Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C.O>[NH2:23][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1
Reactant: CCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(4-iodophenyl)propanoic acid (35.1 g) was dissolved in DMF (200 mL) and to the resulting solution was added N-ethylmorpholine (17.0 mL) followed by TBTU (28.8 g). The mixture was stirred at room temperature for 0.5 h and then cooled to 0° C. 0.880 Ammonia (11.1 mL) was added and the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 16 h and was then to poured into water and the resulting precipitate removed by filtration. The solid was dried in vacuo to give the sub-titled compound (34.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.[F:40][C:41]1[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43][N:42]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:45]3[CH:44]=[CH:43][N:42]=[C:41]([F:40])[CH:46]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(-c4ccnc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 2-fluoropyridine-4-boronic acid (40 mg, 0.27 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture, 0.4 ml of aqueous sodium carbonate (1M) was added, followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, and the residue was dissolved in 2.5 ml of methanol. The product was purified with Preparative HPLC to give 70 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[OH-].[Li+:25].O1CCCC1>O.C(#N)C>[Li+:25].[C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][C:3]([O-:23])=[O:2])[CH2:8][CH2:9]2)=[CH:18][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)CCCC1CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)c1ccc(N2CCC(CCCC(=O)[O-])CC2)cc1
Yield: 138.1 %

Procedure:
To 4-[1-(4-tert-butyl-phenyl)-piperidin-4-yl]-butyric acid methyl ester (385 mg; 1.21 mmol, prepared in accordance with Example 135) is added lithium hydroxide (72 mg; 3.00 mmol) dissolved in water (6.5 mL). After dilution with tetrahydrofuran (10 mL) the reaction mixture is stirred for 2-4 hours. The mixture is then diluted with acetonitrile until a precipitate is formed. The solid is collected by filtration and dried under high vacuum to afford the desired product (517 mg) which is used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[C:5]=1[O:15][CH2:16][CH2:17][CH3:18].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:12])([F:13])[F:14])[C:5]=1[O:15][CH2:16][CH2:17][CH3:18])[C:19](=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: CCCOc1c(CNC)cccc1OC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1cccc(OC(F)(F)F)c1OCCC
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a solution of methyl-(2-propoxy-3-trifluoromethoxybenzyl)amine (0.890 g, 3.35 mmol) in CH2Cl2 (30 mL) was added acryloyl chloride (0.30 mL, 3.6 mmol) drop-wise. After stirring for five minutes, triethylamine (0.51 mL, 3.6 mmol) was added. The solution was allowed to stir under N2 for 3 h. The solution was diluted with CH2Cl2 (30 mL), washed with H2O (3×50 mL) and brine (2×50 mL), dried (Na2SO4) filtered and concentrated to yield the title compound (0.95 g, 90%) as a yellow oil and as a mixture of amide rotamers: 1H NMR (500 MHz, CDCl3) δ 7.21-7.00 (m, 3H), 6.67-6.48 (m, 1H), 6.41-6.36 (m, 1H), 5.76-5.66 (m, 1H), 4.75-4.65 (m, 2H), 3.99-3.93 (m, 2H), 3.03 (s, 3H), 1.83-1.78 (m, 2H), 1.07-1.03 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.C(O)CO>O>[Cl:1][C:2]1[CH:11]=[C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: C1COCCN1
Solvent: O
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(Cl)cc(N3CCOCC3)c2c1
Temperature: 145 °C

Procedure:
A mixture of 2,4-dichloro-6-methoxyquinoline (0.228 g), morpholine (262 μL), N,N-diisopropylethylamine (348 μL), and ethylene glycol (4 mL) was heated with microwave (145° C.) for 75 min with stirring. The reaction mixture was cooled to room temperature, followed by addition of water, the mixture was extracted with chloroform and washed with saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The desiccant was removed by filtration, the residue concentrated under reduced pressure was purified by silica gel column chromatography (chloroform/hexane=1/1) to obtain 2-chloro-6-methoxy-4-morpholinoquinoline (0.182 g). (2) To a mixture of 2-chloro-6-methoxy-4-morpholinoquinoline (0.160 g), Pd2(dba)3 (0.026 g), (±)-BINAP (0.054 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.210 g), and 1,4-dioxane (3 mL) was added sodium t-butoxide (0.111 g) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 1.5 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate/hexane) to obtain light yellow amorphous (S)-1-(3-(6-methoxy-4-morpholinoquinolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.081 g).
Reaction SMILES: CC(=C)C([C:18]1(O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)C[Si](CCCC)(CCCC)CCCC.C[C:27]([C:44]1(O)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)([CH2:30][Si:31]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37]CC)CCCC)C=C.CC(C)=CCCC(=C)C(C1(O)CCCCC1)C[Si](C)(C)C.C(C(C1(O)CCCCC1)(C[Si](C)(C)C)CCC=C(C)C)=C>O>[C:18]1([C:42]2[CH2:43][Si:31]3([CH2:36][CH:37]=[C:27]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:30]3)[CH2:40][CH:41]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C(C)C(C[Si](CCCC)(CCCC)CCCC)C1(O)CCCCC1
Reactant: C=CC(C)(C[Si](CCCC)(CCCC)CCCC)C1(O)CCCCC1
Agent: C=C(CCC=C(C)C)C(C[Si](C)(C)C)C1(O)CCCCC1
Agent: C=CC(CCC=C(C)C)(C[Si](C)(C)C)C1(O)CCCCC1
Solvent: O
Product: C1=C(c2ccccc2)C[Si]2(C1)CC=C(c1ccccc1)C2

Procedure:
1-(2-Methyl-I-tri(n-butyl)silylmethyl-2-propenyl)cyclohexanol and 1-(1-Methyl-1-(tri-n-butyl)silylmethyl-2-propenyl)cyclohexanol (92:8, 94% total yield). Major isomer: 1H NMR δ 4.85 (m, 1 H), 4.77 (d, J=1.9 Hz, 1 H), 2.12 (dd, J=8.5, 6.1 Hz, 1 H), 1.76 (d, J=0.4 Hz, 3 H), 1.68-1.10 (m, 22 H), 0.87 (t, J=7.0 Hz, 9 H), 0.76-0.70 (m, 2 H), 0.52-4.44 (m, 6 H); 13C NMR δ 147.2, 114.1, 73.2, 52.3, 35.6, 35.5, 26.9, 26.2, 25.9, 22.3, 22.2, 13.8, 12.4, 9.8; IR (neat) 3491 (br), 3068, 2954, 2924, 2870, 2856, 1637, 1456, 1375, 1196, 1082, 964, 887 cm-1 ; EIMS m/z (relative intensity) 309 ([M--C4H9 ]+ 0.5), 297 (4.3), 268 (7.8), 199 (100), 143 (67), 99 (19); HRMS calcd for C23H46OSi and C2213CH46OSi: 366.3318, 367.3347, found (EI Peak Match): 366.3301, 367.3338. Anal. Calcd: C, 75.33; H, 12.64. Found: C, 75.60; H, 12.77. Minor Isomer (difficult to isolate): 1H NMR δ 5.92 (dd, J=17.6, 10.8 Hz, 1 H), 5.11 (dd, J=10.8, 1.2 Hz, 1 H), 5.01 (dd, J=17.6, 1.2 Hz, 1 H), 1.70-1.10 (m, 22 H), 1.07 (s, 3 H), 0.88 (t, J=7.0 Hz, 9 H), 0.95-0.75 (m, 2 H), 0.53-0.45 (m, 6 H). 1-(2-(4-Methyl-3-pentenyl)-1-trimethylsilylmethyl-2-propenyl)cyclohexanol and 1-(1-Ethenyl-5-methyl-1-trimethylsilylmethyl-4-hexenyl)cyclohexanol (94:6). Major isomer: 1H NMR δ 5.17- 5.09 (m, 1 H), 4.89 (s, 1 H), 4.86 (s, 1 H), 2.20-2.00 (m, 5 H), 1.67 (s, 3 H), 1.60 (s, 3 H), 1.68-1.05 (m, 10 H), 0.84-0.69 (m, 2 H), 0.03 (s, 9 H); 13C NMR δ 151.1, 131.5, 124.4, 111.4, 73.2, 53.0, 35.6, 35.5, 25.9, 25.8, 25.7, 22.3, 22.1, 17.6, 14.9, -0.9; IR (neat) 3485 (br), 3080, 2931, 2858, 1633, 1448, 1375, 1246, 972, 891, 860, 837 cm-1 ; EIMS m/z (relative intensity) 290 ([M--H2O]+, 0.3), 275 (0.2), 210 (7), 171 (28), 141 (87), 99 (16), 73 (100); HRMS calcd for C19H36OSi and C1813CH36OSi: 308.2535, 309.2563, found (HREI Peak Match): 308.2530, 309.2559. Anal. Calcd: C, 73.96; H, 11.76. Found: C, 74.15; H, 11.80. Minor isomer: 1H NMR δ 5.81 (dd, J=17.6, 11.0 Hz, 1 H), 5.15-4.95 (m, 3 H), 2.10-0.95 (m, 14 H), 1.65 (s, 3 H), 1.59 (s, 3 H), 0.91 (d, J=15.0 Hz, 1 H), 0.75 (d, J=15.0 Hz, 1 H), 0.04 (s, 9 H); 13C NMR δ 145.5, 131.0, 125.3, 114.1, 75.8, 50.6, 33.3, 31.6, 31.5, 25.7, 24.0, 22.0, 21.8, 19.8, 17.8, 1.6; IR (neat) 3566 (br), 3080, 2933, 2858, 1631, 1450, 1375, 1259, 1246, 1155, 958, 912, 860, 845 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:18]1[S:19][CH:20]=[CH:21][N:22]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C@@H:14]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[OH:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)c1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1nccs1
Reaction time: 48 h
Yield: 4.6 %

Procedure:
To a solution of 10.8 g of t-butoxycarbonyl-L-leucinal in 40 of dichloromethane was added 9.4 g of 2-trimethylsilyl thiazole in 10 ml of dichloromethane. The reaction was allowed to stand for 48 hours, then was cooled in an ice bath and treated cautiously with 30 ml of 1M tetra-n-butylammonium fluoride in tetrahydrofuran. This mixture was refluxed for 1.5 hours and then concentrated to an oil. The oil was dissolved in 100 ml of ethyl acetate, washed with 50 ml each of 2N citric acid, 1M sodium bicarbonate and brine and dried. The solution was treated with activated carbon, filtered through a pad of hydrous magnesium silicate and concentrated to an oil. This oil was dissolved in 50 ml of 10% ethyl acetate in dichloromethane and chromatographed on two columns in the same solvent. Refractive index was monitored at S 20, 250 ml/minute. The main peak in hold-back volumes 6-10 was cut into 1 liter portions which were separately evaporated. The first three of these all crystallized and the solids were recrystallized form isopropyl ether and hexane, giving 0.7 g of (S)2-(t-butoxycarbonyl)amino-4-methyl-(S)1-(2-thiazolyl)pentan-1-ol as crystals, mp 121°-122° C.
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([OH:10])[CH2:2]2.[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:10][CH:3]1[CH2:2][C@H:1]2[N:8]([CH3:9])[C@H:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: CN1[C@@H]2CC[C@H]1CC(O)C2
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1[C@@H]2CC[C@H]1CC(Oc1ccc([N+](=O)[O-])cc1Cl)C2
Yield: 60.6 %

Procedure:
To a solution of 3-tropanol (6.7 g), 2-chloro-4-nitrophenol (8.2 g) and triphenylphosphine (16.1 g) in a mixture of dichloromethane (200 ml) and tetrahydrofuran (50 ml), diethyl azodicarboxylate (9.7 ml) was added dropwise with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (19:1) as the eluent to afford the title compound (8.5 g, yield: 60%) as a pale yellow amorphous solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>>[C:15]([O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12)(=[O:18])[CH2:16][CH3:17]
Reactant: Cc1cc(NCCO)c2[nH]ncc2n1
Reactant: CCC(=O)Cl
Product: CCC(=O)OCCNc1cc(C)nc2cn[nH]c12

Procedure:
The title compound was prepared from 7-(2-hydroxyethylamino)-5-methyl-1H-pyrazolo[4,3-b]pyridine (2 g) and propionyl chloride by the method of Example 4. After purification by column chromatography on basic alumina with ethyl acetate and then a rising percentage of methanol as eluant the title compound was obtained as a white solid (1.7 g, 66%), m.p. 187°-190° C.
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].[NH2:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25].Cl.C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C>ClCCl>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of Z-Gly-Ala-OH (3) (20.0 g, 0.071M) and Leu-OMe.HCl (12.9 g, 0.071M) in 250 ml dichloromethane was added 21.9 ml (0.157M) triethylamine (TEA) dropwise over a period of 10 min. This addition was followed by the addition of 11.9 ml (0.078M) of diethylcyanophosphonate (DECP). The mixture was stirred overnight and the solvent removed. The residue was dissolved in ethyl acetate and washed with 1N HCl, saturated NaHCO3, and brine. The solution was dried with MgSO4, filtered and the solvent removed. Recovered 29.0 g of product that is homogeneous by TLC. 13C NMR (CDCl3) 15.93, 18.60, 21.77, 22.69, 24.72, 40.80, 44.20, 48.70, 50.87, 52.13, 65.28, 66.84, 127.92, 128.00, 128.41, 136.36, 156.76, 169.31, 172.58, 173.24.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[CH3:18][S:19]([CH2:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([CH2:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:25][CH:24]=1)(=[O:20])=[O:21]
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Product: CS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-methylsulfonylmethylaniline according to Procedure J: 1H NMR (DMSO-d6): δ11.1 (d, 1H), 11.0 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (q, 4H), 7.1 (d, 1H), 4.45 (s, 2H), 2.9 (s. 3H); APCI−MS m/z 384 (M−H)−.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:32][CH3:33])=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:22]([CH:24]=3)[NH2:23])[O:15][N:14]=2)[CH:12]=1>N1C=CC=CC=1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:32][CH3:33])=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:22]([NH:23][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=3)[O:15][N:14]=2)[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(N)c2)n1
Solvent: c1ccncc1
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(NS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (20 μL; 0.26 mmol; 1.2 eq.) was added to a solution of Example 69 (83 mg; 0.22 mmol; 1 eq.) in pyridine (1 mL) and the resulting solution was stirred at room temperature for 16 hours. The solution was then partitioned between water and ethyl acetate. The two phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed (3×) with 0.1M HCl, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 60/40) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([C:13](=O)[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Br:20])[CH:15]=2)=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.O.[NH2:23][NH2:24]>CO>[Br:20][C:16]1[CH:15]=[C:14]([C:13]2[C:8]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:6]=[N:24][N:23]=2)[CH:19]=[CH:18][N:17]=1
Reactant: COc1cc(C=O)c(C(=O)c2ccnc(Br)c2)cc1OC
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1cc2cnnc(-c3ccnc(Br)c3)c2cc1OC

Procedure:
To a solution of 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde (4.5 g) in methanol (70 ml) is added dropwise hydrazine monohydrate (0.8 ml). The reaction mixture is cooled with ice, and the precipitates are collected by filtration, and recrystallized from methanol to give 2-bromo-4-(6,7-dimethoxyphthalazin-1-yl)pyridine (4.01 g) as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(OC([NH:41][CH2:42][CH2:43][C:44](N(OC)C)=[O:45])=O)(C)(C)C>C1COCC1>[NH2:41][CH2:42][CH2:43][C:44]([C:21]1[N:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)[CH2:19][CH2:18]2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)=[O:45]
Reactant: c1ccc(C2(N3CCC(n4cnc5ccccc54)CC3)CCCCCC2)cc1
Reactant: CON(C)C(=O)CCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NCCC(=O)c1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole (Example 12, 66.3 mg, 0.178 mmol) in THF(4 ml) was added n-butyllithium (1.54M solution in hexane, 0.923 ml, 1.42 mmol) at −78° C. After 1 h stirring at −78° C., a solution of 3-t-butoxycarbonylamino-N-methoxy-N-methylpropionamide (140 mg, 0.604 mmol, this was prepared according to the reported procedure: G. Bitan et al, J. Chem. Soc., Perkin Trans. 1, 1997, 1501-1510) in THF (1.5 ml) was added to the reaction mixture at −78° C. After 0.5 h stirring at −78° C. and 15 h stirring at ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (1 mm plate×3, n-hexane/acetone: 5/1, 6 times developed) to give 71.7 mg (74%) of pale brown amorphous solid. This solid (70 mg, 0.131 mmol) was dissolved in HCl solution in MeOH (10 ml). After evaporation of the solvent, the residue was dried in vacuo at 45° C. for 18 h to afford 60 mg (89%) of pale brown amorphous solid.
Reaction SMILES: C[Sn](C)(C)[N:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:6][N:5]=[N:4]1.[C:23]1([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:23]1([C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:3]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:6][N:5]=[N:4]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-trimethylstannyl-5-(4'-methylbiphenyl-2-yl)tetrazole (Example 10, 0.4 g) and anhydrous pyridine (10 mL) was treated with triphenylmethyl chloride (0.3 g) and stirred at room temperature under a nitrogen atmosphere for 48 hours. The resulting solution was evaporated and the residue was partitioned between dichloromethane and saturated aqueous CuSO4. The organic layer was dried over MgSO4 and evaporated. The residual solid was triturated with diisopropyl ether and collected by filtration to give the title compound, mp 163°-165° C. (decomp., gas evol.).
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].CN(C)C=O>O>[F:21][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][N:26]3[C:25](=[O:27])[C:24]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]4[C:22]3=[O:32])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C1O[C@@H](CCl)CN1c1ccc(N2CCOCC2)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
The mixture of (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone (60 g), potassium phthalimide (40 g) and Dimethyl formamide (400 ml) is heated for 5 hours at reflux temperature. The reaction mixture is cooled to ambient temperature, poured in to 2 L water and filtered the solid to give 50 gm (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide.