Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Fc1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 6-fluoro-1H-indazole (6.46 mmol, 880 mg) in DMF (15 mL) cooled to 0° C. under Ar was added 95% NaH (6.46 mmol, 163 mg). The resulting mixture was stirred for 15 minutes before tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (7.11 mmol, 2.52 g) was added. After an additional 15 minutes at 0° C., the ice bath was removed and the reaction vessel placed in a 110° C. bath for 2.75 hours. After cooling to ambient temperature, the DMF was removed in vacuo and ethyl acetate (100 mL) was added. The organic layer was washed with water and brine, dried (MgSO4), filtered and the solvent removed in vacuo. The resulting residue was purified by SiO2 column chromatography (0-40% EtOAc/hexanes) to yield tert-butyl 4-(6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate.
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([C:25]([C:28]([F:31])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].Br[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1[CH3:41].CS(C)=O.[I-].[K+]>[Cu].ClCCl>[F:2][C:1]([F:3])([C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1[CH3:41])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:12])([F:11])[C:13]([F:15])([F:14])[C:16]([F:18])([F:17])[C:19]([F:21])([F:20])[C:22]([F:24])([F:23])[C:25]([F:27])([F:26])[C:28]([F:31])([F:30])[F:29]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Cc1ccc(C)c(Br)c1
Agent: [Cu]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(C)c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
A solution of C10F21I (4.2 g, 6.5 mmol) was added dropwise over 10 min to a stirred mixture of 2-bromo-p-xylene (1 g, 5.4 mmol), copper powder (1.9 g, 29.7 mmol), and DMSO (80 mL) at 130° C. The reaction mixture was subsequently stirred for a further 2 d at this temperature. After cooling to room temperature, it was poured into a beaker containing dichloromethane (50 mL) and saturated potassium iodide solution (50 mL). After filtering, the organic layer was separated, washed with water (3×30 mL), and dried over MgSO4. Recrystallization from hexane gave the product 215 as a white solid (2.7 g, 82%): 1H NMR (300 MHz, CDCl3): 7.31 (1H, s), 7.24 (1H, d, J=8.1 Hz)), 7.17 (1H, d, J=8.1 Hz)), 2.46 (3H, t, J=3.0 Hz)), 2.39 (3H, s); 19F NMR (282 MHz, CDCl3): −81.4, −106.7, −121.1, −121.8, −122.0, −122.9, −126.3; HR-MS (EI) calcd. for C18H9F21 (M+): 624.0363, found: 624.0353.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18]C)=[O:17])[C:10](=[O:20])[CH2:9]2)(=[O:4])=[O:3].Cl>O1CCOCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:20])[CH2:9]2)(=[O:3])=[O:4]
Reactant: COC(=O)CN1C(=O)Cc2cc(NS(C)(=O)=O)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of methyl 2-(5-(methylsulfonamido)-2-oxoindolin-1-yl)acetate (0.133 g, 0.446 mmol) in dioxane (5 ml), 12M HCl (4 ml, 48.0 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The volatiles fractions were evaporated and the residue was dried under vacuum. Crude of 2-(5-(methylsulfonamido)-2-oxoindolin-1-yl)acetic acid (0.130 g, 0.446 mmol, 100% yield) was used for the next step without any further purification. MS/ESI+ 284.9 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:17][O:18][CH2:19][C:20]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)=[O:21]
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 79 %

Procedure:
3-(2-Methoxy-acetyl)-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with 2-methoxy-acetic acid chloride in pyridine.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I>CCCCCC.CN(C)C=O>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ccc(O)cn1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To sodium hydroxide (50% oil dispersion, 43.2 g, 21.6 g of active NaH, 900 mmol), prewashed in dry hexane, in 800 ml of dimethylformamide (DMF) is added 5-hydroxy-2-methylpyridine (98.8 g, 906 mmol) in 700 ml of DMF at 15° and over 0.75 hour. The reaction is allowed to warm to RT and is stirred for 2 hours. It is then cooled to 10°, and methyliodide is added over 0.5 hour. The reaction is again allowed to warm to RT and is stirred overnight. It is then filtered through celite, and the solid is washed with chloroform, filtered and rotoevaporated. The resulting solid is washed with chloroform 3×, and is stirred with chloroform overnight. It is filtered and rotoevaporated, after which ether is added, followed by 10% sodium hydroxide and water. The mixture is extracted with ether (3×). The combined ether extracts are washed with water and with brine, dried over calcium sulfate, filtered and rotoevaporated to give 5 -methoxy-2-methylpyridine.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.CON(C)[C:12]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]>O1CCCC1>[O:17]1[CH2:16][CH2:15][CH:14]([C:12](=[O:13])[CH3:4])[CH2:19][CH2:18]1
Reactant: CCOCC
Reactant: CON(C)C(=O)C1CCOCC1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Add 3 M methyl magnesium bromide in diethyl ether (1.14 L, 2.0 eq) to a solution of N-methoxy-N-methyl-tetrahydropyran-4-carboxamide (296 g, 1.71 mol) in tetrahydrofuran (2.96 L) over one hour at 0° C. Stir for an additional two hours, then pour the contents into a mixture of ice/water. Extract with methyl tert-butyl ether. Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give 1-(tetrahydro-pyran-4-yl)-ethanone (105 g, 48%). 1H NMR (300 MHz, DMSO-d6) δ 3.98 (m, 2H), 3.42 (m, 2H), 2.52 (m, 1H), 2.15 (s, 3H), 1.74 (m, 4H).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([C:13]2(Br)[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]2=[O:21])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CO>[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH:29]1[C:13]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:24])[CH3:23])[CH:8]=2)[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]1=[O:21]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C2(Br)C(=O)NC(=O)NC2=O)c1
Reactant: OCCN1CCNCC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C2(C3CNCCN3CCO)C(=O)NC(=O)NC2=O)c1
Yield: 14.1 %

Procedure:
A solution of 5-[3-(tertbutyldimethylsilyloxy)phenyl]-5-bromobarbituric Acid (444 mg) and N-(2-hydroxyethyl)piperazine (420 mg) in 10 ml of methanol is stirred at room temperature for 5 hours, then the solvent is evaporated off and the residue is purified by silica gel chromatography (13 g, eluent:ethyl acetate/methanol 3:1), to give 70 mg of the product.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1CC(O)=O>CN(C)C=O.C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (38 ml) and a few drops of N,N-dimethylformamide was added to a solution of (2-chlorophenyl)acetic acid (50 g) in CH2Cl2 (300 ml). The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. The residue was distilled under reduced pressure to give (2-chlorophenyl)acetyl chloride (41.24 g) as an oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: FC(F)(F)c1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1

Procedure:
A mixture of 2.2 mmol 2-bromo-5-trifluoromethyl-[1,3,4]thiadiazole (CA 37461-6-3; prepared according to DE2533605), 2.3 mmol piperazine-1-carboxylic acid tert-butyl ester and 4.3 mmol potassium carbonate in 10 ml acetonitrile was refluxed for 4 hours. The reaction mixture was cooled, poured into water and extracted 3 times with ethyl acetate. Concentration and recrystallisation of the crude material from diethyl ether yielded the title compound as a colorless solid. MS (m/e): 397.2 ([M+CH3COO]31 , 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:8][C:6]([NH:9]C(=O)C)([CH2:7]1)[CH2:5]2)[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]12[CH2:8][C:6]([NH2:9])([CH2:7]1)[CH2:5]2)[CH3:2]
Reactant: CCOC12CC(NC(C)=O)(C1)C2
Agent: [Na+]
Agent: [OH-]
Product: CCOC12CC(N)(C1)C2

Procedure:
Hydrolysis of N-(3-ethoxybicyclo[1.1.1]pentan-1-yl)acetamide (2) with sodium hydroxide (or basic aqueous conditions) gives 3-ethoxybicyclo[1.1.1]pentan-1-amine (6) (Scheme 5).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:32][O:33][CH2:34][CH2:35]Br>CCO>[CH3:32][O:33][CH2:34][CH2:35][N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1
Reactant: COCCBr
Reactant: c1cnc2ccc(Cc3nnc4ccc(-c5cn[nH]c5)nn34)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCCn1cc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 6-[6-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinoline as prepared in Example 3 (19 mg, 0.06 mmol) and K2CO3 (12 mg, 0.09 mmol) in EtOH (2 mL) was added 2-bromoethyl methyl ether (8 μL, 0.09 mmol). The reaction was stirred at rt overnight. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (2.8 mg, 15%) as a clear glass. 1H-NMR (CD3OD): δ 9.05-9.03 (1H, dd, J=3.7, 5.3 Hz), 9.02-8.99 (1H, d, J=7.8 Hz), 8.32 (1H, s), 8.27 (1H, s), 8.18-8.08 (4H, m), 7.95-7.91 (1H, q, J=3.0, 5.5 Hz), 7.66-7.63 (1H, d, J=9.8 Hz), 4.84 (2H, s), 4.30-4.28 (2H, t, 4.8 Hz), 3.70-3.76 (2H, t, J=5.3 Hz), 3.23 (2H, br s). ESI-MS (m/z): Calcd. For C21H19N7O: 385.17; found: 386.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:30]3[CH2:31][CH2:32][CH:28]([N:27]([CH3:33])[CH3:26])[CH2:29]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)C1
Yield: 48 %

Procedure:
The compound (40 mg, 0.11 mmol) prepared in Example 27 and 3-dimethylaminopyrrolidine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (24 mg, Yield 48%).
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][Br:29])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(NC1CCCCC1)c1ccc(CBr)c2ccccc12

Procedure:
To a solution of 4-methyl-naphthalene-1-sulfonic acid cyclohexylamide 40 (3.0 g, 10 mmol) in CCl4 (100 mL) was added NBS (2.1 g, 12.0 mmol) and benzoyl peroxide (240 mg, 1.0 mmol), The reaction mixture was heated at reflux overnight. The solid was filtered and the filtrate was concentrated in vacuo. The title compound was a yellow residue (2.5 g, solidified on standing) which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.70 (m, 1H), 8.25 (m, 2H), 7.70 (m, 2H), 7.60 (d, 1H), 4.94 (s, 2H), 4.58 (m, 1H); 3.15 (m, 1H), 1.55 (m, 5H), 1.05 (m, 5H); LC/MS m/z 356 (M+H)+ 382.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[S:7][N:6]=1)([CH3:4])[CH3:3].[CH3:11][CH:12]([CH2:16][CH2:17][Cl:18])[C:13](Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:18][CH2:17][CH2:16][CH:12]([CH3:11])[C:13]([NH:10][C:8]1[S:7][N:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=1)=[O:14]
Reactant: CC(CCCl)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)sn1
Solvent: Cc1ccccc1
Product: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)ns1
Yield: 12 %

Procedure:
To a solution of 2.4 g of 3-(1,1-dimethylethyl)-5-aminoisothiazole dissolved in 150 ml of toluene under nitrogen was added 2.3 g of 2-methyl-4-chlorobutyric acid chloride. The reaction mixture was refluxed for about 24 hours and cooled. The solvent was evaporated under reduced pressure, and the product was isolated from the residue by chromatography over silica gel eluting with an ethyl acetate/Skellysolve B solvent mixture. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford, following crystallization from toluene/Skellysolve B, 0.5 g of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2-methylbutanamide. Yield 12%. mp 144°-146° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12]O)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][N:29]=[N+:30]=[N-:31])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Yield: 96.5 %

Procedure:
To a solution of ((1S)-1-hydroxymethyl-2-methylpropyl)carbamic acid t-butyl ester (3.00 g, 14.8 mmol) (obtained as described in Reference Example 61(1)) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (4.78 ml, 22.2 mmol), triphenylphosphine (5.82 g, 22.2 mmol) and a 40% solution of diethylazodicarboxylate in toluene (9.67 g, 22.2 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred for 2 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (9:1) as the eluant to afford ((1S)-1-azidomethyl-2-methylpropyl)carbamic acid t-butyl ester (3.26 g, yield 90%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH:20]1[CH2:23][CH2:22][CH2:21]1>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: BrCC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1cc(OCc2ccccc2)ccn1CC1CCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.1 %

Procedure:
A solution of 4-benzyloxy-1H-pyridin-2-one (0.60 g, 2.98 mmol) in N,N-dimethylacetamide (10 mL) at 0° C. was treated with sodium hydride (0.086 g, 3.58 mmol) for 30 min, then bromomethyl cyclobutane (0.40 mL, 3.58 mmol) was added and the mixture was stirred at 25° C. for 48 hours. The solution was partitioned between 10% aqueous ammonium chloride solution and dichloromethane, the organic layer was separated, concentrated under reduced pressure and the residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane to provide the title compound (0.426 g, 53%).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[H-].[Na+].[CH3:12][O:13][C:14](=[O:26])[C:15]1[C:16](=[C:21](I)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1.[Cu]Br>[CH3:12][O:13][C:14](=[O:26])[C:15]1[C:16](=[C:21]([O:3][C:2]2[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=2[O:8][CH3:9])[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1ccccc1O
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccccc2OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
A mixture of guaiacol (0.77 g, 6.2 mmol), copper (I) bromide (0.89 g, 6.2 mmol), and sodium hydride (0.3 g of a 60% dispersion, 7.5 mmol) in 100 mL pyridine was heated to reflux and stirred under nitrogen for 15 min. 3-Iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol) was added, and the resulting mixture was stirred at reflux for 20 h. The mixture was cooled to room temperature and quenched by the addition of saturated NH4Cl (15 mL). Volatiles were removed under reduced pressure. The residue was partitioned between dilute aqueous HCl (100 mL) and ethyl acetate (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with dilute aqueous HCl (2×100 mL), saturated Na2CO3 (2×100 mL), again with dilute aqueous HCl (2×100 mL) and finally with water (100 mL), and were evaporated. Chromatography in hexanes-ethyl acetate gradient provided 0.75 g of 3-(2-methoxy-phenoxy)-phthalic acid dimethyl ester, eluting at 25-30% ethyl acetate, in 38% yield; 1H NMR (CDCl3) δ 3.79 (s, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 6.86-6.91 (m, 1H), 6.93-7.01 (m, 2H), 7.05 (dd, J=7.9 Hz, J=1.6 Hz, 1H), 7.13-7.20 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.66-7.69 (m, 1H).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=O)[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[NH:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:15])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 95.3 %

Procedure:
By using 8.66 g of Boc-Thr(Bzl)-OH and 7.42 g of HCl.H-Pro-OBzl, and the same procedure as in Reference Example 15 was repeated to obtain 13.25 g (yield: 95.3%) of the above mentioned objective product.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:35])=O.CN(C)C=O>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([Cl:35])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cc1ccc(C(Cc2ccc(C(=O)O)cc2)c2ccc(CC(C)C)cc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(Cc2ccc(C(=O)Cl)cc2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2,2-bis(4-isobutylphenyl)ethyl]benzoic acid (400 mg) in dichloromethane (10 ml) were added oxalyl chloride (0.1 ml) and a drop of N,N-dimethylformamide at 0° C. After stirred at 20° C. for 1 hour, the,mixture was evaporated to give 4-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl chloride (450 mg) as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethylphenyl)-6-methyl-pyrimidine (example E.47) (0.175 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.021 g, 10%). MS (ISP) 408.3 [(M+H)+]; mp 290° C.