Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[CH:11][C:10]=1[OH:23])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].N1C(C)=CC=CC=1C.Cl[Sn](Cl)(Cl)Cl.[CH2:37]=[O:38].Cl>C1(C)C=CC=CC=1>[CH3:8][C:2]([C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[C:11]([CH:37]=[O:38])[C:10]=1[OH:23])([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: C=O
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)CC(C)(C)C)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2,4-bis(1,1,3,3-tetramethylbutyl)phenol (26.2 g, 82.4 mmol, synthesized by the method described in U.S. Pat. No. 3,373,210), toluene (200 ml) and 2,6-lutidine (14.4 g, 135 mmol) was placed in a stirred flask under a blanket of nitrogen and the mixture was cooled to 0° C. SnCl4 (8.57 g, 33 mmol) was then carefully added. The mixture was subsequently stirred at room temperature for 20 minutes, before paraformaldehyde (15.1 g, 502 mmol) was added. The mixture was then stirred at 100° C. for 12 hours. After cooling, hydrochloric acid (1 M, 272 ml) was added. The resulting suspension was filtered through Celite and the solid was washed with 100 ml of ethyl acetate. The organic phase of the filtrate was then separated off, washed twice with 100 ml of NaCl solution, dried over MgSO4 and evaporated at reduced pressure. A slightly yellowish oil was formed as product. According to GC/MS, this crude product contains only about 3% of starting material. Yield: 26.9 g (94%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[CH:16]=[C:15]([N:17]([CH:25]2[CH2:27][CH2:26]2)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C>[CH2:33]([S:40][C:11]1[CH:16]=[C:15]([N:17]([CH:25]2[CH2:27][CH2:26]2)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Reactant: SCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1cc(SCc2ccccc2)nc2c(C=O)cnn12)C1CC1
Reaction time: 0.03 h
Yield: 47.1 %

Procedure:
Diisopropylethylamine (256 μL, 1.48 mmol) was added to tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (250 mg, 0.74 mmol) suspended in ethanol (2.5 mL). Benzyl mercaptan (191 μL, 1.48 mmol) was added and the reaction was homogeneous after ˜2 min. After 10 min, the reaction was diluted with ethanol (3 mL) and the precipitate was filtered and washed with ethanol (10 mL) to yield tert-butyl 5-(benzylthio)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (148 mg, 47%). LCMS (ES): >95% pure, m/z 425 [M+1]+.
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:13][N:14]2[CH:18]=[C:17]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:16]=[N:15]2)[CH2:12][CH2:11]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:26][C:21]1([CH3:27])[C:22]([CH3:24])([CH3:25])[O:23][B:19]([C:17]2[CH:16]=[N:15][N:14]([CH2:13][C:10]3([CH2:9][OH:8])[CH2:12][CH2:11]3)[CH:18]=2)[O:20]1
Reactant: CC1(C)OB(c2cnn(CC3(COCc4ccccc4)CC3)c2)OC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OB(c2cnn(CC3(CO)CC3)c2)OC1(C)C
Temperature: 50 °C
Yield: 53 %

Procedure:
A solution of −({1-[(benzyloxy)methyl]cyclopropyl}methyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 63C, 8 g, 21.7 mmol) in ethanol (100 mL) was treated with palladium on charcoal (10%, 6 g) and heated to 50° C. under hydrogen atmosphere for 24 hrs. The catalyst was filtered off and the filtrate was concentrated to a residue under reduced pressure. The residue was triturated with isopropyl ether to give 3.2 g (53%) of the required material as white solid. 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.7 (s, 1H), 4.14 (s, 2H), 3.38 (s, 2H), 1.33 (s, 12H), 0.54-0.65 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.CCOC(C)=O.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A solution of 4-iodopyrazole (20 g, 0.10 mol) in anhydrous DMF (300 mL) was treated with Cs2CO3 (32.5 g, 0.10 mol) and 2-(2-bromoethoxy)tetrahydro-2H pyran. The resultant reaction mixture was stirred at 70° C. overnight. The cooled mixture was diluted with EtOAc (500 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated to afford yellow oil. Purification on a silica gel provided 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (22 g, 66.2% yield). 1H-NMR (300 MHz, CDCl3): δ 7.55 (s, 1H), 7.50 (s, 1H), 4.53 (s, 1H), 4.33 (m, 2H), 4.03 (m, 1H), 3.74 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H), 1.60-1.48 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-bromophenyl)ureido]-3-methylphenylacetate (1.27 g, 3.03 mmol) in CH2Cl2 (10 ml) was added TFA (5 ml) at room temperature. After 1 h stirring, the mixture was concentrated in vacuo. The residue was triturated by the addition of water, to give 4-[N′-(2bromophenyl)ureido]-3-methylphenylacetic acid (1.05 g, 95%) as a pale yellow powder. mp 245-248° C. (dec.); 1H-NMR (CDCl3) δ2.24 (s, 3H), 3.48 (s, 2H), 6.96 (dt, J=7.3, 1.5 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 7.07 (s, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.59-7.66 (m, 2H), 8.44 (s, 1H), 8.62 (s, 1H); MS (ESI), m/z 363 (M++1), 365 (M++3); Anal. Calcd. for C16H15BrN2O3.0.7H2O: C, 51.13; H, 4.40; Br, 21.26; N, 7.45. Found: C, 50.84; H, 4.62; Br, 21.72; N, 7.18.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:30])[CH:23]=2)[CH:19]=[C:18]([N:31]2[C@H:36]([CH3:37])[CH2:35][O:34][C@H:33]([CH2:38][NH2:39])[CH2:32]2)[N:17]=1>C1COCC1>[NH2:15][C:16]1[N:17]=[C:18]([N:31]2[C@H:36]([CH3:37])[CH2:35][O:34][C@H:33]([CH2:38][NH:39][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:32]2)[CH:19]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:30])[CH:23]=2)[N:21]=1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 124.5 %

Procedure:
Triethylamine (0.05 mL, 0.36 mmol) and pivaloyl chloride (0.04 mL, 0.33 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (99 mg, 0.29 mmol) in THF (5 mL), and the mixture was stirred at room temperature under nitrogen for 45 minutes. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a yellow foam (154 mg, about 75% pure). LC-MS (ES) m/z=427 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:25][OH:26])=[N:21][CH:22]=[CH:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:20]2[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cccnc1CO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1COc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (3-methyl-pyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [N+]([O-])(O)=O.[C:5]12([OH:15])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.C12([C:26]([OH:28])=[O:27])CC3CC(CC(C3)C1)C2>>[OH:15][C:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][C:7]([C:26]([OH:28])=[O:27])([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Solvent: O=[N+]([O-])O
Product: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 75.2 %

Procedure:
The same operations as conducted in Example 1 were repeated, except that the reaction mixture temperature after dropwise addition of nitric acid was set to 50° C. In the first carboxylation reaction step, the conversion of 1-adamantanol was found to be 99.0% and 1-adamantane carboxylic acid was generated in a reaction yield of 97%. In the second oxidation reaction step, the conversion of 1-adamantane carboxylic acid was found to be 99% and white crystals of 3-hydroxy adamantane-1-carboxylic acid (28.3 g, yield: 75.2%) were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cc(OC)ccc2c1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1oc2cc(O)ccc2c1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
The above prepared 3-isopropyl-6-methoxy-benzofuran-2-carboxylic acid ethyl ester (2.52 g, 10 mmol) was dissolved in 65 mL of CH2Cl2, cooled to 0° C., and treated with BBr3 (19.2 mL of 1M solution in CH2Cl2, 2 eq.). After 1 h at 0° C. and one additional at ambient temperature, the reaction mixture was carefully poured onto crashed ice, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) afforded 0.930 g of the title compound as purple crystals.
Reaction SMILES: [N:1]([CH:4]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:5]([OH:20])[CH2:6]OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)=[N+:2]=[N-:3].C(OCC)(=O)C.[OH-].[K+].O>C(O)C.C(Cl)Cl>[N:1]([C@H:4]([C@H:5]1[CH2:6][O:20]1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(Cc1ccccc1)C(O)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H]1CO1
Yield: 95.1 %

Procedure:
A solution of 1.0 g (2.5 mmol) of 4-Nitro-benzenesulfonic acid 3-azido-2-hydroxy-4-phenyl-butyl ester (Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427-30) in 12 mL of Ethanol and 8 mL of ethyl acetate is treated with KOH (157 mg, 2.8 mmol). After 2 h at rt 10 mL of water is added and 20 mL of CH2Cl2 is added. The organic layer is separated, washed with brine and Na2SO4, and concentrated. Chromatography eluting with hexanes/ethyl acetate 5:1 provides 450 mg (95%) of the desired product. 1H NMR (δ) 7.21-7.36 (m, 5H), 3.58 (dt, 2H, J=9, 5 Hz), 3.05 (m, 1H) 2.97 (dd, 1H, J=13.9, 4.8), 2.77-2.83 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([O:35][C:36]([CH3:43])([CH3:42])[C:37](OCC)=[O:38])[CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].[OH-].[K+]>C(OCC)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([O:35][C:36]([CH3:43])([CH3:42])[CH2:37][OH:38])[CH2:14][O:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(C)(C)O[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1c(C)cc2ccccc2c1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc2ccccc2c(Cl)c1[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(C)(C)CO
Reaction time: 0.08 h

Procedure:
A solution of (S)-ethyl 2-(1-(1-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropanoate (1.58 g, 2.66 mmol) in diethyl ether (62 mL) was treated with DIBAL-H (1.0 M in hexanes, 13.3 mL, 13.3 mmol) at 23° C. After 5 min, aq. Rochelle's salt (excess) was added dropwise over 5 min until bubbling ceased. The quenched reaction was agitated manually for 1 min to ensure full quenching. The system transitioned from a slurry to a gel. 50% w/v aw KOH (10 mL) was added, followed by H2O (40 mL), and the reaction was manually agitated until magnetic stirring was achievable (the reaction transitioned from a gel to a biphasic solution). After 15 min of stirring the reaction was extracted with diethyl ether (3×30 mL). Combined organic layers were dried quickly over MgSO4 for 1 min and promptly filtered and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-2-(1-(1-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropan-1-ol. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.2 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.52-7.38 (m, 9H), 7.31-7.18 (m, 9H), 5.87 (dd, J=9.5, 3.9 Hz, 1H), 3.76 (d, AB-spin system, J=11.8 Hz, 1H), 3.60 (dd, J=9.6, 9.6 Hz, 1H), 3.32 (d, AB-spin system, J=11.8 Hz, 1H), 3.26 (dd, J=9.8, 3.9 Hz, 1H), 2.49 (s, 3H), 1.16 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][OH:33])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][OH:33])[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)Cl
Product: CC(=O)N(CCO)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 21 %

Procedure:
The procedure described in Example 5 was repeated using 2-({2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}amino)ethanol and acetyl chloride to give the title compound in 21% yield; NMR spectrum (DMSO-d6) 2.00 (s, 3H), 3.43 (t, 2H), 3.54-3.59 (m, 2H), 3.88-3.97 (m, 2H), 4.41 (t, 2H), 4.85 (t, 1H), 5.31 (s, 2H), 7.16 (d, 1H), 7.25 (d, 1H), 7.33 (d, 1H), 7.35-7.40 (m, 1H), 7.57-7.62 (m, 2H), 7.70-7.75 (m, 1H), 7.86-7.92 (m, 1H), 7.96 (d, 1H), 8.45 (s, 1H), 8.61 (d, 1H), 9.83 (s, 1H); Mass spectrum MH+ 508.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]([NH:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccccc2)c1O

Procedure:
20 mmol of methyl 3-amino-2-hydroxy-benzoate were stirred at room temperature in toluene with 20 mmol of benzoyl chloride for 4 hours with the addition of dimethylaniline, the mixture was concentrated and the residue was recrystallized from EtOH. M.p.: 105° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([OH:15])=[O:14].C(Cl)(=O)C(Cl)=O.[CH:26]1[CH:31]=[CH:30][CH:29]=CC=1>>[CH:31]1([CH2:26][O:14][C:13](=[O:15])[CH:12]=[C:11]([CH3:16])[CH:10]=[CH:9][CH2:8][CH:7]([CH3:17])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:18])[CH3:19])[CH2:29][CH2:30]1
Reactant: c1ccccc1
Reactant: COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OCC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, to a stirred solution of 3.42 g. of 11-methoxy-3,7,11-trimethyldodeca-2,4-dienoic acid (mostly trans, trans) in dry benzene, is added 3.5 ml. of oxalyl chloride. The reaction mixture is stirred for 2 hours at room temperature and then solvent and any excess oxalyl chloride are removed in vacuo. Then about 130 ml. of fresh dry benzene is added followed by 4.46 of cyclopropylmethyl alcohol and the reaction mixture stirred, under nitrogen, overnight. The reaction is worked up by pouring into water, washing with brine, drying over calcium sulfate, removing solvent in vacuo and stirring the concentrate in pentane with neutral alumina. Pentane is removed to yield cyclopropylmethyl-11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate which is purified by distillation to give a product having a boiling point of 90° (bath) at 0.01 mm.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@:10]([OH:26])([C@@H:17]([CH3:25])[C@@H:18](OS(C)(=O)=O)[CH3:19])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@:10]1([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C@@H:17]([CH3:25])[C@@H:18]([CH3:19])[O:26]1
Reactant: C[C@H](OS(C)(=O)=O)[C@H](C)[C@](O)(Cn1cncn1)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1O[C@@](Cn2cncn2)(c2ccccc2Cl)[C@H]1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
11 mg of a 60% by weight dispersion of sodium hydride in mineral oil were added to a solution of 51 mg of (2R*,3S*,4S*)-2-(2-chlorophenyl)-4-(methanesulfonyloxy)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-pentanol [which was synthesized by a similar procedure to that described in Preparation 2(b) and 2(c) and derived from the 4,5-epoxy compound having the lower polarity of the stereoisomers at the C4 position prepared by a similar procedure to that described in Preparation 2(a)] in 2 ml of dimethylformamide; the mixture was then stirred at 60° C. for 2 hours. At the end of this time, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting oily residue was purified by preparative thin layer chromatography on silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the developing solvent, to afford 10 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[O:9][N:8]=2)[NH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Br)[CH:31]=1>CN(C=O)C.O>[Br:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[CH2:36][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[O:9][N:8]=2)=[N:5]1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1n[nH]c(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a suspension of 3-(5-methyl-2H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl) isoxazole (400 mg, 1.3 mmol) and K2CO3 (445 mg, 3.3 mmol) in DMF (5 mL) was added 1-bromo-3-(bromomethyl)benzene (323 mg, 1.3 mmol). The mixture was stirred at RT for 2 h, then diluted with H2O (30 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with H2O (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether:EA=1:1) to afford the title compound as a light yellow solid (350 mg, 56.6%). MS (ES+) C20H14BrF3N4O2 requires: 478. found: 479 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Reactant: [H][H]
Agent: N
Solvent: O
Solvent: CO
Product: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Temperature: 40 °C

Procedure:
A solution of 0.13 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid in 20 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.2 g of water wet Raney nickel #30. The solution is heated at 40° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.13 f of (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].C(=O)(O)[O-].[Na+].[I-].[K+].[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]/[C:48]([OH:50])=[O:49]>C(O)CCC.CCOCC.CO>[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]/[C:48]([OH:50])=[O:49].[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Solvent: CCOCC
Solvent: CO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 58.26 g (0.203 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 54.5 g (0.225 mole) of 1-chloro-3-(4-acetyl-2-methoxyphenoxy)propane, 18.7 g (0.223 mole) of sodium bicarbonate and 1.2 g (0.0072 mole) of potassium iodide in 800 ml of 1-butanol was refluxed for 16 hr. The hot reaction mixture was filtered, and the solvent was removed in vacuo from the filtrate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. The oil was dissolved in 600 ml of anhydrous ether, and 4.91 g of a solid was collected at room temperature. The ether solution was then treated with a solution of 30.2 g (0.26 mole) of fumaric acid in methanol. Anhydrous ether was added and 99.88 g (77.7%), m.p. 160°-163° C. of title compound was isolated. This was recrystallized from isopropanol-diethyl ether, (2.5 g, 0.0216 mole of additional fumaric acid was added) to give 2 crops of title compound. [Crop I-44.15 g, m.p. 163°-164.5° C.; Crop II-38.75 g, m.p. 161°-163° C⟧ An additional 10.00 g (8.786%), m.p. 159°-162° C. of title compound collected from the original ether-methanol filtrate.