Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.C(=O)=O.CC(C)=O>O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([B:15]([OH:16])[OH:14])[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OB(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Magnesium turnings (1.32 g) were stirred under nitrogen for 10 mins then anhydrous tetrahydrofuran (30 ml) followed by 1-bromo-3,4-difluorobenzene (7.0 g) were added over 5 mins. The mixture was maintained at reflux for 30 mins and then allowed to cool to room temperature. A solution of tri-isopropylborate (13.65 g) in dry tetrahydrofuran (80 ml) under nitrogen was cooled to -78° (dry ice-acetone) and the preformed Grignard solution was added over 10 mins. The mixture was stirred for 2 h and then allowed to warm to room temperature over 45 mins. The reaction was quenched with hydrochloric acid (4M, 80 ml) and stirred at room temperature overnight. The solution was extracted with ethyl acetate (3×100 ml) and the combined organic solutions extracted with aqueous sodium hydroxide (1M, 4×100 ml). The combined aqueous basic solutions were acidified to pH3 (4M hydrochloric acid), extracted with ethyl acetate (3×150 ml) and the combined organic fractions washed with acidified brine (200 ml) and dried (MgSO4). Removal of the solvent gave the title compound as a white solid (2.7 g). δ (d6 -DMSO+D2O) 7.42 (dt, 1H, J=10.5 and 7.5 Hz), 7.60-7.78 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C@H:5]1[C@H:12]2[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][CH2:6]1)[OH:4].[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:15][C:16]1[C:21]([NH:1][CH2:2][C@H:3]([C@H:5]2[C@H:12]3[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]3)[CH2:7][CH2:6]2)[OH:4])=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CN)CC[C@H]2O1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)CC[C@H]2O1

Procedure:
(S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-6) (3.22 g, 15.0 mmol, 1.0 eq) was dissolved in dioxane (150 mL). 2,3-Dichloropyrazine (4.46 g, 29.9 mmol, 2 equiv) was added followed by triethylamine (8.34 mL, 59.8 mmol, 4 equiv) and the reaction mixture was heated to reflux overnight. Concentration and purification via flash chromatography on a silica gel column (ethyl acetate/hexanes) yielded desired (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-7) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.88 (dd, J=5.5, 2.7 Hz, 1H); 7.60 (d, J=2.7 Hz, 1H); 5.74 (d, J=31.9 Hz, 1H); 4.68-4.63 (m, 1H); 4.34 (t, J=5.4 Hz, 1H); 3.88 (ddd, J=14.5, 6.7, 2.5 Hz, 1H); 3.81-3.69 (m, 2H); 3.63-3.46 (m, 2H); 2.15-2.04 (m, 1H); 2.03-1.88 (m, 1H); 1.83-1.72 (m, 1H); 1.69-1.52 (m, 1H); 1.50 (d, J=13.2 Hz, 3H); 1.32 (d, J=4.5 Hz, 3H). LRMS m/z (M+H) 313.9 found, 314.1 required.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[N-:22]=[N+:23]=[N-:24].[Na+].O>CS(C)=O>[N:22]([CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1)=[N+:23]=[N-:24]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.65 g, 1.587 mmol) and sodium azide (0.114 g, 1.746 mmol) were combined in DMSO (7 mL) and stirred overnight at 25° C. Water was added to the reaction mixture to give a white precipitate. The reaction mixture was stirred for 15 min at room temperature, filtered, washed with water, and air dried to give 3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.565 g, 1.521 mmol, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (d, J=2.20 Hz, 1H), 7.50-7.63 (m, 2H), 7.31 (d, J=1.74 Hz, 1H), 4.61 (s, 2H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)(=S)C.C(OC(=O)C)(=O)C.[S:20](Cl)([Cl:23])(=O)=[O:21]>ClCCl>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][S:20]([Cl:23])=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=S)OCc1cccc(Cl)c1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=S(Cl)Cc1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a -20° C. solution of the thioester from Step G (1 mmol) in 3 mL of dichloromethane under argon are added 1 mmol acetic anhydride and 2 mmol sulfuryl chloride. The reaction is stirred for 1 hr during which time the temperature is allowed to rise to -5° C. The mixture is concentrated in vacuo and the crude product used for coupling in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:7]([C:12](=O)[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[C:21]([O:27][CH3:28])(=[O:26])[CH2:22][C:23]([CH3:25])=O.Cl.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:19][C:15]1[CH:14]=[C:13]([C:12]2[C:7]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:9]([O:10][CH3:11])[CH:8]=3)[N:6]=[C:23]([CH3:25])[C:22]=2[C:21]([O:27][CH3:28])=[O:26])[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)CC(C)=O
Reactant: COc1cc(N)c(C(=O)c2ccnc(Cl)c2)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 3,4-dimethoxy-6-(2-chloroisonicotinoyl)aniline (2.93 g), methyl acetoacetate (2.16 ml), conc. hydrochloric acid (0.1 ml) and acetic acid (30 ml) is heated under reflux for two hours. The reaction mixture is cooled to room temperature, and thereto is added an aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=9:1) to give 2-chloro-4-(6,7-dimethoxy-3-methoxycarbonyl-2-methylquinolin-4-yl)pyridine (3.0 g).
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.[CH2:7]([O:9][C:10](=[O:26])[C:11]1[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[C:13]([C:14]([N:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:12]=1)[CH3:8]>ClCCl>[CH2:7]([O:9][C:10](=[O:26])[C:11]1[CH:23]=[C:22]([CH2:24][O:25][CH:3]([CH3:4])[CH3:2])[CH:21]=[C:13]([C:14]([N:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:12]=1)[CH3:8]
Reactant: c1ccncc1
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(COC(C)C)cc(C(=O)OCC)c1
Reaction time: 0.08 h

Procedure:
Mix dichloromethane (1.8 mL), pyridine (56 μL, 0.7 mmol), and trifluomethanesulfonic anhydride (97 μL, 0.58 mmol) to a flask at −35 to −45° C. Add premixed 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (65 mg, 0.23 mmol) in dichloromethane (4 mL) dropwise at −40° C. Stir for 5 min and quench with isopropyl alcohol (2 mL). Dilute the reaction mixture with dichloromethane (10 mL), wash with water (2×10 mL), and concentrate to give the title compound and used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[CH3:16][S:17][CH2:18][CH2:19][C:20](O)=[O:21].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:2]1([NH:1][C:20](=[O:21])[CH2:19][CH2:18][S:17][CH3:16])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: CSCCC(=O)O
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CSCCC(=O)NC1(c2ccccc2Cl)CCC=CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexen-1-one (50 mg, 0.23 mmol), 3(methylthio)propanoic acid (prepared by the known base hydrolysis from the commercial methyl ester)(33 mg, 0.28 mmol), hydroxybenzotriazole (31 mg, 0.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 18 h. The reaction was partitioned between saturated bicarbonate and ethyl acetate, the organic phase was washed with brine, dried (Na2SO4), and the solvent removed by evaporation. Purification was achieved by preparative thin layer chromatography on silica gel eluting with 1:1 ethyl acetate/hexane. Isolation of the UV active band at Rf 0.4 gave 6-(2-chlorophenyl)-6-(3-(methylthio)propanoyl)amino-2-cyclohexen- 1-one (60.6 mg, 65%). The title compound was found to be active at 6μm in the CMK assay.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](N(OC)C)=[O:8])=[C:4]([Cl:13])[CH:3]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:8])[CH3:14])=[C:4]([Cl:13])[CH:3]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1sc(Br)cc1Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1sc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a stirred solution of 5-bromo-3-chloro-N-methoxy-N-methylthiophene-2-carboxamide (1 g, 3.5 mmol) in THF (10 mL) was added MeMgBr (1.1 mL, 3.5 mmol) under N2 at RT. The mixture was stirred at RT for 0.5 h and quenched by aqueous NH4Cl. The resulting solution was extracted with EtOAc. The organic layers were dried over Na2SO4, concentrated and purified by column to give 0.6 g of 1-(5-bromo-3-chlorothiophen-2-yl)ethanone. MS (M+H): 239, 241. 1H NMR (400 MHz, CDCl3): δ 6.95 (s, 1H), 2.57 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:6]([Cl:19])[N:5]=[CH:4][CH:3]=1.[CH:20](=O)[C:21]1[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C(#N)C.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:19][C:6]1[C:7]2[C:8](=[O:9])[N:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[NH:1][C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: Nc1ccnc(Cl)c1C(=O)NCCc1ccccc1
Reactant: COc1ccccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1C1Nc2ccnc(Cl)c2C(=O)N1CCc1ccccc1
Temperature: 20 °C
Yield: 93.6 %

Procedure:
To a solution of 4-amino-2-chloro-N-phenethyl-nicotinamide (808 mg, 2.93 mmol) in 8 mL of acetonitrile at 20° C. was added 0-anisaldehyde (399 mg, 2.93 mmol) and a catalytic amount of p-toluenesulfonic acid (10 mg, 0.059 mmol). The resulting solution was then heated to reflux under Dean-Stark trap for 12 hours. The reaction mixture was cooled to 20° C. and diluted with ethyl acetate. The mixture was then partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed 3× with NaHCO3, 1× with water, 1× with brine and then dried over anhydrous Na2SO4, filtered and evaporated to dryness. 1.08 g of pale yellow sticky solid was obtained. The resulting crude material was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CS(C)=O.O>[CH2:3]([O:7][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution prepared by diluting 8.6 g (2.0 eq.) of 60% sodium hydride with 200 mL of dimethylsulfoxide, 16.0 g (2.0 eq.) of 1-butanol was added, and the mixture was allowed to react for one hour at 60° C. The reaction liquid was cooled to 30° C., and then a liquid containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and was concentrated to dryness under reduced pressure. The obtained residue was purified on a silica gel column, to obtain 20.3 g of 4-butoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: [Cl:1][C:2]1([Cl:12])[C:5]2([CH2:10][CH2:9]O[CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11].[CH2:13]=C1CCCCC1.ClC(Cl)(Cl)C(Cl)=O>CCOCC>[Cl:1][C:2]1([Cl:12])[C:5]2([CH2:10][CH2:9][CH2:13][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11]
Reactant: O=C1CC2(CCOCC2)C1(Cl)Cl
Reactant: C=C1CCCCC1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1CC2(CCCCC2)C1(Cl)Cl
Reaction time: 3 h
Yield: 97.2 %

Procedure:
This was prepared according to a literature procedure (Tetrahedron 1993, 49(36), 8159). Activated zinc (5.00 g; 76.5 mmol) (prepared according to Example 150, Step B) and methylenecyclohexane (2.40 g; 25.0 mmol) in dry ether (100 mL) under nitrogen were mixed in a 250 mL 3-neck flask with an addition funnel and condenser attached. The mixture was placed in a sonic bath at 25° C. Trichloroacetyl chloride (5.91 g; 32.5 mmol) in dry ether (50 mL) was added dropwise as the solution was sonicated. The sonication was continued for 3 hours. The mixture was filtered through Celite® and the solution was washed with saturated aqueous ammonium chloride solution (50 mL) and aqueous sodium bicarbonate solution (50 mL). The solution was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was passed through a plug of silica gel using ether. The filtrate was evaporated to give the product as a yellow oil (5.03 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)=[O:41]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Reactant: O=C(Cl)CCCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)CCCCCl)CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(trans-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (400 mg, 1.065 mmol) was dissolved in dichloromethane (6 ml) and triethylamine (445 μl, 3.20 mmol) was added followed by dropwise addition of 5-chlorovaleryl chloride (151 μl, 1.172 mmol). The reaction was stirred under nitrogen at room temperature for 4 h. The reaction mixture was quenched with sat. sodium hydrogen carbonate solution (10 ml) and extracted with dichloromethane (3×15 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography, eluting with 95:5 dichloromethane/methanol, clean fractions were combined and the solvent was removed under reduced pressure to obtain the title compound (220 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][N:24]([CH3:36])[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=3)[C:25]([N:24]([CH3:36])[CH3:23])=[O:26])[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Product: CC(On1ccc2ncc(-c3cccc(C(=O)N(C)C)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and [3-(dimethylcarbamoyl)phenyl]boronic acid according to the procedure described in example 4.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][OH:24]>>[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][O:24][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cccc(F)c1F
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cccc(F)c3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3difluorophenyl)methanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13].N1C=CC=CC=1.Cl[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[CH3:30][O:29][C:27](=[O:28])[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[CH:17]=1
Reactant: COc1ccc(CO)cc1Oc1cccc(C#N)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)OCc1ccc(OC)c(Oc2cccc(C#N)c2)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
In an 40 mL vial equipped with a stir bar was placed (17) (940 mg, 3.68 mmol), anhydrous tetrahydrofuran (18 mL) and pyridine (774 μL, 9.57 mmol). The resulting clear solution was cooled in an ice water bath for 10 minutes and then methyl chloroformate (626 μL, 8.10 mmol) was added and reaction mixture was slowly warmed to room temperature and reacted for 16 hours. The reaction was concentrated by a stream of nitrogen followed by treatment with water (50 mL) and 1M HCl (40 mL). The aqueous portion was extracted with dichloromethane (3×50 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated to produce 1.09 g (95% yield) of (18) as a colorless, viscous oil.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O-].[Na+].[Na].CI>CO>[CH3:11][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2o1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CO
Product: CSc1nc2ccccc2o1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2-Mercaptobenzoxazole (6.0 g, 0.04 mole) was slowly added, with stirring, to a solution of sodium methoxide prepared by the addition of sodium (1.0 g) to anhydrous methanol (150 ml). Methyl iodide (5 ml) was added and the mixture was stirred at a temperature of 50° C. for a period of 3 hours and allowed to stand overnight at room temperature. The methanol was removed by distillation under reduced pressure and the solid residue was triturated with ice water and the insoluble material was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous magnesium sulfate and the solvent removed to give 2-(methylthio)benoxazole (5.8 g) as a brown oil.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:37][C:34]2[NH:35][N:36]=[C:32]([O:31][CH2:30][C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:33]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(N2CCN3CCCC3C2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN5CCCC5C4)cc3)[nH]n2)cc(OC)c1
Yield: 27 %

Procedure:
4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl]methoxy]-2H-pyrazol-3-yl)benzamide was prepared following the procedure as for Example 159, but starting from methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (0.25 g, 0.96 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.239 g, 0.96 mmol) and 2M trimethylaluminium in toluene (1.2 ml, 2.4 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.124 g, 27%) as a white solid.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:17]=4)[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>C(OCC)C.C(=O)(O)[O-].[Na+]>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]4=[O:47])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)[C@@H]2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of 3β-benzoyloxy-4,4-dimethyl-5α-cholest-8,14-diene (5.0 g, 10.2 mmol) in diethyl ether solution (300 mL) and 0.5 M aqueous sodium bicarbonate (300 mL) was added meta-chloro-perbenzoic acid (2.44 g, 11.3 mmol) (Aldrich). After 30 min, the ether fraction was separated from the sodium bicarbonate layer and the aqueous fraction was repeatedly extracted with diethyl ether (5×500 mL). The organic fractions were combined, washed with brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to about 150 ml. This ether solution of 38a was promptly cooled (0°) and treated dropwise with boron trifluoride etherate (26 mL, 22.5 mmol (Aldrich). After 30 min, the reaction was quenched with ice water (200 mL) and the aqueous phase was reextracted with ether (3×100 mL). The combined ether fractions were extracted with saturated sodium bicarbonate solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from isopropanol (75 mL) to afford 4.10 g of 3β-benzoyloxy-4,4-dimethyl-5α,14β-cholest-8-en-15-one (Compound 40a) in 75% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[C:13]([C:17]3[N:18]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[N:19]=[C:20]4[C:25]=3[CH:24]=[CH:23][CH:22]=[C:21]4[C:26]([F:29])([F:28])[F:27])[CH:14]=[CH:15][CH:16]=1)=[CH:5]2.[H-].[Na+].I[CH3:43]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:43])[C:6]([C:11]1[CH:12]=[C:13]([C:17]3[N:18]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[N:19]=[C:20]4[C:25]=3[CH:24]=[CH:23][CH:22]=[C:21]4[C:26]([F:27])([F:28])[F:29])[CH:14]=[CH:15][CH:16]=1)=[CH:5]2
Reactant: CI
Reactant: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2cccc(-c3cc4cc(F)ccc4[nH]3)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)cc2cc(F)ccc21
Reaction time: 0.33 h
Yield: 32.3 %

Procedure:
A solution of 3-[3-(5-fluoro-1H-indol-2-yl)phenyl]-2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazole (0.03 g, 0.056 mmol) in 2 mL THF was treated with sodium hydride (0.004 g, 0.1 mmol, 60% in oil). The reaction mixture was stirred for 20 minutes and treated with iodomethane (0.007 mL, 0.1 mmol). Stirring was continued for 1 hour. The reaction mixture was concentrated and purified by normal phase HPLC (silica, hexane-EtOAC, 19:1) to give 0.01 g of product as a white solid.