Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([O:23]CC)(=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:14]([CH2:15][C:16](=[CH:1][C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])([OH:23])=[O:22]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cc(OC)c(O)c(OC)c1)CC(=O)O
Temperature: 0 °C
Yield: 48 %

Procedure:
A 3.6 g of syringaldehyde and 5 ml of diethyl succinate were dissolved in 60 ml of tetrahydrofuran. To the solution was added 4.9 g of potassium t-butoxide, and the mixture was heated under reflux for 24 hours. The mixture was poured into ice water. The aqueous solution was acidified with 6N hydrochloric acid and extracted with 100 ml of ethyl acetate. An organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 3 g (yield 48%) of ethyl α-carboxymethyl-3,5-dimethoxy-4-hydroxycinnamate. The product was dissolved in 20 ml of N,N-dimethylformamide. To the solution was added 2.1 g of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added methanol to filter off an insoluble material, which was washed with methanol and dried to give 2 g (yield 80%) of the corresponding acid anhydride compound.
Reaction SMILES: [C:1]([C:5]1[Se:9][C:8]([C:10]#[N:11])=[C:7]([OH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:13]S(O)(=O)=O>FC(F)(F)C(O)=O>[C:1]([C:5]1[Se:9][C:8]([C:10]([NH2:11])=[O:13])=[C:7]([OH:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)c(C#N)[se]1
Reactant: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(O)c(C(N)=O)[se]1
Temperature: 0 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To an ice cold solution of 5-tert-butyl-3-hydroxyselenophene-2-carbonitrile (0.5 g) in trifluoroacetic acid (2 mL) was added H2SO4 (0.5 mL) dropwise for 15 min. The reaction mixture was allowed to rt and stirred for 6 h. The reaction mixture was poured into ice cold water extracted with chloroform (3×50 mL). The combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (75:25) as eluents to give the product as a brown color solid (460 mg, 86%), mp 164-168° C. 1H NMR (400 MHz, CDCl3): δ 11.53 (1H, br s), 6.81 (1H, s), 5.35 (2H, s), 1.35 (9H, s); LC-MS (negative ion mode): m/z 244, 246 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[C:3]=1[CH3:19].[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:3]1([CH3:19])[C:4]2[C:5](=[O:18])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:17])[C:13]=2[C:14]([CH3:16])=[CH:15][CH2:2]1
Reactant: Cc1cc(Cl)c(C)c2c1C(=O)c1ccccc1C2=O
Reactant: OCCN1CCNCC1
Solvent: O
Product: CC1=CCC(C)(C2CNCCN2CCO)C2=C1C(=O)c1ccccc1C2=O
Temperature: 150 °C

Procedure:
A mixture of 2-chloro-1,4-dimethylanthraquinone (1 g) and 1-(2-hydroxyethyl)piperazine (5 g) is heated at 150° C. for 30 min. After cooling to room temperature, water is added, and the material is filtered. Recrystallization from chloroform yields 1-[1-(2-hydroxyethyl)piperazinyl]-1,4-dimethylanthraquinone.
Reaction SMILES: [N:1]1([C:8]2[C:9](=[O:22])[NH:10][CH:11]3[CH:16]([N:17]=2)[CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[N:1]1([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1=CC2N=C(N3CCCCCC3)C(=O)NC2C=C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-oxo-1,2,4a,8a-tetrahydroquinoxaline-6-carboxylate (150.0 mg, 0.50 mmol) in dichloromethane (50 mL) was added pyridine (210 mg, 2.64 mmol) and Tf2O (375 mg, 1.32 mmol) with stirring overnight under atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3×15 mL), the organic layers combined and dried over anhydrous magnesium sulfate, concentrated in vacuo to afford methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude), which was used directly in the next step.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][O:13][CH2:14][CH2:15]Br.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:15][CH2:14][O:13][CH3:12])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(C=O)cc1OC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a flask was added vanillin (3.28 g, 21.6 mmol) and 2-bromoethyl methyl ether (3.04 mL, 1.5 equiv) in a solution of DMF (20 mL). K2CO3 (5.5 g, 2 equiv) was then added to the solution and the reaction slurry was stirred at 90° C. for 16 h under N2. The reaction solution was diluted with EtOAc (100 mL), filtered, washed with sat NH4Cl, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was chromatographed (SiO2, Hex/EtOAc 100:D to 70:30) to afford the intermediate compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2oc(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Yield: 80.7 %

Procedure:
A mixture of 1.1 g (4.0 mmol) methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate 9ee and 3.7 mL of 3N aqueous NaOH in 10 mL of THF was refluxed overnight. After cooling the reaction mixture was poured into water and acidified with conc. HCl. The resulting solid was filtered and dried to give 830 mg (79%) of 2-(4-fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9ff. MS m/z (M+H+) 258.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:21](B1OB(C=C)OB(C=C)O1)=[CH2:22]>COCCOC.O.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>[N+:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH:21]=[CH2:22])[CH:11]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: C=CB1OB(C=C)OB(C=C)O1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cc([N+](=O)[O-])ccc1C(=O)OC
Reaction time: 0.33 h
Yield: 47.1 %

Procedure:
12.0 g (46.1 mmol) of methyl 2-bromo-4-nitrobenzoate were initially charged in 240 ml of 1,2-dimethoxyethane, 2.66 g (2.30 mmol) of tetrakis(triphenylphosphine)palladium were added, and the mixture was stirred for 20 min. Subsequently, a solution of 6.38 g (46.1 mmol) of potassium carbonate in 80 ml of water and 11.11 g (46.1 mmol) of 2,4,6-trivinylcyclotriboroxane were added. The reaction mixture was stirred at reflux temperature for 20 hours. After cooling, the mixture was added to water and extracted with ethyl acetate, the organic phases were dried with magnesium sulphate, and the solvent was distilled off under reduced pressure. The residue was chromatographed using silica gel with cyclohexane/ethyl acetate (ratio 6:1) as the eluent. 4.5 g (46% of theory) of methyl 4-nitro-2-vinylbenzoate were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:13]=2)=[N:3]1.ClC(OCC(C)C)=O.C([N:33](CC)CC)C.[NH4+]>C1COCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20]([NH2:33])=[O:22])[CH:13]=2)=[N:3]1
Reactant: O=C(O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reaction time: 1 h
Yield: 48.2 %

Procedure:
3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionic acid (0.31 g, 1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) and triethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), and the mixture was stirred under ice cooling condition for 1 hr. 25% aqueous ammonium solution was added to the mixture, and the mixture was stirred under ice cooling condition for 0.5 hr. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.15 g, 49%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:10][NH2:11]>CCO>[NH:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCO
Product: N#Cc1ccc(NN)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
To a suspended mixture of 6-chloronicotinonitrile (7 g, 50.8 mmol) in EtOH (50 mL), was added NH2NH2 (10 g, 310.2 mmol). The mixture was stirred at room temperature for 10 min, and then 60° C. for 5 h. The mixture was cooled to room temperature. The solids were filtered out, washed with water and dried under high vacuum to give 6-hydrazinylnicotinonitrile (3.5 g). Compound 6 was prepared from 6-hydrazinylnicotinonitrile following the procedure of the synthesis of compound 4. 1H NMR (400 MHz, CDCl3-CD3OD 10:1) δ ppm 11.37 (s, 1H), 8.70 (t, J=1.2 Hz, 1 H), 8.14 (s, 1 H), 8.11(dd, J=1.04 and 9.52 Hz, 1 H), 7.96 (dd, J=1.12 and 9.52 Hz, 1 H), 7.61 (dd, J=1.52 and 9.48 Hz, 1 H), 7.38 (d, J=9.0 Hz, 1 H), 1.77 (m, 1 H), 1.06 (m, 2 H), 0.90 (m, 2H) ESI-MS:m/z 377.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:2]1.F[C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[N:1]1[CH2:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:2]1)=[O:21]
Reactant: O=C(OCc1ccccc1)C1CCCNC1
Reactant: COC(=O)c1ccccc1F
Product: COC(=O)c1ccccc1N1CCCC(C(=O)OCc2ccccc2)C1
Yield: 17.3 %

Procedure:
Using benzyl nipecotate (5.90 g, 26.9 mmol) and methyl 2-fluorobenzoate (3.70 mL, 29.0 mmol), the same procedure was followed as in Step 1c of Example 1 to give 1.64 g (17%) of the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][O:26][C:27]([F:30])([F:29])[F:28])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][O:26][C:27]([F:29])([F:30])[F:28])[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CCOC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
384 mg (789 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoate (racemate) in 7.9 ml of dichloromethane and 2.28 ml (29.6 mmol) of TFA were reacted according to General Method 6A. Yield: 330 mg (96% of theory)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:32][C:33]([NH:35][C@@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:39]([O:46][C:47]3[CH:48]=[CH:49][C:50]4[N:51]([C:53]([N:56]5[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:57]5[CH3:62])=[N:54][N:55]=4)[CH:52]=3)[CH2:38][CH2:37]2)=[O:34])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[C:12]([O:28][CH2:29][CH2:30][OH:31])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:63][S:64](Cl)(=[O:66])=[O:65].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:32][C:33]([NH:35][C@@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:39]([O:46][C:47]3[CH:48]=[CH:49][C:50]4[N:51]([C:53]([N:56]5[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:57]5[CH3:62])=[N:54][N:55]=4)[CH:52]=3)[CH2:38][CH2:37]2)=[O:34])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])=[C:12]([CH:11]=2)[O:28][CH2:29][CH2:30][O:31][S:64]([CH3:63])(=[O:66])=[O:65])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCO)(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCOS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of Intermediate 55eB (26.0 mg, 0.30 mmol), methanesulfonyl chloride (70.0 μL, 0.90 mmol) and DIPEA (208 μL, 1.20 mmol) in DCM (8 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, separated through a phase separating cartridge and concentrated in vacuo to afford the title compound (275 mg, 97%). LCMS (Method 3): Rt 5.23 min, m/z 943 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: BrCc1ccoc1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 1, part F, starting with 1.22 g (4.46 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethyl ester and 6.3 ml (6.24 mmol) of a freshly prepared 1 M solution of 3-bromomethylfuran in ethyl ether. The crude mixture was stirred at 60° C. for 3 hours. After standard work-up, 1 g (63% of yield) of the expected product was isolated.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4].[H-].[Na+].[CH3:22]I.O>CS(C)=O>[CH3:22][N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[C:3]([N:2]([CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4]
Reactant: CN(C(=O)c1nc2ccccc2[nH]1)c1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C(=O)c1nc2ccccc2n1C)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
N-Methyl-N-(2-pyridyl)benzimidazole-2-carboxamide (1.0 g) prepared in Example 5 was suspended in dry DMSO (20 ml), sodium hydride (0.16 g) was added in an argon atmosphere and stirred at room temperature for 1 hr. Methyl iodide (0.62 g) was added and stirred at room temperature for 2 hrs. The mixture was poured into water and extracted with chloroform. The chloroform layer was dried over anhydrous Na2SO4, and the solvent was distilled off to obtain the residue. Purification of the residue by column chromatography on silica gel gave the title compound (0.99 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])C.[NH3:36].CO>>[C:4]([CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(=[O:3])[NH2:36]
Reactant: CCOC(=O)CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: N
Solvent: CO
Product: NC(=O)CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a sealed tube, a solution of [4-({[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]amino}-methyl)-pyridine-2-sulfonyl]-acetic acid ethyl ester (40 mg, 0.08 mmol) in a 7 N solution of ammonia in methanol (345 μL, 2.41 mmol) was warmed at 100° C. After 6 hours, the mixture was cooled to room temperature, and the resulting precipitate collected by filtration. The solid was purified by reversed-phase HPLC(C18 column, flow rate=25 mL/minute) using a 20 minute gradient of 5-95% acetonitrile (0.1% TFA) in water (0.1% TFA). Desired fractions from the column were combined and neutralized with saturated aqueous sodium bicarbonate, concentrated and extracted with a 10% solution of methanol in dichloromethane (3×30 mL). The combined organic layer were dried over magnesium sulfate, filtered and concentrated. The solid was triturated with methanol (3×1 mL), filtered and dried to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[C:13]([O:15][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)[N:14]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CC(C)c1cc(OCc2ccc(C(F)(F)F)cc2)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenyl)-6-isopropyl-pyrimidin-4-ol (which was obtained in Intermediate 6) and 4-(trifluoromethyl)benzyl bromide according to Method A; LC retention time 4.57 min; MS: m/z (ESI) 441 (M+H).
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:25][CH2:24]1>>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)[CH:30]=4)[N:21]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)c1ccc(Oc2cccn3nc(Cl)nc23)cc1
Product: CN1CCN(c2cccc(Nc3nc4c(Oc5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (0.070 g, 0.21 mmol) and 3-(4-methylpiperazin-1-yl)aniline (0.056 g, 0.29 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (56 mg, 54%). MP=Softened at 114-119° C. then melted at 199-201° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.76 (d, J=6.56 Hz, 1H), 7.89 (d, J=8.00 Hz, 2H), 7.50 (d, J=7.69 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J=8.04 Hz, 2H), 7.10-7.11 (m, 3H), 6.46 (d, J=6.60 Hz, 1H), 3.20 (s, 3H), 3.04 (s, 4H), 2.42 (s, 4H), 2.22 (s, 3H). MS=479 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[O-][CH2:21]C.[Na+].[Na].CI>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([O:9][CH3:21])=[O:8])=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CCO
Product: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
25.0 g (0.095 mol) of 4,4′-difluorobenzilic acid are added to freshly prepared sodium ethoxide solution containing 2.17 g (0.095 mol) of sodium and 200 mL of ethanol at 20° C. and stirred for 3 h. The solution is evaporated to dryness, the residue is dissolved in DMF, 22.57 g (0.16 mol) of methyl iodide are added dropwise at 20° C. and the mixture is stirred for 24 h. It is worked up and purified analogously to compound 3b. Yield: 21.06 g of 11 (80% of theory).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:9]1([S:15][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1sccc1Br
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=Cc1sccc1Sc1ccccc1
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a stirred solution of 3-bromothiophene-2-carboxaldehyde (1.9 g, 10 mMol) in ethanol (15 mL) is added thiophenol (2.2 g, 20 mMol) and powdered potassium carbonate (3.04 g, 22 mMol). The mixture is stirred overnight and concentrated. The residue is partitioned between water and ether. The aqueous layer is washed with ether and the organics combined, dried(MgSO4) and concentrated. Purification by flash column (SiO2, eluted with 3% ethylacetate/hexanes) afforded the desired aldehyde (2.02 g, 92%) as a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](OCC)([O:27]CC)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(OCC)CCN(c2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C1CCN(c2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)CC1
Yield: 86.8 %

Procedure:
1-(4′-Benzyloxybiphenyl-4-yl)-4,4-diethoxy-piperidine (10.0 g, 23.2 mmol), acetone (100 ml) and a 5 N hydrochloric acid aqueous solution (35 ml) were mixed and heated under reflux for 5 hours. 1 N sodium hydroxide was added to the residue obtained by removing the solvent by distillation, followed by extraction with dichloromethane. The organic layer was washed with water and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting crude crystal was washed with diethylether to afford the title compound as a white powder (7.2 g, yield 87%).