N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-4-[(phenylmethyl)oxy]-1H-benzimidazole-6-carboxamide (29.0 g, 62.6 mmol, STEP 3) and 10% palladium on carbon (6.0 g) in tetrahydrofuran (200 mL) was stirred under hydrogen gas (1 atmosphere) at room temperature for 24 hours. Another 4.0 g of 10% palladium on carbon was added, and the mixture was stirred under hydrogen gas (1 atmosphere) at room temperature for additional 6 hours. The resulted mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuum to afford the title compound as a white solid (23.0 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH2:23])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:33]=[C:34]=[S:35])(=O)C1C=CC=CC=1>CC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:34]([NH2:33])=[S:35])=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2c(N)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Solvent: CC(C)=O
Product: COc1cc2c(NC(N)=S)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
(4-Amino-6,7-dimethoxy-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (277 mg, 0.831 mmol) was dissolved in dry acetone, and benzoylisothiocyanate (149 mg, 0.914 mmol) was added dropwise. The reaction was stirred at room temperature for 2 h, and was concentrated to yield a yellow solid. This solid was triturated with 50% aqueous EtOH, filtered, and suspended in 10% NaOH (5.0 mL). The reaction mixture was placed in an oil bath that was pre-heated to 98° C. for 1 h, (the solid was dissolved in 10 min). The mixture was cooled and filtered. The yellow solid was washed with water, and dried in vacuo to give (6,7-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (165 mg; 51%). 1H-NMR (CDCl3): δ, 8.31 (s, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 4.81 (s, 2H), 4.05 (s, 3H), 4.00 (s, 3H), 2.81 (s, 2H), 1.46 (s, 9H); MS: calculated for C18H24N4O4S+H 393.0; found: 392.9.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=[C:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:17][C:18]2([C:19](=[O:20])[O:21][CH2:22][CH2:23]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C1CCOC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCCC12CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A stirred solution of N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (D8, 160 g of 75% purity, assume 0.51 mole) and α-methylene-γ-butyrolactone (D10, 50 g, 0.51 mole) in dichloromethane (1 liter) under nitrogen was cooled to 0° C. and then treated with a 1 M solution of trifluoroacetic acid in dichloromethane (50 ml, 0.05 mole), keeping the temperature below 5° C. The reaction mixture was allowed to warm to room temperature over 2 h, then washed with saturated sodium bicarbonate solution. The aqueous wash was extracted with dichloromethane and the organic solutions then combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to leave a pale yellow oil. This was distilled in vacuo to give the title compound (D11) as a colourless oil (96 g, 81%) b.p. 160°-170° C. at 1 mmHg.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[C:7]([C:13]([O:15]C)=O)=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]=1[C:32](OC)=O)([CH3:3])[CH3:2].[Br-].[CH2:37]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:38][CH2:39][CH2:40]C.C(OCC)(=O)C.FC(F)(F)C(O)=O>CC#N>[CH:10]([C:8]1[C:7]([CH2:13][OH:15])=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:5]([CH:32]=[CH:37][CH2:38][CH2:39][CH3:40])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:9]=1)([CH3:11])[CH3:12]
Reactant: COC(=O)c1c(C(C)C)cc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1OCc1ccccc1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC=Cc1c(C(C)C)cc(C(C)C)c(CO)c1-c1ccc(F)cc1OCc1ccccc1
Reaction time: 0.33 h

Procedure:
The desired compound was prepared from dimethyl 3,5-diisopropyl-2′-benzyloxy-4′-fluoro-1,1′-biphenyl-2,6-dicarboxylate (Example 246, Step D) by the procedure described in Example 241, Steps F-I (using pentyl triphenylphosphonium bromide in Step H). The pure product obtained was a clear oil (4.73 g, 52% over 4 steps). 1H NMR (300 MHz, CDCl3): δ 0.67-0.78 (m, 3H), 1.09-1.34 (m, 14H), 1.66-1.88 (m, 3H), 3.16-3.46 (m, 2H), 4.29-4.44 (m, 2H), 4.88-5.04 (m, 2H), 5.27-5.41 (m, 1H), 5.94-6.01 (m, 1H), 6.69-6.78 (m, 2H), 7.00-7.06 (m, 3H), 7.22-7.26 (m, 3H), 7.35 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.18, 14.52, 22.89, 23.05, 24.39, 24.64, 24.94, 25.11, 25.38, 29.73, 30.50, 30.66, 31.68, 35.85, 60.78, 71.07, 71.45, 102.25, 102.59, 108.08, 108.37, 122.33, 122.54, 127.11, 127.22, 127.92, 128.11, 128.51, 129.16, 132.70, 132.83, 133.39, 134.06, 135.96, 136.96, 137.29, 137.35, 147.48, 147.63, 147.79, 156.90, 156.93, 163.26 (d, J=246.6 Hz, 1C). FAB-MS: calculated for C31H37O2F 460; found 460 (M+). Anal. calc for C31H37O2F: C, 80.83; H, 8.10. Found: C, 80.91; H, 8.01. Rf=0.34 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05% aqueous trifluoroacetic acid, B=CH3CN; linear gradient: 80%-100% B over 20 min; 254 nm, 1 mL/min): R.T. 14.8 min (37.7 area %), 15.2 min (56.0 area %); 93.7% purity (cis- and trans-).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH:12]([OH:14])[CH3:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>[Pd].O1CCCC1>[ClH:15].[OH:14][CH:12]([CH3:13])[CH2:11][NH:10][C:5]1[C:4]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(O)CNc1ncccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)CNc1ncccc1NC(=O)c1ccc(Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A mixture of 1-[(3-nitro-2-pyridinyl)amino]-2-propanol (9.9 g, 0.05 mole) and 5% palladium on carbon (1.0 g) in 150 ml of tetrahydrofuran was hydrogenated in a glass Parr apparatus for 1/2 hour. The mixture was dried over magnesium sulfate and filtered through a Celite pad to give a colorless filtrate. The p-chlorobenzoyl chloride (8.79 g, 0.05 mole) and triethylamine (6.98 ml, 0.05 mole) were added dropwise to the stirred filtrate at 12°-15° C. (ice bath). The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was recrystallized from isopropyl alcohol and water. The solid was collected by filtration, then treated with boiling methanol. The insoluble solid was collected by filtration, and the filtrate was evaporated to dryness, azeotroped with benzene, and dried under high vacuum. The residue was partitioned between water and methylene chloride. The methylene chloride was extracted with 5% potassium hydroxide and water. The methylene chloride layer was dried, filtered, and evaporated to a foam. A 1.5-g sample was dissolved in ethyl acetate, acidified with ethereal and methanolic hydrogen chloride, and seeded. The crystalline solid was collected by filtration, washed with ethyl acetate, and dried under high vacuum to give 1.2 g of solid, mp 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:19]([Sn](CCCC)(CCCC)C=C)[CH2:20]CC.[NH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:19][CH2:20][NH:34][CH2:35][CH2:36][O:37][C:38]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:39]=2[C:40]#[N:41])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCCN
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCNCCc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 110 °C
Yield: 20.6 %

Procedure:
A mixture of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.1 g, 0.353 mmol), tributylethenylstannane (0.118 g, 0.371 mmol), tetrakis(triphenylphosphine)palladium (0.0081 g, 0.0070 mmol) in toluene (20 mL) was refluxed at 110° C. for 2 h under nitrogen. The solvent was removed under reduced pressure (high vacuum) and the residue was dissolved in 4 mL of THF/MeOH (3:1). 2-(2-Aminoethoxy)-4-nitrobenzonitrile (0.088 g, 0.424 mmol) was added and the mixture was refluxed at 75° C. for 18 h while monitoring by LC-MS. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (4 g RediSep silica column, 10% methanol in chloroform) to get 2-(2-((2-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)ethyl)amino)ethoxy)-4-nitrobenzonitrile (0.035 g, 20.56%) as a dark brown gummy liquid. LC-MS (M+H)+=482.0. 1H NMR: (400 MHz, CDCl3) δ ppm 7.93 (1H, d, J=8.4 Hz), 7.87 (1H, s), 7.74 (1H, d, J=8.4 Hz), 7.13-7.10 (2H, m), 7.02-6.98 (2H, m), 4.45-4.44 (2H, m), 4.36 (1H, t, J=8.4 Hz), 3.44-3.41 (4H, m), 3.11-3.09 (2H, m), 2.97-2.88 (2H, m), 2.74-2.66 (1H, m), 2.21-2.12 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[O:11][C:12]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:45]=[CH:46][C:47]([CH3:63])=[C:48]([NH:50][C:51]2[CH:52]=[C:53]3[C:58](=[CH:59][CH:60]=2)[N:57]=[CH:56][N:55]([CH3:61])[C:54]3=[O:62])[CH:49]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[O:11][C:12]=2[C:13]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([CH3:63])=[C:48]([NH:50][C:51]3[CH:52]=[C:53]4[C:58](=[CH:59][CH:60]=3)[N:57]=[CH:56][N:55]([CH3:61])[C:54]4=[O:62])[CH:49]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: O=C(O)c1oc(C(F)(F)F)nc1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2oc(C(F)(F)F)nc2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 1 h
Yield: 67 %

Procedure:
To a flask containing DCM (3 mL) on ice was added 4-(4-fluorophenyl)-2-(trifluoromethyl)oxazole-5-carboxylic acid (S-41) (76 mg, 0.28 mmol), EDC (47.2 mg, 0.3 mmol), HOAt (48.9 mg, 0.36 mmol), and DIPEA (0.193 mL, 1.10 mmol). The resulting solution was stirred for 1 hr followed by the addition of 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)-one (HGM-7) (77.4 mg, 0.28 mmol). The reaction was stirred for 18 hours at ambient temperature at which point the solution was made basic by the addition of saturated sodium bicarbonate (10 mL) which was then extracted with DCM (2×10 mL) and EtOAc (2×10 mL). The organic extracts were washed with brine, combined, dried over Na2SO4, and concentrated. The crude material was fractionated by SiO2 chromatography (stepwise gradient of DCM to 90% DCM/10% MeOH, desired product elutes in 5% MeOH)(101 mg, 67% yield). 1HNMR (400 MHz, CDCl3): d 8.9 (s, 1H), 7.82 (m, 2H), 7.80 (s, 1H), 7.55 (d, 1H, J=2.4 Hz), 7.50 (s, 1H), 7.41 (d, 1H, J=8.4 hz), 7.27 (m, 2H), 7.03 (d, 1H, J=8.4 Hz), 6.95 (t, 2H, J=8.8 Hz), 3.44 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1.CS(O)(=O)=O>C(O)C>[CH3:15][C:16]1[N:20]([CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:19][CH2:18][N:17]=1
Reactant: CC1=NCCN1
Reactant: C=C(C)C(=O)Nc1c(C)cccc1C
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CC1=NCCN1CC(C)C(=O)Nc1c(C)cccc1C

Procedure:
Combine 30.0 gm. (0.16 M) N-(2,6-dimethylphenyl)-2-methylpropenamide [methacroyl-2',6'-xylidide], 13.3 gm. (0.16 M) lysidine, 3 gm. (0.03 M) methanesulphonic acid and 150 ml. of ethanol in a pressure bottle and heat at about 150° C. for about 48 hours. Remove the solvent in vacuo, add 200 ml. of water and adjust the pH to 7.8 with conc. HCl. Extract the aqueous phase with 4×100 ml. of methylene chloride and set these aside. Treat the aqueous phase with 20% NaOH to obtain a pH of about 13. Extract the aqueous phase with 4×100 ml. of methylene chloride. Wash the combined methylene chloride extracts with 3×10 ml. water and dry organic layer over sodium sulfate. Evaporate off the solvents to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:32]=[C:31](Cl)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>O1CCCC1>[Cl:22][C:23]1[N:32]=[C:31]([NH:14][CH2:13][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NCC1(c2ccccc2)CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nc(NCC2(c3ccccc3)CCCCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of C-(1-phenyl-cyclohexyl)-methylamine (0.28 g; 1.48 mmol) in tetrahydrofuran (10 mL) at room temperature was treated with triethylamine (0.3 mL; 2.2 mmol) and 2,4-dichloro-quinazoline (0.32 g; 1.62 mmol). The reaction was stirred at room temperature 12 h at which time the solvent was removed by rotary evaporation. The crude residue was portioned between ethyl acetate and 10% aqueous HCl. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated. The product was recrystallized from methylene chloride to give (2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine as a white solid. LCMS m/z=352.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH:7]1([N+:13]#[C-:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1)=O>Cl(O)(=O)(=O)=O>[CH:7]1([NH:13][C:14]2[N:3]3[NH:4][CH:5]=[N:6][C:2]3=[N:1][C:15]=2[C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: Nc1nc[nH]n1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)Nc1ccc(-c2nc3nc[nH]n3c2NC2CCCCC2)cc1

Procedure:
Compound 48 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) cyclohexylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) N-(4-formyl-phenyl)-acetamide solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.