Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C.[CH2:22]([N:24]([CH:27](O)[CH2:28][CH3:29])[CH2:25][CH3:26])[CH3:23]>CN(C=O)C.O>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:23]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCC(O)N(CC)CC
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cccc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a stirred solution of 3-nitrophenol (2 mmol) in DMF (6 mL) at rt, solid potassium carbonate (4 mmol) was added. A solution of the mesylate of N,N-diethylaminopropanol (2.2 mmol) in DMF (2 mL) was then added to the reaction mixture and heated to 80° C. until completion, according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was then treated with cold H2O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine. The crude product was used directly for further transformation.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:9]=1)=O)CCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:13]([N:12]1[C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:10][N:9]=[C:8]1[CH2:6][OH:5])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOC(=O)c1nnc(-c2ccccc2)n1CCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCn1c(CO)nnc1-c1ccccc1

Procedure:
4-Butyl-5-phenyl-4H-[1,2,4]triazole-3-carboxylic acid butyl ester (169) (1.38 g, 5 mmol) is taken up in 50 ml anhydrous THF. LAH is added (3 eq.). The reaction is refluxed for 12 hours and then quenched carefully with water. Purification by column with 2.5% MeOH/DCM gives the desired product (170). 1HNMR(CDCl3): δ=7.40–7.60(5H, m, phenyl-H), 4.88(2H, s, —CH2OH), 4.26(1H, br, —OH), 4.10(2H, t, J=7.8 Hz, —CH2—), 1.58–1.70(2H, m, —CH2—), 1.08–1.30(2H, m, —CH2—), 0.82(3H, t, J=7.5 Hz, —CH3)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH2:15][CH3:16]>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:15][CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CCI
Reactant: Clc1cc2[nH]ccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ccc2c(Cl)nc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A solution of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (250 mg, 1.34 mmol) in tetrahydrofuran (4 mL) at 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (64.2 mg, 2.67 mmol) followed by iodoethane (229 mg, 1.47 mmol). After stirring at 0° C. for 0.5 h, the reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. At this time, the resulting mixture was quenched with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (30% ethyl acetate/hexane) afforded 4,6-dichloro-1-ethyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 69.6%). LC-MS calcd. for C9H8Cl2N2 [(M)+] 214, obsd. 214.9.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12](=[CH:15]NC1C=CC=CC=1)[C:13]#[N:14].C[O-].[Na+].Cl.[NH2:27][C:28]([NH2:30])=[NH:29]>C(O)C>[NH2:29][C:28]1[N:30]=[C:13]([NH2:14])[C:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:15][N:27]=1
Reactant: N=C(N)N
Reactant: N#CC(=CNc1ccccc1)Cc1ccc2ccccc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ncc(Cc2ccc3ccccc3c2)c(N)n1
Reaction time: 8 h
Yield: 51.2 %

Procedure:
2-(2-Naphthylmethyl)-3-anilinoacrylonitrile (6.65 g, 23.4 mmol) was dissolved in absolute ethanol (225 ml) and heated to reflux. A solution of sodium methylate (4.27 g, 79 mmol) in ethanol (75 ml) was mixed with guanidine hydrochloride (6.87 g, 72 mmol), filtered from salt, and added to the solution of 2-(2-naphthylmethyl)-3-anilinoacrylonitrile. The mixture was then refluxed for 8 hours, and allowed to stand at room temperature overnight. A yellow precipitate formed, which was isolated (2.66 g). An additional 1.33 g was obtained by concentration of the mother liquor. The combined fractions were recrystallized from absolute ethanol, yielding light cream colored 2,4-diamino-5-(2-naphthylmethyl)pyrimidine (3.0 g), m.p. 231°-233° C. Anal. Calcd. for C15H14N4 : C, 71.98; H, 5.64; N, 22.38. Found: C, 71.93; H, 5.68; N, 22.35.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.CN(C)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:14]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(=O)c(O)co1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)C
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OC(=O)c2ccccc2)co1
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
Allomaltol (600 mg; 4.76 mmol) was weighed out into a round bottom flask (100 ml) containing a stir-bar. The contents were diluted with anhydrous THF (˜20 ml) and stirred (˜5 min) to afford a solution. Next, trimethyl amine (833 μl; 6.33 mmol; 1.33 equiv.) was added drop-wise and the contents stirred (˜5 min). Benzoyl chloride (517 μl; 627 mg; 4.46 mmol) was then added drop-wise, capped and stirred at room temperature. The reaction was monitored via silica gel TLC. Once complete, the reaction mixture was concentrated under reduced pressure and the contents purified by silica gel chromatography to afford 930 mg of light yellow crystalline product (4.04 mmol; 91% yield). This compound was found to have an EC50 of >1 mM. 1H NMR (DMSO-d6) δ 8.58 (s, 1H; 2-H); 8.09-8.07 (dd, 2H); 7.78-7.76 (t, 1H); 7.63-7.59 (t, 2H); 6.43 (s, 1H; 5-H); 2.34 (s, −3H; 6-CH3).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1.IC.[CH3:23]N(C)C=O.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1
Reactant: CN(C)C=O
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 0.48 g (0.0016 mole) of (rac)-2-chloro-9-cyclohexyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-18), 0.2 mL (0.0032 mole) of iodomethane and 5 mL of dimethylformamide was added 0.13 g (0.0032 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at room temperature for 1 hour, then 100 mL of water was added and the mixture was extracted with twice with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (85:15), followed by recrystallization from dichloromethane-hexanes to give 0.41 g of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19) as white needles.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[NH:25]1[CH2:34][CH2:33][CH2:32][C@H:26]1[C:27]([O:29]CC)=[O:28].[OH-].[K+]>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9][CH2:10][CH2:11][C:12]([N:25]2[CH2:34][CH2:33][CH2:32][C@H:26]2[C:27]([OH:29])=[O:28])=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)CC(C)(C)N(CCCC(=O)O)C(=O)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)CC(C)(C)N(CCCC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-fluorobenzoyl)-4-[(1,1,3,3-tetramethylbutyl)amino]butyric acid and ethyl L-prolinate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-fluorobenzoyl)-4-(1,1,3,3-tetramethylbutylamino)butyryl]-L-proline.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[N:16]=[C:15]([C:25]([F:28])([F:27])[F:26])[CH:14]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>CC(O)=O>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:31]=[CH:35][CH:34]=[CH:33]4)=[CH:20][CH:19]=3)[N:16]=[C:15]([C:25]([F:26])([F:28])[F:27])[CH:14]=2)=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(N)cc2)cc1
Solvent: CC(=O)O
Product: CC(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(-n3cccc3)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A mixture of 2-{4-[1-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate 165.6 mg and 2,5-dimethoxytetrahydrofuran 112 mg in AcOH 3 ml was stirred at 50° C. for 3 hours. 2,5-Dimethoxytetrahydrofuran 0.22 ml was added and the mixture was stirred at 50° C. for 2 hours. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=20%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate 136.1 mg as an oil.
Reaction SMILES: [C:1]1([C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O.[N+:29]([O-])([OH:31])=[O:30]>>[N+:29]([C:3]1[CH:2]=[C:1]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8])([O-:31])=[O:30]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: COC(=O)c1ccc(C(=O)OC)c([N+](=O)[O-])c1

Procedure:
Czech Patent Specification No. 138,287 discloses a process for preparing 1-nitrobenzene-2-methoxycarbonyl-5-carboxylic acid. In this process, dimethyl benzene-1,4-dicarboxylate is nitrated in fuming sulfuric acid by means of a mixed acid of 20% strength oleum and 98% strength nitric acid; the dimethyl 1-nitrobenzene-2,5-dicarboxylate obtained is then first isolated and subsequently partially hydrolyzed by means of a large excess of 70% strength aqueous sulfuric acid. 1-Nitrobenzene-2-methoxycarbonyl-5-carboxylic acid precipitated in the acidic medium is then dissolved by means of sodium carbonate and reprecipitated by means of hydrochloric acid. In carrying out this process in industry, it suffers from the disadvantage that the waste water is very heavily polluted. The process moreover requires an additional isolating step as well as a purification operation, and it is impossible to prevent explosive dimethyl ether from forming from the methyl alcohol resulting in the hydrolysis of the ester group.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH:32](OC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH3:32])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reactant: CC(C)OC(C)C
Product: CC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 312, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde. Crystals (diisopropyl ether).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:21]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:13](=[O:21])[CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a vigorously stirred solution of RuCl3.H2O (2.39 g, 11.5 mmol) and NaIO4 (24.6 g, 115.0 mmol) in water (250 mL) was added (S)-piperidine-1,2-dicarboxylic acid di-tert-butyl ester (8.22 g, 28.8 mmol) in ethyl acetate (250 mL) at room temperature. After stirring for 4 h, the reaction mixture was partitioned and the aqueous layer washed with ethyl acetate. To the combined organic layers was added iPrOH (2.5 mL) and stirring was continued for 2 hours in order to destroy excess RuO4. The precipitate was removed by filtration through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to afford the title compound as a pale yellow oil, which crystallized upon standing (6.69 g, 78%): 1H NMR (400 MHz, CDCl3) δ 1.49 (9H, s), 1.52 (9H, s), 1.75-1.82 (2H, m), 1.97-2.06 (1H, m), 2.15-2.21 (1H, m), 2.41-2.61 (2H, m), 4.59 (1H, dd, J=3.5 Hz)
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31](OB(O)O)[CH:32]=[CH:33][CH:34]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:40])([F:39])[F:27])[CH:34]=3)=[CH:21][N:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3cccc(C(F)(F)F)c3)cn2)cs1
Yield: 91.9 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (920 mg) synthesized in Example 162-1 and 3-(trifluoromethyl)phenylboric acid (380 mg) were dissolved in dioxane (10 mL) and 2 mol/L sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (115 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1 to 2:1) to give the title compound (890 mg) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.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>[CH2:18]([N:10]1[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=[C:9]1[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:29]=2)[N:3]=1)[CH3:19]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3cccc(S(C)(=O)=O)c3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 3 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 3-(methylsulfonyl)phenylboronic acid (0.040 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by mass directed HPLC to give 0.0012 g of the title compound. MS m/z 395 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:18]=1>CN(C)C(=O)C>[CH3:30][O:29][CH:26]([O:27][CH3:28])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24])[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3-hydroxybenzonitrile (0.129 mol) in N,N-dimethyl-acetamide (200 mL) was stirred at room temperature and K2CO3 (0.147 mol) was added, then 4-chloro-2-dimethoxymethyl-1-nitrobenzene (0.086 mol) was added and the reaction mixture was stirred for 24 hours at 130° C. The solvent was evaporated and the residue was stirred in H2O. After extraction with CH2Cl2, the organic layer was separated, dried, filtered off and the solvent was evaporated. The residue was purified over a silica gel filter (eluent: CH2Cl2 100%). The purest product fractions were collected and the solvent was evaporated to yield the title compound as residue.
Reaction SMILES: CS([C:5](=[CH:9][CH2:10][O:11][CH3:12])[CH2:6][O:7][CH3:8])(=O)=O.[CH2:13]([C:20]1[O:21][CH:22]=[C:23]([CH3:25])[N:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:25][C:23]1[C:22]([OH:21])=[C:5]([CH2:6][O:7][CH3:8])[C:9]([CH2:10][O:11][CH3:12])=[C:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:24]=1
Reactant: COCC=C(COC)S(C)(=O)=O
Reactant: Cc1coc(Cc2ccccc2)n1
Product: COCc1c(Cc2ccccc2)nc(C)c(O)c1COC
Temperature: 190 °C

Procedure:
A mixture of 19.4 g (0.1 mole) of 2-methylsulfonyl-1,4-dimethoxy-but-2-ene and 34.6 g (0.2 mole) of 2-benzyl-4-methyloxazole is heated for 10 hours at 190° C. After it has cooled, unconverted oxazole and sulfone are distilled off in a high vacuum. The residue is chromatographed over silica gel (using ethyl acetate and methanol). 5.5 g of 2-methyl-4,5-di-(methoxymethyl)-6-benzyl-pyridin-3-ol, identified by the NMR spectrum, are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1>O1CCCC1.CCCCCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([OH:23])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:3][CH:4]=1
Reactant: COc1cccc(C=O)c1
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A solution of 35.0 g (183 mmole) of 4-bromochlorobenzene in 300 ml of dry tetrahydrofuran was cooled to -78° C. under nitrogen and 115 ml (183 mmole) of 1.59 M n-butyllithium in hexane was added dropwise at a rate to maintain temperature below -60° C. After stirring an additional 15 minutes, 23.0 ml (183 mmole) of m-anisaldehyde was added dropwise and the reaction was stirred for 15 minutes. The reaction was quenched at -78° C. with saturated aqueous ammonium chloride and allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 150 ml portions of 1.0 M sodium bisulfite, followed by 100 ml of 1.0 M sodium hydroxide, 100 ml of water, and 50 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 45.2 g (99%) of crude 4-chloro-α-(3-methoxyphenyl)benzyl alcohol as a pale yellow oil.
Reaction SMILES: C1(S([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:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:22]1([CH2:21][C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[OH:27])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 2.6 %

Procedure:
A solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethanol (5.1 g, 9.4 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 20 mL, 20 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-methanesulfonyl-phenyl)-ethanol (100 mg) as a white solid: LC/MS m/e calcd for C21H23FN2O3S [M+H]+ 403.49, observed 403.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (br. s., 1H), 7.95-8.00 (m, J=8.3 Hz, 2H), 7.88-7.94 (m, J=8.6 Hz, 2H), 7.77 (dd, J=9.1, 2.3 Hz, 1H), 6.60 (s, 1H), 3.16-3.23 (m, 3H), 2.54-2.64 (m, 2H), 1.83-1.98 (m, 2H), 1.43-1.71 (m, 5H), 1.25-1.40 (m, 1H), 1.05-1.15 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:12]([CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCNCC
Reactant: BrCc1ccccc1Br
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 1-Bromo-2-bromomethyl-benzene (2.17 g, 0.008 mmol) in toluene (15 mL) was added diethylamine (3.05 mL) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered and concentrated to give Example 229A as an oil.