Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:19]([CH3:21])[CH3:20])C2C=CC=CC=2N=N1.[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]([OH:46])=O)[CH2:40][CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(Cl)Cl.CN1CCOCC1.CNC>O1CCCC1.C(OCC)(=O)C>[CH3:20][N:19]([CH3:21])[C:44]([CH:41]1[CH2:42][CH2:43][N:38]([C:36]([O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[CH2:39][CH2:40]1)=[O:46]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.442 g, 0.00100 mol) was added to a solution of 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid (0.263 g, 0.00100 mol) in methylene chloride (3.00 mL, 0.0468 mol), followed by 4-methylmorpholine (0.440 mL, 0.00400 mol) and dimethylamine in tetrahydrofuran (2.00 M, 0.750 mL). The mixture was stirred at rt for 1 h and was diluted with ethyl acetate (20 mL). The solution was washed with NaHCO3 (7.5%, 3×5 mL) and with brine (5 mL) successively. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combiflash eluting with ethyl acetate/hexane to give the desired product.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][O:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][C:9]([F:18])([F:19])[F:8])=[CH:16][CH:15]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
Sodium hydride (60% in oil, 2.12 g) wad added to an N,N-dimethylformamide solution (100 ml) of 4-trifluoromethoxyphenol (9.0 g) under ice cooling and stirred for 30 minutes. After adding 4-[2-(toluene-4-sulfonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (17.7 g), the mixture was heated to room temperature and stirred. The mixture was further stirred at 50° C. for 1 hour. After cooling the reaction mixture to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The result was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=67:33) to afford the title compound as a pale yellow oil (18.64 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:10]([O:15][C:16]3[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:1][O:2][C:3]1[C:8]([C:9]2[C:10]([O:15][C:16]3[CH:22]=[CH:21][C:19]([NH:20][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1-c1nccnc1Oc1ccc(N)cc1
Reactant: Brc1ccccn1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Product: COc1ncccc1-c1nccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)aniline (0.1874 g, 0.637 mmol), 2-bromopyridine (0.075 mL, 0.764 mmol), BrettPHOS precatalyst (10.19 mg, 0.013 mmol), and sodium tert-butoxide (0.153 g, 1.592 mmol). The flask was placed under vacuum then flushed with argon. Dioxane (2.122 mL) was added and the reaction was heated to 90° C. to stir overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed to give the title compound. MS (ESI, pos. ion) m/z: 372.0, IC50 (uM)=0.002903.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(s1)CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2sccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1[CH2:6][C@H:7]([NH:11][C:12]([CH2:14][CH2:15][NH2:16])=[O:13])[C:8]([OH:10])=[O:9].C(=O)([O-])[OH:18].[Na+].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.Cl>O.OC1OC(O)=C(O)C=1O>[NH2:16][CH2:15][CH2:14][C:12]([OH:18])=[O:13].[CH:1]1[N:5]=[CH:4][NH:3][C:2]=1[CH2:6][C@H:7]([NH:11][C:12]([CH2:14][CH2:15][NH2:16])=[O:13])[C:8]([OH:10])=[O:9]
Reactant: O=C([O-])O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: Cl
Agent: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Solvent: O
Product: NCCC(=O)O
Temperature: 25 °C

Procedure:
In 10 ml of water, 226 mg (1 m.mol) of carnosine and 84 mg (1 m.mol) of sodium hydrogen carbonate were dissolved. The resultant solution and a solution of 380 mg (1 m.mol) of the N-hydroxysuccinimide ester of oleic acid of high purity obtained in Reference Example in 10 ml of tetrahydroxyfuran added thereto were stirred at normal room temperature with a magnetic stirrer and thus left reacting with each other for 15 hours. From the resultant reaction solution, about 200 mg of N-oleoyl-carnosine of high purity was obtained by acidifying the reaction solution with 6N hydrochloric acid, extracting the acidified reaction product from ethyl acetate, and repeatedly subjecting the extract to a treatment for crystallization with hexane/ethyl acetate (4:1 v/v). This N-oleoyl-carnosine was analyzed by IR, , 1H-NMR and 13C-NMR. In the infrared spectrum, the absorption peaks, region of 2,920 cm-1 and 2,830 cm-1 (CH expansion), originating in oleic acid and the absorption peaks, 1,650 to 1,400 cm-1 (C=C, C=N expansion), originating in imidazole were discernible. Further, a marked decrease was found in the peak, 1,4580 cm-1 (NH deformation), prominent in the chart of carnosine. In the 1H-NMR spectrum, a chemical shift of the C9, C10 cis-form proton in the magnitude of 5.30 ppm originating in oleic acid was discernible. The integral ratio implied the presence of an amide bond between an oleic acid and a carnosine. From the --COOH of oleic acid, the magnitude of chemical shift of the proton of carbon at the alpha position was found to have shifted from 2.30 ppm to 2.00 ppm and that of chemical shift of the proton of carbon at the beta position was found to have shifted from 1.60 ppm to 1.45 ppm. In the 13C-NMR spectrum, the magnitude of chemical shift of the carbon of --COOH of oleic acid was found to have shifted from 180.40 ppm to 170.59 ppm. These results indicate that the oleic acid formed an amide bond with the beta-alanine residue of carnosine. The infrared absorption spectrum is shown in FIG. 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:3]=1>[Pd].O1CCOCC1>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: Cc1ccc([N+](=O)[O-])c(OCCOc2ccccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1ccc(N)c(OCCOc2ccccc2N)c1

Procedure:
100 g 4-methyl-1-nitro-2-(2-(2-nitro-phenoxy)-ethoxy)-benzene and 10 g palladium on charcoal were suspended in 3.5 l dioxane and hydrogenated at room temperature under a hydrogen pressure of 5.5 bar. After flashing three times with nitrogen the catalyst was filtered off under a nitrogen atmosphere and the remaining solution was evaporated and the product was dried under vacuum. Yield: 80 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(#N)C.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1cc(O)ccc1C
Solvent: CC#N
Product: COc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1C
Yield: 95.3 %

Procedure:
To a solution of 4-methyl-3-(methyloxy)phenol (Intermediate 18, 0.800 g) in dry acetonitrile (60 mL) potassium carbonate (1.600 g, 11.58 mmol) and then 1-fluoro-4-nitrobenzene (817 mg, 5.79 mmol) were added and the reaction mixture was refluxed for 6 hours. The solid was filtered off and the solvent evaporated affording the title compound (1.43 g) as an orange solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:24])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[NH4+].[Cl-]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([O:24][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(O)c2cccc(Cl)c2)C1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of NaH (0.608 g, 15.2 mmol) in DMF (60 mL) at 0-5° C. was added dropwise with a solution of (3R)-tert-butyl 3-((3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (4.35 g, 12.68 mmol) in DMF (30 mL). The mixture was stirred for 1 h at rt. A solution of ethyl bromoacetate (2.52 g, 15.2 mmol) in DMF (30 mL) was added dropwise and the mixture was heated to reflux for 3 h. When the reaction was complete, the mixture was poured into satd aq NH4Cl, and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give (3R)-tert-butyl 3-((3-chlorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (2.09 g, 40%). 1H NMR (400 MHz, CDCl3): 1.23-1.27 (m, 3H), 1.43-1.45 (m, 9H), 3.95-3.99 (m, 3H), 4.12-4.17 (m, 4H), 4.32-4.38 (d, 1H), 7.14-7.17 (m, 1H), 7.26-7.28 (m, 3H). MS (E/Z): 412 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:9][C@H:8]1[CH2:7][O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1COc2ccccc2NC1=O
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (2 g, 7.19 mmol, Eq: 1.00) in DCM (16.7 mL) at 0° C. was added trifluoroacetic acid (TFA, 16.4 g, 10.7 mL, 144 mmol, Eq: 20.00). After 1 h the mixture was concentrated, and the residue was triturated with 5 mL of Et2O and 35 ml of pentane to give a gum. The solution was removed and this gummy residue material was dried to give the title compound (2.1 g) as a pink foam which was used without purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C1CCN2C(=NCCC2)CC1>ClCCl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 5 h
Yield: 52 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-hydroxymethylpyrrolidine (1.0 g) in dichloromethane (15 ml) were added triethylamine (0.7 ml), t-butyldimethylsilyl chloride (0.57 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.15 g). The resulting mixture was allowed to stand at ambient temperature for 5 hours. The mixture was diluted with ethyl acetate (150 ml), washed in turn with aqueous ammonium chloride and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (40 ml) eluting with a mixture of n-hexane and ethyl acetate (3:1 V/V) to give (2S,4R)-1-allyloxycarbonyl-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine (0.62 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)(C)(C)C.[H][H].[ClH:30]>C(OCC)(=O)C.O1CCOCC1.[Pd]>[ClH:30].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OCCCNC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccc(C#N)cc1OCCCN
Reaction time: 8 h

Procedure:
3.8 g (10.2 mmol) of ethyl 3-[2-(3-(t-butoxycarbonylamino)propoxy)-4-cyanophenyl]acrylate was dissolved in 100 ml of ethyl acetate. 700 mg of 10% palladium/carbon (50% hydrous) was added to the obtained solution, and they were stirred in the presence of hydrogen for 3 hours. The reaction solution was filtered through Celite. The solvent was evaporated, and the obtained crude product was dissolved in 50 ml of 4 N solution of hydrogen chloride in dioxane. The obtained solution was stirred overnight. The solvent was evaporated to obtain hydrochloride of the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.Cl[C:15]1C(CO)=CC=C(C(F)(F)F)N=1.C(=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:15])[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=1
Reactant: OCc1ccc(C(F)(F)F)nc1Cl
Reactant: OCc1cc(Cl)nc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COCc1cc(Cl)nc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (0.84 g, 4.0 mmol) and [2-chloro-6-(trifluoromethyl)pyridin-3-yl]methanol (0.84 g, 4.0 mmol) (as a mixture of regioisomers from Step A) in N,N-dimethylformamide (8.6 mL) was added potassium carbonate (3.3 g, 24 mmol), followed by methyl iodide (0.99 mL, 16 mmol). The reaction was stirred overnight. Additional DMF (10 mL), methyl iodide (2.0 mL, 32 mmol) and potassium carbonate (3.3 g, 24 mmol) were added and the reaction was stirred for 72 hours. Water was added into the reaction and the product was extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes allowed for isolation of desired isomer, contaminated with a small amount of the undesired isomer. Desired isomer: 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.50 (s, 1H), 4.53 (dd, 2H), 3.48 (s, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[CH:15]([C:16]([O:18]C)=[O:17])[CH2:14][CH2:13][C:12]2=[O:20])[CH:7]=[CH:8][CH:9]=1>O>[F:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:12](=[O:20])[CH2:13][CH2:14][CH:15]2[C:16]([OH:18])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCC(=O)N1Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCC(=O)N1Cc1cccc(F)c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A solution of 19.00 g of sodium hydroxide pellets in 225 ml of water was treated with 115.52 g of (±)-1-[(3-fluorophenyl)methyl]-5-methoxycarbonyl-2-pyrrolidinone and the mixture was heated for four hours (steam bath). The solution was cooled to the ambient temperature and extracted with diethyl ether (3×250 ml). The aqueous phase was acidified with concentrated hydrochloric acid to about pH-1. The aqueous phase was extracted with dichloromethane (2×300 ml) and the combined organic phase was dried over Na2SO4. The solution was vacuum filtered and the filtrate was concentrated to an oil which solidified on standing. The solid was recrystallized from 300 ml of toluene to yield 72.16 g of crystals, m.p. 114°-116.5° C.
Reaction SMILES: [CH:1]([Mg:4][Cl:5])(C)[CH3:2].[CH3:6][O:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][CH:12](C)[CH:13]=C>O1CCCC1>[CH3:6][O:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH2:2][CH2:1][Mg:4][Cl:5]
Reactant: C=CC(C)CCCC(C)(C)OC
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(C)(C)CCCC(C)CC[Mg]Cl

Procedure:
i-Propylmagnesium chloride (0.5 mol) in tetrahydrofuran (200 ml) was treated with 7-methoxy-3,7-dimethyl-1-octene (85 g), followed by dropwise addition of a tri-isobutyl vanadate (7.0 g) in tetrahydrofuran (40 ml) at room temperature. The reaction mixture was then refluxed under nitrogen for 5 h when an aliquot showed a 72% conversion and 87% theoretical yield of the Grignard reagent.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C

Procedure:
21 ml of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 29 grams of powdered potassium hydroxide and 32 ml of 1-bromooctane were stirred in 150 ml benzene and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 100 ml. The reaction mixture was then cooled to room temperature and 200 ml water was added. The reaction mixture was then extracted thrice with 150 ml diethyl ether, the combined organic phase was washed with 100 ml water, and the solvent was then removed under reduced pressure. The obtained residue was dissolved in 100 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated hydrochloric acid, and the resulting solution was refluxed for 2 hours, followed by cooling to room temperature and addition of 100 ml water. The product was extracted thrice with 150 ml chloroform, washed consecutively with 150 ml water, 150 ml of saturated aqueous solution of sodium bicarbonate, and again with 100 ml water. The solvent was dried over anhydrous Na2SO4, filtered, and removed under reduced pressure, yielding 34 grams of (S)-1-octyl-glycerol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1>CN(C=O)C>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:8]([C:7]3[CH:6]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH:12]=4)[CH2:5][C:4](=[O:21])[NH:3][C:2]=3[CH3:1])=[O:9])=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc3ccccc3c2)CC(=O)N1
Temperature: 25 °C
Reaction time: 22 h
Yield: 22.1 %

Procedure:
The product of step 2 (450 mg, 1.60 mmol, 1 equiv) was combined with 1H-indazol-5-amine (212 mg, 1.60 mmol, 1 equiv) and polystyrene-bound carbodiimide (1.78 g, 1.1 mmol/g, 1.97 mmol, 1.2 equiv) in 6 mL DMF. The reaction mixture was stirred for 22 hours at room temperature. The resin was removed by filtration and washed alternately with CH2Cl2 and MeOH, ending with CH2Cl2. The volatile solvents were removed en vacuo and water was added, providing a solid residue. The residue was triturated with ethyl acetate, affording 140 mg of the title compound as a white crystalline solid. MS (ES+) m/e 397 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:12][CH3:13])[C:9]([OH:11])=O.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:12][CH3:13])=[CH:18][CH:17]=1)#[N:14]
Reactant: COC(C(=O)O)c1ccccc1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1F

Procedure:
(RS)-(2-Fluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-phenyl)-2-methoxy-acetamide. Colorless oil. MS 299.2 ([M+H]+)
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](=[S:6])[NH2:5].Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:3]([C:4]1[S:6][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)[CH:2]([CH3:7])[CH3:1]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(CC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methylbutanethioamide (example 72, step b) (5.6 g) in ethanol (100 mL) was added ethyl 3-bromo-2-oxopropanoate (6.7 mL). The resulting mixture was stirred overnight at RT, then heated at reflux for 5 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (250 mL) and saturated sodium hydrogen carbonate solution (100 mL). The layers were separated and the organic phase was washed with brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 20:1 to 10:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 5.2 g.
Reaction SMILES: C([N:8]1[CH2:20][C@H:19]2[C@H:11]([C:12](=[O:23])[C:13]3[C:18]2=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=3Br)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:23])[C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc(Br)c2c(c1)[C@H]1CN(Cc3ccccc3)CC[C@H]1C2=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(c1)[C@H]1CNCC[C@H]1C2=O
Temperature: 20 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
To a solution of cis-3-benzyl-8-bromo-6-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (50 mg, 0.14 mmol) in MeOH (3.0 mL) was added Pd(OH)2 (10.0 mg, 20 wt %). The reaction mixture was stirred at 20° C. for 15 h under H2 atmosphere, filtered through celite and concentrated in vacuo. The residue was chromatographed in silica gel column (CH2Cl2/MeOH 95/5) to give the title compound (20 mg, 0.099 mmol): MS (ES) 202.2 (M+H).