Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[NH2:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28].[Na+].OC1C=CC(NC(=O)C)=CC=1.O>C(#N)C>[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:24][CH2:25][CH2:26][S:27]([OH:30])(=[O:29])=[O:28])=[O:23])=[CH:8][CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NCCS(=O)(=O)[O-]
Agent: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)NCCS(=O)(=O)O)cc1

Procedure:
((4-Acetamidophenoxy)carbonylamino)ethanesulfonic acid (12a) was prepared according to the General Method for the Reaction of Alkali Metal Salts of Amino Acid Derivatives with 4-Acetamidophenyl 4-Nitrophenyl carbonate (3). A solution of 511 mg (3.48 mmol) of sodium 2-aminoethanesulfonate (7) in approximately one (1) mL of degassed water was reacted with a solution of 4-acetamidophenyl 4-nitrophenyl carbonate (3) (1.10 g, 3.48 mmol) dissolved in 5 mL of acetonitrile (MeCN). After work-up procedures, the aqueous layer was lyophilized off to afford 1.0 g (˜quantitative yield) of the crude 2-((4-acetamidophenoxy)carbonylamino)ethanesulfonic acid (12a) which was used directly and without further isolation or purification procedures. The material thus obtained was contaminated with some sodium chloride (NaCl) and other sodium salts. 1H NMR (300 MHz, D2O): δ 7.22 (d, J=9.0 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 3.40 (t, J=6.6 Hz, 2H), 2.95 (t, J=6.6 Hz, 2H), 1.96 (s, 3H). LC/MS (ESI): m/z=303.0 [M+H]+, 602.8 [2M−H]−.
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH2:12]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:29]1[CH2:33][CH2:32][CH2:31][CH:30]=1.Cl>CO>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:28])[CH2:27][CH:30]2[CH2:31][CH2:32][CH2:33][NH:29]2)=[CH:24][CH:25]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1=NCCC1
Reactant: CC(=O)c1ccc(CCc2ccccc2)cc1
Agent: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CO
Product: O=C(CC1CCCN1)c1ccc(CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 63 %

Procedure:
Magnesium methyl carbonate (0.4 mole, 2 M in dimethylformamide) is heated to 120°C. under carbon dioxide. The compound 4'-phenethylacetophenone, 22.4 g (0.1 mole), is added and the mixture is stirred at 120°C. for 4 hours under a stream of nitrogen allowing the methanol that forms to escape. The reaction mixture is allowed to cool to room temperature under an atmosphere of carbon dioxide and 8.3 g (0.12 mole) of 1-pyrroline (as the trimer) added and stirred at room temperature under carbon dioxide for a period of 40 hours. The solution is poured into a mixture of 200 ml of concentrated HCl and 800 g of ice and the product removed by filtration. The 4'-phenethyl-2-(2-pyrrolidinyl)-acetophenone when twice recrystallized in the form of its hydrochloride salt from an aqueous isopropanol solution is obtained in 63% yield (20.1 g) and has a M.P. of 200-1°C. (dec).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]([C@H:33]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]([CH3:36])[CH3:35])[CH:26]=[C:25]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:24]2=[O:51].[Br-].[Cl:53][C:54]1[C:55]([F:62])=[C:56]([CH:59]=[CH:60][CH:61]=1)[CH2:57][Zn+].[Cl-].[NH4+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1.CN1CCCC1=O>[C:40]([SiH2:39][O:38][C:37]([CH3:45])([CH3:44])[C@@H:33]([N:27]1[C:28]2[C:23](=[CH:22][C:21]([CH2:57][C:56]3[CH:59]=[CH:60][CH:61]=[C:54]([Cl:53])[C:55]=3[F:62])=[C:30]([O:31][CH3:32])[CH:29]=2)[C:24](=[O:51])[C:25]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:26]1)[CH:34]([CH3:35])[CH3:36])([CH3:43])([CH3:41])[CH3:42]
Reactant: Fc1c(Cl)cccc1C[Zn+]
Reactant: CCOC(=O)c1cn([C@@H](C(C)C)C(C)(C)O[SiH2]C(C)(C)C)c2cc(OC)c(Br)cc2c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn([C@@H](C(C)C)C(C)(C)O[SiH2]C(C)(C)C)c2cc(OC)c(Cc3cccc(Cl)c3F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0) (332 mg) and triphenylphosphine (299 mg) were added to tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 1 hr. Ethyl 6-bromo-1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (10.0 g) obtained in Step 7 of Example 1/1-methyl-2-pyrrolidinone (80 mL) solution and a solution (26.2 g) of 29% 3-chloro-2-fluorobenzylzinc bromide in tetrahydrofuran were successively added dropwise at room temperature. After completion of the dropwise addition, the mixture was stirred at 65° C. for 3 hr, and the completion of the reaction was confirmed by HPLC. After cooling the reaction mixture, toluene (50 mL) and 12.5% aqueous ammonium chloride solution (100 mL) were added, sufficiently stirring, and the aqueous layer was discarded. The organic layer was washed successively with 25% aqueous ammonium chloride solution (50 mL), twice with 2% aqueous ethylenediamine solution (50 mL), and with 10% aqueous sodium chloride solution (50 mL). After washing, the solvent was evaporated under reduced pressure. Isopropanol (50 mL) was added to the concentrated residue to give a solution of ethyl 1-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl)-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate in isopropanol. This was directly used in the next step.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]#[C:9][CH2:8][CH2:7][CH2:6][N:19]=[N+:20]=[N-:21])=[CH:12][CH:13]=1)#[N:18]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C#CCCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of the product of step B (13.40 g, 50.9 mmol) in dimethylformamide (35 mL) was added NaN3 (16.5 g, 255 mmol). The reaction was stirred at room temperature for 18 hours then at 60° C. for 2 hours, cooled to room temperature, diluted with water (400 mL) and extracted with ethyl acetate. The organic layer was washed with water (2×) then with brine and dried (Na2SO4). Evaporation under reduced pressure afforded 10.70 g (100%) of product as a tan oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(/[CH:14]=[CH:15]/[C:16](OCC)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(/[CH:14]=[CH:15]/[CH2:16][OH:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/C1(c2ccc(F)cc2)CCCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC/C=C/C1(c2ccc(F)cc2)CCCCC1
Reaction time: 5.5 h
Yield: 75.8 %

Procedure:
To a solution of (E)-ethyl 3-(1-(4-fluorophenyl)cyclohexyl)acrylate (Intermediate I-7B, 1.5 g, 5.43 mmol) in toluene (30 mL) was added 2.5 M DIBAL-H in toluene (6.51 mL, 16.28 mmol) dropwise at room temperature, and the mixture was stirred at the same temperature for 5.5 hrs. The reaction was quenched by dropwise addition of methanol (1.34 mL) and stirring was continued for a few minutes. Then water (1.96 mL) was added dropwise and the mixture was stirred overnight at room temperature. The resulting mixture was filtered through CELITE® and evaporated to give an oily residue. It was purified by Combiflash (silica gel, 40 g) eluting with 5:95 followed by 1:9 and 2:8 ethyl acetate-hexane to give the desired (E)-3-(1-(4-fluorophenyl)cyclohexyl)prop-2-en-1-ol (964 mg, 76% yield) along with 232 mg of the unreacted starting material. 1H NMR (400 MHz, CDCl3) δ ppm 7.30 (2H, dd, J=8.91, 5.39 Hz), 7.00 (2H, t, J=8.80 Hz), 5.70 (1H, d, J=15.85 Hz), 5.43 (1H, dt, J=15.74, 5.94, 5.83 Hz), 4.11 (2H, dd, J=5.72, 1.32 Hz), 1.97-2.05 (2H, m), 1.78-1.86 (2H, m), 1.53-1.63 (3H, m), 1.40-1.52 (5H, m).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]=1[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20].[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>C(#N)C>[O:42]=[C:41]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)[C:25]2[CH2:26][CH2:27][C:28](=[O:29])[C:24]=2[CH:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[NH:9]1
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (125 μL, 0.89 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1-enyl)methyl)-3-(ethylsulfonyl)benzonitrile hydrochloride (intermediate 20.2, 1.78 g, 3.56 mmol) and 1,1′-carbonyldiimidazole (720 mg, 4.45 mmol) in acetonitrile (20 mL), and the mixture is stirred at room temperature for 1 h. The mixture is concentrated under reduced pressure, and the residue is treated with water (20 mL). The precipitate is filtered and dried. Yield: 1.61 g. ESI mass spectrum: [M+H]+=490; Retention time HPLC: 0.56 min (X012_801).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([C:45](=[O:53])[CH2:46][N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)=[O:53])[CH2:52][CH2:51]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN1CCN(C(=O)CN2CCNCC2)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(4-methylpiperazin-1-yl)-2-piperazin-1-yl-ethanone (Ibscreen-BB) to give the title compound. HR-MS (ES, m/z) calculated for C40H52Cl2N7O3 [(M+H)+] 748.3503, observed 748.3504.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:33].C(OCC)(=O)C>>[ClH:33].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(trans-2-{4-[(biphenyl-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate (154 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (81.9 mg).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:16])[CH2:13][CH:14]=[CH2:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:13]([C:12]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:16][C:31](=[O:33])[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1)[CH:14]=[CH2:15]
Reactant: C=CCC(O)(CCNCCc1ccccc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(c2ccccc2)CCN(CCc2ccccc2)C(=O)O1
Temperature: 85 °C
Yield: 543.3 %

Procedure:
To a solution of 1-phenethylamino-3-phenyl-hex-5-en-3-ol (120 mg, 0.41 mmol) and Et3N (0.5 mL) in anhydrous CH2Cl2 (5 mL) was added triphosgene (40 mg, 0.134 mmol) in portions at 0° C. under N2. Then the solution was refluxing at 80-90° C. overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC to afford 6-allyl-3-phenethyl-6-phenyl-[1,3]oxazinan-2-one (234 mg, yield: 19%). 1H NMR (CDCl3): 2.07-2.17 (m, 2H), 2.44-2.60 (m, 2H), 2.62-2.84 (m, 4H), 3.25 (m, 1H), 3.52 (m, 1H), 3.09 (m, 1H), 5.04 (m, 2H), 5.47-5.58 (m, 1H), 6.94 (m, 2H), 7.10 (m, 3H), 7.27 (m, 3H), 7.31 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:17]=1[C:18](Cl)=[O:19].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:18](=[O:19])[C:17]2[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH3:14])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1C(=O)N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 2.94 g (15.8 mmol) (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (commercially available), 2,6-dimethoxybenzoyl chloride (commercially available) and 2.08 g (2.05 mmol) NEt3 in 15 mL DCM was stirred at room temperature over night. The mixture was absorbed on isolute SPE and purified by column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate to yield 3.78 g (68%) of the title compound as white foam. (MH+) 351.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1F.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.[Li]CCCC.Cl.[OH-].[Na+]>C1COCC1.CCOC(C)=O.O>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([B:21]([OH:26])[OH:22])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(Oc2ccc(OC(F)(F)F)cc2)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
In a flame-dried 25 mL schlenk tube backfilled with argon (×3) a solution of 4-bromo-3-fluorophenol (0.346 g, 2 mmol) in N-methylpyrrolidine (8 mL) under an argon atmosphere was added 4-(trifluoromethoxy)iodobenzene (0.626 mL, 4 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (0.092 mL, 0.44 mmol) and cesium carbonate (1.30 g, 4 mmol). The slurry was degassed by bubbling argon for 15 min and CuCl (0.099 g, 1 mmol) was then added. The reaction mixture was again degassed and then warmed to 100° C. for 7 h. After cooling to room temperature, Et2O (75 mL) was added slowly. The resulting slurry was filtered and the solid washed with Et2O (3×50 mL). The combined filtrates were washed with 2 M NaOH (100 mL), water (100 mL), 1 M aq HCl (100 mL), water (100 mL) and saturated brine (100 mL), the subsequently dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography with 100% Hexane. This column was repeated three times combining the purest fractions each column to obtain pure material due to similarly eluting 4-(trifluoromethoxy)iodobenzene to afford 1-bromo-2-fluoro-4-(4-(trifluoromethoxy)phenoxy)benzene (0.15 g, 45%) as a colorless liquid. To a solution of 1-bromo-2-fluoro-4-(4-(trifluoromethoxy)phenoxy)benzene (2.1 mmol, 0.7 g) and triisopropyl borate (2.7 mmol, 0.63 mL) in dry THF (15 mL) at −78° C. was added dropwise 2.5M BuLi (6.5 mL) in Hexanes over 5 minutes. The reaction was stirred for 3 h at −78° C. at which point 10 mL of 6M HCl is added and the solution is allowed to warm up to room temperature and stir overnight. The reaction mixture was diluted with EtOAc (150 mL) and water (150 mL). The organic layer is taken separately and rinsed with water (150 mL), followed by brine (150 mL) and then dried over Na2SO4. The EtOAc is then concentrated in vacuo to afford a waxy solid which is then treated with 2M NaOH (40 mL) and stirred for 15 min diluted with water (300 mL) and stirred for 20 minutes. The solution is then filtered and the filtrate washed with hexane (3×100 mL). The aqueous layer was carefully acidified to pH 1 with 6 m HCl. The resulting white solid was filtered and dried on a high vacuum overnight to afford the titled compound in 67% yield.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:6]=1[C:7]([NH2:9])=[NH:8].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[ClH:1].[NH2:8][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH3:3])[NH:14][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:9]=1
Reactant: COc1cccc(N)c1C(=N)N
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(cccc1OC)N2

Procedure:
This was prepared by the method of Example 173 using 2-methoxy-6-aminobenzamidine dihydrochloride (Example E) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound as a yellow solid, MS (+CI) 319 ([M+H]+), 1H NMR (d6 -DMSO) 9.97 (1H, s), 8.69 (1H, s), 8.64 (1H, s), 7.70 (1H, s), 7.40 (1H, dd), 6.48 (1H, d), 6.42 (1H, d), 4.05 (2H, q), 3.88 (3H, s), 3.6-3.72 (2H, m), 3.4-3.55 (2H, m), 1.85-2.0 (2H, m), 163-1.80 (2H, m), 1.19 (3H, t).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([NH:17][C:18](=[O:20])[CH3:19])=[CH:12][C:11]=1[CH3:21])=O.[NH2:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[C:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CCO>[CH3:24][O:23][C:6]1[CH:5]=[CH:4][C:3]([CH:1]2[N:30]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:28](=[O:29])[C:27]3[C:26](=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:25]2)=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[C:11]([CH3:21])=[CH:12][C:13]([NH:17][C:18](=[O:20])[CH3:19])=[CH:14][C:15]=1[CH3:16]
Reactant: Nc1ccccc1C(=O)NCc1cccnc1
Reactant: COc1ccc(C=O)cc1COc1c(C)cc(NC(C)=O)cc1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COc1ccc(C2Nc3ccccc3C(=O)N2Cc2cccnc2)cc1COc1c(C)cc(NC(C)=O)cc1C
Yield: 41.6 %

Procedure:
N-(4-(5-formyl-2-methoxybenzyloxy)-3,5-dimethylphenyl)acetamide (100 mg, 0.305 mmol), 2-amino-N-(pyridin-3-ylmethyl)benzamide (83 mg, 0.367 mmol), and 0.2 equiv of Yb(OTf)3 in 5 mL of EtOH were heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica-gel using 2-40% Methanol in DCM to give the desired product N-(4-(2-methoxy-5-(4-oxo-3-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroquinazolin-2-yl)benzyloxy)-3,5-dimethylphenyl)acetamide (68.2 mg, 0.127 mmol, 41.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.96 (s, 3 H), 2.08 (s, 6 H), 3.74 (s, 3 H), 3.98 (d, J=15.7 Hz, 1 H), 4.61 (s, 2 H), 5.07 (d, J=15.3 Hz, 1 H), 5.82 (d, J=2.3 Hz, 1 H), 6.58-6.74 (m, 2 H), 6.97 (d, J=8.2 Hz, 1 H), 7.12-7.37 (m, 6 H), 7.46 (d, J=2.0 Hz, 1 H), 7.64 (t, J=6.8 Hz, 2 H), 8.35-8.47 (m, 2 H), 9.67 (s, 1 H); LC/MS (electrospray+ve), m/z 537.2 (MH)+, Retention time t=4.23 min; Purity: UV220>98%, UV254>98%; HRMS (ESI): m/z calcd for C32H32N4O4 [M+H]+537.2511, found 537.2511.
Reaction SMILES: C([Li])CCC.[CH:6]([N:9]([CH3:13])[CH2:10][C:11]#[CH:12])([CH3:8])[CH3:7].[C:14](=[O:16])=[O:15].O>CCCCCC.O1CCCC1.CO>[CH:6]([N:9]([CH3:13])[CH2:10][C:11]#[C:12][C:14]([OH:16])=[O:15])([CH3:8])[CH3:7]
Reactant: O=C=O
Reactant: C#CCN(C)C(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)N(C)CC#CC(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (18.4 mL, 2.5 M in n-hexane) was slowly added to isopropyl-methyl-prop-2-ynyl-amine (5.1 g, 46 mmol) in 50 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at −78° C., then dry carbon dioxide was passed through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 5.5 g of 4-(isopropyl-methyl-amino)-but-2-ynoic acid: mass spectrum (m/e): M−H 154.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[C:13]3[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26]>>[C:1]1([C:7]#[C:8][C:9]2[C:13]3[CH:14]=[C:15]([CH:18]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2occ(C#Cc3ccccc3)c2c1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3occ(C#Cc4ccccc4)c3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 3-Phenylethynyl-benzofuran-5-carbaldehyde (intermediate 59) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C@@H:13]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[N+:29]([O-:31])=[O:30])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@@H:13]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[N+:29]([O-:31])=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(C=C[C@H](CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CC[C@H](CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Yield: 95.9 %

Procedure:
A solution of 2.75 g (6.17 mmol) of (S)-2-t-butyl-5-(3-t-butyldimethylsilyloxy-4-cyclohexyl-1-butenyl)-1-nitrobenzene [prepared as described in step (v) above] in 30 ml of diethyl ether was vigorously stirred for 20 minutes at 0° C. in a stream of hydrogen and in the presence of 303 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up in a similar manner to that described in step (iii) above, to give 2.65 g (yield 96%) of the title nitrobenzene derivative as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCNc1ccc(Cl)cn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCCNc2ccc(Cl)cn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-[(2-aminoethyl)amino]-5-chloropyridine hydrochloride and DBU in DME. ES-MS m/e (%): 356 (M+H+, 100).