Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:9]#[N:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:12].C(=O)([O-])[O-].[Ba+2].S([O-])([O-])(=O)=O.[Ba+2]>C(O)C.O>[OH:1][C:2]1([C:9](=[O:12])[NH2:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCC(O)(C#N)CC1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: O
Product: CN1CCC(O)(C(N)=O)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
The compound 4-hydroxy-4-cyano-1-methylpiperidine (36.4 g, 0.26 mole) was gradually added to sulfuric acid (80 ml), under external cooling. The mixture was maintained at room temperature for 41 hours, then was added to powdered ice (30 g). The resulting solution was neutralized with barium carbonate (376 g) to pH 8-9 and after addition of water the resulting barium sulfate was separated and washed with methanol. The filtrate was concentrated under reduced pressure. The product, 4-hydroxy-4-carbamoyl-1-methylpiperidine (28.16 g, 0.18 mole, 69% yield), crystallized from ethanol as a white solid (mp. 180° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:21])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:5]([N:7]1[CH:13]2[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:6].[Cl-:22].[NH4+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:22][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([F:1])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:15]([F:21])[CH:14]=1
Reactant: [Cl-]
Reactant: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2Cl)cc1F
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4 ml of chloroform and 298 mg of zinc (II) chloride was stirred at 60° C. After 5 minutes, a mixture of 291 mg of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and 2 ml of chloroform was added dropwise thereto at 60° C., and the resulting mixture was heated under reflux for 5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.22 g of N-(2-chlorocyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 87 of the present invention) represented by the formula:
Reaction SMILES: N#N.[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1)(=[O:6])=[O:5].CCN(CC)CC.S([Cl:25])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][CH2:12][C:10]1[O:11][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.5 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-methanesulfonyl-furan-2-yl)-methanol (692 mg, 3.93 mmol) in dry CH2Cl2 (7.0 mL) was treated at 0° C. with Et3N (0.71 mL, 5.11 mmol) followed by DMAP (50 mg, 0.39 mmol) and Ms-Cl (0.37 mL, 4.71 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 868 mg of crude 2-chloromethyl-5-methanesulfonyl-furan as a yellow oil. 150 mg of this crude material in acetone (2.0 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (87 mg, 0.77 mmol) in acetone (2.0 mL). K2CO3 (320 mg, 2.13 mmol) followed by TBA bromide (50 mg, 0.15 mmol) were added and the reaction mixture was stirred at rt overnight. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (40:60 hept-EA) gave the title compound as a yellow oil. TLC: rf (40:60 hept-EA)=0.27. LC-MS-conditions 02: tR=0.82 min.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (141.3 mL of a 0.32M stock solution, 45.0 mmol) cooled to −78° C. was treated with (3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7 mL, 3:1). The resulting reaction solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (4.64 g, 22.08 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. The solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (1×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0915.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][C:15]=2[F:22])[O:3]1.[OH2:24].OOS([O-])=O.[K+].C[OH:32]>>[CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:21])(=[O:32])=[O:24])=[CH:16][C:15]=2[F:22])[O:3]1
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)c(F)c1
Reactant: CO
Reactant: O
Agent: O=S([O-])OO
Agent: [K+]
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2F)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
305 mg of 2,2-dimethyl-5-{2-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone (Example 314) was dissolved in 30 ml methanol, 20 ml TBF and 20 ml water, to which 1.4 g of OXONE was added. The reaction mixture was stirred overnight at room temperature. Then the solvent was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and then was purified by column chromatography (hexane/acetate=3:2) to obtain 70 mg of 2,2-dimethyl-5-{2-fluoro-4-(methylsulfonyl)phenyl}-4-phenyl-3(2H)-furanone as a solid. mp: 175-176° C. NMR: δ1.57 (s, 6H), 3.10 (s, 3H), 7.22 (m, 2H), 7.28 (m, 3H), 7.75 (dd, J=8.7, 1.8 Hz, 1H), 7.77 (m, 2H). IR (cm−1): 1702, 1408, 1321, 1147. MS (FAB): 361 (m+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C@H:33]([C:40]([OH:42])=[O:41])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1>O1CCCC1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][C:8]([O:10][NH:32][C@H:33]([C:40]([OH:42])=[O:41])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1)=[O:9]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)ON[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
To a diclofenac solution (3 g, 10.13 mmoles) in tetrahydrofuran (50 ml) cooled at 0° C., 1,1′-carbonyldiimidazol (1.69 g, 10.13 mmoles) is added under stirring. After 10 minutes the solution is treated with (L) histidine (1.57 g, 10.13 mmoles) and left under stirring at room temperature for 4 hours. The reaction mixture is concentrated under vacuum, treated with methylene chloride and then washed in sequence with HCl 1% and then with water. The organic phase is anhydrified with sodium sulphate and evaporated under vacuum. The obtained residue is purified by chromatography on silica gel column, eluting with ethyl acetate. [2-[(2,6-dichlorophenyl)amino] benzeneacetyloxy] (L)-histidine is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[CH:9]=1)=[O:7].[OH-].[K+].Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CS(C)=O>[Br:15][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[O:14][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(c1ccc(O)c(Br)c1)c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)c2cccs2)cc1Br
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-thienyl-(3-bromo-4-hydroxy-phenyl)ketone (14.5 g; M.p.=185° C.) in dimethylsulfoxide (50 ml) is added potassium hydroxide (2.8 g) and the mixture is heated to 50° C. for 30 minutes, after which ethyl α-bromoisobutyrate (9.75 g) is added thereto at room temperature. After a period of time of 3 hours, the solution is poured into water (100 ml) and the aqueous phase is extracted with ethyl ether. The organic phase is washed with an aqueous sodium hydroxide solution, and then with water, and the solvent is evaporated off after drying over sodium sulfate. The final product is recrystallized from petroleum ether (7 g; M.p.=80° C.).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][S:11](=[O:15])(=[O:14])[O:12]C.O>C(OCC)C>[S:11]([O-:15])([O-:14])(=[O:12])=[O:10].[CH3:8][S+:7]([CH3:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][S+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9]
Reactant: COS(=O)(=O)OC
Reactant: CSc1ccccc1
Solvent: O
Solvent: CCOCC
Product: C[S+](C)c1ccccc1
Product: O=S(=O)([O-])[O-]

Procedure:
Thioanisol (6.2 g, 0.05 mole) and 6.9 g (0.055 mole) of dimethyl sulfuric acid were stirred at room temperature for 12 hours. Into the reaction solution were added 100 g of water and 50 mL of diethyl ether to separate the water layer to obtain the aqueous solution of the intended dimethylphenyl sulfonium sulfate.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:15])=[C:6]([CH:13]=O)[C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:4]1[C:5]([OH:15])=[C:6]([CH2:13][N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)[C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)c1cc2c(c(C=O)c1O)OCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(CN3CCN(C(=O)OC(C)(C)C)CC3)c1O)OCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of 6-acetyl-5-hydroxybenzo[d][1,3]dioxole-4-carboxaldehyde (0.14 g, 0.67 mmol) in methylene chloride (5.0 mL) was added with N-Boc-piperazine (0.13 g, 0.67 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.14 g, 0.67 mmol). After completion of the addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with methylene chloride, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (2:1→3:7)) to obtain tert-butyl 4-[(6-acetyl-5-hydroxybenzo[d][1,3]dioxol-4-yl)methyl]piperazine-1-carboxylate (0.18 g, 71%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[C:15]1([CH2:21][CH2:22][CH2:23][NH:24][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-phenylpropylamine (0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-(3-phenylpropyl)amino-piperidine carboxylate. Yield: 110 mg. To a solution of tert-butyl 4-(3-phenylpropyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-(3-phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-(3-Phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 61 mg; 13C-NMR (CD3OD, rotamers): δ 27.8, 29.4, 30.8, 32.3, 32.7, 33.3, 40.2, 40.5, 42.0, 44.5, 44.6, 44.9, 52.7, 54.56, 54.57, 54.9, 114.0, 114.1, 125.7, 126.1, 127.0, 127.4, 128.2, 128.3, 128.5, 129.47, 129.55, 141.2, 141.8, 158.9, 159.0, 172.5, 172.7.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20])=[O:8]
Reactant: NC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
To solution of (2,4,5-trichloro-phenoxyacetic acid (100 mg, 0.39 mmol), 2-amino isonicotinamide (107 mg, 0.78 mmol) and DMAP (96.22 mg, 0.78 mmol) in DMF 12 ml was added PyBOP (409.7 mg, 0.78 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1-2:4:1) to afford 2-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.06 g, 41% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[N:11]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][NH2:22].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:20][O:21]/[N:22]=[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)\[CH2:9][C:10]1[N:11]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:13][N:14]=1
Reactant: CON
Reactant: CCCn1ccnc1CC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCn1ccnc1C/C(=N\OC)c1ccc(N)cc1
Yield: 34.2 %

Procedure:
A solution of 1-(4-aminophenyl)-2-(1-propylimidazol-2-yl)ethanone (600 mg) and O-methylhydroxylamine hydrochloride (227 mg) in ethanol (20 ml) was refluxed for 8 hours. After the mixture was allowed to be at room temperature, and saturated sodium bicarbonate solution was added to the mixture, the mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1), and washed with diisopropyl ether to give (1E)-1-(4-aminophenyl)-2-(1-propylimidazol-2-yl)ethanone O-methyloxime (230 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[CH:5]=N[N:3]=[N:2]1.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1>[Pd]>[N:1]([CH2:5][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)=[N+:2]=[N-:3].[NH2:1][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: c1nnn[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN=[N+]=[N-])cc1

Procedure:
Following the procedures described in Example 1A, replacing N-triphenylmethyl-5-[2-(4'-bromomethyl)biphenyl)]tetrazole with t-butyl 4'-bromomethyl-biphenyl-2-carboxylate, prepared as described by D. J. Carini, et al. in European Patent Application Number 324,377, published Jul. 19, 1989, the intermediate t-butyl 4'-azidomethyl-biphenyl-2-carboxylate is prepared. The intermediate azidomethyl compound is then hydrogenated as described in Example 1B, using palladium on carbon catalyst instead of Lindlar catalyst, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[NH2:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]1[CH:3]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=2)[CH:15]=[CH:14][C:5]=1[C:6]([CH3:13])=[CH2:12]
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: C=C(C)c1ccc(Nc2ncc(Cl)c(Nc3c(C)cccc3C(=O)NC)n2)cc1CCC(N)=O

Procedure:
A suspension of 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (46 mg), 2-(2,5-dichloropyrimidin-4-ylamino)-N,3-dimethylbenzamide (42 mg), and camphorsulfonic acid (40 μL of a 100 mg/mL aqueous solution) were heated in isopropanol (2 mL) for 4 hours at 120° C. using microwave irradiation. The solvent was evaporated to afford crude 2-(2-(3-(3-amino-3-oxopropyl)-4-(prop-1-en-2-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-N,3-dimethylbenzamide The crude mixture was dissolved in TFA and allowed to stand for 4 hours, then concentrated. Purification by semi-preparative HPLC provided 2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N,3-dimethylbenzamide as the TFA salt. The non-salt was obtained by stirring the TFA salt in acetonitrile with 300 mg of MP-carbonate (Argonaut, 2.91 mmol/g) for 2 days. The resin was separated by filtration, then washed with methanol and methylene chloride. The filtrate was concentrated and the residue triturated with ethyl ether to provide 14 mg of the neutral compound: 1H NMR (300 MHz, CDCl3 with 5% CD3OD) δ 8.05 (s, 1H), 7.5-7.4 (m, 2H), 7.35 (dd, 1H), 7.3 (d, 1H), 7.15 (d, 1H), 7.1 (dd, 1H), 2.9 (s, 3H), 2.8 (m, 2H), 2.6 (m, 2H), 2.3 (s, 3H) 1.8 (s, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=[O:23].C[O:33][C:34](=[O:57])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48](OC(=O)C)C=2)=O)=[CH:37][C:36]=1[Cl:56].C[Si]([N:62]=[N+:63]=[N-:64])(C)C>C1COCC1.CO.[OH-].[Li+]>[Cl:56][C:36]1[CH:37]=[C:38]([N:41]2[C:42]([NH:44][C:45]3[CH:46]=[CH:51][CH:50]=[C:49]([OH:23])[CH:48]=3)=[N:64][N:63]=[N:62]2)[CH:39]=[CH:40][C:35]=1[C:34]([OH:33])=[O:57]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COC(=O)c1ccc(NC(=O)NCc2cccc(OC(C)=O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-n2nnnc2Nc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.6 %

Procedure:
In a dry argon atmosphere, a solution of triphenylphosphine (1.684 g; 6.42 mmol), diethyl azodicarboxylate (1.13 g; 6.42 mmol) and 4-[3-(3-acetoxybenzyl)ureido]-2-chlorobenzoic acid methyl ester (1.21 g; 3.21 mmol) in dry THF (30 mL) was treated with trimethylsilyl azide (0.86 mL; 6.48 mmol) and was stirred at room temperature for 24 hr. Examination of the reaction mixture by TLC suggested the presence of considerable starting material, so additional amounts of triphenylphosphine (0.842 g; 3.21 mmol), diethyl azodicarboxylate (0.565 g; 3.21 mmol) and trimethylsilyl azide (0.43 mL; 3.21 mmol) were added. The reaction was stirred at room temperature for an additional 40 hr. After the solvents were removed under reduced pressure, the residue was taken up in dichloromethane (100 mL) and washed with water (2×50 mL). The aqueous extracts were backwashed in turn with dichloromethane (50 mL) and the combined, dried (MgSO4) extracts were evaporated in vacuo. From a previous experiment it had been established that the reaction yielded a complex, difficultly separable, mixture of several products, some deacetylated and/or de-esterified. Accordingly, in this experiment, the residue was dissolved in a mixture of methanol (30 mL) and 1N lithium hydroxide (15 mL) and the mixture was stirred at room temperature for 2 hr to complete the hydrolyses of both the ester and phenolic acetate groups. Most of the volatiles were removed under reduced pressure then the basic solution was diluted with water (20 mL) and washed with dichloromethane (2×30 mL). The aqueous layer was then acidified with 1N HCl (16 mL) and extracted with ethyl acetate (2×50 mL). The dried (MgSO4) ethyl acetate extracts were evaporated and the residual solid (810 mg), approximately a 4:1 mixture of the desired aminotetrazole and its positional isomer, was crystallized from ether to furnish 560 mg of 2-chloro-4-[5-[(3-hydroxyphenyl)amino]tetrazol-1-yl]benzoic acid as a colorless solid. FAB HRMS: (C15H12ClN5O3) Obs. Mass 345.0624 Calcd. Mass 345.0629 (M+H).