Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([N:16]=[C:17]=[S:18])[C:13]([F:19])=[CH:12][C:11]=2[Cl:20])[CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1>C(O)C>[CH3:1][O:2][C:3]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]3)=[S:18])[C:13]([F:19])=[CH:12][C:11]=2[Cl:20])[CH2:6][CH2:7][CH2:8]1)=[O:4]
Reactant: COC(=O)C1(Sc2cc(N=C=S)c(F)cc2Cl)CCC1
Reactant: C1CCNNC1
Solvent: CCO
Product: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CCC1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
While stirring at room temperature, a solution of 13.1 g of 1-(2-chloro-4-fluoro-5-isothiocyanato-phenylthio)-cyclobutanecarboxylic acid methyl ester obtained in accordance with Example P2 in 200 ml of ethanol is added dropwise to a solution of 4 g of hexahydropyridazine in 30 ml of ethanol. After stirring for 3 hours at room temperature, the reaction mixture is concentrated by evaporation in vacuo, yielding 10.8 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclobutanecarboxylic acid methyl ester having a melting point of from +112° to +113° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(C#N)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[Mg+].[Br-].CC[O:22][CH2:23][CH3:24].O.Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:23](=[O:22])[CH3:24])[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: N#CC1(c2ccc(C(F)(F)F)cc2)CCC1
Reactant: CCOCC
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC1
Temperature: 95 °C
Yield: 88 %

Procedure:
The starting nitrile, 1-(4-Trifluoromethyl-phenyl)-cyclobutanecarbonitrile, has been described (Parke Davis & Co., U.S. Pat. No. 3,536,656; 1970 and Chemical Abstracts 1970, 73, 109539). To the carbonitrile (2 g) in 5 mL of toluene in a pressure tube was added 10 mL of 3M MeMgBr ether solution (3 equiv.). The tube was sealed and the reaction mixture was heated at 95° C. for 24 hr, cooled to room temperature, poured into 50 mL of water, acidified with 25 mL of 5 M HCl, and this solution was heated at 70° C. for 2 h, cooled, and extracted with ether. The extracts were dried, filtered, concentrated, and purified on silica gel to give pure 1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanone (1.9 g, 88%). Data for this ketone: MS 242 (M); 1H NMR (300 MHz, CDCl3) δ 7.6 (d, 8.0 Hz, 2H), 7.4 (d, 8.0 Hz, 2H), 2.75-2.85 (m, 2H), 2.35-2.5 (m, 2H), 1.8-2.0 (3H s and 2H m overlapping); 13C NMR (75 MHz, CDCl3): δ 207.7, 147.5, 129.5, 126.9, 126.1, 125.9 (CF3), 59.5, 30.9, 24.6, 16.1.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([F:14])[CH:5]=1)#N.C([O:17]CC)C>>[F:14][C:6]1[CH:5]=[C:4]([CH:2]=[O:17])[CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ccc(C#N)cc1F
Reactant: CCOCC
Agent: Cl
Product: CC(=O)Nc1ccc(C=O)cc1F
Reaction time: 8 h
Yield: 98 %

Procedure:
Stannous chloride (98%, 17.3 g, 91.5 mmol) was placed in a dry 3-neck 500 mL round bottom flask under argon. Anhydrous diethyl ether (100 mL) was added via cannula. The suspension was stirred as dry HCl gas was bubbled in until the solid dissolved. Anhydrous methylene chloride (100 mL) was added via cannula to homogenize the two layers and the solution was stirred for an additional 0.5 h while a continuous stream of dry HCl gas was bubbled through the solution. N-(4-Cyano-2-fluoro-phenyl)-acetamide (10.5 g, 58.7 mmol) was added and the suspension stirred at rt for an additional 3 h under a continuous stream of dry HCl gas. During this time a sticky, yellow solid formed which eventually crystallized. The reaction mixture was left standing overnight after the introduction of HCL was stopped. The residue was partioned between methylene chloride (100 mL) and water (100 mL) and the phases were separated. The aqueous phase was extracted with methylene chloride (100 mL) and the combined organic extracts were washed with brine (100 mL) and dried over anhydrous potassium carbonate (essential for purity of the product). Concentration of the solvent provided 10.5 g (57.7 mmol) of a crystalline residue. Yield: 98%; mp 133° C.; 1H NMR (400 MHz, CDCl3) δ 10.1 (s, 1H, NH), 9.9 (s, 1H, CHO), 8.39 (t, J=8.0 Hz, 1H), 7.76–7.72 (m, 2H), 2.18 (s, 3H, Me).
Reaction SMILES: C([O:4][P:5]([CH2:11][O:12][CH2:13][C:14]([CH2:37][CH3:38])=[CH:15][CH2:16][C:17]1[C:18]([O:30]CC[Si](C)(C)C)=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])(=[O:10])[O:6]C(C)C)(C)C.N1C(C)=CC=CC=1C.Br[Si](C)(C)C>C(#N)C>[CH2:37]([C:14](=[CH:15][CH2:16][C:17]1[C:18]([OH:30])=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])[CH2:13][O:12][CH2:11][P:5](=[O:4])([OH:6])[OH:10])[CH3:38]
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)COCP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CCC(=CCc1c(O)c2c(c(C)c1OC)COC2=O)COCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of {2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enyloxymethyl}-phosphonic acid diisopropyl ester (347 mg, 0.61 mmol) in acetonitrile (5 mL) was added 2,6-lutidine (0.71 mL, 6.1 mmol) and bromotrimethylsilane (0.786 mL, 6.1 mmol). The mixture was stirred at room temperature for 3 hours, quenched with methanol (5 mL), concentrated, and partitioned between ethyl acetate and 1N HCl (aqueous). The organic layer was concentrated to give the free phosphonic acid as a colorless oil (205 mg, 70%). This material (20 mg) was dissolved in a solution of trifluoroacetic acid (0.3 mL) and dichloromethane (2.7 mL) and stirred for 30 minutes at ambient temperature. After concentration, the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide the product, after lyophilization, as a white solid (10 mg). 1H NMR (300 MHz, CDCl3) δ 1.007 (t, 3H, J=7.5 Hz), 2.13 (s, 3H), 2.32 (q, 2H, J=7.5 Hz), 3.41 (d, 2H, J=6.3 Hz), 3.56 (d, 2H, J=9 Hz), 3.75 (s, 3H), 3.95 (s, 2H), 5.16 (s, 2H), 5.43 (t, 1H, J=6.3 Hz) ppm; 31P (121.4 MHz, CDCl3) δ 22.8 ppm; MS (m/z) 385.2 [M−H]+, 387.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C@@H:13]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([OH:28])[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[O:22])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:42]([O:44][C:45]([C:47]1(Br)[CH2:50][CH2:49][CH2:48]1)=[O:46])[CH3:43]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C@@H:13]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][C:47]3([C:45]([O:44][CH2:42][CH3:43])=[O:46])[CH2:50][CH2:49][CH2:48]3)[N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:24]=2)=[O:22])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-{(S)-2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-4-methanesulfonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 127 mg of cesium carbonate and 81 mg of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:29])=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([NH:8][CH2:9][CH:10]2[CH2:25][CH2:24][CH2:23][C:12]3([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]3)[CH2:11]2)[CH:7]=1.[Cu][C:31]#[N:32]>CN(C=O)C.[Cl-].[Na+].O>[Cl:29][C:3]1[CH:4]=[C:5]([N+:26]([O-:28])=[O:27])[C:6]([NH:8][CH2:9][CH:10]2[CH2:25][CH2:24][CH2:23][C:12]3([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:13]3)[CH2:11]2)=[CH:7][C:2]=1[C:31]#[N:32]
Reactant: N#C[Cu]
Reactant: CC(C)(C)CN1CC2(CCCC(CNc3cc(Br)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CN1CC2(CCCC(CNc3cc(C#N)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
A suspension containing 7-(((5-bromo-4-chloro-2-nitrophenyl)amino)methyl)-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.260 g, 0.532 mmol) and copper (I) cyanide (0.333 g, 3.72 mmol) in DMF (2 mL) was subject to microwave heating at 180° C. for 1.5 h. The reaction was cooled to rt, diluted with brine solution, and stirred for 20 min. The mixture was filtered through a pad of celite, and the celite was washed with EtOAc. The combined filtrates were washed with EtOAc. The combined organics were washed with water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified on a 24 g silica gel column (0-75% EtOAc/hexanes, 15 min gradient; 75% EtOAc/hexanes, 10 min; 35 mL/min elution; 254 nm detection) to afford the title compound as an orange solid. MS (m/z) 435.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[I:12]I>CO.[Ag+].FC(F)(F)C([O-])=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[C:11]([I:12])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: COC(=O)c1cnc(N)c(I)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.5 %

Procedure:
To a stirred suspension of methyl 6-aminonicotinate (10 g, 65.7 mmol) and trifluoroacetic acid silver salt (36.3 g, 164.3 mmol) in methanol (250 mL) was added iodine (41.7 g, 164.3 mmol) at 25° C. and the reaction mixture was stirred at 25° C. for 72 h. The mixture was filtered, washed with methanol and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed consecutively with a saturated sodium thiosulfate solution, brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford 6-amino-5-iodo-nicotinic acid methyl ester (13.8 g, 77%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 3.89 (s, 3H), 5.46 (br. s., 2H), 8.47 (br. s., 1H), 8.67 (br. s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([OH:8])[CH3:7])=[CH:4][CH:3]=1.[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1>Cl.CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH3:7])[O:8][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][O:15]2)=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: CCOCC
Product: CC(OC1CCCCO1)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 269 parts of p-bromo-α-methylbenzyl alcohol and 225 parts of 2H-3,4-dihydropyran is stirred and cooled to 0° C. Then there are added dropwise 10 drops of concentrated hydrochloric acid solution and the whole is stirred in an ice-bath (room temperature is reached). After stirring for 24 hours, the reaction mixture is poured onto 1200 parts of ether. The organic phase is washed twice with a sodium hydrogen carbonate solution and twice with water, dried, filtered and evaporated. The residue is distilled, yielding 2-(p-bromo-α-methylbenzyloxy)tetrahydropyran; bp. 165°-177° C. at 20 mm. pressure.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>ClCCl>[C:1]([NH:8][C@@H:9]([C:13]([N:47]1[CH2:46][CH2:45][N:44]([CH:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)[CH2:49][CH2:48]1)=[O:15])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C2CCN(C)CC2)CC1
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a stirring solution of Boc-D-valine (5.0 g, 23 mmol) in dichloromethane (230 mL) is added HOBt (3.42 g, 25.3 mmol), followed by EDCI (4.85 g, 25.3 mmol), followed by 4-(1-methylpiperidin-4-yl)piperazine (4.2 g, 23 mmol). After stirring overnight, the solution is washed with saturated aqueous NaHCO3, followed by brine, and then concentrated in vacuo. The residue is chromatographed over silica gel, eluting with a gradient of 0-10% (2 N ammonia/methanol) in chloroform. The product-containing fractions are combined and concentrated in vacuo to give the title product (8.98 g, quantitative) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(O[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CC#N>[N+:12]([C:3]1[C:2]([O:1][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])([O-:14])=[O:13]
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OC2CCOCC2)c1[N+](=O)[O-]
Yield: 136.7 %

Procedure:
Methyl 3-hydroxy-2-nitrobenzoate (95 g, 0.52 mol), tetrahydro-2H-pyran-4-yl methanesulfonate (234 g, 1.3 mol) and K2CO3 (358 g, 2.6 mol) was suspend in MeCN (2 L). The mixture was heated at reflux for 20 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was filtered; the filtrate was concentrated in vacuo. The residue was purified by chromatography (petroleum ether: ethyl acetate=10:1, 5:1, 2:1) to give the title compound (200 g 100%) as a yellow oil.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([OH:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>>[N+:8]([C:7]1[C:2]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([OH:18])[CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: OC1CCC(O)CC1
Reactant: O=[N+]([O-])c1cccnc1F
Product: O=[N+]([O-])c1cccnc1O[C@H]1CC[C@H](O)CC1

Procedure:
Prepared analogously to III.1 from 3.6 g 2-fluoro-3-nitropyridine and 2.9 g 1,4-cyclohexanediol.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]1)=[O:7].C(N(C(C)C)CC)(C)C.[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([CH:45](Br)[C:46]2[CH:51]=[CH:50][C:49]([CH2:52][CH:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=2)=[CH:41][CH:40]=1)[CH:36]([CH3:38])[CH3:37].Cl>ClCCl>[CH2:52]([C:49]1[CH:50]=[CH:51][C:46]([CH:45]([NH:2][C:3]2[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=2)[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]2)=[O:7])[C:42]2[CH:43]=[CH:44][C:39]([CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:40][CH:41]=2)=[CH:47][CH:48]=1)[CH:53]([CH3:55])[CH3:54]
Reactant: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3ccccc32)c1
Reactant: CC(C)Cc1ccc(C(Br)c2ccc(CC(C)C)cc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)n3cc(CCCC(=O)O)c4ccccc43)c2)c2ccc(CC(C)C)cc2)cc1
Reaction time: 15 h
Yield: 95.5 %

Procedure:
To a solution of 4-[1-(3-aminobenzoyl)indol-3-yl]butyric acid hydrochloride (14.5 g) and diisopropylethylamine (22 ml) in dichloromethane (300 ml) was added bis(4-isobutylphenyl)methyl bromide (14.5 g) at room temperature. After stirring for 15 hours, diisopropylethylamine (7 ml) and bis(4-isobutylphenyl)methyl bromide 2.0 g) were added to the mixture. The mixture was stirred for 6 hours at room temperature and acidified by 7% hydrochloric acid (50 ml). The separated organic layer was washed with water and dried over magnesium sulfate. After the solvent was removed in vacuo, the residue was chromatographed on a column of silica gel (200 g) and eluted with chloroform to give a solid of 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-3-yl]butyric acid (23.15 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[CH3:33][C:34]([CH3:63])([O:36][C:37](=[O:62])[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.NC1C=CC(N(CC)CC)=CC=1C1C=C(C=CN=1)C(NCC1C=CC=C(C(F)(F)F)C=1)=O>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:56]([C:55]2[CH:54]=[C:53]([CH2:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][C:37]([O:36][C:34]([CH3:63])([CH3:35])[CH3:33])=[O:62])[CH:61]=[CH:60][CH:59]=2)=[O:57])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH:30]=[CH:31][N:32]=2)[CH:4]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.42 h
Yield: 77.3 %

Procedure:
To a solution of 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (1.77 g, 4.0 mmol), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid (1.70 g, 3.86 mmol) and DIPEA (1.47 g, 11.4 mmol) in DMF (20 ml) was added HATU (1.56 g, 4.10 mmol). The reaction mixture was stirred for 30 minutes, at which time additional 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (0.06 g, 0.14 mmol) was added. After stirring an additional 25 minutes, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (200 mL), washed with water (4×50 mL), dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (50% to 100% EtOAc in hexanes) gave the title compound (2.58 g) as an oil.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:21]=[CH:22]S(C2C=CC=CC=2)(=O)=O)[CH:15]=[CH:16][C:17]=1[CH3:18].COC(C)(C)C>C1COCC1>[CH2:1]([O:8][CH:22]=[CH:21][C:20](=[N:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=1)[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(OC(C=CS(=O)(=O)c2ccccc2)=Nc2ccc(C)c(C)c2)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cccc(OC(C=COCc2ccccc2)=Nc2ccc(C)c(C)c2)c1
Reaction time: 0.5 h
Yield: 114.8 %

Procedure:
To a solution of benzyl alcohol (0.78 g) in THF (15 mL) was added 60% sodium hydride (90 mg) under a nitrogen atmosphere under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added dropwise to a solution of 3-methylphenyl N-(3,4-dimethylphenyl)-3-(phenylsulfonyl)acrylimidate (0.78 g) in anhydrous THF (15 mL) under ice-cooling. The mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added tert-butyl methyl ether (80 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 3-methylphenyl 3-benzyloxy-N-(3,4-dimethylphenyl)acrylimidate (0.82 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(O)[CH2:10][C@H:9]1[C:23](=[O:34])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:41])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([F:41])[CH2:10][C@H:9]1[C:23](=[O:34])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@](F)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 1.5 h

Procedure:
To a solution of (2S,4S)-4-(tert-butyl-dimethyl-silanyloxymethyl)-2-(3-chloro-2-fluoro-benzyl carbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.35 mmol) in CH2Cl2 (10 mL) under N2 atmosphere at −78° C. was added DAST (92 μL, 0.7 mmol). The reaction mixture was then allowed to reach RT and further stirred for 1.5 h then poured into an aqueous saturated solution of NaHCO3 and extracted twice with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated to give the desired material which was used without further purification in the next step. TLC, Rf (c-hexane/EtOAc 1:1)=0.75; MS (LC/MS): 541.2/543.1 [M+Na]+, 463.1/465.1 [MH−tBu]+, 419.0/421.1 [MH−Boc]+; tR (HPLC conditions f): 2.81 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[OH-].[Na+].[C:25](OC(=O)CC)(=O)[CH2:26][CH3:27]>C(Cl)(Cl)Cl>[CH2:26]([C:27]1[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:5]3[C:10]([N:9]=[CH:8][N:7]=2)=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N:22]=1)[CH3:25]
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Reactant: CCC(=O)OC(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCC1=Nc2c(OC)c(OC)cc3ncnc(c23)N1c1ccccc1

Procedure:
A solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (130 mg, 0.44 mmol) (from Example 1, Step C, supra) in propionic anhydride (3 mL) (Aldrich) was heated at 170° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.05) as eluent to give the desired 2-ethyl-8,9-dimethoxy-3-phenyl-3H-1,3,4,6-tetraaza-phenalene as an orange solid. (Yield 21 mg, 14%).