Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].Cl.[C:20](=O)(O)[O-].[Na+]>CO>[CH3:20][O:17][C:16](=[O:18])[C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)phenylalanine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, driedover MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)phenylalanine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>S(Cl)(Cl)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(F)ccc3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3cc(F)ccc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-(8-Fluoro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (1 g, 2.9 mmol) was dissolved in thionyl chloride (10 mL) and the solution was stirred for 2 h. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in N-methyl-2-pyrrolidone (6 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (1.7 g, 31 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5% MeOH-DCM. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.85 (d, 2H), 8.40 (d, 2H), 7.80 (s, 1H), 7.30 (m, 2H), 7.05 (m, 1H), 4.75 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.30 (m, 2H), 3.18 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[CH:8][CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=2[O:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu].C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[CH:8][CH:9]=[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:5]=2[O:4][CH:3]=1
Reactant: Cc1c(C(=O)O)oc2c(C(C)(C)C)ccc(O)c12
Agent: [Cu]
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: Cc1coc2c(C(C)(C)C)ccc(O)c12
Temperature: 210 °C

Procedure:
A mixture of 3-methyl-4-hydroxy-7-tert-butylbenzofuran-2-carboxylic acid (0.250 g, 1.0 mmol), quinoline (0.75 mL), and copper powder (0.064 g, 1.0 mmol) was heated to 210° C. until gas evolution ceased (about 10 minutes) and then poured into 2N HCl (15 mL). Carbon tetrachloride (15 mL) was added and the biphasic mixture was filtered through celite. The layers were separated and the aqueous layer extracted with an additional portion of carbon tetrachloride (15 mL). The combined extracts were dried (Na2SO4) and concentrated. Flash chromatography using 10% ethyl acetate in hexane as eluant afforded 3-methyl-4-hydroxy-7-tert-butylbenzofuran, compound 10a. Recrystallization from hexane provided analytically pure material. 1H NMR d 1.46 (9H, s), 2.43 (3H, s), 6.49 (1H, d, J=8 Hz), 6.98 (1H, d, J=8 Hz), 7.36 (1H, s).
Reaction SMILES: [Na+].[F:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][S:11]([O-])(=[O:13])=[O:12])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>CN(C)C=O.C(OCC)C>[F:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][S:11]([Cl:19])(=[O:13])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CCCOc1ccc(F)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCCOc1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-fluorophenol (5.0 g, 44.6 mmol) in 50 mL of toluene was added sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.6 mmol) at ambient temperature (22° C.). After 20 minutes, a solution of 1,3-propane sulfone (3.9 mL, 44.6 mmol) in toluene was added slowly and the mixture was stirred for 16 hours. The reaction was quenched by the addition of methanol and the mixture was concentrated in vacuo to an off-white solid. This solid was suspended in ethyl acetate, filtered, and the solids were collected and dried to give 10.9 g of 3-(4-fluorophenoxy)-propane-1-sulfonic acid sodium salt as an off-white powder. A stirred solution of 3-(4-fluorophenoxy)-propane-1-sulfonic acid sodium salt (2.0 g, 7.8 mmol) in 10 mL of thionyl chloride and one drops of dimethylformamide was heated at reflux for 16 hours. The mixture was then cooled to 0° C., diluted with 25 mL of diethyl ether, and the reaction was quenched by the slow addition of water. The organic layer was removed and the aqueous layer was extracted with 25 mL of diethyl ether. The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration gave 1.75 g of 3-(4-fluoro-phenoxy)-propane-1-sulfonyl chloride as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 6.96-7.00 (m, 2 H), 6.80-6.84 (m, 2 H), 4.10 (t, 2 H, J=5.5 Hz), 3.91 (t, 2 H, J=7.5 Hz) 2.47-2.54 (m, 2 H).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=O.[CH3:7][C:8]1([CH3:37])[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][N:12]=[C:11]([N:18]3[CH2:24][C:23]4[CH:25]=[C:26]([C:29]5[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[N:33][CH:34]=5)[CH:27]=[CH:28][C:22]=4[O:21][CH2:20][CH2:19]3)[C:10]=2[CH2:9]1>>[F:1][CH:2]([F:6])[C:3]1[NH:35][C:32]2=[N:33][CH:34]=[C:29]([C:26]3[CH:27]=[CH:28][C:22]4[O:21][CH2:20][CH2:19][N:18]([C:11]5[C:10]6[CH2:9][C:8]([CH3:37])([CH3:7])[CH2:17][CH2:16][C:15]=6[N:14]=[CH:13][N:12]=5)[CH2:24][C:23]=4[CH:25]=3)[CH:30]=[C:31]2[N:36]=1
Reactant: O=C(O)C(F)F
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6[nH]c(C(F)F)nc6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 4 by omitting step 3, and using difluoroacetic acid and 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine in step 4. 1H NMR (400 MHz, Methanol-d4): 8.70 (br, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 7.64 (s, 1H), 7.55 (d, 1H), 7.12 (d, 1H), 7.05 (t, 1H), 4.63 (s, 2H), 4.37 (m, 2H), 3.95 (m, 2H), 2.79 (t, 2H), 2.49 (s, 2H), 1.66 (t, 2H), 0.88 (s, 6H); MS (EI) for C26H26F2N6O: 477 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([OH:20])[CH:18]=[CH2:19]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([O:20][CH2:17][CH:18]=[CH2:19])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: C=CCO
Reactant: COc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCOc1nc(Cl)ncc1OC
Temperature: 70 °C
Yield: 99.7 %

Procedure:
A mixture of 2,4-dichloro-5-methoxypyrimidine (85 g, 475 mmol), and K2CO3 (78.8 g, 570 mmol) in allyl alcohol (320 mL, 4.75 mol) was heated to 70° C. for 5 h before being cooled to r.t. and diluted with DCM, filtered through Celite (DCM wash) and concentrated to give 95.0 g (99.7%) of 2-chloro-5-methoxy-4-(prop-2-en-1-yloxy)pyrimidine. 1H-NMR (CDCl3, 300 MHz) δ 7.85 (s, 1H), 6.09-5.99 (m, 1H), 5.43-5.38 (m, 1H), 5.31-5.27 (m, 1H), 4.91 (m, 2H), 3.87 (s, 3H). MS (ESI) m/z (M+H)+ 201.0.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[Br:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[CH:14][CH:13]=1
Reactant: COC(=O)CCCC(=O)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCCC(O)c1ccc(Br)cc1
Yield: 80.6 %

Procedure:
Using the procedure described in Preparation 3, 5-(4-bromophenyl)-5-oxopentanoic acid methyl ester (12.8 g, 45 mmol) (Preparation 12) was reduced with LiAlH4 (3.4 g, 90 mmol) to yield 1-(4-bromophenyl)-pentane-1,5-diol (9.4 g) as a yellow oil. 1H NMR (CDCl3): 7.42 (2H, d, J=8.3 Hz), 7.15 (2H, d, J=8.3 Hz), 4.56 (1H, m), 3.63 (1H, br s), 3.45-3.6 (2H, m), 2.96 (1H, br s), 1.25-1.9 (6H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[N:2]1.ClCCl.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:17](=[O:18])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8][CH:7]=2)=[N:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(-c2ccon2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccon2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
4-Isoxazol-3-ylphenylamine (Intermediate 5, 4 g, 24.69 mmol) was added to dichloromethane (20 ml) followed by pyridine (4.6 ml). The solution was cooled to 0° C. and benzyl chloroformate (5.27 ml, 37.02 mmol) was added drop wise. The solution was allowed to stir for 2 hours at room temperature and then concentrated under vacuum. The residue was added to 30 ml of 1:1 hexane:EtOAc mixture. The crystals were collected by filtration to yield the product (2.26 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]1[CH2:15][NH:14][CH2:13]1.Cl.[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2([CH2:32][C:31]3[C:26](=[N:27][CH:28]=[C:29](/[CH:33]=[CH:34]/[C:35](O)=[O:36])[CH:30]=3)[NH:25][C:24]2=[O:38])[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:17][N:18]1[CH2:19][CH2:20][C:21]2([CH2:32][C:31]3[C:26](=[N:27][CH:28]=[C:29](/[CH:33]=[CH:34]/[C:35]([N:14]4[CH2:13][CH:12]([C:4]5[O:5][C:6]6[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=6[C:3]=5[CH3:2])[CH2:15]4)=[O:36])[CH:30]=3)[NH:25][C:24]2=[O:38])[CH2:22][CH2:23]1
Reactant: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Reactant: Cc1c(C2CNC2)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C2CN(C(=O)/C=C/c3cnc4c(c3)CC3(CCN(C)CC3)C(=O)N4)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.7 %

Procedure:
To a solution of 3-(3-methylbenzofuran-2-yl)azetidine hydrochloride (21.7 mg, 0.097 mmol) and (E)-3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid hydrochloride (22.0 mg, 0.065 mmol) in DMF (3 mL) were added EDCI.HCl (18.9 mg, 0.099 mmol), HOAt (13.9 mg, 0.102 mmol) and N,N-diisopropylethylamine (57 μL, 0.333 mmol). The reaction was stirred at rt for 20 h., after which the mixture was partitioned between DCM and H2O. The layers were separated and the aqueous layer extracted with DCM (3×). The combined organic layers were washed with brine (3×), dried over Na2SO4 and concentrated and the residue was purified by flash chromatography (DCM/MeOH, 5%→20%). The product (10.6 mg, 35%) was obtained as a white powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[S:11][CH:12]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:7][CH2:6][N:25]3[CH2:30][CH2:29][N:28]([CH2:6][CH2:7][C:8]4[N:9]=[C:10]([C:13]5[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=5)[S:11][CH:12]=4)[CH2:27][CH2:26]3)[N:9]=2)[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: COc1cc(-c2nc(CCOS(C)(=O)=O)cs2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2nc(CCN3CCN(CCc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-(2-Methanesulfonyloxyethyl)-2-(3,4,5-trimethoxy-phenyl)thiazole (164 mg) and piperazine (17 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1cc(O)ccc1C=O
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-benzaldehyde (Intermediate 146, 880.0 mg, 3.17 mmols) in 6 mL THF at 0° C. was added tetrabutylammonium fluoride (1.66 g, 6.33 mmols; 6.3 mL of a 1M solution in THF). The pale-yellow solution was stirred for 30 minutes and quenched by the addition of ice cold H2O. The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (20% EtOAc-hexanes) afforded 500.0 mg (96%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:4]1[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=[C:3]1[CH2:1][CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc(CC)[nH]c1C(=O)OCC
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1nc(CC)n(Cc2ccccc2)c1C(=O)OCC

Procedure:
Following a procedure similar to that described in Preparation42(i), 4.00 g of diethyl 2-ethylimidazole-4,5-dicarboxylate were benzylated, using 2.20 ml of benzyl bromide. The product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 5.19 g of the title compound as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.C[N:36](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:36])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a mixture of 0.050 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.41 g), 1 mL of dimethylformamide and 0.0418 g (0.11 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) was added 0.016 g (0.3 mmole) of ammonium chloride and 0.052 mL (0.3 mmole) of ethyldiisopropylamine. The mixture was stirred at ambient temperature for 1 hour. The solid was removed by filtration and the filtrate was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 20:80-100:0) to give 0.032 g of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.41) as a white powder. MH+/Z=496
Reaction SMILES: [CH3:1][C@@H:2]([CH2:9][CH3:10])[CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[Li]CCCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:1][C@@H:2]([CH2:9][CH3:10])[CH2:3][C:4]1[O:5][C:6]([Sn:17]([CH3:19])([CH3:18])[CH3:16])=[CH:7][CH:8]=1
Reactant: CC[C@H](C)Cc1ccco1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C)Cc1ccc([Sn](C)(C)C)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of (S)-2-(2-methylbutyl)furan (4.10 g, 29.7 mmol) in dry THF (100 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 18.0 mL, 45.0 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 20 minutes, and then allowed to warm to room temperature and stirred at room temperature for 60 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 45 mL, 45.0 mmol) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water (20 mL), and reaction mixture was diluted with hexane (300 mL), washed with water (200 mL×2), dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (7.43 g, 83.2%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.[O-:18][Mn](=O)(=O)=O.[K+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:18])=[O:10])[CH2:3][CH2:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMnO4 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60° C. for 1 h. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added, and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HCl 37% (pH=1) and extracted twice with EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83% yield). This product was used without any further purification.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C@@:2]1([CH2:12][CH2:11][C@H:7]([C:8]([OH:10])=[O:9])[C:4]1([CH3:6])[CH3:5])[CH3:3].[CH3:15]O>Cl>[CH3:15][O:9][C:8]([C@H:7]1[CH2:11][CH2:12][C@@:2]([CH3:3])([C:1]([OH:14])=[O:13])[C:4]1([CH3:6])[CH3:5])=[O:10]
Reactant: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1CC[C@@](C)(C(=O)O)C1(C)C
Yield: 83 %

Procedure:
To a stirred solution of (1R,3S)-(+)-camphoric acid (5 g, 25 mmol) in 30 mL of methanol, anhydrous HCl was bubbled for 2 h at room temperature. Methanol was evaporated and the residue was mixed with 5% sodium bicarbonate solution until the effervescence ceased and then 5% sodium hydroxide was added. The diester by-product was removed by extraction with diisopropyl ether. The aqueous layer was acidified with 10% HCl and extracted with diisopropyl ether. The combined ether extracts were dried over anhydrous sodium sulfate and evaporated to obtain (1R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (4.38 g) in 83% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.84 (s, 3H), 1.25 (s, 6H), 1.53-1.55 (m, 1H), 1.80-1.84 (m, 1H), 2.19-2.22 (m, 1H), 2.25-2.57 (m, 1H), 239-2.84 (m, 1H); 3.70 (s, 3H); m/z (M+1): 214. Step II: To a solution of (1R,3S)-3-(methoxycarbonyl)-1,2,2-trimethyl cyclopentanecarboxylic acid (4.1 g, 19.2 mmol) in 18 mL of DCM and oxalyl chloride (2.1 mL, 24.9 mmol), 2 drops of DMF were added. The solution was stirred for 5 hours at −15° C. All the volatiles were removed by passing nitrogen gas. The residue was dissolved in THF and the solution added dropwise to 80 mL of anhydrous acetonitrile saturated with NH3 gas maintained at −30° C. The reaction mixture was stirred for another 15 minutes and the volatiles were removed under reduced pressure. The residue was taken in hot ethyl acetate and the solution was filtered; the crude product obtained after evaporation of the solvent was purified by column chromatography to furnish methyl (1S,3R)-3-carbamoyl-2,2,3-trimethyl cyclopentanecarboxylate (3.45 g) in 84% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (s, 3H), 1.22 (s, 3H), 1.30 (s, 3H), 1.45-1.48 (m, 1H), 1.80-1.91 (m, 1H), 2.20-2.27 (m, 1H), 2.35-2.43 (m, 1H), 2.79-2.84 (m, 1H), 3.69 (s, 3H), 5.60 (d, J=37.96, 2H); m/z (M+1): 213. Step III: To a stirred solution of methyl (1S,3R)-3-carbamoyl-2,2,3-trimethyl cyclopentanecarboxylate (2.6 g; 12.2 mmol) in 12 mL of t-butanol, 0.2 mL of stannic chloride was added followed by lead tetraacetate (7.02 g, 15.86 mmol). The reaction mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure; the residue was taken up in diethyl ether, washed with 10% K2CO3 solution. The ether extract was concentrated and the crude product was purified by column chromatography to obtain methyl (1S,3R)-3-[(t-butoxycarbonyl)amino]-2,2,3-trimethylcyclopentanecarboxylate (2.58 g) in 74% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.86 (s, 3H), 1.18 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.8-1.9 (m, 1H), 1.98-2.05 (m, 3H), 2.72-2.76 (m, 1H), 3.71 (s, 3H), 4.73 (bs, 1H); m/z (M+1): 285.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.Br[C@@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][O:29][C:27](=[O:28])[C@@H:26]([N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COC(=O)[C@@H](Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (300 mg, 0.905 mmol, 1 equiv), (S)-methyl 2-bromo-2-phenylacetate (207.4 mg, 0.905 mmol, 1 equiv) and potassium carbonate (312.7 mg, 2.26 mmol, 2.5 equiv) in N,N-dimethylformamide was stirred at 65° C. for 2 hours. The reaction mixture was cooled to ambient temperature and the mixture was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, 20% ethyl acetate/hexanes) to afford (S)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an oil (183 mg, 42.3%). MS for C27H33N3O5 m/z 479.57 (M+H)+.