Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH2:23])[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.[Si:24]([O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH2:44][CH2:45][CH2:46][C:47]2=O)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH:23][C@H:47]1[C:48]2[C:43](=[C:42]([O:41][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:51]=[CH:50][CH:49]=2)[CH2:44][CH2:45][CH2:46]1)[C:6]1[O:7][C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1
Reactant: N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 78.3 %

Procedure:
The mixture of (1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (5.8 g), 5-tert-butyldiphenylsilyloxy-1-tetralone (11 g) and p-toluenesulphonic acid (32 mg) in toluene (150 ml) was heated under reflux in Dean-Stark apparatus for 48 hours. After the solvent was removed in vacuo, the residue was dissolved in a mixture of methanol (50 ml) and THF (200 ml) and NaBH4(0.4 g) was added to the solution at −78° C. After being stirred for 4 hours at the same temperature, the solution was allowed to stand at the room temperature for 30 minutes, then poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-[[(1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (10.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH2:12].[CH3:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23](Cl)=[O:24])[CH:18]=[C:19]([CH3:21])[CH:20]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:23](=[O:24])[CH2:22][C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: Cc1cc(C)cc(CC(=O)Cl)c1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Product: COC(=O)c1cc(I)c(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-4-chloro-5-iodobenzoic acid methyl ester (2.26 g in 25 mL dichloroethane) was added (3,5-dimethylphenyl) acetyl chloride (1.2 g in 15 mL dichloroethane) and the mixture heated to 75° C. on an oil bath. After 3 hours, the reaction was cooled and the solvent removed in vacuo. The title compound was isolated by crystallization from methanol (2.7 g).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][CH3:31])[C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=1.[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]1[C:48]([C:49]2[NH:50][CH:51]=[CH:52][N:53]=2)=[CH:47][N:46]=[C:45]([NH:54][CH2:55][CH2:56][NH:57]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:44]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]1[C:48]([C:49]2[NH:53][CH:52]=[CH:51][N:50]=2)=[CH:47][N:46]=[C:45]([NH:54][CH2:55][CH2:56][NH:57][C:24]2[CH:25]=[CH:26][C:27]([N+:32]([O-:34])=[O:33])=[C:28]([NH:30][CH3:31])[N:29]=2)[N:44]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CNc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl](2-{[6-(methylamino)-5-nitro(2-pyridyl)]amino}ethyl)amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-methylamino-3-nitro-pyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CCN(C(C)C)C(C)C>CCO>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:19]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]3)[C:3]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1

Procedure:
A solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (900 mg, 3.17 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (709 mg, 3.80 mmol) and DIPEA (618 mg, 4.75 mmol) in EtOH (20 mL) was stirred at refluxed temperature for 3 hours. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc (100 mL), washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the tile compound. MS (m/z): 434 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([O:14]CC)=[O:13])[O:4][N:3]=1.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([C:12]([OH:14])=[O:13])[O:4][N:3]=1
Reactant: CCOC(=O)c1onc(C)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)noc1C(=O)O
Reaction time: 16 h

Procedure:
65 g of diethyl 3-methylisoxazole-4,5-dicarboxylate, dissolved in 100 ml of ethanol, are added dropwise to 18.9 g of potassium hydroxide in 100 ml of water at room temperature. After 16 hours, the mixture is poured onto 300 ml of water and extracted with ether, and the aqueous phase is acidified with concentration hydrochloric acid. Extracting with dichloromethane and evaporating down give 3-methyl-4-ethoxycarbonylisoxazole-5-carboxylic acid as colorless crystals of melting point 54°-58° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[S:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[S:38][C:34]([CH3:33])=[CH:35][N:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)s5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine (0.07 g, 1 eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA (0.19 ml, 3 eq) were dissolved in dichloromethane and the above solution was stirred at room temperature for 18 h. Then water was added to the mixture and the organic layer was separated. The organic layer was washed with water and the product was purified by Prep. HPLC. Yield: 65 mg (25%)1HNMR (400 MHz, CDCl3): δ 1.43-1.46 (m, 2H), 1.74-1.77 (m, 2H), 2.32 (s, 3H), 2.37 (s, 3H), 3.01-3.03 (d, J=5.2 Hz, 3H), 4.04 (s, 3H), 5.89 (m, 1H), 6.91 (s, 1H), 7.16 (t, 2H), 7.27 (m, 2H), 7.51 (d, J=4 Hz, 1H), 7.66 (s, 1H), 8.00 (m, 2H), 8.13 (s, 1H), 8.7 (s, 1H). LCMS: (ES+) m/z=570.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[C:26]5[C:21]([CH:22]=[CH:23][CH:24]=[N:25]5)=[CH:20][CH:19]=4)=[CH:14][C:13]=3[F:28])[C:8](=[O:11])[NH:9][N:10]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:38][N:39]1[CH2:43]CC[C:40]1=[O:44].CN(C)C(Cl)=O>ClCCl>[F:28][C:13]1[CH:14]=[C:15]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]=1[N:7]1[C:8](=[O:11])[NH:9][N:10]=[C:6]1[CH2:5][CH:3]1[CH2:4][N:1]([C:40]([N:39]([CH3:43])[CH3:38])=[O:44])[CH2:2]1
Reactant: CN1CCCC1=O
Reactant: O=c1[nH]nc(CC2CNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1F
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 18 %

Procedure:
In a round bottom flask under nitrogen at room temperature, a mixture of 5-(3-azetidinylmethyl)-4-[2-fluoro-4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.38 mmol) in dichloromethane (2 mL) was treated with N,N-diisopropylethylamine (0.77 mmol) by syringe and stirred for 2 min. The starting material did not dissolve. N-methyl-2-pyrrolidone (2 mL) was added to the mixture and some material dissolved. The mixture was heated with a heat gun to accelerate dissolution and was then left to cool to room temperature. Dimethylcarbamoyl chloride (0.38 mmol) was then added dropwise by syringe to the reaction, which was stirred for 1 h. The reaction mixture was concentrated to remove the dichloromethane. The resultant solution was directly purified by reverse phase HPLC (10-70% acetonitrile/water with 0.1% NH4OH) and subsequently purified by silica gel chromatography (0-3% methanol/ethyl acetate) to provide the title compound as a white solid (31 mg, 18%). MS(ES)+ m/e 447.2 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Cl.[H][H]>C(O)C.[Pt]=O>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CC(=O)NCCC1CCNCC1
Yield: 52.6 %

Procedure:
4-(2-Acetamidoethyl)pyridine (33 g.) in ethanol (250 ml.) was acidified to pH 4 with hydrochloric acid and hydrogenated at 60 p.s.i./60° C. over a platinum oxide catalyst for 18 hours, after which time the uptake of hydrogen was complete. The catalyst was then removed by filtration and the filtrate was treated with a solution of potassium hydroxide flakes in methanol (1.1 molar equivalents) and refiltered. The solvents were distilled off in vacuo, leaving a clear oil, which on standing gave 4-(2-acetamidoethyl)piperidine (18 g.) as a white solid, m.p. 60° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: Cc1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C
Temperature: 0 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
In methylene chloride (200 ml) was dissolved 2,3-dimethylpyridine (9.50 g) and the resulting solution was. cooled to 0° C. Metachloroperbenzoic acid (21.9 g) was added to the reaction mixture, followed by heating to room temperature. Stirring was conducted for 3 days. An aqueous solution of sodium sulfite was added and the resulting mixture was separated using methylene chloride (200 ml). The organic layer was dried over anhydrous magnesium sulfate, the filtrate was concentrated and the concentrate was purified by chromatography on a silica gel column (5% methanol—methylene chloride). Petroleum ether was added to the residue. Colorless powder so precipitated was collected by filtration, followed by drying, whereby the title compound (5.47 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[CH:17]1([C:2]2[CH:16]=[CH:15][C:5]3[NH:6][C:7]([CH:9]4[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]4)=[N:8][C:4]=3[CH:3]=2)[CH2:19][CH2:18]1
Reactant: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2[nH]c(C3CCNCC3)nc2cc1C1CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
The mixture of 5-bromo-2-piperidin-4-yl-1H-benzoimidazole (200 mg, 0.53 mol), cyclopropanylboronic acid (58.4 mg, 0.687 mmol), K3PO4 (391 mg, 1.85 mmol), Pd (OAc)2 (6.8 mg, 0.005 mmol) and tricyclohexylphosphine (14.9 mg, 0.053 mmol) in toluene (10 mL) and H2O (3 mL) was stirred at 90° C. under N2 for 12 h. Then it was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 5-Cyclopropyl-2-piperidin-4-yl-1H-benzoimidazole (58 mg, 30%) as white solid.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:24])=[N-]>ClCCl>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:24])=[O:18])=[CH:20][CH:21]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2ccn(-c3ccccc3)n2)cc1

Procedure:
4-(1-Phenyl-1H-pyrazol-3-yl)aminobenzoic acid (0.110 g) in dry dichloromethane was treated with an excess of ethereal diazomethane. After 5 minutes the solvents were evaporated to yield the title compound, mp 160°-161°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])N.N([O-])=O.[Na+].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc([N+](=O)[O-])c1OC
Reactant: c1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ccccn2)cc([N+](=O)[O-])c1OC
Reaction time: 0.25 h

Procedure:
10 g of finely powdered 3,4-dimethoxy-5-nitroaniline are suspended in 15 ml of 12N hydrochloric acid and 40 ml of water, whereupon the suspension is stirring at 30° for 1 hour. Thereupon, 3.8 g of sodium nitrite dissolved in 20 ml of water are added dropwise thereto at -5° within 15 minutes. The solution is stirred at -5° for 30 minutes and the cold diazonium salt solution is added dropwise within 45 minutes to 100 ml of pyridine of 40°. The mixture is subsequently stirred at 70° for 1 hour. The reaction mixture is evaporated and the residue is taken up in 300 ml of ethyl acetate. It is extracted three times with 200 ml of 2N hydrochloric acid each time. The acidic-aqueous phase is adjusted to pH 9 with conc. ammonia and extracted with methylene chloride. The combined methylene chloride extracts are dried over sodium sulfate and evaporated, and the residue is chromatographed on 250 g of silica gel with ethyl acetate. After crystallization from methylene chloride/hexane there is obtained 2-(3,4-dimethoxy-5-nitrophenyl)pyridine of m.p. 89°-90°.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=1>CCO>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:2]=[C:3]([CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[N:26]=2)[CH:25]=1
Reactant: Nc1ccc(F)cn1
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[Si](C)(C)C#CCCc1cn2cc(F)ccc2n1
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To a stirred solution of 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (2.50 g, 10.11 mmol) in EtOH (8 mL) was added potassium carbonate (350 mg, 2.53 mmol) and 5-fluoropyridin-2-amine (567 mg, 5.06 mmol). The mixture was heated at 80° C. overnight. The mixture was concentrated, the residue was dissolved in EtOAc, and the organic layer was washed with brine, dried over MgSO4 filtered and concentrated under reduced pressure. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, from DCM/MeOH: 100/0 to 96/4 as eluent) to afford 400 mg of 6-fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 30%) as an orange-brown solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].[CH2:25](O)[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>>[O:31]1[C:32]2[CH:33]=[CH:34][C:26]([CH2:25][O:20][C:19]([C:17]3[S:18][C:14]([CH3:13])=[C:15]([N+:22]([O-:24])=[O:23])[CH:16]=3)=[O:21])=[CH:27][C:28]=2[O:29][CH2:30]1
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Reactant: OCc1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1[N+](=O)[O-]
Yield: 77.8 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.75 g, 4.3 mmol), 5-methyl-4-nitro-thiophene-2-carboxylic acid (0.6 g, 3.2 mmol), and piperonyl alcohol (0.5 g, 3.3 mmol) to afford 0.8 g of 5-methyl-4-nitro-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester. A sample of the product was triturated in ethanol, cooled, filtered, and dried to give product with a mp 78-79° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][NH:10][C:9]1([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+].CCOCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][N:10]([C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[C:9]1([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)NCC(=O)N1Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)N(Cc2ccccc2)C(=O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A cold (0° C.) solution of 3-benzyl-2,2-dimethylimidazolidin-4 -one (2.28 g, 11.16 mmol) in CH2Cl2 (25 mL) was treated with benzylchloroformate (0.96 mL, 6.70 mmol), a solution of 4-dimethylaminopyridine (1.71 g, 13.95 mmol) in CH2Cl2 (10 mL), and again with benzylchloroformate (0.96 mL, 6.70 mmol). The solution was stirred for 30 min and poured into aqueous 10% KHSO4 solution. The layers were separated, and the organic was washed twice with water and once with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford an orange oil. The oil was treated with Et2O causing a precipitate which was filtered to afford the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 10H), 5.14 (s, 2H), 4.54 (s, 2H), 4.11 (s, 6H), 1.56 (s, 6H); ES MS (M+1)=339.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:42])[NH2:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 54 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 54% of theory, C27H29N7O3 (499.6) ##EQU49##
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([NH2:22])[CH:16]=2)=[O:12])([CH3:4])([CH3:3])[CH3:2].FC1C([O:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][C:39]([C:43](=[O:55])[NH:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:38][CH:37]=3)=O)=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:51]([O:50][C:48](=[O:49])[NH:47][CH2:46][CH2:45][NH:44][C:43]([C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:32](=[O:31])[NH:22][C:17]1[CH:16]=[C:15]3[C:20]([CH:21]=[C:13]([C:11](=[O:12])[NH:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23])[NH:14]3)=[CH:19][CH:18]=1)=[CH:42]2)=[O:55])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2ccc(N)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Nc3ccc4cc(C(=O)NCCNC(=O)OC(C)(C)C)[nH]c4c3)cc2c1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
A mixture of above amine 36 and compound 33 (0.226 g, 0.44 mmol) in dry DMF (6 ml) in the presence of DIEA (77 μl, 0.44 mmol) was stirred at 55° C. for 2 days. After removal of solvent, the residue was recrystalized from MeOH-ether to give compound 37 in a quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.CO.[CH2:13](Cl)CCl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: Cc1cccc(C(=O)O)n1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) in methylene chloride (200 mL) cooled to 0° C. is added methanol (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and EDC (18.2 g, 94.8 mmol). The mixture is stirred at room temperature for 6 h, washed with water and brine, and dried over sodium sulfate. The mixture is filtered and concentrated in vacuo. The residue is chromatographed on SiO2 (50% ethyl acetate/hexanes) to yield the title compound, 9.66 g (92%), as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[C:4]([Cl:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:19]=[C:18]([Cl:20])[C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]1=[O:17]
Reactant: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1N(Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCC12CCCCC2
Temperature: 90 °C
Yield: 102.7 %

Procedure:
Purged with N2 a mixture of 2-(4-bromo-2,6-dichloro-benzyl)-2-aza-spiro[4.5]decan-1-one (0.091 g, 0.23 mmol) and 4-fluorophenylboronic acid (0.097 g, 0.69 mmol) in toluene (6 mL) and 2M sodium carbonate (0.8 mL). Treat the reaction with Pd(PPh3)4 (0.013 g, 0.011 mmol) and heat to 90° C. for 2 hours under N2. Cool the reaction and dilute with ethyl acetate, and then wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.096 g (100%) of the titled product. Rf=0.25 (3/1 hexanes/ethyl acetate). MS (m/z): 406 (M+).