Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([CH2:35][N:36]1[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:38]([CH:47]=O)=[CH:37]1)[CH:29]=[CH:28]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([CH2:35][N:36]1[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:38](/[CH:47]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:37]1)[CH:29]=[CH:28]2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Sodium hydride (60%, oily, 0.20 g) was added to a mixture of ethyl diethylphosphonoacetate (0.992 ml) and tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. A solution of 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carbaldehyde (2.09 g) in tetrahydrofuran (20 ml) was slowly added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield ethyl(E)-3-[1-(6-benzyloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propenoate (1.65 g, yield: 68%). This was recrystallized from ethyl acetate-hexane. Melting point: 119–120° C.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:13].[CH3:15]C([O-])(C)C.[K+].CI>C1COCC1>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:15])[N:8]=[C:7]2[I:13]
Reactant: CC(C)(C)[O-]
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2cc(OC(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 5-(difluoromethoxy)-3-iodo-1H-indazole (562 mg, 1.81 mmol) in THF (10.00 mL) at 0° C. was added KOtBu (1M in THF, 2.54 mL, 2.54 mmol) and the mixture stirred at 0° C. for 30 min then MeI (360 mg, 159 μL, 2.54 mmol) added. The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Purification by chromatography (80 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) gave 5-(difluoromethoxy)-3-iodo-1-methyl-1H-indazole (465 mg, 1.43 mmol, 79.2%) as a waxy off-white solid. MS (M+H)+=324.9; 1H NMR (CDCl3) δ: 7.32-7.40 (m, 1H), 7.24-7.30 (m, 1H), 7.21 (d, J=2.3 Hz, 1H), 6.55 (t, J=73.7 Hz, 1H), 4.10 (s, 3H). The regioisomeric product, 5-(difluoromethoxy)-3-iodo-2-methyl-2H-indazole, (108 mg, 333 μmol, 18%) was also obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[CH:14]=[O:15].[N:16]1([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:26][CH:27]=1)=[C:3]([CH:14]=[O:15])[CH2:4][CH2:5]2
Reactant: Oc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2c(c1)CCC(C=O)=C2Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1)CCC(C=O)=C2Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 122.4 %

Procedure:
To a 3-necked round bottom flask, add 1-chloro-6-methoxy-3,4-dihydronaphthalene-2-carbaldehyde (2.25 g, 10.1 mmol), 4-(2-(piperidin-1-yl)ethoxy)phenol (1.8 g, 8.24 mmol), tetra-N-butylammonium iodide (50 mg, 0.14 mmol), potassium carbonate (4.1 g, 29.8 mmol), and 4-dimethylaminopyridine (120 mg, 0.99 mmol). Purge the reaction vessel with nitrogen. Add dimethylformamide (30 mL) slowly to the reaction. Heat the mixture to 100° C. with stirring and hold for 4 hours. Cool the reaction mixture to room temperature and quench with ice-water. Extract the mixture with ethyl acetate three times. Dry the combined organic layers over MgSO4, filter, and concentrate to give 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)-3,4-dihydronaphthalene-2-carbaldehyde (4.11 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[C:12](=N)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:13]1([C:12](=[N:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CCCC(N)C1
Solvent: ClCCl
Product: COC(=O)C1CCCC(N=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a flask, methyl 3-aminocyclohexanecarboxylate (3.86 g, 19.94 mmol) was dissolved in dichloromethane (80 mL). Benzophenone imine (3.33 mL, 19.94 mmol) was added to the reaction, and the reaction was stirred at room temperature for 24 hrs. Upon completion, the reaction was concentrated and triturated with diethyl ether. The suspension was filtered. This trituration process was done twice. The remaining filtrate was concentrated and progressed to the next step without further purification.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:2][C:1]([CH3:3])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](=[O:5])[CH3:6]
Reactant: ClCc1ccccc1
Reactant: CC(=O)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(C)(C)Cc1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 47.9 %

Procedure:
516 g (6 mols) of methyl isopropyl ketone, 759 g (6 mols) of benzyl chloride and 60 g (0.186 mol) of tetrabutylammonium bromide are dissolved in 1 liter of toluene, and the solution is heated to 100° C. 420 g (7.49 mols) of powered potassium hydroxide are slowly metered in at this temperature. The reaction mixture is stirred for 12 hours at 100° C. and cooled, and 1.5 liters of water are added. The organic phase is separated off, dried over sodium sulphate and distilled fractionally. 507 g of 3,3-dimethyl-4-phenylbutan-2-one of boiling point 82° C./0.05 mbar are obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:36][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(N)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(N)=O

Procedure:
4-[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanamide (4.3 g, 14 mmol) was treated with mCPBA (6.1 g, 27 mmol), concentrated ammonium hydroxide (50 mL of 29%), and p-toluenesulfonyl chloride (4.6 g, 24 mmol) according to a modification of the method described in Part E of Example 3. The mCPBA addition was carried out at 0° C., and the reaction was carried out in dichloromethane (150 mL). At the end of the reaction the layers were separated, and saturated aqueous sodium bicarbonate (100 mL) and 5% aqueous sodium hydroxide (10 mL) were added to the organic layer. The aqueous layer was extracted with dichloromethane (1.3 L), and the combined extracts were dried over potassium carbonate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol containing 4 mL/L of ammonium hydroxide) followed by recrystallization five times from ethanol containing a small amount of water. The resulting solid was recrystallized from water:acetonitrile (5:L), dried overnight in a vacuum oven at 70° C., triturated with 25% aqueous ammonium hydroxide, diluted with water, isolated by filtration, recrystallized from ethanol:water, and dried overnight in a vacuum oven at 70° C. to provide 0.4704 g of 4-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanamide as tan crystals, mp 233-235° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[H-].[Na+].[CH2:37](Cl)[C:38]([OH:40])=[O:39].Cl>CN(C)C=O>[C:38]([CH2:37][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)([OH:40])=[O:39]
Reactant: O=C(O)CCl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.953 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 10 ml of N,N-dimethylformamide is admixed with stirring at room temperature with 0.16 g of sodium hydride dispersions (60%). The reaction mixture is stirred at 60° C. over 10 minutes, admixed with 0.191 g of chloroacetic add and then stirred at 60° C. over 24 hours. The reaction mixture is admixed with 0.5N HCl and extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (95:5 dichloromethane-methanol); Rt=5.18.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])[CH2:10][O:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+]>C(CC(C)(C)C)(C)C>[C:18]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]([CH2:10][OH:9])[CH2:12][N:13]([CH:14]([CH3:15])[CH3:16])[C:8]2=[O:17])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)NCC1COC(=O)C1(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)CC(C)(C)C
Product: CC(C)N1CC(CO)C(c2ccccc2)(c2ccccc2)C1=O
Reaction time: 8 h

Procedure:
Fifty-three grams (0.17 mole) of 4,5-dihydro-3,3-diphenyl-4-isopropylaminomethylfuran-2-(3H)one was dissolved in 300 ml. of boiling isooctane and 0.25 g. of 67% sodium hydride added. After refluxing for 6.5 hours an additional 0.25 g. of 57% sodium hydride was added and refluxing was continued overnight. The cooled mixture was filtered and the solid was recrystallized from toluene. The 3,3-diphenyl-4-hydroxymethyl-1-isopropyl-2-pyrrolidinone weighed 42 g. (80%) and melted at 159°-161° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH:17]C(=O)C)[CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[C:6]1=[O:21])(=[O:3])[CH3:2].C(NC1CCC2C(=C(NC(=O)C)C=CC=2)C1=O)(=O)C>>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[C:6]1=[O:21])(=[O:3])[CH3:2]
Reactant: COc1ccc(NC(C)=O)c2c1CCC(NC(C)=O)C2=O
Agent: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Product: COc1ccc(N)c2c1CCC(NC(C)=O)C2=O

Procedure:
The same procedure as in Example 1-(4) was carried out, except that 200 mg of the compound prepared in (2) above was used instead of 2,8-diacetylamino-1-tetralone. Upon the post-treatment in the same manner as in Example 1-(4), 130 mg of the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C)C=O.O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11])#[N:2]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1ccncn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccncn2)cc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 75, 125 mg, 0.389 mmol) in methylene chloride (3 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.050 mL, 0.583 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then concentrated in vacuo. The resulting yellow gel was diluted with methylene chloride (2 mL) and then slowly added to a solution of 4-aminopyrimidine (56 mg, 0.583 mmol) and triethylamine (0.108 mL, 0.778 mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 then 1/3 hexanes/ethyl acetate) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide (34.7 mg, 22%) as a pale yellow foam: mp 79-84° C. (foam to gel); EI-HRMS m/e calcd for C20H22N4O3S (M+) 398.1413, found 398.1411.
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])C.[C:10]1([NH:16][C:17]([NH:19][C:20]([NH2:22])=[NH:21])=[NH:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH3:7][C:6]1[N:21]=[C:20]([NH:19][C:17]([NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[NH:18])[NH:22][C:4](=[O:9])[CH:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)NC(=N)Nc1ccccc1
Solvent: CCO
Product: Cc1cc(=O)[nH]c(NC(=N)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxobutyric acid ethyl ester (2.6 grams, 0.020 mol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added at room temperature to a solution of 1-phenylbiguanide (3.5 grams, 0.020 mol, prepared as described in Part D of Example I) in anhydrous ethanol (15 milliliters). The mixture was heated at reflux and stirred for 4 hours. After a few minutes, all the components dissolved. Cooling the resulting yellow solution mixture to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with water, then with cold ethanol (0° C.), and finally with hexanes. The solid was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-N′-phenylguanidine as a colorless solid (3.60 grams, 74 percent yield): mp=265° C.; 1H NMR (DMSO-d6, 303 K) δ: 11.19 (s, 1H), 9.05 (s, 1H), 9.5-6.5 (br, 2H), 7.65 (d, 2H, 3J=7.7 Hz), 7.26 (m, 2H), 7.00 (t, 1H, 3J=7.3 Hz), 5.60 (s, 1H), 2.09 (s, 3H); 13C NMR (DMSO-d6, 303 K) δ: 164.0, 163.2, 158.3, 156.2, 138.9, 128.8, 122.7, 120.7, 103.7, 23.6. Exact mass calculated for C12H13N5O=243.1120. Measured High Resolution Mass Spectrum (MAB/HR/N2)=243.1120. Anal. Calcd for C12H13N5O: C, 59.25; H, 5.39; N, 28.79. Found: C, 59.17; H, 5.39; N, 29.04.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:13](OC)[C:14](=[O:17])NC)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14](=[O:17])[CH3:20])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CNC(=O)C(OC)N(CC(=O)O)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of N-[(tert-butoxy)carbonyl]-N-[(methoxy)-(methyl)carbamoylmethyl]glycine (1.0 g, 3.6 mmol; Helvetica Chimica Acta 2000, 83 1825), in anhydrous THF (30 mL) under an atmosphere of nitrogen, a solution of methyl magnesium bromide in ether (2.6 mL, 3M, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, cooled back to 0° C., quenched with aqueous HCl, and diluted with ether. The organic extract was washed with brine (pH adjusted to ˜4-5 with addition of aqueous sodium hydroxide), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([OH:23])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].S(OC)(O[CH3:47])(=O)=O.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([O:23][CH3:47])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:8])=[O:9]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](OC)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 53.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (120 mg, 0.199 mmol) prepared in Example 121c, dimethyl sulfate (18.8 μL, 0.199 mmol), sodium hydride (63%; 11.1 mg, 0.291 mmol) and THF (2.0 mL), to yield the title compound (65.0 mg, 53%) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.O.CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[N:13][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)C1CCN(c2ccc(C(C)=O)cn2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccc(N2CCC(C(=O)O)CC2)nc1
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a stirred solution of 5′-acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (15.8 g, 0.057 mol) in THF (75 mL), H2O (75 mL) and MeOH (8 mL) was added LiOH.H2O (2.64 g, 0.0629 mol). Stirring was continued overnight at RT before the organic solvent were removed under vacuo. The pH of the was adjusted to 5 with acetic acid, and the white precipitate was filtered off and dried to yield 13 g (92%) of 5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid. ES-MS m/e: 249.2 (M−H+)
Reaction SMILES: [S:1]1[C:12]2[C:11]3[NH:10][CH:9]=[CH:8][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=[C:2]1[NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15].[C:19](C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:17]([NH:16][C:14]([NH:13][C:2]1[S:1][C:12]2[C:11]3[N:10]([CH3:19])[CH:9]=[CH:8][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1)=[O:15])[CH3:18]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCNC(=O)Nc1nc2c(s1)-c1[nH]ccc1CC2
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2c(s1)-c1c(ccn1C)CC2
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a suspension of N-(5,8-dihydro-4H-[1,3]thiazolo[4,5-g]indol-2-yl)-N′-ethylurea in toluene is added DDQ (1.1 eq.). The reaction mixture is stirred at about 45° C. for about 4 hrs. The reaction mixture is pumped down and the crude material is purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>COCCOC>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][N:15]([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: NS(N)(=O)=O
Solvent: COCCOC
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(S(N)(=O)=O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A mixture of Example 1 (42 mg, 0.0896 mmol) and sulfamide (15 mg, 0.155 mmol) in DME (1 mL) in a sealed tube was heated at 90° C. overnight. After condensation, the residue was purified by CombiFlash (eluent: 5% 7N NH3 in methanol in DCM) to give the product as a yellow oil. LC/MS: C23H32F3N5O5S: m/z 548.2 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)[CH2:10][CH2:9]1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[CH3:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:20]([O:25][CH3:26])[CH:19]=2)[CH2:12][CH2:13]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)cc1OC
Reaction time: 0.33 h

Procedure:
1.03 g of potassium carbonate was added to a solution of 2.15 g of N-(cis-4-methylcyclohexyl)-4-hydroxy -3-methoxycinnamamide (Example 105) in 200 ml of ethanol. The solution was stirred for 20 minutes, while it was refluxed. Next, 8.0 ml of ethyl bromoacetate was slowly added dropwise to the solution by means of a dropping funnel. Thereafter, the solution was stirred for 4 hours. After reaction, the potassium carbonate was filtered from the reaction solution, and the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 2.12 g of N-(cis-4-methylcyclohexyl) -4-(ethoxycarbonylmethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>CS(C)=O.O>[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[CH2:4][O:19]2)=[CH:16][CH:15]=1
Reactant: C[S+](C)C
Reactant: Cn1ccnc1-c1ccc(C=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1ccnc1-c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a suspension of 0.045 g (1.1 mmol) of sodium hydride in DMSO (2 mL) was added a 0.225 g (1.10 mmol) of trimethylsulfonium iodide as a solution in DMSO (2 mL). The mixture was allowed to stir at room temperature for 10 min then a solution of 0.100 g (0.537 mmol) of the above aldehyde in DMSO (1 mL) was added dropwise. The mixture was stirred at room temperature for 4 h then diluted with H2O and washed with EtOAc. The combined organic phase was washed with H2O, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.056 g (52.1%) of 1-methyl-2-(4-oxiranyl-phenyl)-1H-imidazole as a yellow oil.