Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([CH3:20])[CH:17]=[N:16]1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl>ClCCl.CO.O1CCOCC1>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([CH3:20])[CH:17]=[N:16]1
Reactant: Cc1cnn(CC[C@](C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c1
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (19 mg, 0.053 mmol, 0.5 eq) in dichloromethane (0.5 mL) and MeOH (0.1 mL) was added a 4.0 M solution of HCl in 1,4-dioxane (0.5 mL). The reaction was allowed to stir for 1 h. The solvent was removed under reduced pressure. The crude material was triturated in pentane/Et2O. The product was filtered, washed with heptane, and dried under reduced pressure to provide (2R)—N-hydroxy-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanamide as an off-white solid (5 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.51-7.43 (m, 1H), 7.24-7.17 (m, 1H), 3.74-3.60 (m, 1H), 3.51-3.41 (m, 1H), 3.02 (s, 3H), 2.70-2.54 (m, 1H), 2.21-2.06 (m, 1H), 1.92 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7].[C:34](Cl)(=[O:36])[CH3:35].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:34]([NH:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N)c(OCc1ccccc1)c2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 23 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a solution of intermediate 169, N-(2-amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.033 g, 0.073 mmol) in dry tetrahydrofuran (10 mL) was added acetyl chloride (5.7 μL, 0.08 mmol) and diisopropylethylamine (38 μL, 0.22 mmol). The reaction mixture was stirred at 23° C. for 3 h. NaHCO3 (0.25 M, 20 mL) was then added and the organic material extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate:Hex (1:2 to 2:1) as eluent to afford the title compound (0.025 g, 69% yield). 1HNMR 400 MHz (MeOD) δ (ppm): 7.66 (1H, dd, J=10.5, 2.8 Hz), 7.43-7.25 (6H, m), 6.87 (1H, ddd, (dt), J=8.8, 2.6 Hz), 5.19 (2H, s), 4.47 (2H, m), 4.08 (2H, t, J=4.9 Hz), 3.99 (2H, t, J=4.9 Hz), 2.19 (3H, s), 1.62 (6H, s). LCMS (M+H)+ m/z 495.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CN(C)[CH:22]=[O:23].[Cl-].[NH4+]>C1CCCCC1.O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:22]=[O:23])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A 1.3M solution of sec-butyl lithium in cyclohexane (6.6 ml) was added to a stirred solution of 4'-fluoro-4-bromobiphenyl (1.76 g) in tetrahydrofuran (35 ml) at a temperature below -75° C. and under an atmosphere of argon. The reaction mixture was stirred at -75° C. for 15 minutes. A solution of dry dimethylformamide (1.74 ml) in dry tetrahydrofuran (3.5 ml) was added to the reaction mixture whilst maintaining the temperature below -75° C. and the reaction mixture was then stirred at -75° C. for a further 30 minutes. The mixture was then allowed to warm to ambient temperature over a period of 2 hours and was then poured into saturated ammonium chloride solution (35 ml). The mixture was extracted with diethyl ether (3×35 ml), the diethyl ether extracts combined, washed with saturated brine (50 ml), dried (MgSO4) and evaporated. The residue was purified by medium pressure chromatography on silica gel using a mixture of 5% ethyl acetate/hexane as eluant to give 4'-fluoro 4-biphenylcarboxaldehyde as a colourless oil (33% yield), microanalysis, found: C, 75.1; H, 4.4%; C13H9FO. 0.5H2O requires: C, 75.0; H, 4.8%; NMR (CDCl3): 7.2 (2H, m), 7.6 (6H, m), 7.9 (2H, d) and 10.0 (1H, s), m/z 201 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:15]([Br:26])[CH:14]=2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44]O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44][N:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=2)=[CH:14][C:15]=1[Br:26])[C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reactant: O=C(Nc1ccc(-c2nc(Cc3ccccc3)cs2)cc1Br)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCN(C(=O)C(F)(F)F)c1ccc(-c2nc(Cc3ccccc3)cs2)cc1Br
Yield: 97 %

Procedure:
4-(4-Benzyl-1,3-thiazol-2-yl)-2-bromo-1-trifluoroacetylaminobenzene and (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used. Chromatography using elution with a 1-5% either gradient in methylene chloride afforded the title compound (97%) as a white foam: FAB LRMS (m/z, relative intensity) 686 (MH2+, 100), 685 (MH+, 60), 684 (M+, 90), 640 (23), 578 (15), 441 (17), 371 (20); FAB HRMS calculated for [C33H29BrF3N3O3S·H]+ [with 78Br and 32S] 664.1145, found 684.1157.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11]1[O:13][CH2:12]1.C1C[O:17]CC1>>[OH:13][CH2:11][CH2:12][C:5]1[O:1][C:2](=[O:17])[CH2:3][CH:4]=1
Reactant: c1ccoc1
Reactant: C1CO1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=C1CC=C(CCO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a cooled solution of furan (3.40 g, 50.0 mmol) in THF (150 mL) was added n-BuLi (22 mL, 2.5M solution in hexane, 55.0 mmol) at 0° C. under inert gas atmosphere. The solution was allowed to warm to room temperature and stirred for 3 h. Then TMSCI (5.34 g, 50 mmol) was added dropwise at 0° C. and the solution was stirred for further 3 h at room temperature. Subsequently, the solution was again cooled to 0° C. and n-BuLi (22 mL, 2.5M solution in hexane, 55.0 mmol) was added a second time. After stirring for 3 h at room temperature ethyleneoxide (2.42 g, 55.0 mmol) was condensed by an acetone/dry ice condenser into the solution and the solution was stirred for further 12 h at room temperature. The mixture was quenched with aq NH4Cl, and then extracted with EtOAc and the combined organic layers were dried over Na2SO4 to afforded the desired product (5 g, 27.1 mmol, 54% over two steps) as a yellow liquid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:8]=1[C:9]([C:11]1[CH:12]=[N:13][N:14]([CH3:17])[C:15]=1O)=[O:10]>>[Cl:6][C:7]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:8]=1[C:9]([C:11]1[CH:12]=[N:13][N:14]([CH3:17])[C:15]=1[Cl:3])=[O:10]
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1Cl
Temperature: 0 °C
Yield: 98 %

Procedure:
To 5 ml of phosphorus oxychloride was added 2.71 g (0.01 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole and the resulting mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was poured into ice water. Oily product was extracted with ethyl acetate, washed successively with 5% aqueous sodium bicarbonate and saturated brine and dried over anhydrous sodium sulfate. Then the solvent was distilled off therefrom under reduced pressure and the resulting oil was purified through silica gel column chromatography using benzene as an eluant to give 2.84 g of the title compound as pale yellow crystals, (yield: 98%), m.p. 81.0°-83.0° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.Cl.[CH3:43][N:44]([CH3:51])[CH2:45]/[CH:46]=[CH:47]/[C:48](Cl)=[O:49].CCN(C(C)C)C(C)C>C1COCC1>[CH3:43][N:44]([CH3:51])[CH2:45]/[CH:46]=[CH:47]/[C:48]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:49]
Reactant: CN(C)C/C=C/C(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)/C=C/CN(C)C)c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b, 255 mg, 0.56 mmol) was added in one portion as a solid to a suspension of (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (283 mg, 1.538 mmol) in THF (10 mL) at 0° C. The resulting orange suspension was treated with DIEA (0.39 mL, 2.23 mmol) slowly and stirred for 30 min at 0° C. The reaction mixture was removed from the ice bath and stirred at RT for 30 min. The reaction mixture was treated with silica gel, concentrated on the rotovap and purified on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 0-20% MeOH in DCM) affording enriched product as a yellow solid. This sample was repurified on the Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated in the genevac overnight and the resulting orange solid was then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 10% MeOH/DCM then concentrated and dried again in the genevac for 3 h affording (E)-4-(dimethylamino)-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)but-2-enamide (35 mg, 0.062 mmol, 11% yield) as an orange solid. m/z (ESI, +ve ion) 569.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (1H, s), 8.74 (1H, s), 8.14 (1H, s), 7.90 (1H, d, J=9.4 Hz), 7.79-7.88 (1H, m), 7.59 (1H, s), 7.49 (1H, t, J=8.0 Hz), 7.27 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=8.6 Hz), 6.73 (1H, dt, J=15.4, 5.8 Hz), 6.51 (1H, d, J=2.3 Hz), 6.44 (1H, Hz), 6.27 (1H, d, J=15.3 Hz), 6.02 (1H, br. s.), 3.77 (3H, s), 3.04 (6H, d, J=5.7 Hz), 2.36-2.46 (4H, m), 2.22 (3H, s), 2.16 (6H, s).
Reaction SMILES: CON(C)[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:24][Mg]Cl>O1CCCC1>[C:16]1([NH:15][C:6]2[C:5]([C:4](=[O:22])[CH3:24])=[CH:10][CH:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
A solution of N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide (5.10 g, 15.7 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was treated with a solution of 3 M methylmagnesium chloride (15.7 mL, 47.0 mmol). The reaction was then stirred at 0° C. for 90 min. At this time, the reaction was warmed to 25° C. and was quenched with water (150 mL). The reaction was then partitioned between ethyl acetate (250 mL) and water (250 mL). The aqueous layer was back extracted with ethyl acetate (2×150 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (50 mL), filtered, rinsed with ethyl acetate and concentrated in vacuo. Flash chromatography (20%-40% ethyl acetate/hexanes) afforded 1-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-ethanone (4.28 g, 97.4%) as a yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:13]([CH2:14][F:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]1[C@@H:13]([CH2:14][F:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A solution of (3S,4S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (Pk1) (1.012 g, 2.87 mmol) in CH2Cl2 (10 mL) at 0° C. was added TFA (2.212 mL, 28.7 mmol) and the resulting mixture was allowed to warm to rt and stir for 1 hr. The reaction mixture was concentrated and redissolved in 70 mL of CH2Cl2 and was washed with 20 mL of 2M Na2CO3 solution and 20 mL of brine then dried over Na2SO4. Filtration and concentration afforded the title compound (0.718 g, 99% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.41-7.31 (m, 5H), 5.24-5.08 (m, 2H), 4.77-4.43 (m, 2H), 3.75-3.57 (m, 3H), 3.37 (s, 2H), 2.66-2.49 (m, 1H). MS (ES+) m/z: 253.2 (M+H); HPLC retention time: 1.023 min (analytical HPLC Method H). Chiral purity: 99.9% ee (chiral HPLC conditions: column: Chiralpak AD-H (25×0.46 cm, 5 μm), 35% MeOH in CO2, 3 mL/min, 45° C., 220 nm, 100 bar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:25][CH3:26])[C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Compound 13B (800 mg, 2.76 mmol) dissolved in DMF (10 ml) was added with K2CO3 (1.1 equiv., 420 mg) and ethyl iodide (1.1 equiv., 0.3 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 750 mg of 14B as a semisolid. Yield=85.5%. 1HNMR (DMSO, 200 MHz) δ 1.096 (3H, t, J=7.2 Hz), 1.17 (2H, m), 1.43 (2H, bs), 3.34 (2H, m), 3.43 (3H, s), 7.68 (2H, m), 7.79 (2H, m)
Reaction SMILES: [C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(N(C)C)=O>[CH2:31]([O:2][C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:3])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C1Nc2ccccc2CCC1NC(CCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (as described in example 6, 13.0 g), sodium bicarbonate (10.0 g), and benzyl bromide (19.0 g) in dimethylacetamide (750 ml) was stirred at room temperature under a nitrogen atmosphere for 72 hours. The reaction mixture was filtered and evaporated under high vacuum. Water (150 ml) was added, and the resulting solution extracted with dichloromethane (2×400 ml). The combined extracts were washed with water (100 ml), dried over magnesium sulfate and evaporated under reduced pressure to give the crude benzyl ester. Recrystallization from ethyl acetate gave 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 139°-141°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>C1COCC1>[CH2:14]([O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]=[CH2:12]
Reactant: OCCc1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-phenylethanol (9.09 g; 72.9 mmol) dissolved in THF (75 ml) and cooled to 0° C. is added NaH (60%; 3.5 g; 87 mmol) in portions over 10 minutes. The mixture is allowed to warm to room temperature, stirred for 45 minutes and cooled. Allyl bromide (6.3 ml; 73 mmol) is added and the mixture is brought to room temperature and stirred vigorously. The reaction mixture is heated at 45° C. for 3 hours, quenched with MeOH, diluted with Et2O, washed with H2O 3× and brine, dried (MgSO4) and concentrated to dryness. The resultant yellow oil is purified by column chromatography using 10% ether/petroleum ether to give 2-allyloxyethylbenzene as a clear oil which is used directly in Step B.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[CH:3]=1.[OH-].[K+].CCO.C(O)(=O)C>O>[I:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(I)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnn2ccc(I)cc12
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A 22 L round bottom flask was charged with ethyl 5-iodopyrazolo[1,5-a]pyridine-3-carboxylate (I-41) (376 g, 1.19 mol), KOH (133.5 g), EtOH (3856 mL) and water (290 mL). The mixture was heated to 55° C. and stirred at 55° C. for 3 hours. A sample was taken for analysis and HPLC showed no (I-41) remaining. Water (2.5 L) was added to obtain a dark solution with some insoluble solids which were removed by filtration. To the filtrate was added acetic acid (150 g, 2.5 mol) until pH˜6 followed by water (4 L). The mixture was stirred at 15 to 20° C. over 30 minutes to form a slurry that was filtered and rinsed with EtOH/H2O (1:2 v/v) to yield 5-iodopyrazolo[1,5-a]pyridine-3-carboxylic acid (I-42) as a red solid. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (b, 1 H), 8.65 (d, 1 H), 8.44 (d, 1 H), 8.37 (s, 1 H), 7.37 (dd, 1 H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=1)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 3.88 g, 96.98 mmol) was added portionwise to a stirring solution of ethyl 5-bromo-1H-indole-2-carboxylate (20.0 g, 74.6 mmol) in DMF (140 mL) at 0° C. under a nitrogen atmosphere over a period of 10 min. The mixture was then warmed to room temperature. After the reaction mixture was stirred at room temperature for one hour, 4-methylbenzyl bromide (14.2 g, 74.6 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride and diluted with water. The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate. This mixture was concentrated to give a semi-solid contained 0.8 mole equivalent DMF. Mass spectrum (ESI, [M+H]+) m/z 372. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, 1H, J=7.94 Hz), 7.55 (d, 1H, J=9.01 Hz), 7.40 (dd, 1H, J=8.85 and 1.98 Hz), 7.32 (s, 1H), 7.04 (d, 2H, J=7.96 Hz), 6.90 (d, 2H, J=7.94 Hz), 5.79 (s, 2H), 4.28 (q, 2H), 2.20 (s, 3H), and 1.28 ppm (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[NH:21][C:22]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][C:20]2[NH:21][C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)CCc1[nH]c(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cc2nc(-c3ccccc3)c(CCC(=O)O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-1H-imidazol-5-yl]propionate (250 mg), lithium hydroxide hydrate (62.0 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (1.5 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-1H-imidazol-5-yl]propionic acid (132 mg, yield 54%) as colorless crystals. The crystals were recrystallized from acetone. melting point: 193–196° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:15][C@H:16]([OH:32])[C@@H:17]([NH:25]C(=O)C(F)(F)F)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:15][C@H:16]([OH:32])[C@@H:17]([NH2:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cnccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cnccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
11.75 g (21 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane are suspended in 500 ml of methanol and, at 60° C., 105 ml of a 1M K2CO3 solution in water are added. The mixture is stirred at 75° C. for about 3 hours; the methanol is evaporated off and the residue is extracted with ethyl acetate. The organic phase is washed once each with water and brine and concentrated. The title compound is obtained in the form of orange-brown crystals, which can be recrystallised from ethyl acetate/petroleum ether. M.p.: 146°-148° C. TLC: Rt= 0.08 (methylene chloride/methanol 10:1). HPLC20-100 : tRet =11.23.