Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[CH:23]=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][Mg]Br.CCOCC.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[CH:23]([OH:24])[CH3:25])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=CC1CCCC(c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)C1CCCC(c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of the product of step 1 (232 mg; 0.64 mmol) in THF (6 mL) at 0° C. was added methyl magnesium bromide solution 3 N in Et2O (0.27 mL; 0.83 mmol) and the reaction was allowed to warm to room temperature for 1 h. The mixture was poured into saturated ammonium chloride, extracted with DCM, and dried over Na2SO4. After concentration of the solvents, the residue was purified by chromatography over silica gel (eluting Hexanes/EtOAc 8:2) to give 240 mg (100%) of 1-[1-(4-chloro-benzenesulfonyl)-6-phenyl-piperidin-2-yl]-ethanol as a ca 4.5:1 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N+:13]([O-])[CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:12]1[C:11]2[S:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:17][C:16]=2[C:15]([F:18])=[CH:14][N:13]=1
Reactant: [O-][n+]1cc(F)c2nc(-c3c(F)cccc3Cl)sc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cccc(Cl)c1-c1nc2c(F)cnc(Cl)c2s1
Temperature: 25 °C
Yield: 22 %

Procedure:
A stirred solution of 2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine 5-oxide (3.0 g, 10.5 mmol) in phosphoryl chloride (50 mL) was heated at 110° C. for 45 minutes. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between a potassium carbonate saturated solution (100 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with water (100 mL), dried and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 10% diethyl ether in pentane to afford the title compound as a colourless solid (0.71 g, 22% yield). 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1H), 7.56-7.46 (m, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[C:15]2[O:14][C:13]3[CH2:16][CH2:17][CH2:18][CH:19](O)[C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[C:15]2[O:14][C:13]3[CH2:16][CH2:17][CH:18]=[CH:19][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(Nc1cccc2c3c(oc12)CCCC3O)c1c(Cl)cccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2c3c(oc12)CCC=C3)c1c(Cl)cccc1Cl
Yield: 36.3 %

Procedure:
A mixture of 6-(2,6-dichlorobenzoylamino)-1-hydroxy-1,2,3,4-tetrahydrodibenzofuran (500 mg), methanesulfonyl chloride (880 mg) and triethylamine (1.19 g) in dichloromethane was refluxed for 4 hours. The mixture was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of 2-propanol and water to give 6-(2,6-dichlorobenzoylamino)-3,4-dihydrodibenzofuran (173 mg).
Reaction SMILES: CS(OCCCOC1C=CC=C(C2N(C3C=CC=C(Cl)C=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=1)(=O)=O.CN.[CH:38]([OH:40])=[O:39].[Cl:41][C:42]1[CH:43]=[C:44]([N:48]2[C:52]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH2:61][CH2:62][N:63](C)[CH3:64])[CH:54]=3)=[CH:51][C:50]([C:66]([N:68]3[CH2:72][C:71](=[O:73])[NH:70][CH2:69]3)=[O:67])=[N:49]2)[CH:45]=[CH:46][CH:47]=1>O1CCCC1>[CH:38]([OH:40])=[O:39].[Cl:41][C:42]1[CH:43]=[C:44]([N:48]2[C:52]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH2:61][CH2:62][NH:63][CH3:64])[CH:54]=3)=[CH:51][C:50]([C:66]([N:68]3[CH2:72][C:71](=[O:73])[NH:70][CH2:69]3)=[O:67])=[N:49]2)[CH:45]=[CH:46][CH:47]=1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN
Agent: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: CNCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and methylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 46 mg (44% of theory) of the title compound are obtained.
Reaction SMILES: S(O)(=O)(=O)C.O[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][C:18]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH2:29][CH2:28]1
Reactant: O=C1CCC(CCO)CC1
Reactant: Fc1ccc(C(F)(F)F)cc1N1CCNCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CCC(CCN2CCN(c3cc(C(F)(F)F)ccc3F)CC2)CC1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of 11.6 g (52.66 mmol) of 4-(2-hydroxyethyl)cyclohexanone mesylate, of 13.72 g (55.27 mmol) of 1-(2-fluoro-5-trifluoromethylphenyl)piperazine and 8.37 g (60.65 mmol) of potassium carbonate in 220 mL of acetonitrile is refluxed overnight, then cooled back to room temperature. Water (80 mL) is added. Organics are extracted with ethyl acetate (100 mL). The organic phase is washed with water (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to give a crude product. Purification by column chromatography over 320 g of silica gel (eluant dichloromethane/methanol 98/2 to 96/4) yields 15.86 g of 4-(2-fluoro-5-trifluoromethylphenyl)-1-[2-(4-oxocyclohexyl)ethyl]piperazine melting at 75-76° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[O:9][CH2:8]1.C([Sn](CCCC)(Cl)Cl)CCC.C1([SiH3])C=CC=CC=1.Cl>COCCOC.C(Cl)Cl.O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:1]3[CH2:5][CH2:4][C:3]([OH:6])=[CH:2]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: OC1CCNC1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: Cl
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: OC1=CN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
A solution of pyrrolidin-3-ol (0.539 g, 6.2 mmol) in ethyleneglycol dimethylether (DME) (5 mL) was treated with benzo[d][1,3]dioxole-5-carbaldehyde (272) (1.08 g, 7.2 mmol) and dibutyldichlorostannane (0.71 g, 2.3 mmol). After the suspension was stirred for 15 min at room temperature, phenylsilane (1.0 mL, 8.6 mmol) was added neat and the mixture was stirred for 18 h. The reaction mixture was diluted with DCM (50 mL), treated with 1N HCl (13 mL) and stirred for 30 min followed by dilution with H2O (50 mL) and DCM (50 mL). The aqueous layer was collected, basified with solid potassium carbonate (K2CO3), extracted with DCM, dried over MgSO4, filtered and concentrated to provide title compound 273 (0.82 g, 60% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[CH2:7]1>CC(O)C.[Ni]>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([OH:13])[CH2:7]1
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Agent: [Ni]
Solvent: CC(C)O
Product: COC(C)(C)CCC1CC(C)CC(O)C1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A mixture of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohex-5-en-1-one (1.0 g, 0.0048 mol) in 2-propanol (40 mL) and Raney nickel (about 0.1 g) was shaken under hydrogen (37 psi) at 25~C. for 16 hours. Subsequent workup yielded 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-ol (0.78 g) as a mixture of four diastereoisomers (ratio 8.1:20.6:57.8:7.8).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[CH3:14].[C:15](=[O:17])=[O:16]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:15]([OH:17])=[O:16])=[C:9]([F:13])[C:8]=1[CH3:14]
Reactant: O=C=O
Reactant: Cc1c(F)cccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(Cl)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
n-Butyllithium (2.5M in hexane, 100 ml) was added to a cooled solution of 2-chloro-6-fluorotoluene (36.1 g) in dry tetrahydrofuran while maintaining the temperature below -60° C. The mixture was stirred at -78° C. overnight then poured onto solid carbon dioxide pellets. The mixture was stirred and allowed to warm to room temperature. It was acidified to pH 1 and extracted with ether. The organic layer was extracted into aqueous sodium hydroxide solution (2M) and water. The combined aqueous extracts were acidified to pH 1 and the solid formed was filtered off and washed with water and n-hexane to give 4-chloro-2-fluoro-3-methylbenzoic acid (40.35 g) as a white solid, NMR (DMSO-d6) 2.3(d,3H), 7.4(d, 1H) 7.7(t, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][NH:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[C:31]([N:10]3[C:5]4[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:8][CH2:9]3)[N:30]=[CH:29][N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Reactant: Clc1ccc2c(n1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4nc(Cl)ccc43)ncn2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
20a (36 mg, 0.23 mmol) was dissolved in DMF (1.5 mL) with NaH (60% suspension, 9.6 mg, 0.24 mmol). 3a (75 mg, 0.24 mmol) was added slowly. The mixture was stirred at 90° C. for 8 h then cooled down to room temperature, diluted with ethyl acetate and washed with saturated NaHCO3. The organic layer was isolated, dried, filtered and evaporated. The residue was purified by preparative HPLC to afford 20-1, LCMS 432.1 (MH+). tR=5.21 (Method 5). EC50: 751 nM.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[OH:9].[CH:12](OCC)(OCC)OCC>>[CH3:10][N:5]1[CH:6]=[CH:7][C:8]2[O:9][CH:12]=[N:2][C:3]=2[C:4]1=[O:11]
Reactant: CCOC(OCC)OCC
Reactant: Cn1ccc(O)c(N)c1=O
Agent: Cl
Product: Cn1ccc2ocnc2c1=O
Yield: 30 %

Procedure:
The title compound of step 3 (500 mg, 2.8 mmol) in triethyl orthoformate (10 mL) was heated to reflux for 5 h. The mixture was concentrated in vacuo at 55° C. and purified by silica gel chromatography (PE: EA=1:1) to give the title compound (130 mg, yield: 30%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)CCl.ON1C2N=CC=CC=2N=N1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:12]([O:11][C:5]1[CH:4]=[C:3]([CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:2]([Br:1])=[CH:10][C:6]=1[C:7]([NH:44][C:43]1[CH:45]=[CH:46][CH:47]=[C:41]([Cl:40])[CH:42]=1)=[O:8])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Cl)c1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-Bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in D7) (1 g, 2.461 mmol) in N,N-Dimethylformamide (DMF) (20 mL) was added EDC (0.849 g, 4.43 mmol), 1-hydroxy-7-azabenzotriazole (0.503 g, 3.69 mmol), 3-chloroaniline (0.504 mL, 4.92 mmol), DIPEA (0.860 mL, 4.92 mmol) and the mixture was stirred at room temperature overnight. The DMF was removed on a buchi under reduced pressure, the residue was taken up into DCM (50 ml) and washed with water (2×20 ml). The DCM was evaporated on a buchi under reduced pressure and the residue was purified using the Companion eluting with 0-50% ethyl acetate/cyclohexane to give the title compound as pale yellow oil which solidified on standing. Yield: 400 mg
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:41])[C@@H:15]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH:38]2[CH2:40][CH2:39]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:16][C@H]1CCN(C(OC(C)(C)C)=O)C1)C1C=CC=CC=1.[OH-].[Li+].OO.S([O-])([O-])=[O:47].[Na+].[Na+]>O1CCCC1.O>[CH:38]1([S:35]([C:32]2[CH:31]=[CH:30][C:29]([CH:15]([CH3:16])[C:14]([OH:41])=[O:47])=[CH:34][CH:33]=2)(=[O:36])=[O:37])[CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
(S)-tert-Butyl 3-((R)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-oxopropyl)pyrrolidine-1-carboxylate (1.38 g, 2.36 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (3: 1, 12.8 mL), and an aqueous solution (1.9 mL) consisting of lithium hydroxide (113 mg, 4.72 mmol) and a hydrogen peroxide solution (30%, 1.10 mL) was added to the above obtained solution under ice-cold condition. The obtained mixture was stirred for 1 hour. Thereafter, an aqueous solution of sodium sulfite was added to the reaction solution, and the mixed solution was then washed with diethyl ether. The reaction solution was neutralized with a 0.5 M aqueous solution of hydrochloric acid, and was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo, so as to obtain (R)-3-((S)-1-tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(4-(cyclopropylsulfonyl)phenyl)propanoic acid (910 mg, 85%) in the form of a white solid.
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-methoxyaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 85%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:26]([C@@H:32]([OH:34])[CH3:33])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:10][CH2:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([O:16]C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O.CCOC(C)=O.Cl>[CH2:1]([O:8][C@H:9]([C@H:26]([C@@H:32]([OH:34])[CH3:33])[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:10][CH2:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCC[C@H](OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC[C@@H]([C@H](C)O)[C@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To a solution of (2S,6S,7S)-methyl 6-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-7-((S)-1-hydroxyethyl)-10-methylundecanoate (700 mg, 1.46 mmol) in THF (9.73 mL) and H2O (4.87 mL) was added LiOH.H2O (184 mg, 4.38 mmol), and the reaction was stirred at room temperature for 4 h. The reaction was diluted with EtOAc (15 mL) and 0.2 M HCl (15 mL), the phases were separated, and the aq. phase was further extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (8 mL), dried over Na2SO4, filtered, and concentrated to dryness to afford the title compound (600 mg, 1.289 mmol, 88%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.31-7.21 (m, 5H), 5.63 (s, 1H), 4.57-4.45 (m, 2H), 3.89-3.74 (m, 2H), 3.59-3.52 (m, 1H), 1.92-1.63 (m, 2H), 1.63-0.94 (m, 22H), 0.83 (app dd, J=6.6, 2.1 Hz, 6H) (carboxylic acid and alcohol peaks are very broad (not listed)); 13C NMR (101 MHz, CDCl3) δ 179.67, 156.76, 138.11, 128.33, 128.05, 127.64, 80.99, 79.27, 71.52, 68.79, 56.30, 46.67, 37.81, 32.72, 29.56, 28.48, 28.27, 25.15, 23.19, 22.63, 22.50, 22.21; ESIMS m/z 464 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Br:8].[CH2:13]([Zn]CC)C>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][C@H:10]2[CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: OCC=Cc1ccc(Br)c(Br)c1
Reactant: CC[Zn]CC
Solvent: CCCCCC
Product: OC[C@@H]1C[C@H]1c1ccc(Br)c(Br)c1

Procedure:
The above alcohol (2 g) was treated with diethyl zinc (35 ml) and dioodomethyl 15.52 ml) in hexane in the usual manner to give (±)-[Trans-2-(3,4-dibromophenyl)cyclopropyl]methanol (1.3 g). NMR 1H: 7.40(1H,d), 7.30(1H,d), 6.76(1H,dd), 3.53(2H,d), 2.30(1H,s), 1.68(1H,m), 1.33(1H,m), 0.87(2H,m).
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[C:12](=[O:13])[CH:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[O:10][C:9]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][S:36]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47]O)=[CH:42][CH:41]=1)(=[O:38])=[O:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:29]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:8]2[C:12](=[O:13])[CH:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:47][CH2:46][C:43]4[CH:42]=[CH:41][C:40]([O:39][S:36]([CH3:35])(=[O:37])=[O:38])=[CH:45][CH:44]=4)=[CH:17][CH:16]=3)[O:10][C:9]2=[O:22])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1OC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3OC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Reaction time: 3 h
Yield: 53.3 %

Procedure:
0.28 g (0.623 mmole) 3-triphenylmethyl-5-([4-hydroxyphenyl]methyl)oxazolidine-2,4-dione was under argon atmosphere added to a cooled solution of 0.148 g (0.685 mmole) 2-[4-(methylsulfonyloxy)phenyl]-1-ethanol, 0.173 g (0.685 mmole) 1,1′-(azodicarbonyl)-dipiperidine and 0.18 g (0.685 mmole) triphenylphosphine in 6 ml dichloromethane. After stirring for 3 hours the reaction mixture was filtered and the crude product was purified by chromatography on silica gel using heptane:ethyl acetate (2:2) as eluent to give 0.215 g (yield 53%) of 3-triphenylmethyl-5-([4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl]methyl)oxazolidine-2,4-dione.
Reaction SMILES: [CH:1]([CH:3]([CH:6]([CH3:8])[CH3:7])[C:4]#[N:5])=O.O.[NH2:10][NH2:11].C(O)(=O)C>CCO>[CH:6]([C:3]1[CH:1]=[N:10][NH:11][C:4]=1[NH2:5])([CH3:8])[CH3:7]
Reactant: CC(C)C(C#N)C=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)c1cn[nH]c1N

Procedure:
Next, 2-formyl-3-methylbutanenitrile 2 (9.97 g, 90 mmol), hydrazine hydrate (5.68 mL, 117 mmol) and glacial acetic acid (9.02 mL, 158 mmol) were dissolved in EtOH (250 mL) and the mixture was heated under reflux for 16 h. The reaction was then concentrated to approximately one third of the original volume. The residue was diluted with sat. NaHCO3 (100 mL) and the product extracted with CH2Cl2 (3×100 mL). The combined organic fractions were washed with brine, dried over MgSO4 and the solvent was removed in vacuum. Crude 4-isopropyl-1H-pyrazol-5-amine (3) was obtained as a yellow oil (7.17 g, 64%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([C:10](=[O:15])N(OC)C)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH3:9])[C:10](=[O:15])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
In a round-bottomed flask, [(R)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (3.00 g, 12.9 mmol) was dissolved in THF (100 ml). The solution was cooled to −16° C. (NaCl/ice bath) and methylmagnesium bromide (3.0 M in diethyl ether, 12.0 ml, 36.0 mmol) was added dropwise over 20 min. After the addition, the reaction mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was cooled to 0° C., quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 2.21 g (91%) of ((R)-1-methyl-2-oxo-propyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([OH:21])=O)=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(N(CC)CC)C>[O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([NH:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:21])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 43.6 %

Procedure:
To a solution of 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (150 mg) in DMF (2 mL) were added HATU (230 mg) and triethylamine (0.091 mL), and the mixture was stirred at room temperature for 2 min. To the reaction mixture was added aniline (51.7 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (82 mg).
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[NH2:21][C:19]1[S:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:18]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)c1ccc(Cl)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of ethyl 2-bromo-3-(2,4-dichlorophenyl)-3-oxopropanoate (5.14 g, 15.1 mmol) in ethanol (90 mL) was added thiourea (1.26 g, 16.6 mmol) and the solution was stirred at reflux for 2 hours. The reaction was allowed to cool to room temperature, then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (4.79 g, 99%). LCMS: (AA) ES+, 319. 1H NMR (300 MHz, d1-chloroform) δ: 8.11 (br s, 2H), 7.52-7.33 (m, 3H), 4.24-4.16 (m, 2H), 1.23-1.17 (m, 3H).