Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16](=[O:27])[C:15](O)=[C:14]2[C:29](=O)[CH2:30][O:31][CH3:32])=[CH:9][CH:8]=1>CCO.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]3[C:29]([CH2:30][O:31][CH3:32])=[N:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[C:15]=3[C:16](=[O:27])[N:17]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[CH:9][CH:8]=1
Reactant: NNC1CC1
Reactant: COCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)C1c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(Cc1ccc(OC)cc1)C2=O
Temperature: 115 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
Cyclopropylhydrazine (2.71 g) (Step 17.2) was added to a solution of 5-(4-chlorophenyl)-3-hydroxy-4-(2-methoxyacetyl)-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (5 g, 12.4 mmol) (Step 130.2) in a mixture of EtOH and toluene (60 mL, 1:1, v/v). The reaction mixture was stirred 16 h at 115° C., concentrated, quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%) to afford the title compound (2.62 g) as a yellow solid. tR: 1.24 min (LC-MS 2); ESI-MS: 438.1 [M+H]+ (LC-MS 2); Rf=0.50 (hexane/EtOAc 1:1).
Reaction SMILES: NC1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1([O:15][CH2:16][P:17](=[O:20])([OH:19])[OH:18])[CH2:14][CH2:13]1.C1([NH:27]C(N2CCOCC2)=NC2CCCCC2)CCCCC1.C(OCCl)(=O)C(C)(C)C.CO.Cl[CH2:54][Cl:55]>CN(C)C=O>[NH2:27][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH2:11][C:12]2([O:15][CH2:16][P:17](=[O:20])([OH:18])[OH:19])[CH2:13][CH2:14]2)=[C:54]([Cl:55])[N:10]=1
Reactant: ClCCl
Reactant: Nc1ncnc2c1ncn2CC1(OCP(=O)(O)O)CC1
Reactant: C1CCC(N=C(NC2CCCCC2)N2CCOCC2)CC1
Agent: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1nc(Cl)c2ncn(CC3(OCP(=O)(O)O)CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
The compound prepared in Example 1 (1.00 g) was dissolved in 150 ml of dry dimethylformamide, and 2.08 g (7.32 mmol) of N,N′-dicyclohexyl-4-morpholine-carboxamidine and 2.75 g (18.3 mmol) of chioromethyl pivalate were added thereto. When the reaction mixture became homogeneous after about 1 hour, it was stirred for 5 days at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was fractionated with 50 ml of water and 50 ml of toluene to separate the organic layer. The aqueous layer was extracted twice with 50 ml of toluene. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methanol/dichloromethane=1/20, v/v) to give 0.59g (Yield 32%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1)[CH3:2].[CH3:15]CN(C(C)C)C(C)C>C(#N)C.CO>[CH2:1]([N:3]1[C:7](=[O:8])[C:6]([O:9][CH3:15])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C1CN(CC)C(=O)C1=O
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)C1=C(OC)C(=O)N(CC)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.2 %

Procedure:
To a solution of ethyl 1-ethyl-4,5-dioxopyrrolidine-3-carboxylate (200 mg, 1.0 mmol) and DIPEA (0.18 mL, 1.0 mmol) in ACN (1.8 mL) and MeOH (0.2 mL) was added TMS-CH2N2 (2.0 M in Et2O; 0.5 mL, 1.0 mmol). The reaction mixture was stirred at rt for 3.5 h, then evaporated in vacuo. The product was purified by silica gel chromatography (40 g silica gel; linear gradient of 0-50% MeOH:EtOAc (10:1) in hexanes over 15 min) to obtain Intermediate 9A (203 mg, 95% yield). HPLC/MS (Method D) RT=0.73 min, [M+H]+ 214.2.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:9]=1.[Br:52]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:49][Si:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][O:43][CH2:42][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:50])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1[Br:52]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxy late (Int-9h, 3.24 g, 4.44 mmol) in DMF (20 mL) was added N-bromosuccinimide (750 mg, 4.21 mmol). The mixture was allowed to stir at room temperature for one hour. More N-bromosuccinimide (75 mg) was added and the mixture was stirred for another half hour before being diluted with EtOAc (200 mL). The mixture was washed with water three times, brine and dried (MgSO4). After solvent was removed under reduced pressure, and the residue was purified on silica. Elution with EtOAc in hexanes (0-50%) gave the title compound (3 g, 83%). LC/MS: m/z=809 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH2:29])[CH2:27][CH3:28])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH3:28])=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: CC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine, TBTU and DIPEA in THF.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[OH:20])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].O>C1COCC1>[CH3:30][C:26]1([CH3:29])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:20][C:33](=[O:34])[N:17]([CH2:16][CH2:15][C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[CH2:18]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(O[Si](C)(C)C(C)(C)C)cc3)ccc2O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(O)cc4)C(=O)O3)ccc2O1
Reaction time: 21.5 h
Yield: 72.7 %

Procedure:
A solution of (1R)-2-{[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (4.803 g) in THF (100 ml) under nitrogen was treated with 1,1′carbonyldimidazole (1.702 g) and the mixture was stirred at 20° for 21.5 h. Water (125 ml) was added, the mixture was stirred for 10 min and then extracted with Et2O. The extract was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was dissolved in THF (60 ml) and was treated with a solution of tetrabutyl ammonium fluoride in THF (1.0 M, 15.95 ml). The mixture was stirred at 20° for 100 min, water (30 ml) was added and the mixture was extracted with Et2O. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by chromatography on a Biotage cartridge (90 g). Elution with EtOAc-petroleum ether (2:3) gave the title compound (2.82 g). LCMS RT=3.01 min ES+ve 370 (MH)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][O:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC(c2ccccc2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
The compound (III) (50 g, 0.268 mol) obtained in the first step was dissolved in dry pyridine (110 ml) and the solution was cooled to 5° C. or lower. To this solution was dropwise added a solution of p-toluenesulfonic acid chloride (50.1 g, 0.263 mol) dissolved in dry toluene (70 ml), in small portions through a dropping funnel so that the reaction temperature did not exceed 10° C. After completion of the dropwise addition, the cooling bath was removed and the reaction mixture was agitated at room temperature for 4 hours, followed by adding water (100 ml) and toluene (300 ml) and stirring. The mixture was transferred into a separating funnel and the toluene layer was washed twice with 6N-HCl aqueous solution (100 ml), then once with water (200 ml), further twice with 2N-NaOH aqueous solution (100 ml) and then four times with water (200 ml). Toluene was distilled off under reduced pressure and the resulting crystals were recrystallized from toluene (90 ml), followed by separating the crystals by filtration to obtain p-toluenesulfonic acid (trans-4-phenylcyclohexylmethyl) ester (IV) (77 g) having a melting point of 108.0°~108.7° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[N+:12]=[N-:13])[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>C(OCC)C>[CH3:1][O:2][C:3]([C:4]1[N:12]=[N:13][C:7]([OH:8])=[CH:6][C:5]=1[OH:11])=[O:14]
Reactant: COC(=O)CC(=O)C(=[N+]=[N-])C(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1nnc(O)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.1 %

Procedure:
A mixture of 2-diazo-3-oxo-pentanedioic acid dimethyl ester (50.0 g, 249.8 mmol) and triphenylphosphine (65.5 g, 249.8 mmol) in diethyl ether (500 mL) was stirred at room temperature for 24 h. The organic solvent was removed under vacuum and then acetic acid (500 mL) and water (50 mL) were added to the residue and the mixture was refluxed for 10 h. The reaction mixture was concentrated under reduced pressure to obtain a viscous residue. Trituration with ethyl acetate generated a yellow solid that was purified by chromatography (silica, 100-200 mesh, 1-5% methanol in dichloromethane) to give 4,6-dihydroxy-pyridazine-3-carboxylic acid methyl ester (12.8 g, 30%) as a yellow solid. LC-MS 169.2 [M+H]+.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].C=O.O.[C:28]([BH3-])#N.[Na+]>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:28])[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1cn(C2CCCNC2)c2ccc(I)cc2c1=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cn(C2CCCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 132, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then 37% formaldehyde in water (405 μl, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 386 mg (81% yield) of ethyl 6-iodo-1-(1-methylpiperidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]1[O:41][C:40]2[C:33](=[CH:34][C:35]([N+:42]([O-:44])=[O:43])=[C:36]([CH:39]=2)[CH:37]=O)[O:32]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:37][C:36]2[CH:39]=[C:40]3[O:41][CH2:31][O:32][C:33]3=[CH:34][C:35]=2[N+:42]([O-:44])=[O:43])[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2cc3c(cc2[N+](=O)[O-])OCO3)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4,5-methylenedioxy-2-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH3CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CC(=O)C(CCC(=O)O)(Cc2ccccc2Cl)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Methylbenzaldehyde (3.00 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.20 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which forms after scratching is collected and air-dried, yield 7.4 g., m.p. 120°-147°C. Recrystallization from methylcyclohexane, followed by recrystallization from n-butyl chloride, yields a white solid with m.p. 166°-168.5°C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22](O)=[O:23])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:42])([C:38]([F:41])([F:40])[F:39])[CH2:36][NH2:37]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22]([NH:37][CH2:36][C:35]([F:42])([F:34])[C:38]([F:41])([F:40])[F:39])=[O:23])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21)NCC(F)(F)C(F)(F)F

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and N-(2,2,3,3,3-pentafluoro-propyl amine, the title compound was prepared in the same manner as example 1c (73%). White solid. MS: m/e=576(M+H+).
Reaction SMILES: O1CCOCC1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17](=[O:47])[O:18][C:19]([O:42][CH2:43][CH2:44][CH2:45]Br)([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[C:20]=3[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.[S:48]([O-:51])([O-:50])=[O:49].[Na+:52].[Na+].[Na]>O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17](=[O:47])[O:18][C:19]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)([O:42][CH2:43][CH2:44][CH2:45][S:48]([O-:51])(=[O:50])=[O:49])[C:20]=3[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.[Na+:52]
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(C2(OCCCBr)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Agent: [Na+]
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2(OCCCS(=O)(=O)[O-])OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
To 50 mL 1,4-dioxane was added 3-Benzo[1,3]dioxol-5-yl-5-(3-bromo-propoxy)-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)5H-furan-2-one 2.0 g (3.19 mmol). A solution of sodium sulfite, 0.88 g (7.0 mmol) in 50 mL water was added, and the mixture was refluxed for 18 hours. The mixture was evaporated in vacuo and the residue was suspended in ethyl ether and water. The suspension was acidified to pH 1 with 2 N HCl, giving an oily precipitate in the aqueous phase. The ether was decanted, and the oil was extracted into ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and diluted with ethyl ether, giving a solid. The solid was filtered and dried in vacuo, giving a white solid, 1.07 g. The product was identified by 1H NMR, MS [M--H]+ =627.3 Da. Elemental analysis indicated the material to contain 1/2 sodium salt per molecule.
Reaction SMILES: [ClH:1].[N:2]([O:4]CCC(C)C)=O.[CH3:10][C:11](=[CH:13][CH2:14][CH3:15])[CH3:12]>>[Cl:1][C:11]([CH3:12])([CH3:10])[CH:13]([N:2]=[O:4])[CH2:14][CH3:15]
Reactant: Cl
Reactant: CC(C)CCON=O
Reactant: CCC=C(C)C
Product: CCC(N=O)C(C)(C)Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Concentrated HCl (9.0 mL, 0.11 mol) was added to a cooled (0°-5° C.) solution of isoamyl nitrite (14.8 g, 0.1 mol) and 2-methyl-2-pentene (8.4 g, 0.1 mol). The temperature was maintained below 5° C. during the addition and the reaction mixture was stirred at 5° C. for an additional 30 min. The product was filtered and washed with a cold (-20° C.) 1:1 mixture of petroleum ether. The solid was further washed with petroleum ether to afford a white solid. Yield: 4.9 g (34%); mp 85°-86° C. 1H NMR (CDCl3) ε 0.98 (CH2CH3), 1.68 (d, 6H, CH3), 2.05 (m, 2H, CH2CH3), 5.88 (dd, 1H, CHNO). MS: 299 (2M+H)+. Anal. Calcd. for C6H12NOCl: C, 48.17; H, 8.08; N, 9.36, Cl,23.70. Found: C, 48.47; H, 8.33; N, 9.3, Cl,24.04.
Reaction SMILES: [NH3:1].[Li].C([O:10][C:11]([C:13]1([NH2:32])[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH3:30])[C:14]1=[O:31])=O)C1C=CC=CC=1.[C:33](O)([CH3:36])(C)C>C1COCC1>[NH2:1][C@H:33]([C:11]([C:13]1([NH2:32])[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH3:30])[C:14]1=[O:31])=[O:10])[CH3:36]
Reactant: CN1C(=O)C(N)(C(=O)OCc2ccccc2)C=C(c2ccccc2)c2ccccc21
Reactant: N
Reactant: CC(C)(C)O
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@H](N)C(=O)C1(N)CC(c2ccccc2)c2ccccc2N(C)C1=O
Temperature: -45 °C

Procedure:
To a flask containing 300 mL of freshly condensed liquid ammonia at −70° C. was added lithium metal (4.1 equiv.). The dark blue slurry was warmed to −45° C. and treated with a pre-cooled solution of 3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-benzazepin-2-one (Example 4-AC, Steps A-C) in 30 mL distilled THF. After 10 min a solution of tert-butanol (4.0 equiv.) in distilled THF was added. After an additional 10 min the reaction was quenched with ammonium chloride. The cooling bath w as removed and the ammonia allowed to evaporate overnight. The contents were partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. Purified via liquid chromatography eluting with a gradient from 99:1 to 90:10 CH2Cl2/MeOH.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[S:25])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
A solution of 5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (18 g, 67 mmol) in dry THF was treated with Lawesson's reagent (27 g, 67 mmol) in one portion at room temperature. The mixture was refluxed for 2 h. The title compound was obtained by chromatography on silica gel (PE/EtOAc=30:1 to 10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([C:20]4[N:24]([CH3:25])[C:23]([S:26][CH3:27])=[N:22][N:21]=4)O)[CH:16]=3)[N:11]3[N:35]=[N:36][N:37]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:40])=O>>[ClH:1].[Cl:40][C:18]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)([C:20]1[N:24]([CH3:25])[C:23]([S:26][CH3:27])=[N:22][N:21]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]1[N:35]=[N:36][N:37]=[C:10]1[N:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CSc1nnc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)n1C
Reactant: O=S(Cl)Cl
Product: CSc1nnc(C(Cl)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)n1C
Product: Cl
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]-tetrazolo[1,5-a]quinazoline-7-methanol (0.0036 mol) in thionyl chloride (40 ml) was stirred at 60° C. for 5 hours then cooled. The solvent was evaporated. The residue was taken up in DCM. The solvent was evaporated, yielding 2.3 g (quantitative) of 7-[chloro(4-chlorophenyl)[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline monohydrochloride. The product was used without further purification in the next reaction step
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].C=C[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[CH:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:10][CH:12]([C:13]([OH:15])=[O:14])[NH:5]2
Reactant: CCC(=O)C(=O)[O-]
Reactant: C=Cc1ccccc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CC#N
Product: O=C(O)C1CC(c2ccccc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
Compound 15 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol styrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.