Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O>CN1CCCC1=O>[Cl:1][CH2:5][C:4]([F:21])([F:3])[C:17]([F:20])([F:19])[F:18]
Reactant: [Cl-]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)CCl

Procedure:
Until HCFC-225ca becomes available in commercial quantities, HCFC-225ca may be prepared by a standard and well-known organic synthesis technique. For example, to prepare 1,1-dichloro-2,2,3,3,3-pentafluoropropane, 2,2,3,3,3-pentafluoro-1-propanol and p-toluenesulfonate chloride are reacted together to form 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate are reacted together to form 1-chloro-2,2,3,3,3-pentafluoropropane. Chlorine and the 1-chloro-2,2,3,3,3-pentafluoropropane are then reacted together to form 1,1-dichloro-2,2,3,3,3-pentafluoropropane. A detailed synthesis is set forth below.
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=12.N1C2=C(OC3C=CC(N)=CC=3[F:39])N=CC=C2C=C1>>[F:39][C:16]1[CH:15]=[C:3]([O:4][C:5]2[N:6]=[CH:7][CH:8]=[C:9]3[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=23)[CH:2]=[CH:18][C:17]=1[NH2:19]
Reactant: Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reactant: Cn1ccc2ccnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Product: Cn1ccc2ccnc(Oc3ccc(N)c(F)c3)c21
Yield: 89 %

Procedure:
Starting from the compound 264 and following the procedure described above for the synthesis of amine 261 (scheme 59, step 3, example 218), title compound 265 was obtained in 89% yield as an off-white solid. MS (m/z): 258.1(M+H) (found).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([O:22][CH3:23])=[C:12]3[C:16]([C:17](=[O:21])[C:18]([OH:20])=O)=[CH:15][NH:14][C:13]=23)[N:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31]2[CH2:39][CH2:38][NH:37][CH2:36][C:32]=2[N:33]=[CH:34][N:35]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[OH:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([O:22][CH3:23])=[C:12]3[C:16]([C:17](=[O:21])[C:18]([N:37]4[CH2:38][CH2:39][C:31]5[C:30]([C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=6)=[N:35][CH:34]=[N:33][C:32]=5[CH2:36]4)=[O:20])=[CH:15][NH:14][C:13]=23)[N:4]=1
Reactant: COc1cnc(-n2cnc(CO)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(CO)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a solution of 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (23 mg, 0.072 mmol), 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (15.39 mg, 0.072 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (27.9 mg, 0.087 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.127 mL, 0.725 mmol). The mixture was stirred at room temperature for 2 hours, diluted with MeOH and purified by prep. HPLC to give 1-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (9 mg, 0.016 mmol, 22% yield). LCMS: m/z 512.2 (M+H)+, 1.34 min (method 8). 1H NMR (500 MHz, DMSO-d6) d ppm 12.39-12.48 (m, 1H) 9.30-9.33 (m, 1H) 9.06-9.16 (m, 1H) 8.64-8.76 (m, 1H) 8.29-8.39 (m, 1H) 7.98-8.10 (m, 2H) 7.87 (s, 1H) 7.49-7.58 (m, 1H) 4.70-4.92 (m, 2H) 4.65-4.67 (m, 2H) 3.83-3.90 (m, 3H) 3.68 (t, J=5.80 Hz, 2H) 3.16 (t, J=5.65 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[CH2:21][C:22]1[O:26][N:25]=[C:24]([CH:27]2[CH2:29][CH2:28]2)[CH:23]=1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:21][C:22]3[O:26][N:25]=[C:24]([CH:27]4[CH2:29][CH2:28]4)[CH:23]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Oc1ccc(Oc2cccc(Cl)n2)cc1
Reactant: ClCc1cc(C2CC2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc(OCc3cc(C4CC4)no3)cc2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
At room temperature (about 20° C.), 11.1 g of 4-(6-chloro-2-pyridinyloxy)phenol in 100 ml of anhydrous dimethylformamide is dripped into 1.3 g of 100% strength sodium hydride in 40 ml of anhydrous dimethylformamide. To complete the exothermic reaction (evolution of hydrogen) the mixture is stirred for 30 minutes at 50° C. At room temperature, 7.9 g of 5-chloromethyl-3-cyclopropylisoxazole in 30 ml of anhydrous dimethylformamide is then dripped in. The mixture is stirred for 2 hours at 60° C. and overnight at room temperature. It is then poured into 200 ml of ice water and the solution is extracted with methyl tert-butyl ether. The organic phase is then washed with sodium hydroxide solution, water and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is evaporated under reduced pressure. The crude product is recrystallized from methanol. There is obtained 13.5 g of 5-[4-(6-chloro-2-pyridinyloxy)-phenoxymethyl]3-cyclopropylisoxazole of m.p.: 128°-130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1C)([O-:3])=[O:2].BrN1[C:17](=[O:18])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:10][C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:17]=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of nitroxylene (150 g), N-bromo succinimide (160 g) and benzoylperoxide (4.8 g) in carbontetrachloride (1200 ml) was heated to reflux for 4 hours with a mechanical stirrer. The precipitated succinimide was filtered and the filtrate evaporated. The oily residue was dissolved in chloroform (800 ml) and bistetrabutyl ammonium chromate (420 g) was added. The solution was refluxed for 3 hours, cooled to room temperature and diluted with benzene (500 ml) and filtered. The salts were washed with ethyl acetate until no desired material appeared on thin layer chromatography. The combined organic layer was evaporated and the residue, after chromatography, afforded the desired aldehyde in 50% yield. m.p. 81°-82° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:4]([O:21][CH3:22])[CH:3]=1.Br[CH2:24][CH2:25]C>>[ClH:8].[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:4]([O:21][CH2:22][CH2:24][CH3:25])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCCCN1CCCCC1
Reactant: CCCBr
Product: CCCOc1cc(N)c(Cl)cc1C(=O)CCCCN1CCCCC1
Product: Cl

Procedure:
Proceeding as in Example 12, Step (a), but replacing 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{1-[2-(methylsulfonyl)aminoeth yl]piperidin-4-yl}propan-1-one with 1-[4-amino-5-chloro-2-methoxyphen yl]-5-(piperidin-1-yl)pentan-1-one, and then as in Example 12, Step (b), but replacing 3,5-dimethoxybenzyl chloride with 1-bromopropane, gave 1-[4-amino-5-chloro-2-(prop-1-yloxy)phenyl]-5-(piperidin-1-yl)pentan-1-one hydrochloride, m.p. 232°-233° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=4[O:23][CH:24]([CH2:27][CH2:28][CH3:29])[C:25]#[N:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=4[O:23][CH:24]([C:25]4[NH:36][N:35]=[N:34][N:26]=4)[CH2:27][CH2:28][CH3:29])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC(C#N)Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)c1nnn[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
2-{2-{[2-(4-tert-Butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanenitrile (430 mg) was dissolved in dimethylformamide (5 ml), and sodium azide (364 mg) and ammonium chloride (0.3 g) were added. The mixture was stirred at 120° C. for three hours. The reaction mixture was cooled and poured into water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again and the combined organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was purified on a silica gel column (15 g) eluting with a mixed solvent of methylene chloride and methanol (2% vol.) to give 2-(4-tert-butylthiazol-2-yl)-5-{2-[1-(1H-tetrazol-5-yl)butoxy]phenylmethoxy}benzofuran (400 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCOCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 92.1 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess tetrahydro-4H-pyran-4-one (1.16 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 36 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-2 M ammonia in methanol afforded 0.51 g (93%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([OH:19])([CH3:18])[CH2:3][N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1.Cl[C:21]1[C:29]2[C:24](=[CH:25][N:26]=[C:27]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)[CH:28]=2)[N:23](C2CCCCO2)[N:22]=1>>[CH3:18][C:2]([OH:19])([CH3:1])[CH2:3][N:4]1[CH:8]=[C:7]([C:21]2[C:29]3[C:24](=[CH:25][N:26]=[C:27]([C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[CH:28]=3)[NH:23][N:22]=2)[CH:6]=[N:5]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cn1cc(-c2cc3c(Cl)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cnn(CC(C)(C)O)c4)n[nH]c3cn2)cn1
Yield: 40.7 %

Procedure:
Following the procedures in Example 172, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and deprotected to give 250 as a white solid (40.7% over two steps). 1H NMR (500 MHz, DMSO) δ 13.39 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.16 (d, J=10.2 Hz, 2H), 8.10 (s, 1H), 4.78 (s, 1H), 4.13 (s, 2H), 3.90 (s, 3H), 1.13 (s, 6H). LC/MS: m/z 338.1 [M+1]
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:21]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@H](NC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (115 g, 4.26 mmol) in CH2Cl2 (25 mL) at 0° C. under inert atmosphere was slowly added a solution of benzyl(S)-piperidin-3-ylcarbamate (1.0 g, 4.26 mmol) and triethylamine (1.18 mL, 8.52 mmol) in CH2Cl2 (10 mL). The reaction was allowed to warm to room temperature and was then quenched with water. The mixture was extracted with CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated to obtain benzyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (2.03 g). This material was used without further purification. LC/MS: m/z 469.1 (M+H)+ at 2.86 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:14]=1.CS(C)=O.[OH-].[Na+].C(Cl)[Cl:31]>O>[ClH:31].[ClH:31].[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: NCCCCc1cccnc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cl
Product: Nc1ccccc1C(=O)NCCCCc1cccnc1
Reaction time: 8 h

Procedure:
A mixture of 3.25 g of isatoic anhydride, 3.0 g of 4-(3-pyridinyl)butylamine and 20 ml of dimethylsulfoxide was allowed to stand overnight at room temperature, then was treated with 40 ml of water, 10 ml of 1N sodium hydroxide and 200 ml of methylene chloride. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The oily residue was mixed with ethanolic hydrogen chloride and concentrated. The residue was triturated with ether to obtain the desired product, mp 220°-223° C.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[NH:5][CH:4]=1.Br[CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27]>CN(C=O)C>[C:18]1(=[O:27])[N:17]([CH2:16]/[CH:15]=[CH:14]/[CH2:13][N:5]2[C:6]3=[N:11][CH:10]=[CH:9][CH:8]=[C:7]3[N:3]=[CH:4]2)[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]12
Reactant: c1cnc2[nH]cnc2c1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/Cn1cnc2cccnc21
Reaction time: 0.17 h
Yield: 32.2 %

Procedure:
A slurry of NaH (1.02 g, 25.4 mmol) in DMF (50 mL) at room temperature was treated with 4-azabenzimidazole (2.90 g, 24.4 mmol). After 10 min., the reaction mixture was treated with a solution of (E)-N-(4-bromo-2-butenyl)phthalimide (5.7 g, 20.3 mmol) in DMF (5 mL) over 30 min. The reaction mixture was allowed to stir for 1 h, then quenched by careful addition of water (5 mL) and the reaction mixture was concentrated in vacuo. The resulting residue was diluted with CH2Cl2 (50 mL), washed with brine (2×25 mL), dried (MgSO4), and concentrated in vacuo to afford an off-white solid. Purification by flash chromatography (ethyl acetate containing 3% NH4OH) afforded 2.08 g of 3-[(E)-4-phthalimido-2-butenyl]-3H-imidazo[4,5-b]pyridine. Changing the chromatography solvent to 5% methanol/ethyl acetate containing 5% NH4OH afforded 1.66 g of 1-[(E)-4-phthalimido-2-butenyl]-1H-imidazo[4,5-b]pyridine; mass (CI) m/z=319 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:4][CH:5]=[N:6][C:7]=1[CH2:8][S:9][C:10]1[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[N:18]=1.C[OH:26].OO>C[Re](=O)(=O)=O.O>[CH3:1][C:2]1[C:7]([CH2:8][S:9]([C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[O:26])=[N:6][CH:5]=[CH:4][C:3]=1[O:19][CH2:20][C:21]([F:24])([F:22])[F:23]
Reactant: CO
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: C[Re](=O)(=O)=O
Agent: OO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 5 °C

Procedure:
In a 1-liter flask equipped with dropping funnel and mechanical stirring 50 g (0.142 moles) of Lansoprazole sulfide, 35.0 mg (0.00014 moles) of methyltrioxorhenium (Aldrich) and 500 ml of methanol are charged. The temperature of the solution is brought to 5° C., and then 17.8 g (0.173 moles) of a 33% (v/v) aqueous solution of hydrogen peroxide are added. The mixture is maintained at 5° C. for 4 hours, then 1000 ml of cold deionized water are added, whereby a dense precipitate forms. The mixture is stirred for 1 additional hour at 5° C. and is then filtered on a Buchner, the cake is washed with 3×100 ml of cold deionized water and is discharged. The wet solid weighs 59.5 g. A 1 g sample is collected and dried under vacuum (50 mmHg) at 40° C. for 12 hours, which loses 16.5% of its weight. The yield of crude product is thus 95%. The amount of residual water in the crystalline solid is calculated through the Karl-Fischer method and the solid is then recrystallised, talking into account the amount of residual water, from 8 volumes of a 9:1 mixture of ethanol and water. The yield of the crystallized, dried product starting from the sulfide is 75%, the purity of the product is >99.5% (HPLC).
Reaction SMILES: [C:1]([N:5]([C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[C:1]([N:5]([C:7](=[O:16])[C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)[NH:6][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:18]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)Cl)c(F)c1
Reactant: Cc1cc(C)cc(C(=O)N(N)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c(F)c1
Reaction time: 8 h

Procedure:
0.150 g of 3,5-dimethyl-benzoic acid N-tert-butyl-hydrazide (1 eq. 0.68 mmol) and 0.110 mL (1.2 eq, 0.77 mmol) of 2-fluoro-4-ethyl benzoyl chloride were weighed into a 1 oz. vial. A small stirbar was added followed by 2 mL of methylene chloride. The mixture was stirred until the hydrazone dissolved. The stirring was stopped and 2 mL of a 1 M potassium carbonate (K2CO3) solution was added. The mixture was allowed to stir overnight. At the end of this period, 1 mL of water and 1 mL of methylene chloride were added. The aqueous phase was removed and the organic phase was washed twice with 1 M potassium carbonate solution. The organic phase was removed and dried over magnesium sulfate. The organic phase was filtered thru a pad of baste alumina and the solvent removed. The product, 3,5-dimethylbenzoic acid N-tert-butyl-N′-(2-fluoro-4-ethylbenzoyl)-hydrazide, was purified by trituration with 1:1 ether:hexane. 1NMR (300 MHz, CDCl3) δ (ppm): 7.7 (m, 2H), 7.6 (t, 1H), 7.0 (m, 3H), 2.6 (q, 2H), 2.3 (s, 3H), 2.1 (s, 6H), 1.5 (s, 9H), 1.1 (t, 3).
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)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>[N+:8]([C:3]1[C:2]([CH:11]=[CH2:12])=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncccc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC#N
Product: C=Cc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
3-Bromo-2-nitropyridine (1.015 g, 5.0 mmol), tetrabutylammonium chloride (1.390 g, 5.00 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.351 g, 0.500 mmol) were combined. Mixture was suspended in acetonitrile (10 ml). The mixture was stirred at room temperature for 30 minutes while it was degassed by a flow of nitrogen. Tributyl(vinyl)tin (1.754 ml, 6.00 mmol) was added and the mixture was further degassed for 5 minutes. The vial was capped and heated at 90° C. for 4 hours. Solvents were removed from the mixture. The residue was dissolved with dichloromethane. Material was washed with brine and the aqueous phase was discarded. Organic layer was dried over Na2SO4, and filtered. Solvents were removed by roto-vap. Silica gel chromatography afforded the title compound as tan solid in 68% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.39 (dd, J=4.58, 1.53 Hz, 1 H) 8.06 (dd, J=7.94, 1.53 Hz, 1 H) 7.55 (dd, J=7.93, 4.58 Hz, 1 H) 6.90 (dd, J=17.24, 11.14 Hz, 1 H) 5.82 (d, J=17.40 Hz, 1 H) 5.55 (d, J=10.99 Hz, 1 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.S(=O)(=O)(O)O.N>C(O)(=O)C>[CH2:6]([N:8]1[CH2:9][CH2:10][C:11]2[N:15]=[C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]3=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[CH2:13]1)[C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:17]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: c1ccc(CN2CCc3nc4ccccc4c(-c4ccccc4)c3C2)cc1
Yield: 145.7 %

Procedure:
1-t-Butoxycarbonyl-4-piperidone (1.93 g, 10.2 mmol) and 2-aminobenzophenone (2.01 g, 10.2 mmol) were suspended in acetic acid (10 ml), followed by adding thereto sulfuric acid (0.1 ml), and the reaction was carried out at 120° C. for 1 hour. The reaction mixture was poured into cold aqueous ammonia, and the crystals precipitated were washed with water and recrystallized from ethanol to obtain the desired compound (2.60 g, 7.43 mmol).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([N:40]4[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]4)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:47][CH2:48][CH3:49])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:52]I>CN(C)C=O>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:52])[C:42](=[O:46])[CH2:41]4)[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:47][CH2:48][CH3:49])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)C2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCN(C)C(=O)C2)CC1
Reaction time: 0.08 h

Procedure:
4-{1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-piperazin-2-one (61.8 mg, example 117) was dissolved in N,N-dimethylformamide (1 mL), sodium hydride (60% in mineral oil, 20 mg, Aldrich) was added. After stirring for 5 min, methyl iodide (0.03 mL, Aldrich) was added. The mixture was stirred at ambient temperature for 3 h, and the crude product was purified on a HPLC (reversed phase, eluting with acetonitrile and water) to give the title product (34 mg). HR-MS (ES, m/z) calculated for C39H49C12N6O3 [(M+H)+] 719.3238, observed 719.3242.