Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=1)[CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[OH:4].[C:30]1([C:41](O)=[O:42])[CH:31]=[CH:32][CH:33]=[C:34]2[CH2:40][CH2:39][CH2:38][CH:37]=[CH:36][C:35]=12.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[OH:4][CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[CH:2]([NH:1][C:41]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[CH2:40][CH2:39][CH2:38][CH:37]=[CH:36][C:35]=12)=[O:42])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.1 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol (310 mg, 0.73 mmol) in acetonitrile (10 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (132 mg, 0.70 mmol) and 1-hydroxybenzotriazole monohydrate (112 mg, 0.73 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol) was finally added. The mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, 2:1) and recrystallization (hexane-ethyl acetate) to give N-{(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (247 mg, 59%) as colorless crystals.
Reaction SMILES: COC1C=CC(C(C2C=C[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19](=O)[C:20]4[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22]C=4)[CH:15]=3)C=2)=O)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH2:35]>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH:16]1[CH:15]=[C:14]([C:19]2[CH:20]=[CH:25][CH:24]=[C:23]([OH:26])[CH:22]=2)[C:13]([OH:35])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)c2ccc3cc(C(=O)c4ccc(OC)cc4)ccc3c2)cc1
Reactant: O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A 2.5 liter sulfonation flask fitted with thermometer, stirrer, condenser and nitrogen inlet is charged with 153 g (0.39 g mol) of 2,6-bis(4-methoxybenzoyl)naphthalene in 1350 ml of toluene and, with stirring, 282.7 g (2.12 mol) of aluminium chloride are added in portions over 15 minutes at 8° C. The reaction mixture is stirred for 4 hours at 75° C., then cooled to room temperature, and charged into 10 liters of water with vigorous stirring. The resultant suspension is filtered and the residue is vacuum dried at 130° C., giving 142.4 g (99.9% of theory) of a brownish powder which melts at 307° C. 67 g of the crude product are dissolved warm in 320.1 g 5% aqueous sodium hydroxide, and the solution is dried over Hyflo (filter aid based on diatomaceous earth (kieselguhr)) and the clear filtrate is charged to 2 liters of water containing 39.5 g of 37% of hydrochloric acid. The precipitated product is filtered, washed with water and vacuum dried at 130° C., giving 62.3 g (92.8% of theory) of the desired diphenol. The product melts at 307° C.
Reaction SMILES: C1C2C(=CC=CC=2)CC1C#N.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.[CH3:24][C@H:25]1[CH2:30][N:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=2)[CH2:28][C@@H:27]([CH3:42])[N:26]1[S:43]([C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[CH2:48][CH:49]([C:55]([NH2:57])=O)[CH2:50]2)(=[O:45])=[O:44]>ClC(Cl)C>[CH3:24][C@H:25]1[CH2:30][N:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:33][CH:32]=2)[CH2:28][C@@H:27]([CH3:42])[N:26]1[S:43]([C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[CH2:48][CH:49]([C:55]#[N:57])[CH2:50]2)(=[O:45])=[O:44]
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C(N)=O)C2
Agent: N#CC1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C#N)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.4 %

Procedure:
4-|cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl|-indan-2-carbonitrile. Triethylamine (200 μL, 1.4349 mmol) and phosphorus oxychloride (74 μL, 0.7939 mmol) were added to a solution of 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid amide (254 mg, 0.5105 mmol) in dichloroethane (3 mL). The reaction was stirred for 4 h at room temperature then directly purified by silica gel column chromatography (0-50% EtOAc in hexanes) to afford 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carbonitrile (23 mg, 9%). 1H NMR (400 MHz, CD3OD) δ ppm 7.77 (d, 1H), 7.54 (d, 1H), 7.42 (t, 1H), 7.10 (d, 2H), 6.93 (d, 2H), 4.20-4.00 (m, 2H), 3.65-3.60 (m, 1H), 3.60-3.40 (m, 2H), 3.40-3.20 (m, 4H), 2.80-2.60 (m, 2H), 1.50 (d, 6H). LCMS: 480.0 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.O1CCOCC1>C(O)C>[CH2:18]([O:25]/[N:26]=[C:1](/[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)\[CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: C/C(=N\OCc1ccccc1)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (500 mg, 2.281 mmol) in ethanol (6.91 mL) was added O-benzylhydroxylamine hydrochloride (728 mg, 4.56 mmol) and HCl 4N in dioxane (0.277 mL, 9.12 mmol). The mixture was stirred at 65° C. for 1 hour, filtered, and then concentrated in vacuo. Saturated sodium bicarbonate added to the residue, extracted with ethyl acetate twice, dried over MgSO4, filtered, and concentrated in vacuo. Methanol/CH2Cl2 (50/50) was added, then the precipitate was filtered and dried, giving (E)-4-(4-(1-(benzyloxyimino)ethyl)-phenyl)-1,2,4-triazolidine-3,5-dione (I-5a: 167 mg, 23%) as a white solid. LC-MS (M+1) 325.1, t=1.77 minutes. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3 H) 7.68 (d, J=8.84 Hz, 2 H) 8.05 (d, J=8.59 Hz, 2 H) 10.65 (s, 2 H). 1H NMR (400 MHz, CD3CN) δ ppm 2.29 (s, 3 H) 5.26 (s, 2 H) 7.37 (d, J=7.07 Hz, 1 H) 7.42 (t, J=7.33 Hz, 2 H) 7.45-7.50 (m, 2 H) 7.53 (d, J=8.59 Hz, 2 H) 7.75-7.93 (m, 4 H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.CN1CCOCC1.[NH2:21][C@@H:22]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:23][OH:24].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)C.CO>[OH:24][CH2:23][C@@H:22]([NH:21][C:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cn1c(C(=O)N[C@H](CO)Cc2ccccc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
To a stirred solution of 1-methyl-2-indolecarboxylic acid (100 mg, 0.57 mmol) in methylene chloride (1 mL) was added N-methylmorpholine (0.063 mL, 0.57 mmol) followed by (S)-(−)-2-amino-3-phenyl-1-propanol (86 mg, 0.57 mmol), 1-hydroxybenzotriazole hydrate (81 mg, 0.60 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120 mg, 0.63 mmol). The resulting mixture was stirred at room temperature for 20 h. The reaction was diluted with methylene chloride and washed sequentially with 10% citric acid, saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a crude oil. Trituration of the crude oil with methanol and diethyl ether afforded the title compound (68%, 119.7 mg) as an off-white solid. MS (ES) m/e 309.4 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].[OH-].[Na+]>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][S:33]([CH2:32][CH2:31][CH2:30][Cl:29])(=[O:35])=[O:34])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(NS(=O)(=O)CCCCl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-amine (0.15 g, 0.49 mmol) in ethyl acetate (18 mL), cooled to 0° C., was added triethylamine (0.274 mL, 1.37 mmol) then 3-chloro-1-propanesulfonyl chloride (0.070 mL, 0.576 mmol), and the reaction mixture allowed to warm to room temperature. After stirring for 1 h, the reaction was basified with 1N sodium hydroxide (2.5 mL), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to yield the title compound as an oil. This crude product was used in the next step without further purification.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1.O.C(=O)(O)[O-].[Na+]>ClCCl>[F:7][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@H](F)C1
Temperature: -78 °C

Procedure:
A 5-L, 3-neck, round bottom flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 375 mL (2.84 mol) of (diethylamino)sulfur trifluoride and 400 mL of dichloromethane. The solution was cooled to −78° C. To this was added via addition funnel a solution of 304 g (1.37 mol) of benzyl(3R)-3-hydroxypyrrolidine-1-carboxylate in 400 mL of dichloromethane over a 2-h period keeping the reaction temperature <−70° C. The reaction mixture was allowed to stir and warm slowly to ambient temperature overnight. The reaction mixture was added portion-wise with caution to a large extractor containing ice, water, and saturated aqueous sodium bicarbonate solution. The mixture was extracted with 8 L of ethyl acetate. The organic layer was washed with saturated aqueous brine, dried over magnesium sulfate, and concentrated to give a brown oil. Purification by flash chromatography (silica gel, eluting with a 10 to 30% ethyl acetate/hexane gradient) gave the title compound as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[OH-].[K+].[N+:11]([CH2:13][C:14]([N:16]1[CH2:20][CH:19]=[CH:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[O:8][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:20][CH:19]=[CH:18][CH2:17]2)=[O:15])=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: [C-]#[N+]CC(=O)N1CC=CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccncc1)N1CC=CC1
Reaction time: 2 h
Yield: 53 %

Procedure:
SLA 07158 was prepared in accordance with method D using pyridine-4-carbaldehyde (0.293 mL, 2.40 mmol), KOH (0.13 g, 2.32 mmol) in methanol (10 mL) and 2-isocyano-1-(2H-pyrrol-1(5H)-yl)ethanone SLA 07178 (0.301 g, 2.20 mmol). The solution was stirred 2 h with continued cooling. After work-up and column chromatography on florisil (EtOAc), trans-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(2H-pyrrol-1(5H)-yl)methanone SLA 07180 was obtained (0.284 g, 53% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38]>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:26])([F:28])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:19]=1)=[O:38]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Product: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2Cl)c1

Procedure:
The title compound was prepared from {3-[3-(2-methylphenyl)-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-chlorophenyl isocyanate in substantially the same manner as described in Example 65; off-white solid: mp 224-226° C.; MS (EI) m/z 532 (M+H)+.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]([OH:26])[CH:22]([OH:25])[CH2:23]O>>[C:1]([O:20][CH2:23][CH:22]([OH:25])[CH2:21][OH:26])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
Octadecanoic acid, monoester with 1,2,3-propanetriol
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH:47][C:48]([C:50]1[C:58]2[NH:57][C:56]([NH2:59])=[N:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49].C([O-])(O)=O.[Na+]>CN(C=O)C.CCN(C(C)C)C(C)C.O>[NH:44]1[CH:45]=[CH:46][N:42]=[C:43]1[NH:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH:59][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)[N:14]=3)=[O:17])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: N#Cc1cccc(-c2cccc(C(=O)O)n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cccc(-c2cccc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)n2)c1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
0.12 g (0.51 mmol) of 6-(3-cyano-phenyl)-pyridine-2-carboxylic acid, 0.19 g (0.5 mmol) of HBTU in a mixture of 2.0 ml of DMF and 0.26 mL of DIEA was reacted with 0.1 g (0.41 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) as described in general procedure A. The reaction mixture was cooled to r.t. and 5.0 mL of water and 5.0 mL of saturated NaHCO3 was added. The resulting solid was filtered, and the solid was washed with water and ether and dried to provide 0.04 g (17.5%) of 2-{[6-(3-cyano-phenyl)-pyridine-2-carbonyl]-amino}-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. 1H-NMR (400 MHz, DMSO): 9.15 (s, 1H), 8.86 (s, 1H), 8.45(m, 1H), 8.24 (m, 2H), 7.99 (d, 1H), 7.92 (d, 1H), 7.87 (d, 1H), 7.72 (t, 1H), 7.41(t, 1H), 7.30 (s, 2H) ppm. LCMS: 449 (M+1)+.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH:23]=[C:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:19]2[CH2:20][CH:21]=[C:22]([C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: N#Cc1ccc(C2=CCNCC2)cc1
Product: N#Cc1ccc(C2=CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
According to the procedure described for the synthesis of example 1, the title compound has been synthesized from 2-morpholin-4-yl-5-nitro-benzoyl chloride and 4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-benzonitrile (CAS: 460365-22-4). MS (m/e): 417.0 (M−H, 100%)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][O:37][CH2:38][CH2:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH2:39][CH2:38][O:37][CH3:36])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 55.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 99, 1 g, 2 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (1.2 g, 5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (140 mg, 0.2 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-{1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-1H-pyrrolo[2,3-b]pyridine (0.6 g, 57%) as a white solid: LC/MS m/e calcd for C27H27FN2O5S2 [M+H]+ 543.65, observed 543.0.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[NH:5][N:4]=1.Br[CH2:15][C:16]([NH:18][C:19]1[S:23][C:22]2[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=2[C:20]=1[C:28]([NH2:30])=[O:29])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[N:4]=1
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: FC(F)(F)c1n[nH]c2ccncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3cnccc32)sc2c1CCCC2
Temperature: 60 °C
Yield: 4.7 %

Procedure:
A mixture of 3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (20 mg, 0.107 mmol), 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (33.9 mg, 0.107 mmol) and potassium carbonate (29.5 mg, 0.214 mmol) in DMF (0.5 mL) was heated to 60° C. and this temperature maintained for 2 h. The reaction mixture was allowed to cool to RT, and purified by preparative reverse phase HPLC to give a white solid (2.1 mg, 5 μmol, 4.6%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:27][CH2:28][CH3:29])[C:5](=[O:26])[CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].[Cl:30][C:31]1[C:32]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH:48]=O)[CH:42]=2)=[N:33][N:34]([CH3:40])[C:35]=1[O:36][CH:37]([F:39])[F:38]>CN(C)C=O>[Cl:30][C:31]1[C:32]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH:48]=[CH:6][C:5](=[O:26])[CH:4]([O:27][CH2:28][CH3:29])[O:3][CH2:1][CH3:2])[CH:42]=2)=[N:33][N:34]([CH3:40])[C:35]=1[O:36][CH:37]([F:38])[F:39]
Reactant: Cn1nc(-c2ccc(Cl)c(C=O)c2)c(Cl)c1OC(F)F
Reactant: CCOC(OCC)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(OCC)C(=O)C=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 85 °C

Procedure:
5.1 g of (3,3-diethoxy-2-oxopropylidene)(triphenyl)phosphorane were added to a solution of 2 g (6.2 mmol) of 4-chloro-3-(4-chloro-3-formylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 20 ml of dimethylformamide, and the mixture was hen heated at 80-90° C. for 5 hours. The mixture was then concentrated and the crude product thus obtained was purified by chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 2.1 g.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](C1N=CC2C(C=1)=CC=CC=2)=[O:17].[C:38]([OH:41])(=O)[CH3:39]>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:4]1[CH:9]=[CH:39][C:38]([OH:41])=[N:1][CH:5]=1
Reactant: CC(=O)O
Reactant: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1cc2ccccc2cn1
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccc(O)nc1
Reaction time: 0.5 h

Procedure:
To a solution of the above amine (63 mg, 0.14 mmol) in acetic acid (2 mL) was added hydrobromide saturated acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether four times to afford the title compound as a white solid (80 mg), which was dried in vacuo. 1H NMR (D2O) δ 1.81-2.01 (m, 4H), 2.16-2.20 (m, 1H), 2.37-2.41 (m, 1H), 2.50-2.59 (m, 1H), 2.87-2.92 (m, 1H), 3.00 (br s, 2H), 3.11-3.16 (m, 1H), 3.37-3.42 (m, 1H), 3.53 (q, 1H, J=6.0 Hz), 4.25 (ABq, 2H, J=43.8, 15.3 Hz), 4.57-4.79 (m, 1H), 6.36 (d, 1H, J=9.6 Hz), 7.46-7.48 (m, 2H), 7.53 (s, 1H), 7.57-7.63 (m, 3H), 7.85 (t, 1H, J=6.3 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.65 (d, 1H, J=5.4 Hz). 13C NMR (D2O) δ 20.33, 20.45, 36.87, 47.77, 48.22, 59.04, 114.10, 119.38, 125.90, 126.99, 130.69, 137.16, 139.46, 139.85, 140.66, 148.01, 150.87, 151.39. ES-MS m/z 457 [M+H]+. Anal. Calcd. for C26H28N6O2−.3.0HBr.3.4H2O.0.2C4H10O: C, 41.52; H, 5.17; N, 10.84; Br, 30.92. Found: C, 41.70; H, 4.90; N, 10.71; Br, 30.63.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:25]=[CH:26][C:27]1[CH:35]=[CH:34][C:32]([OH:33])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C)C=O>O>[CH:26]([C:27]1[CH:35]=[CH:34][C:32]([O:33][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:25]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of methyl 4-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate (0.80 g), potassium carbonate (0.40 g), vanillin (0.44 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 4-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (1.02 g, 92%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 185-186° C.