Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:15][O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:43]=1[NH:44][C:45]([NH:47][CH:48]1[CH2:50][CH2:49]1)=[O:46])[O:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([OH:40])=[C:34]([C:37]([NH2:39])=[O:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:43]=1[NH:44][C:45]([NH:47][CH:48]1[CH2:50][CH2:49]1)=[O:46])[O:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH2:15][C@H:13]([OH:14])[CH2:12][N:30]([CH2:31][CH3:32])[CH2:29][CH3:28])=[C:34]([C:37]([NH2:39])=[O:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: NC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O

Procedure:
After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (308 mg, 1.35 mmol), potassium carbonate (149 mg, 1.08 mmol) and dimethylformamide (9 ml) to 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide (372.0 mg, 0.90 mmol),
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][N:13]=1)(=[O:10])[CH:7]([CH3:9])[CH3:8].C(O)(=O)C.N>C(#N)C>[C:6]([NH:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH2:19][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[OH:21])=[CH:14][N:13]=1)(=[O:10])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: CC(C)C(=O)Nc1ncc(C(=O)CBr)cn1
Agent: N
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1ncc(C(O)CNC(C)(C)C)cn1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.146 g of tert. -butylamine in 200 ml of dry acetonitrile, 2.05 g of solid 2-isobutyramido-5-(bromoacetyl)pyrimidine was added. The reaction mixture was stirred for 30 minutes and then gaseous hydrochloric acid was bubbled into the reaction mixture. The reaction mixture was then diluted with 300 ml of ether and the resulting precipitate collected by filtration. The precipitate was dissolved in 43 ml of anhydrous methanol and the resulting solution cooled to 5° C. Sodium borohydride (1.46 g) was slowly added (vigorous reaction) to this solution and the resulting mixture stirred for 1 hour in the cold. Acetic acid (5 ml) was added and then the pH of the reaction mixture was adjusted with concentrated aqueous ammonia to approximately pH 6. This solution was extracted with methylene chloride (3×50 ml). The combined extracts were washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The extracts were concentrated and the residue chromatographed on silica gel (90/10/1 methylene chloride/methanol/ ammonia) to afford 980 mg of product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[Cl:18][S:19](O)(=[O:21])=[O:20]>C(Cl)Cl>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:6][C:2]1[S:1][C:5]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccs1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a cold (−78° C.) solution of 2-(thien-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (6.78 g, 27.87 mmol) in DCM (56 mL) was added dropwise (in about 10 min) chlorosulfonic acid (16.237 g, 139.3 mmol, 9.33 mL, d: 1.74) diluted in DCM (9.3 mL). The reaction mixture was stirred 2 h at −78° C., then 1 h at −40° C. and overnight at rt. The resulting brown solution was poured on ice. The mixture was extracted with DCM (3×200 mL), and the combined organic layers were washed with water (3×200 mL), dried over MgSO4, filtered and concentrated to afford a yellowish oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 1/3 to 1/2 in about 1 h) to give the title compound as a white solid (6.42 g, 67%). 1H NMR (CDCl3, 300 MHz) δ 7.89 (d, 1H. J=5.5 Hz), 7.87 (d, 1H. J=5.5 Hz), 7.76 (d, 1H, J=5.5 Hz), 7.75 (d, 1H, J=5.5 Hz), 7.71 (d, 1H, J=4.0 Hz), 7.18 (d, 1H, J=4.0 Hz), 5.05 (s, 2H). HPLC (Condition A), Rt: 4.6 min (HPLC purity: 94.8%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O.CO.C([BH3-])#N.[Na+]>C(O)(=O)C.C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH:12]([CH3:14])[CH3:11])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-fluorophenethylamine (1.4 g) in acetic acid (10 mL) was added dropwise acetone (0.82 mL) and methanol (20 mL). After sodium cyano-borohydride (0.64 g) was added, and the solution was stirred at room temperature for 2.5 hours. After adding water and diluting with ethyl acetate, the solution was washed with water and saturated sodium chloride water. After drying with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by NAM silica gel column chromatography (hexane/ethyl acetate), and the title compound (0.62 g) was obtained as colorless solids.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27]I>CN(C)C=O>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CI
Reactant: CCOC(=O)C(C#N)c1cccc(Sc2ccccc2C)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C#N)c1cccc(Sc2ccccc2C)c1OC
Yield: 102.2 %

Procedure:
Sodium hydride (65%, 1.05 g), ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]acetate (9.4 g), methyl iodide (7.85 g) and dimethylformamide (40 ml) were treated in a similar manner to that of Example 22-(2) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]propionate (10.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:4]3[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=3[O:2][CH3:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: COc1cc(C)ccc1O
Product: COc1cc(C)ccc1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared starting from 2-methoxy-4-methylphenol (162 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 mmol; prepared in Example 52, Step 2) to give 233 mg (67%) of a yellow solid. HRMS m/z calcd for C18H24N4O3(M)+344.1848, found 344.1839.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][O:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[O:22][CH3:21])[CH2:28]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2ccccc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccccc3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-phenylquinazolin-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 19 (11% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.73 and 2.99 (2t, 2H), 3.49 and 4.04 (2t, 2H), 3.69 and 3.75 (2s, 3H), 3.76 and 3.81 (2s, 3H), 4.42 and 4.94 (2s, 2H), 6.63 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.57-7.60 (m, 3H), 7.77-7.79 (m, 1H), 7.89-8.00 (2d, 1H), 8.07-8.19 (m, 2H), 8.50-8.57 (m, 2H); MS (ESI) m/z 426 ([M+H]+).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:9]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:22][C:8]=2[C:7]=1[OH:29])=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>C[O-].[Na+].CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:22][C:8]=3[C:7]([OH:29])=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])[N:11]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccc(C#N)cc2)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2nc(C(=O)NCC(=O)O)c(O)c3sc(-c4ccccc4)nc23)cc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A mixture of 4-(4-cyano-phenyl)-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (132 mg, 0.33 mmole) and glycine (2.46 g, 32.8 mmole) in 0.5 M sodium methoxide/methanol (49 ml) was refluxed for 16 h before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (100 ml) and extracted with dichloromethane (2×50 ml). The remaining aqueous solution was acidified to pH=2 with 0.1 N HCl (28 ml). The resulting precipitate was filtered, washed with water and dried to give the title compound as a white solid (76 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.56 (t, 1H), 8.91 (d, J=8.2 Hz, 2H), 8.19 (m, 2H), 8.00 (d, J=8.2 Hz, 2H), 7.64 (m, 3H), 4.07 (d, J=6.2 Hz, 2H); MS: (+) m/z 429.23 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:15]2[O:16][CH:17]=[CH:18][C:14]=2[CH:13]=[C:12]([CH2:19][CH:20]([O:26][CH:27]([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:15]2[O:16][CH2:17][CH2:18][C:14]=2[CH:13]=[C:12]([CH2:19][CH:20]([O:26][CH:27]([CH3:28])[CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1cc(CNC(=O)OC(C)(C)C)c2occc2c1)OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc2c(c(CNC(=O)OC(C)(C)C)c1)OCC2)OC(C)C
Yield: 92.6 %

Procedure:
29 mg of ethyl 3-(7-[(tertiary butoxycarbonyl)amino]methylbenzo[b]furan-5-yl)-2-isopropoxypropionate was dissolved in ethanol, and 30 mg of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 3 days in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated, to give 27 mg of ethyl 3-(7-[(tertiary butoxycarbonyl)amino]methyl-2,3-dihydrobenzo[b]furan-5-yl)-2-isopropoxypropionate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[C:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=O)#[CH:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[C:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)#[CH:15]
Reactant: C#Cc1cnccc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: C#Cc1cnccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
A mixture of 0.29 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.27 g of 3-ethynylisonicotinic acid, 0.35 g of WSC and 8 ml of pyridine was stirred for 2 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 2-(3-ethynylpyridin-4-yl-)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 211).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([NH:14][C:15]([CH3:19])([CH3:18])[CH:16]=O)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CO.C(OCC)C.[Cl-].[NH4+]>[C:7]([NH:14][C:15]([CH3:18])([C:16]#[CH:1])[CH3:19])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: C#CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a solution of dimethyl 1-diazo-2-oxopropyl phosphonate (see Ohira, S. Synth. Commun. 19, 561-564, (1989)) (2.97 g, 15.5 mmol) in methanol (50 ml) at 0° C. was added potassium carbonate (1.71 g, 12.4 mmol) and slowly a solution of N-Boc-2-amino-2-methyl-propionaldehyde (1.45 g, 7.74 mmol) in methanol (5 ml). The reaction mixture was stirred at 0-10° C. for additional 6 h, diluted with diethylether (˜150 ml) and with saturated aqueous ammonium chloride solution (150 ml). The organic layer was washed with saturated aqueous ammonium chloride solution (100 ml), water (100 ml), and finally with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography over silica gel using ethyl acetate/hexane (1/10) provided N-Boc-2-amino-2-methylbut-3-yne (1.38 g) as yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[C:18]([O:20][CH3:21])=[O:19]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[N:14]([C:18]([O:20][CH3:21])=[O:19])[N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Reactant: COC(=O)Cl
Solvent: Cc1ccccc1C
Product: COC(=O)n1nc(-c2cc(Cl)c(C)c(Cl)c2)ccc1=O
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 2.55 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone, 4.7 g of methyl chloroformate and 25 ml of xylene was heated under reflux for 1.5 hours. The reaction mixture was then left to cool at room temperature and the precipitate thus produced was collected by filtration and washed with hexane, giving 2.94 g (94%) of the desired Compound No. 23 in the form of colourless prisms having, after recrystallization from benzene, a melting point of 203°-206° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C1COCC1.CO>[CH3:24][O:14][C:13]([C@:9]1([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(Cc1ccccc1)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@]1(Cc2ccccc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirred solution of (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.23 g, 4.0 mmol) in THF (10 mL) and methanol (10 mL) at 0° C. under nitrogen was added TMS-diazomethane (5.0 mL of a 2.0 M solution in hexanes, 5.0 mmol) dropwise. The reaction mixture was warmed to ambient temperature then concentrated in vacuo to an oil (1.36 g). Purification by chromatography (silica, 5-15% EtOAc in hexanes) gave (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.03 g, 3.23 mmol, 81%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:25]([F:28])([F:27])[F:26])=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[O:8])[N:6]=1.Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]23[CH2:43][CH2:42][C:39]([CH2:44][C:45]([O:47][CH3:48])=[O:46])([CH2:40][CH2:41]2)[O:38][CH2:37]3)=[CH:32][CH:31]=1.O.[F-].[Cs+]>O1CCOCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:1][C:2]1[O:3][C:4]([C:25]([F:26])([F:27])[F:28])=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:30]3[CH:31]=[CH:32][C:33]([C:36]45[CH2:41][CH2:40][C:39]([CH2:44][C:45]([O:47][CH3:48])=[O:46])([CH2:42][CH2:43]4)[O:38][CH2:37]5)=[CH:34][CH:35]=3)=[CH:14][CH:15]=2)=[O:8])[N:6]=1
Reactant: COC(=O)CC12CCC(c3ccc(Br)cc3)(CC1)CO2
Reactant: Cc1nc(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C(F)(F)F)o1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(NC(=O)c5nc(C)oc5C(F)(F)F)cc4)cc3)(CC1)CO2
Temperature: 90 °C
Yield: 50 %

Procedure:
To a mixture of 2-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)oxazole-4-carboxamide (300 mg, 0.757 mmol) and methyl 2-(4-(4-bromophenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (257 mg, 0.757 mmol) in dioxane (3 ml) was added H2O (0.33 ml) at room temperature. CsF (345 mg, 2.272 mmol) and Pd(amphos)Cl2 (53.6 mg, 0.076 mmol) were added and the mixture was degassed several times before being heated to 90° C. for overnight. The reaction mixture was cooled to room temperature and directly purified by column chromatography to afford the title compound as white solid after drying (200 mg, 50% yield). LC/MS, ESI-MS(+): 529.0, RT: 1.52 (Condition E).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH:17]=[CH2:18])[N:8]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2/[CH:17]=[CH:18]/[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:8]=1
Reactant: C=Cc1cccc2nc(NCc3ccccc3OC)ccc12
Reactant: Brc1cccnc1
Product: COc1ccccc1CNc1ccc2c(/C=C/c3cccnc3)cccc2n1

Procedure:
(2-Methoxy-benzyl)-(5-vinyl-quinolin-2-yl)-amine (150 mg, 0.517 mmol) was reacted with 3-bromopyridine (108 mg, 0.688 mmol) as described in example 2 step B. The title compound was obtained as a light brown solid (93 mg, 49%), MS: m/e=368.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:27]1[CH:31]=[C:30]([CH2:32][OH:33])[N:29]=[CH:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:34]([O:41][CH:42]([C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=1)[C:43](O)=[O:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>ClCCl>[Si:34]([O:41][CH:42]([C:46]1[CH:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=1)[C:43]([O:33][CH2:32][C:30]1[N:29]=[CH:28][N:27]([C:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:31]=1)=[O:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)O)c1ccc(C#N)cc1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(C(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mmol of triethylamine and 1.0 mmol propanephosphonic acid cyclic anhydride [68957-94-8] (50% in ethyl acetate) are added to a solution of 1.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol [33769-07-2] and 1.0 mmol of (tert-butyldimethylsilanyloxy)(4-cyanophenyl)acetic acid in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature for 3 hours and diluted with dichloromethane. The phases are separated and the organic phase is washed with 1M HCl and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: Br[C:2]1[S:6][C:5](/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.B([O-])([O-])O[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C(CCO)=CC=CC=1.O.O1CCCC1.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.O>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[S:6][C:5](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)/C=C/c1ccc(Br)s1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(/C=C/C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 48 %

Procedure:
Under argon atmosphere, a solution of methyl (E)-3-(5-bromothiophen-2-yl)acrylate (4.0 g), 4-methylphenyl borate (2.64 g) and potassium carbonate (4.48 g) in toluene-ethanol-water (160-16-16 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.56 g), and the mixture was refluxed for 16 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give crude product (5.24 g). To a solution of the resulting carboxylic acid ester (5.24 g) in tetrahydrofuran (100 ml) was added 1N sodium hydroxide (20 ml) at room temperature, and the mixture was stirred for 5 days. To the reaction mixture was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give (E)-3-[5-(4-methylphenyl)-thiophen-2-yl]acrylic acid (1.9 g) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:4]2[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:4]2[CH:3]=1)(=[O:23])[CH3:22]
Reactant: Oc1cc2nc(-c3ccccc3)nn2c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2nc(-c3ccccc3)nn2c2ccccc12
Reaction time: 12 h

Procedure:
0.8 Gram (0.00306 mole) of the compound of Example 1 is dissolved in 10 ml. of pyridine, then 1 ml. of acetic acid anhydride is added and the resulting mixture is kept at room temperature for about 12 hours. The obtained precipitate is purified by column chromatography and eluting with a mixture of chloroform:methanol=98.2. After recrystallization from a mixture of methanol and methylene chloride, 0.200 g. of the title compound is obtained, m.p. 200°-202° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH2:14])=[NH:13].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>>[CH3:1][CH:2]([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[NH:14][C:19](=[O:18])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][N:13]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)COc1ccccc1NC(=N)N
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a solution of N-[2-(2-methylpropoxy)phenyl]guanidine (89 g) in denatured alcohol (300 ml) is added dropwise diethyl ethoxymethylenemalonate (93 g), and the mixture is refluxed with stirring for 3 hours. After cooling, the precipitate is collected by filtration, washed with denatured alcohol and petroleum ether and dried to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (94 g). M.p. 188°-190° C.