Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])[C:4](=[O:8])[C:5]([O-:7])=O)C.[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[C:13]3[C:26]([CH3:27])=[C:9]([NH:3][C:4](=[O:8])[C:5](=[O:7])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=3[O:16][CH2:15]2)=[CH:18][CH:19]=1)([CH3:24])[CH3:25]
Reactant: CCN(C(=O)C(=O)[O-])c1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)C(=O)C(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a solution of ethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate (100 mg, 0.25 mmol) obtained in Example 15 in THF (3 ml) was added dropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride (2.0 M THF solution, 0.26 mL, 0.5 mmol) and the mixture was stirred for 30 minutes. After the reaction solution was stirred at room temperature for 1 hour, the reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to obtain 29 mg (yield: 28%) of the title compound. Melting point: 142-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([CH3:8])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of 4-bromo-3-fluorotoluene (10 g, 52.9 mmol) in H2SO4 (100 mL) was added KNO3 (5.34 g, 52.9 mmol) at 0° C. After stirring overnight at room temperature, the reaction mixture was poured into ice (200 g) and extracted with EtOAc (3×300 mL). The organic solution was washed with brine (200 mL), dried (Na2SO4), and concentrated to give 12.35 g (100%) of title compound as a pale yellow oil. 1H NMR (CDCl3): 300 MHz δ 8.29 (d, J=6.30 Hz, 1H), 7.12 (d, J=8.61 Hz, 1H), 2.60 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.Cl.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C@@H:2]([C:13]([NH:16][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:14])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1
Reactant: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.0 g (5.39 mmol) Chas-D-Phe(4-NO2)—OH and 1.42 g (5.39 mmol) H-Phe(4-NO2)—OMe.HCl were suspended in 30 ml of DMF and 2.82 g (5.39 mmol) of PyBOP and 2.81 ml (16.16 mmol) of DIPEA was added at 0° C. After 2 h of stirring at 0° C., the solvent was removed in vacuo and the brown residue resuspended in 5% KHSO4 soln./EtOAc. The organic phase was washed 3× with 5%-KHSO4 soln., 1× with sat. NaCl soln., 3× with sat. NaHCO3-soln., and 3× with sat. NaCl soln., subsequently dried with MgSO4, filtered, and the solvent was removed in vacuo.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH:21]=[CH:20]2>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH:21]=[CH:20]2
Reactant: O=C(Nc1ccc2cc(O)ccc2c1)OCc1ccccc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)OCc5ccccc5)ccc4c3)c2cc1OC
Temperature: 25 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (prepared by the method described in WO 03/33472) (223 mg, 1.0 mmol), N-(6-hydroxy-(2-naphthyl))(benzyloxy)carboxamide (Step a, 293 mg, 1.0 mmol) and DMAP (122 mg, 1.0 mmol, Aldrich) in toluene (5 mL, Aldrich) were microwaved (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. After cooling to RT, the white precipitate was collected and purified by silica gel column chromatography (80% EtOAc/hexane) to give title compound as a white solid. MS (ESI, pos. ion) m/z: 481.3 (M+1). Mass Calc'd for C29H24N2O5: 480.17.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(=O)OCC>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: ClCc1nc2cccnc2s1
Reactant: Clc1ccccc1N1CCNCC1
Solvent: CCOC(C)=O
Product: Clc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (60 mg, 0.3 mmol), 1-(2-chlorophenyl)piperazine (70 mg, 0.31 mmol), and D1 EA (110 μL, 0.66 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 2.77 (m, 4H) 3.12 (m, 4H) 4.06 (s, 2H) 7.03 (m, 1H) 7.19 (m, 1H) 7.29 (m, 1H) 7.39 (dd, J=7.96, 1.40 Hz, 1H) 7.54 (dd, J=8.11, 4.68 Hz, 1H) 8.31 (dd, J=8.11, 1.56 Hz, 1H) 8.58 (dd, J=4.68, 1.56 Hz, 1H) (ESI) m/z 345 (M+H)+.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1.[BH4-].[OH-].[Na+].OO>O1CCCC1>[CH3:15][N:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[C@H:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1
Reactant: CN1CCC(=O)C(c2ccccc2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [BH4-]
Solvent: C1CCOC1
Product: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The procedure of Example 1a. through 1e. is repeated. 25 ml of a 1.0 M solution of lithium tri-secondary-butylborohydride in THF are added dropwise over a 10-minute period to a solution of 3.79 g of 1-methyl-3-phenyl-4-piperidone and 20 ml of tetrahydrofuran (THF) (distilled over lithium aluminum hydride), maintained at 0° C. The mixture gradually warms to 15° C. after two hours of stirring and an additional 5 ml of borohydride reagent are added and the mixture is stirred 18 hours at room temperature under a nitrogen atmosphere. The mixture is then treated with 90 ml of 10 weight percent aqueous NaOH solution followed by 61 ml of 30 percent by weight aqueous H2O2 solution. The mixture is stirred for 18 hours at room temperature under a nitrogen atmosphere and is then extracted with ether and then CH2Cl2. The organic extracts are combined and washed with saturated aqueous NaCl solution and dried over Na2SO4. The organic extracts are then filtered and concentrated in vacuo to a solid. The solid is triturated with petroleum ether, filtered and dried for 3 hours at 60° C. over P2O5. The solid product of cis-1-methyl-3-phenyl-4-piperidinol has a melting point s 127° C., 131°-133° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]=[O:9].C(O)C.[BH4-].[Na+].O.[O:22]1[CH2:26]CC[CH2:23]1>>[CH3:23][O:22][CH2:26][O:1][CH2:2][C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1oc(-c2ccccc2)nc1CO
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCOCc1nc(-c2ccccc2)oc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 4-hydroxymethyl-2-phenyloxazole-5-carbaldehyde (0.25 g) in tetrahydrofuran (5 mL)-ethanol (3 mL) was gradually added sodium borohydride (0.04 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (4-methoxymethoxymethyl-2-phenyl-1,3-oxazol-5-yl)methanol as colorless crystals (0.19 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 70-71° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([CH:25]=[O:26])=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.Br[C:28]([F:35])([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1.[Zn]>[F:34][C:28]([F:35])([CH:25]([OH:26])[C:22]1[CH:21]=[CH:20][C:19]([C:4]2[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:24][N:23]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C=O)nc2)c1
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 25 °C

Procedure:
A flask fitted with a stirring bar was charged with zinc (64.9 mg, 0.992 mmol) and anhydrous THF (5.00 mL) under a nitrogen atmosphere. Then, a solution of 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carbaldehyde (250 mg, 0.698 mmol) in THF (5.00 mL) was added to the flask and the mixture was brought to reflux. Ethyl bromodifluoroacetate (135 μL, 1.048 mmol) was slowly added via syringe to the reaction mixture and refluxed for 1 hour. The reaction mixture was cooled to room temperature, quenched by the addition of saturated aqueous sodium thiosulfate (3.00 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:7 ethyl acetate:hexanes) to afford ethyl 2,2-difluoro-3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate. MS APCI C22H20F5N4O3 [M+H]+ 483. found 483. 1H NMR (500 MHz, CDCl3) δ 8.84 (d, J=1.7 Hz, 1H), 8.66 (d, J=4.8 Hz, 1H), 7.98 (dd, J=2.2 Hz, 8.1 Hz, 1H), 7.89 (s, 1H), 7.52 (d, J=9.1 Hz, 2H), 7.38 (s, 1H), 7.14 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 5.26 (dd, J=4.9 Hz, 17.5 Hz, 1H), 4.47-4.29 (m, 2H), 2.45 (s, 3H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>Cl[Pd]Cl.O.O1CCOCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:4]2[S:5][CH:6]=[C:2]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[C:3]=2[CH:10]=1
Reactant: Clc1ccc2scc(Br)c2c1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc2scc(-c3ccncc3)c2c1
Yield: 127.6 %

Procedure:
To 3-bromo-5-chloro-benzo[b]thiophene (9.80 g, 39.6 mmol) was added pyridine-4-boronic acid (4.445 g, 36.2 mmol), K3PO4 (19.5 g, 91.9 mmol), 61 mL of 1,4-dioxane and 6 mL of water. The mixture was placed under house vacuum for several minutes and flushed with nitrogen. This was repeated 5 times. Pd(dppf)Cl2.CH2Cl2 (2.71 g, 3.31 mmol), PdCl2 (0.0563 g, 0.318 mmol) and 1,1″-bis(diphenylphosphino)ferrocene (0.1747 g, 0.3151 mmol) were purged in the same way. The catalyst was added to the reaction flask which was purged with nitrogen 3 more times. The mixture was stirred (stir bar) at 80° C. for 22 hours. TLC showed little change. The mixture was mechanically stirred at 80° C. for 4 hours. The mixture was partitioned between water and ethyl acetate, filtered through Celite and the layers were separated. The organic layer was evaporated. The residue was dissolved in ethyl acetate, washed with water twice. Saturated brine was added the second time to separate the layers more quickly. The organic solution was dried over magnesium sulfate. Filtration and contration in vacuum gave 11.35 g of black oil. This was eluted from silica gel with a gradient of hexane and ethyl acetate to give 3.86 g of recovered starting material and 4.28 g of the title compound as light brown crystals, m.p. 90-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([Cl:11])([Cl:10])=O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([Cl:11])[Cl:10])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(P(Cl)Cl)cc1
Yield: 85 %

Procedure:
167 g (0.73 mole) of p-chlorophenylphosphonic acid dichloride and 121 g (0.46 mole) of triphenylphosphane were stirred for 2 hours at 180° C. and for 10 hours at 200° C. under an atmosphere of nitrogen. Distillation was then carried out at 0.04 kPa until a top temperature of 140° C. was reached. This gave 145 g, containing 58.5% of p-chlorophenyldichlorophosphane and 41.5% of p-chlorophenylphosphonic acid dichloride (according to 31P-NMR spectrum). The distillate was fractionated using a 70 cm silvered-jacketed column, packed with Raschig rings. Pure p-chlorophenyldichlorophosphane (boiling point: 71° C./0.093 kPa) was obtained. This corresponds to a yield of 85% of theory, based on triphenylphosphane employed.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:5]=1)[CH3:3].C1C(=O)N([Cl:21])C(=O)C1>>[Cl:21][C:5]1[N:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:8][C:4]=1[CH:2]([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1ncc(C(C)C)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Product: CCOC(=O)c1nc(Cl)c(C(C)C)[nH]1
Yield: 76.9 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-(propan-2-yl)-1H-imidazole-2-carboxylate obtained in Example (35d) (0.82 g, 4.50 mmol) and NCS (0.60 g, 4.51 mmol), to obtain 0.75 g of the title compound as a white solid (77%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:12]([CH3:26])([CH3:25])[C:13]([NH:15][C:16]1[O:20][N:19]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1)=[O:14]>C1COCC1>[C:21]([C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[C:12]([CH3:25])([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH3:26])[O:20][N:19]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(OCC1CCOCC1)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of (tetrahydro-pyran-4-yl)-methanol (4 mL) at room temperature is added NaH (55 mg of a 60% dispersion in oil, 1.4 mmol). The reaction is warmed to 50° C. and stirred for 30 min. After this time, 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (0.20 g, 0.69 mmol) is added and THF (2 mL) is introduced. The reaction is stirred at 60° C. for 5 h before it is quenched by the addition of methanol. The solvent is removed under reduced pressure and the crude residue that remains is purified by preparative HPLC to give the title compound (38 mg, 17%). m/z 289 [M+H+].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:8]1[C:9](=O)[NH:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)#[N:7].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[C:8]([C:6]#[N:7])=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1cc(-c2ccccc2)c[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccccc2)cnc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Under a nitrogen atmosphere, 68.4 grams (0.45 mole) of phosphorus oxychloride is warmed to a gentle reflux, and 38.9 grams (0.18 mole) of 3-cyano-5-phenylpyridin-2-one is added. Upon completion of addition, 93.6 grams (0.45 mole) of phosphorous pentachloride is added in small portions to maintain the gentle reflux. Upon completion of addition, the reaction mixture is then warmed slowly to about 140° C. where it is stirred for one hour. The reaction mixture is cooled, and excess phosphorus oxychloride is removed under reduced pressure. The concentrate is then poured into 400 grams of ice, where it is stirred until the ice melts. The mixture is then extracted with three 200 mL portions of methylene chloride and 100 mL of diethyl ether. The combined extracts are washed with 150 mL of water and 150 mL of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure at 30° C. to a residue. The residue is distilled under vacuum, yielding 35.4 grams of 2-chloro-3-cyano-5-phenylpyridine, bp 175°-179° C./4 mm Hg., as a crystalline material. The crystalline 2-chloro-3-cyano-5-phenylpyridine is recrystallized from hexane/methylene chloride, mp 149°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:24])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 283.4 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of DMSO was added hydrogen peroxide (0.24 mL of 30% aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0° C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was collected by filtration and air-dried to give 0.32 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide as a white solid (67% yield), mp: 230-231° C. Anal. Calc'd for C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Reaction SMILES: C(OCC)(=O)C.[CH3:7][C@H:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)C>C(Cl)(Cl)Cl>[CH3:7][CH:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mother liquors from above were acidified with 167 ml. 1N hydrochloric acid, extracted with 5×125 ml. ethyl acetate, the extracts combined, washed with brine, dried (MgSO4) and the solvent evaporated to obtain 49 g. of residue. This was dissolved in 350 ml. warm ethyl acetate, 22.4 g. l-(-)-alpha-methylbenzylamine added and the solution cooled to room temperature. Ethyl ether, 350 ml. was added and the mixture refrigerated overnight. The precipitated solid was collected by filtration, washed with cold ether and dried in vacuo to obtain 44.0 g. of salt. This was dissolved in 880 ml. ethyl acetate and set aside at room temperature for six hours. Filtration gave 12.4 g., M.P. 139°-140° C. After standing overnight, the mother liquor afforded a second crop, 11.66 g., M.P. 139°-140° C. The optical rotation (in chloroform) for the first crop was [alpha]D -30.9°, and [alpha]D -26.6° for the second crop.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([OH:19])=O)[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Si]([O:40][CH2:41][C:42]1[N:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=1)(C(C)(C)C)(C)C.Cl>ClCCl.O.C1COCC1.N1C=CC=CC=1.CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([NH:48][C:45]3[CH:44]=[N:43][C:42]([CH2:41][OH:40])=[CH:47][N:46]=3)=[O:19])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(N)cn1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: O=C1CC[C@H](C[C@@H](C(=O)Nc2cnc(CO)cn2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoic acid (252 mg) in dichloromethane (2.5 mL) were added oxalyl chloride (68 μL) and DMF (104 μL) under ice-cooling, followed by stirring for 20 minutes. Thereafter, pyridine (65 μL) and 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrazin-2-amine (240 mg) were added thereto under ice-cooling, followed by stirring for 20 minutes under ice-cooling. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:chloroform=20:80). Further, it was purified by preparative TLC using the same solvent system to obtain a white amorphous substance (200 mg). A mixture of the obtained amorphous substance, 2 M hydrochloric acid (1 mL), and THF (1 mL) was stirred at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide (136 mg) as a white amorphous substance.
Reaction SMILES: [CH2:1]([Si:4]1(C2C=CC=CC=2)[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([OH:23])=[C:18]([F:24])[CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:31][C@@H:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33]O>>[CH2:1]([Si@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:33][C@H:32]([F:31])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:18]([F:24])[CH:17]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCCCC[C@H](F)CO
Reactant: CCC[Si]1(c2ccccc2)CCC(c2ccc(-c3cc(F)c(O)c(F)c3)cc2)CC1
Product: CCCCCC[C@@H](F)COc1c(F)cc(-c2ccc([C@H]3CC[Si@H](CCC)CC3)cc2)cc1F

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(4-n-propyl-4-phenyl-4-silacyclohexyl)phenyl) -2,6-difluorophenol and (S)-2-fluoro-1-octanol, thereby obtaining the intended compound.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([O:10][C:11]1[C:19]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])(=[O:9])[CH3:8]>ClCCCl>[C:7]([O:10][C:11]1[C:19]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:15]=[C:2]=[O:3])=[O:14])(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cccc(C(N)=O)c1OC(C)=O
Solvent: ClCCCl
Product: CC(=O)Oc1cccc(C(=O)N=C=O)c1OC(C)=O

Procedure:
Oxalyl chloride (5.3 g) was added to a solution of 2,3-diacetoxybenzamide (4.0 g) in 1,2-dichloroethane (40 ml) while stirring under cooling. The mixture was gradually heated to a reflux temperature and allowed to react under reflux for 10 hours. Then, the solvent and excess oxalyl chloride was distilled off under reduced pressure to give 2,3-diacetoxybenzoyl isocyanate, which was dissolved in dried dichloromethane (40 ml) for the subsequent reaction.