Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(F)cc(F)c2)nc1
Temperature: 90 °C
Yield: 93 %

Procedure:
To round-bottom flask was added 3,5-difluoro phenylboronic acid (1.84 g, 11.6 mmol), palladium tetrakis(triphenylphosphine) (89.5 mg, 0.08 mmol) and tert-butyl 6-bromonicotinate (2.0 g, 7.75 mmol) and the mixture was evacuated 3× with N2. The solids were dissolved in 50 mL of DMF, followed by addition of 11 mL of 2 M cesium carbonate. The resulting mixture was heated to ˜90° C. until no starting bromide material was apparent by HPLC. The mixture was cooled to rt and then poured into a separatory funnel, followed by addition of EtOAc and water (1×200 mL). The layers were separated and the organic extract washed with brine (1×200 mL), dried MgSO4, filtered and concentrated to afford an orange oil. The crude mixture was purified by silica gel column chromatography on Biotage (silica, 2-10% EtOAc in Heptane)-ca 2.5 L to afford the title compound 2.1 g (93%) as white solid. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.10-9.14 (1H, m), 8.29-8.35 (1H, m), 8.20-8.25 (1H, m), 7.90 (2H, dd, J=9.0, 1.5 Hz), 7.42 (1H, s), 1.59 (9H, s).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1.Cl[CH2:26][CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]1)=[O:30].C(N(CC)CC)C.Cl>C(#N)C.C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][C:29]([N:31]4[CH2:32][CH2:33][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:35][CH2:36]4)=[O:30])[CH2:21][CH2:20]3)[N:14]=2)[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1
Reactant: CN(C)C1CCN(C(=O)CCCCl)CC1
Reactant: O=c1oc(-c2cc(Cl)cc3c2OCCC3)nn1C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(C(=O)CCCN2CCC(n3nc(-c4cc(Cl)cc5c4OCCC5)oc3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g (2.68 mmol) of 5-(6-chloro-3,4-dihydro-2H-benzopyran-8-yl)-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one hydrochloride, in solution in 50 ml of acetonitrile, is introduced into a 250 ml three-necked round-bottomed flask, 1.24 ml (5.36 mmol) of 1-(4-chloro-1-oxobutyl)-N,N-dimethylpiperidin-4-amine and 1.12 ml (8 mmol) of triethylamine are added and the mixture is stirred at room temperature overnight. The mixture is evaporated under reduced pressure and the residue is taken up in water and extracted three times with chloroform. The organic phase is dried over magnesium sulphate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with 98/2, 95/5 and then 90/10 mixtures of dichloromethane and methanol. A white solid is obtained which is treated in a solution of gaseous hydrochloric acid in ethanol and, after recrystallizing from ethanol, 0.22 g of hydrochloride is finally isolated. Melting point: 193° C.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH:16]([CH3:18])[CH3:17].C([Li])(C)(C)C.CN([CH:27]=[O:28])C>CCCCC.O>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:14]=[CH:15][C:2]([CH:27]=[O:28])=[C:3]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A solution of (4-bromo-3-isopropyl-phenoxy)-tert-butyl-dimethyl-silane (Intermediate 145, 1.03 g, 3.13 mmols) in 25 mL E2O was cooled to −78° C. and treated with tert-butyllithium (401.0 mg, 6.26 mmols; 3.7 mL of a 1.7M solution in pentane). After 30 minutes the reaction was quenched with DMF (913.0 mg, 12.5 mmols) and warmed to room temperature. The solution was diluted with H2O, extracted with Et2O and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Column chromatography (2% EtOAc-hexanes) afforded 480.0 mg (55%) of the title compound as a colorless oil.
Reaction SMILES: O=[C:2]([CH2:12][CH3:13])[CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]1=[O:11].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[CH2:12]([C:2]1[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:11])[C:4]=2[CH:3]=1)[CH3:13]
Reactant: NCc1ccccc1
Reactant: CCC(=O)CC1C(=O)CCCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc2c(n1Cc1ccccc1)CCCC2=O
Reaction time: 0.08 h

Procedure:
2-(2-oxobutyl)cyclohexane-1,3-dione (1000 gms, 4.995 moles) was suspended in toluene (6000 ml, 6 vol). The mixture was warmed to 85 deg c and stirred for 5 minutes. Benzylamine (562.6 gms, 5.25 moles, 1.05 eq) was added dropwise over 30-45 minutes. Following the addition the mixture turned to an amber colored solution. Heat was applied to the solution and water was azeotroped off until the reaction temperature reached 110° C. The reaction was allowed to stir at 110° C. for 2 hrs at which time ˜4000 mls of solvent was distilled off at atmospheric pressure. Solution was transferred to a flask and further evaporated to an amber viscous oil which was used directly in the following step.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4].C(Cl)Cl.[Br:23]N1C(=O)CCC1=O>CC(O)=O>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([Br:23])=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)c1sc(Br)c(C)c1Nc1nc(Cl)ncc1Cl
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a solution of 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (0.22 g, 0.7 mmol) in 1:1 DCM:AcOH was added N-bromosuccinimide (0.37 g, 2.1 mmol). The mixture was stirred for 16 hours. Evaporation and chromatography on silica gel with 3:1 methylene chloride/ethyl acetate gave 85 mg of 5-bromo-3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (31%): 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 6.45 (br, 1H), 2.83 (d, 3H), 2.04 (s, 3H); MS (m/e): 395.1 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].[CH3:11]I>C1COCC1.O>[CH3:11][O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OCC1CC=CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclohexene-1-methanol (8.92 mmol, 1.00 g) and NaH (17.8 mmol, 428 mg) were mixed in THF (30 mL) at rt, and the THF solution was stirred for 1 h at rt. MeI (17.8 mmol, 1.10 mL) was added slowly into the above THF solution. After stirring for 16 h at rt, the solution was diluted with water (30 ml), and then was extracted with diethyl ether (2×30 mL). The organic layer was dried over Na2SO4, was concentrated by rotory evaporation, and then was distilled to generate the final product 17 as a colorless liquid (460 mg, 41%). 1H-NMR (500 MHz) δ 5.68 (m, 2H), 3.36 (s, 3H), 3.28 (dd, J=6.5 Hz, J=4 Hz), 2.06-2.14 (m, 3H), 1.92 (m, 1H), 1.83 (m, 1H), 1.75 (m, 1H), 1.29 (m, 1H). 13C-NMR (100 MHz) δ 127.2, 126.1, 78.0, 58.9, 34.0, 28.6, 25.8, 24.7. LC-MS (APCI): Peak time=1.59 min, m/z calcd for C8H15O [M+H]+ 127.11, found 127.10.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN(C)C=O>[CH:25]1([NH:28][CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[N:9]=[CH:10][N:11]4[C:17]5[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=5[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=34)[N:4]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CNC4CC4)n3)ncn2-c2ccc(F)cc2C1=O
Yield: 63.5 %

Procedure:
1.7 g (5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 2 hours with 5 ml (7.2 mmol) of cyclopropylamine and 15 ml of N,N-dimethylformamide. After evaporation of the reaction mixture the residue was taken up in methylene chloride and washed with aqueous ammonia. After drying the organic phase over magnesium sulfate, evaporation of the solvent and recrystallization of the residue from ethyl acetate and hexane there were obtained 1.17 g (65%) of 3-(5-cyclopropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 176°-178°, which was converted into the hydrochloride.
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH:11]=[C:12]2[O:16][C:15]([N:17]([CH2:19][CH2:20][O:21]COCCOC)[CH3:18])=[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:13]2=[O:33])=[CH:3]1>O1CCOCC1>[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH:11]=[C:12]2[O:16][C:15]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])=[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:13]2=[O:33])=[CH:3]1
Reactant: CCOC(=O)C1=C(N(C)CCOCOCCOC)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(N(C)CCO)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Cooled with ice bath, 4M hydrochloric acid in dioxane (4.0 mL) was added to ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({2-[(2-methoxyethoxy)methoxy]ethyl}-N-methylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.020 mg, 0.046 mmol) which afforded in the Example 201. The mixture was stirred at ambient temperature for 3 h. The solvent was removed under reduced pressure, and the precipitate was suspended in diethyl ether, then collected by filtration. The solid was washed with diethyl ether then dried to afford the titled compound as solid (0.012 g, y. 75%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[C@@H:19]1([NH2:25])[CH2:23][CH2:22][CH2:21][C@@H:20]1[NH2:24]>N1C=CC=CC=1>[NH2:24][C@H:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[NH:25][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: N[C@@H]1CCC[C@@H]1N
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N[C@@H]3CCC[C@@H]3N)cc21
Yield: 63.3 %

Procedure:
The procedure of Example 1 was followed using 0.6 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and 1.0 g of cis-1,2-cyclopentanediamine in 4 ml of pyridine, giving 0.5 g of the desired product, m.p. 233°-235° C.
Reaction SMILES: [C:1]1(=[C:6]([CH3:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][CH:3]=[CH:2]1>C(OCC)(=O)C>[CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCC(=O)O)=C1C=CC=C1
Solvent: CCOC(C)=O
Product: CC(CCC(=O)O)C1CCCC1
Yield: 92.4 %

Procedure:
4-Cyclopenta-2,4-dienylidenepentanoic acid (25 g; 0.15 mol; obtained according to Coe, J. W.; Vetelino, M. G.; Kemp, D. S., Tetrahedron Lett., 1994, 35, 6627.) in ethyl acetate (270 ml) was hydrogenated as in example 4 to give 23.6 g (92% yield) of crude 4-cyclopentylpentanoic acid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([C:18]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=2[CH:20]=[O:21])=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.[CH3:28][Mg]Br>O1CCCC1>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([C:18]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=2[CH:20]([OH:21])[CH3:28])=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C=O)c1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C(C)O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]-5-methoxybenzaldehyde, the free base of EXAMPLE 16 (0.03 g, 0.08 mmol), in 5 mL of tetrahydrofuran at 0° C. was added methyl magnesium bromide (0.52 mL of a 3M solution in THF, 1.58 mmol). Stirred with warming to ambient temperature for several hours and then quenched with sat'd ammonium chloride. Extracted with ethyl acetate, washed organics with brine, dried (MgSO4) and concentrated. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). Fractions containing desired compound were then immediately free based with 1 N sodium hydroxide, extracted with ethyl acetate, dried (MgSO4) and concentrated to afford the title compound of EXAMPLE 21. LRMS (ES+): 397.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:25]3[N:30]=[CH:29][C:28]([C:31]4[N:35]=[C:34]([CH2:36][OH:37])[O:33][N:32]=4)=[CH:27][CH:26]=3)([CH3:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[CH:11]=[N:12][CH:13]=1.C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH3:1][S:2]([O:37][CH2:36][C:34]1[O:33][N:32]=[C:31]([C:28]2[CH:29]=[N:30][C:25]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:10]4[CH:11]=[N:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=4)=[CH:15][CH:16]=3)([CH3:24])[CH:21]([CH3:22])[CH3:23])=[CH:26][CH:27]=2)[N:35]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cncc(-c2ccc(C(C)(c3ccc(-c4noc(CO)n4)cn3)C(C)C)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cncc(-c2ccc(C(C)(c3ccc(-c4noc(COS(C)(=O)=O)n4)cn3)C(C)C)cc2)c1
Reaction time: 0.33 h

Procedure:
Methanesulfonyl chloride (28.0 μL, 0.362 mmol) was added to a stirred solution of 1d (104 mg, 0.241 mmol) and N,N-diisopropylethylamine (105 μL, 0.602 mmol) in DCM (2.00 mL) at 0° C. After approximately 20 min, the reaction mixture was poured into water and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 1e, which was used without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([NH:17][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)=[O:16])=[CH:14][C:9]=2[C:8]([CH3:30])([CH3:29])[CH2:7][CH2:6][C:5]1=[O:31]>C(O)C.O1CCCC1>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=3)=[O:16])=[CH:14][C:9]=2[C:8]([CH3:29])([CH3:30])[CH2:7][CH2:6][C:5]1=[O:31]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC(=O)N3C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1C(=O)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
1.69 ml of 3N sodium hydroxide solution were added to 1.00 g of ethyl p-(2,3,4,5-tetrahydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepin-7-carboxamido)benzoate in 10 ml of ethanol/tetrahydrofuran (1:1). The reaction mixture was stirred at room temperature for 3 days and thereafter poured on to ice/conc. hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried and evaporated. Recrystallization from ethyl acetate yielded 0.81 g of p-(2,3,4,5-tetrahydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepine-7-carboxamido)benzoic acid, m.p. >275° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.C(O[B:23]([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26])(C)C.C([Li])CCC.OC(C(O)(C)C)(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:23]2[O:24][C:25]([CH3:26])([CH3:27])[C:29]([CH3:30])([CH3:31])[O:28]2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(COc2cc(Br)ccc2Cl)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-methoxy-benzyloxy)-benzene (0.35 g) in tetrahydrofuran (10 ml) under nitrogen was added triisopropylborate (0.29 ml). The mixture was cooled to −78° C. and 2.5M n-butyllithium solution in hexanes was added. The reaction mixture was stirred at −40° C. for 1 hour, then warmed to 20° C. and quenched with 2M hydrochloric acid (aq) (2 ml). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was adjusted to pH 7 using saturated sodium bicarbonate solution, then partitioned between ethyl acetate and water, dried (MgSO4) and the solvents removed in vacuo to yield a crude residue (0.31 g). A mixture of this crude residue and pinacol (0.25 g) in toluene (10 ml) were stirred under reflux overnight in a Dean-Stark apparatus. The solvents were removed in vacuo, the residue was then partitioned between ethyl acetate and water, the combined organics were washed with water then brine and dried (MgSO4), the solvents were removed in vacuo to yield 2-[4-chloro-3-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.28 g).
Reaction SMILES: [C:1]1([C:7]2N=N[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)([Cl:14])=[S:13]>C(COC)OC>[Cl:14][C:12]1[S:13][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][N:10]=1
Reactant: S=C(Cl)Cl
Reactant: c1ccc(-c2nn[nH]n2)cc1
Solvent: COCCOC
Product: Clc1nnc(-c2ccccc2)s1
Yield: 41.2 %

Procedure:
A stirred mixture of 74.4 g (0.50 mole) of 5-phenyl-2H-tetrazole and 74.0 g (0.65 mole) of thiophosgene in 550 ml of dimethoxyethane was allowed to reflux overnight. The reaction mixture was cooled and filtered. The filtrate was taken to dryness at reduced pressure and the resulting residue leached with two 220-ml portions of hexane. Upon cooling and concentration of the combined hexane portions 40.5 g of the desired product was obtained: mp 82°-84° (lit. 86°-88°).
Reaction SMILES: C(OP([CH:9]1[S:14][CH2:13][CH2:12][CH2:11][S:10]1)(OCC)=O)C.CCCCCC.C([Li])CCC.[CH:26]1[CH:31]=[CH:30][C:29]([C:32]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=O)=[CH:28][CH:27]=1.[Cl-].[Na+]>O1CCCC1>[O:36]([C:35]1[CH:27]=[CH:28][C:29]([C:30](=[C:9]2[S:10][CH2:11][CH2:12][CH2:13][S:14]2)[CH2:31][CH3:26])=[CH:32][CH:34]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(CCOc1ccccc1)c1ccccc1
Reactant: CCOP(=O)(OCC)C1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
2-Diethoxyphosphoryl-1,3-dithiane, 4.18 g, was dissolved in 40 ml of tetrahydrofuran and 10.5 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -65° C. The mixture was stirred at the same temperature for an hour. Then, a solution of 36.2 g of 4-phenoxypropiophenone in 15 ml of tetrahydrofuran was dropwise added to the mixture at the same temperature. The reaction mixture was gradually warmed to room temperature overnight. This suspension was poured onto saturated sodium chloride aqueous solution followed by extraction with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =1 : 1) to give 4.15 g of the product.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CNCCN1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C32H39N6O2Cl2 [(M+H)+] 609.2506 observed 609.2509.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38](O)=[S:39])=[C:32]2[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[NH2:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1.C(N(CC)CC)C>CN(C)C=O>[N:51]1[CH:52]=[CH:53][CH:54]=[C:49]([CH2:48][NH:47][C:38]([C:33]2[NH:34][C:35]3[C:31]([C:32]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:30][C:29]([Cl:28])=[CH:37][CH:36]=3)=[S:39])[CH:50]=1
Reactant: NCc1cccnc1
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: S=C(NCc1cccnc1)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (0.73 g, 1.6 mmol) was added to a solution of 5-chloro-3-phenylthio-indole-2-carboxylic acid (0.50 g, 1.6 mmol), 3-aminomethylpyridine (0.35 g, 3.2 mmol) and triethylamine (0.50 mL, 3.2 mmol) in degassed dimethylformamide (25 mL). The reaction was stirred at room temperature overnight. The precipitated product was filtered and the filter cake washed well with water. The solid was triturated with 30% ethyl acetate in hexane, filtered and dried at 60° C. in vacuo for 72 h. The title compound was obtained as an off-white solid, mp 240°-241° C. Anal. Calc. for C21H16ClN3OS.0.25 H2O: C, 63.31; H, 4.17; N, 10.54. Found: C, 63.34; H, 4.06; N, 10.71. NMR (DMSO-d6): δ12.54 (1H, s), 8.91 (1H, t, J=6 Hz), 8.51 (1H, s), 8.42 (1H, d, J=5 Hz), 7.58 (2H, m), 7.45 (1H, m), 7.25 (4H, m), 7.15 (1H, t, J=7 Hz), 7.04 (2H, d, J=8 Hz), 4.58 (2H, d, J=6 Hz).