Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[C:15](=[O:17])[NH:14][CH2:13][CH2:12]2.C1C(=O)N([Br:25])C(=O)C1>>[Br:25][C:8]1[C:7]([CH3:6])=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][C:15]2=[O:17])=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c1C(=O)NCC2
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc2c1C(=O)NCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
To cooled conc. H2SO4 (10 mL) was added 8-methyl-3,4-dihydroisoquinolin-1(2H)-one (76b, 1 g, 6.21 mmol) and the reaction mixture was stirred for 10 minutes. NBS (1.1 g, 6.21 mmol) was added and the reaction mixture stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and poured into ice-water (30 mL) with stirring. The suspension was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=1:1) to give 7-bromo-8-methyl-3,4-dihydroisoquinolin-1(2H)-one (76c, 0.63 g, 42%) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:39])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:39][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncccc5C(F)(F)F)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ncccc5C(F)(F)F)cc4)CC3)n2CCS1
Yield: 65.4 %

Procedure:
A solution of the compound (535 mg, 0.93 mmol) obtained in Example 29-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (280 mg, 65%) as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:15]C(=O)OC(C)(C)C)[C@@H:9]([OH:14])[CH:10]([OH:13])[CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl>C1(C)C=CC=CC=1>[NH2:15][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@@H:9]([OH:14])[CH:10]([OH:13])[CH2:11][OH:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CO

Procedure:
A solution of 270 mg of tert-butyl [(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3,4-trihydroxybutyl]carbamate, 15 ml of methanol and 10 ml of 2N hydrochloric acid is heated to 50° overnight. Subsequently, the reaction solution is evaporated to dryness under reduced pressure, the residue obtained is taken up twice in toluene and evaporated to dryness under reduced pressure each time. The crude (2RS,3R,4S)-4-amino-5-cyclohexyl-1,2,3-pentanetriol obtained is used in the next step without further purification; MS: 218 (M+H)+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[SH:11][C:12]1[O:13][C:14]2[C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.Cl>C1(C)C=CC=CC=1.C1COCC1>[OH:22][CH2:21][C:20]1[C:14]2[O:13][C:12]([SH:11])=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc2nc(S)oc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cccc2nc(S)oc12
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A 1.0M solution of diisobutyl aluminum hydride in toluene (10 ml) was slowly dropped, under argon atmosphere at −78° C., into a solution of 2-mercapto-7-methoxycarbonylbenzoxazole (1.1 g, 5.0 mmol) in THF (20 ml) followed by stirring for 30 minutes. At that temperature, a 1.0M solution of diisobutyl aluminum hydride in toluene (5 ml) was slowly dropped thereinto followed by stirring for 30 minutes. After cooling, diluted hydrochloric acid was added to the reaction mixture to decompose the excessive diisobutyl aluminum hydride, after then extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid solution and a saturated sodium chloride solution, dried over sodium sulfate and the solvent was evaporated therefrom. The resulting crude product was recrystallized from hexane-acetone-methanol to provide 848 mg (yield 94%) of 7-hydroxymethyl-2-mercaptobenzooxazole as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc2c(Cl)ccnc2c1
Product: Cc1ccc(-c2cc(Cl)c3ccc(C)cc3n2)cc1

Procedure:
The title compound, m. p. 110-111 ° C., MS: m/e=267 (M+), was prepared from 4-chloro-7-methyl-quinoline and 4-bromotoluene.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:30])[F:31])[CH:22]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)Oc1cccc(-c2ccc3c(ccn3Cc3ccccc3)c2)c1
Yield: 37.6 %

Procedure:
1-Benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indole was prepared by coupling 1-benzyl-5-bromo-1H-indole (2.28 g, 7.97 mmol), and 3-(trifluoromethoxy)phenylboronic acid (1.66 g, 8.06 mmol), using potassium carbonate (2.75, 19.9 mmol), palladium (II) acetate (0.0731 g, 0.326 mmol), and tetrabutylammonium bromide (2.78 g, 8.62 mmol) in water (45 mL) and THF (5 mL), according to the procedure described in Step 1 of Example 21. Following work-up the residue was purified by reverse phase HPLC using 81% acetonitrile and 0.1% TFA in water as the mobile phase. Evaporation of the acetonitrile, extraction of the aqueous phase with ethyl acetate, and evaporation to dryness afforded the title compound as an orange solid (1.10 g, 38%), mp: 62-65° C. Mass spectrum (+ESI, [M+H]+) m/z 368.5; 1HNMR (500 MHz, DMSO-d6): δ7.9 (s, 1H), 7.7 (m, 1H), 7.5-7.6 (m, 4H), 7.45 (dd, 1H, J=8.6 Hz and 1.8 Hz), 7.2-7.3 (m, 6H), 6.55 (m, 1H), and 5.45 ppm (s, 1H). Elemental Analysis for C22H16F3NO: Calculated: C, 71.93; H, 4.39; N, 3.81. Found: C, 71.53; H, 4.16; N, 3.79.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]2([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:10][CH3:11])[C:5]([F:26])=[CH:4][C:3]=1[C:27]#[N:28].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:27]([C:3]1[CH:4]=[C:5]([F:26])[C:6]([NH:8][C@@H:9]([C:12]2([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:10][CH3:11])=[N:7][C:2]=1[NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)#[N:28]
Reactant: CC[C@@H](Nc1nc(Cl)c(C#N)cc1F)C1(NC(=O)OCc2ccccc2)CC1
Reactant: Cc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1nc(Nc2ccc(C)cc2)c(C#N)cc1F)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Yield: 67.6 %

Procedure:
To a solution of (R)-benzyl 1-(1-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)propyl)cyclopropylcarbamate (100 mg, 0.25 mmol) in dioxane (1.5 mL) was added p-toluidine (32 mg, 0.30 mmol), BINAP (31 mg, 0.05 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol) and Cs2CO3 (244.5 mg, 0.75 mmol). After degassed with Argon, the mixture was heated at 80° C. for 5 h. The mixture was diluted with dioxane, precipitate was filtered off, filter cake was washed with ACN, the filtrate was concentrated and purified by column to give of (R)-benzyl 1-(1-(5-cyano-3-fluoro-6-(p-tolylamino)pyridin-2-ylamino)propyl)cyclopropylcarbamate (80 mg).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([Mg]Cl)[CH:2]=1.[CH:10]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(OCC)C>O1CCCC1>[CH3:9][C:1]1[CH:2]=[C:3]([C:21]2([OH:23])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:22]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: Cc1cccc([Mg]Cl)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C2(O)c3ccccc3-c3ccccc32)c1
Temperature: 0 °C
Yield: 89 %

Procedure:
A 1.0 M solution of m-tolylmagnesium chloride in tetrahydrofuran (10 mL, 10 mmol) (Aldrich) was added dropwise to a solution of 9-fluorenone (1.8 g, 10 mmol) (Aldrich) in anhydrous tetrahydrofuran (5 mL) with stirring under argon at 0° C. The mixture was stirred at room temperature for 1 h, anhydrous diethyl ether (20 mL) was added and the formed precipitate was filtered and dissolved in chloroform (50 mL). The chloroform solution was washed with a saturated solution of ammonium chloride (10 mL), brine (10 mL), dried (MgSO4), the solvent evaporated and the residue recrystallized from diethyl ether/hexane to give the title compound as a white solid (2.42 g, 89%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH3:22][C:20]1[CH:21]=[C:16]([C:13]2[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[O:15][N:14]=2)[CH:17]=[C:18]([CH3:24])[C:19]=1[O:23][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A mixture of 4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (370 mg, 1.14 mmol) and epichlorohydrine (317 mg, 3.42 mmol) in isopropanol (5 mL) and 3 N aq. NaOH (1.5 mL) is stirred at rt for 16 h. The mixture is diluted with EA, washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on prep. TLC plates with heptane:EA 3:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazole (256 mg) as white solid; LC-MS: tR=1.14 min, [M+1]+=381.18.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2/[CH:18]=C/C(O)=O)=[CH:4][CH:3]=1.[OH2:25]>C1COCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:18][OH:25])=[CH:4][CH:3]=1
Reactant: O
Reactant: COc1cnc2c(c1)cc(/C=C/C(=O)O)n2Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COc1cnc2c(c1)cc(CO)n2Cc1ccc(Cl)cc1

Procedure:
To Ethyl 1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate from step 4 (170 mg, 0.493 mmol) in THF (4 mL), was added LiA1H4 (21 mg, 0.542 mmol) and heated to reflux for 30 min. After cooling, the reaction mixture was poured into water, extracted with EtOAc (4×25 mL), the organic phase dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 40% EtOAc in hexanes to yield the title alcohol.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][CH2:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:38][CH2:39][NH:40][S:41]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=1)(=[O:43])=[O:42])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CO.Cl>O.C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:15]([CH2:38][CH2:39][NH:40][S:41]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=1)(=[O:43])=[O:42])=[C:16]2[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 94.8 %

Procedure:
A solution of ethyl 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]-amino}ethyl)-1H-indol-3-yl]propyl}benzoate (0.50 g, 0.65 mmol), LiOH (0.24 g, 10.0 mmol), methanol (5 mL), THF (5 mL) and water (5 mL) was stirred for 18 h at rt, then diluted with water (200 mL). 1 N HCl (10 mL) was added. The reaction mixture was extracted with EtOAc (2×50 mL). The organic extracts were dried over Na2SO4. The solvent is evaporated to give a white solid (0.46 g, 96%). 1H NMR (DMSO−d6): 512.80 (br.s, 1H), 7.89 (d, 2H, J=2 Hz), 7.59 (d, 1H, J=1.5 Hz), 7.53 (d, 1H, J=6 Hz), 7.48 (d, 1H, J=1.5 Hz), 7.38 (m, 9H), 7.20 (m, 5H), 6.77 (dd, 1H, J=6.9 & 1.5 Hz), 6.46 (d, 1H, J=6.9 Hz), 4.36 (s, 2H), 3.18 (m, 2H), 2.96 (m, 2H), 2.76 (m, 4H), 1.90 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.O>[CH3:25][S:26]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:3]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCN2CC[C@H](O)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCCN2CC[C@H](OS(C)(=O)=O)C2)cc1

Procedure:
(S)-3-Hydroxy-1-[3-(4-methoxyphenyl)propyl]pyrrolidine (310 mg, 1.32 mmol) was dissolved in dichloromethane (10 ml). Triethylamine (173 mg, 1.71 mmol) and methanesulfonyl chloride (196 mg, 1.71 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture (50:1) of dichloromethane and methanol. The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-[3-(4-methoxyphenyl)propyl] pyrrolidine in the form of a light yellow oil (336 mg, 81%).
Reaction SMILES: C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[CH2:18]=[C:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:34]([CH2:35][CH2:36][C@:20]12[CH3:21])[C@@H:33]1[C:28](=[CH:29][C:30](=[O:37])[CH2:31][CH2:32]1)[CH2:27][CH2:26]3.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH2:18]=[C:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:34]([CH2:35][CH2:36][C@:20]12[CH3:21])[C@@H:33]1[C:28](=[CH:29][C@@H:30]([OH:37])[CH2:31][CH2:32]1)[CH2:27][CH2:26]3
Reactant: C=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Li+]
Solvent: CCOCC
Product: C=C1CC[C@H]2[C@@H]3CCC4=C[C@@H](O)CC[C@@H]4[C@H]3CC[C@]12C
Reaction time: 4 h

Procedure:
Lithium tri-t-butoxyaluminohydride (766.6 mg, 3.015 mmol) was added to a solution of 17-methylenestr-4-en-3-one (16, 203.7 mg, 0.7533 mmol) in 10 mL of anh. ether and the reaction was stirred 4 h. See FIG. 18. Glauber's salt (3.80 g) was added and the suspension was stirred an additional ½ h. The mixture was filtered through diatomaceous earth and the residue was washed five times with 10 mL portions of ether. The combined filtrates were concentrated under reduced pressure and then subjected to preparative TLC (5% ethyl acetate/methylene chloride on silica gel GF, 1000μ thickness) to give white needles (60.2 mg. 0.221 mmol, 29%) homogeneous to TLC (Rf 0.37, 5% ethyl acetate/methylene chloride on silica gel).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH3:11])[CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].O.O1CCC[CH2:16]1>>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:16])[N:9]=[C:8]([CH3:11])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(C)nn1C
Reaction time: 2 h

Procedure:
Dissolve ethyl-3-methylpyrazole-5-carboxylate (1.0893 g, 7.07 mmol) in 10 mL tetrahydrofuran and add it dropwise to a suspension of sodium hydride (60%) (377.6 mg, 9.44 mmol) in 10 mL tetrahydrofuran. After 2 hours, quench the reaction with methyl iodide (excess) and stir for an additional 2 hours. Add water to the reaction and remove the tetrahydrofuran in vacuo. Partition the residue between ethyl acetate and brine. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to afford 950.0 mg of crude 2,5-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester. Dissolve this material (950.0 mg, 5.65 mmol) in 10 mL tetrahydrofuran and add it dropwise to a slurry of lithium aluminum hydride (220.2 mg) in 20 mL tetrahydrofuran at 0° C. After 30 minutes at this temperature, heat the reaction to reflux for 2 hours. Cool the reaction to room temperature and add 20 mL ethyl acetate to the reaction. Add 5N sodium hydroxide to the reaction until a white precipitate appears. Filter the reaction and concentrate the filtrate in vacuo. Partition the residue between ethyl acetate and water. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to afford 493.7 mg of crude (2,5-dimethyl-2H-pyrazol-3-yl)-methanol. Dissolve this crude material (493.7 mg, 3.91 mmol) in 20 mL methylene chloride and add MnO2 (1.2939 g, 14.88 mmol) to the reaction mixture. Heat the reaction mixture to reflux and allow it to stir for 16 hours. Cool the reaction and filter it through a pad of celite. Concentrate the filtrate in vacuo to afford 444.5 mg of crude product. Purify via Biotage chromatography (25% ethyl acetate/Hexanes) to afford 138.7 mg of the title compound 1H NMR (CDCl3) δ 9.81 (1H, s), 6.46 (1H, s), 3.82 (3H, s), 2.24 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][OH:13])=[CH:4][C:3]=1[Cl:14]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH:12]=[O:13])=[CH:4][C:3]=1[Cl:14]
Reactant: Nc1c(Cl)cc(CO)cc1C(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1c(Cl)cc(C=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 17.0 g (75.4 mmol) of (4-amino-3-chloro-5-trifluoromethyl-phenyl)-methanol, 100 g (1.15 mol) of manganese dioxide and 300 mL of DCM was stirred overnight at RT. The precipitate was suction filtered and the solution evaporated down i. vac. The desired product was obtained as a white solid.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC(OCC)=O.[CH2:18]([N:20](CC)CC)[CH3:19].C(N)C.[Cl-].[Na+]>C1COCC1>[CH2:18]([NH:20][C:9](=[O:11])/[CH:8]=[CH:7]/[CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)[CH3:19]
Reactant: O=C(O)/C=C/C1CC=CCC1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCOC(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCNC(=O)/C=C/C1CC=CCC1
Yield: 39 %

Procedure:
3-(3-Cyclohexenyl)-2E-propenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, ethylamine 1.5 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=39%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C:28]5([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: O[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Reactant: COC(=O)C1(C=O)CCCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](O)CC5)c34)CC2)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexanol (EXAMPLE 43, Step 2) and methyl 1-formylcyclopentanecarboxylate (Synthesis 1997, 32-34) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]=2)(=O)=O)=CC=1.[OH-].[K+].Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][C:14]=1[O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(OCCN3CCCCC3)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Oc1ccc(Br)c(OCCN2CCCCC2)c1
Yield: 102.6 %

Procedure:
4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenyl 4-methylbenzenesulfonate (24.2 g), potassium hydroxide (16.1 g), water (96 ml) and ethanol (860 ml) were heated on the steam bath for 2 h. The pH was adjusted to 4 with concentrated hydrochloric acid, then to pH 7 with solid sodium bicarbonate. After evaporation to near dryness, water (200 ml) was added and the mixture was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water, brine, dried (MgSO4) and evaporated to give an oil (16.4 g).