Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([S:10]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)(=[O:12])=[O:11])[NH:9][C:5]=2[C:4]=1[S:26]([C:29]1[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37]C)=[O:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27].[OH-].[Na+]>C(COC)OC>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([S:10]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)(=[O:12])=[O:11])[NH:9][C:5]=2[C:4]=1[S:26]([C:29]1[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: COC(=O)COc1ccc(S(=O)(=O)c2c(OC)ccc3nc(S(=O)(=O)Cc4ncc(C)c(OC)c4C)[nH]c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1ccc2nc(S(=O)(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1S(=O)(=O)c1ccc(OCC(=O)O)cc1
Reaction time: 1 h
Yield: 123.1 %

Procedure:
A 3L 3-necked flask equipped with a mechanical stirrer was charged with methyl 2-{4-[(5-methoxy-2-{[(4-methoxy-3,5-dimethyl(2-pyridyl))methyl]sulfonyl}benzimidazolyl)sulfonyl]phenoxy}acetate (Intermediate A27, 13.75 g, 0.024 mol) in glyme (1200 mL). To this vigorously stirring solution was added 0.1 N NaOH solution (300 mL). The resulting mixture was concentrated under reduced pressure at 47° C. The residue was triturated with fresh ethyl acetate (100 mL) for a total of four times. The residue was placed under high vacuum for 1 hr to give 17 g of a gummy solid. In a 1L 3-necked flask equipped with a mechanical stirrer was placed 16 g of this solid (equivalent to 13.3 g sodium salt, 0.0226 mol) in water (250 mL). The solution was washed by stirring with ethyl acetate (250 mL) for 1 hr and then the layers were separated. HPLC analysis of the ethyl acetate layer showed 64% omeprazole and 33% unreacted sulfoxide methyl ester. A fresh 250 mL of ethyl acetate was added to the aqueous layer. The resulting mixture was stirred and acidified to pH 3-4 with ca. 40 mL of 0.5 N hydrochloric acid. The ethyl acetate layer was separated quickly, because product started to crystallize, and placed in a freezer overnight. The crystals were collected and air dried to give 6.7 g (53%) of the methyl 2-{4-[(5-methoxy-2-{[(4-methoxy-3,5-dimethyl(2-pyridyl))methyl]sulfonyl}benzimidazolyl)sulfonyl]phenoxy}acetate.
Reaction SMILES: Cl.[CH2:2]1[C@H:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C@H:5]2[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[C:30]([F:33])([F:32])[F:31].O>CN(C=O)C>[F:31][C:30]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:20]=1[CH2:19][N:3]1[CH2:4][C@@H:5]2[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7][C@@H:6]2[CH2:2]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: OCC1C[C@H]2CNC[C@H]2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC1C[C@@H]2CN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethanol hydrochloride (0.79 g) and potassium carbonate (1.53 g) in DMF (15 ml) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (1.5 g). The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-])=O.Cl[Sn]Cl>CCO>[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: N#Cc1cc(N)c(N)c([N+](=O)[O-])c1
Yield: 42.4 %

Procedure:
To 4-amino-3,5-dinitrobenzonitrile (9.4 g, 0.045 mol) in EtOH (100 mL) was added SnCl2 (30 g, 0.16 mol). The mixture was refluxed for 1 h. The reaction was then filtered and the filtrate concentrated to afford 3,4-diamino-5-nitrobenzonitrile (3.4 g, 42%) of an orange solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[CH3:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:19][CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)OC(C)C)ccc1[N+](=O)[O-]

Procedure:
In a similar manner to Example 2, starting material step (b), isopropyl bromoacetate (13.9 ml), 3-methyl-4-nitrophenol (15 g), anhydrous potassium carbonate (16.25 g) and acetone (500 ml) were reacted to give isopropyl 3-methyl-4-nitrophenoxyacetate (22.2 g) as an off-white solid: NMR Spectrum (DMSO-d6) 1.22 (6H, d), 2.54 (3H, s), 4.89 (2H, s), 5.00 (1H, m), 6.96 (1H, dd), 7.04 (1H, d), 8.03 (1H, d); Mass Spectrum m/Z 254 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.CC(C)=O>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[S:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCCSc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCCSc2ccc3ccccc3c2)cc1
Yield: 93.9 %

Procedure:
A mixture of 4-[[4-(2-naphthalenylthio)butyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.53 g) in methanol (5 mL), acetone (2 mL), and 0.5N sodium hydroxide (4 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from diethyl ether-hexane to give 0.48 g of colorless 4-[[4-(2-naphthalenylthio) butyl]oxy]-alpha-oxobenzeneacetic acid, mp 113°-115° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[C:7](=[O:20])[C:6]=2[CH:21]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C(Cl)Cl.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.O>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]4([CH2:10][CH2:11][C:12]5[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=5[CH2:14][CH2:15]4)[C:7](=[O:20])[C:6]=3[CH:21]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: O=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1c2cc(-c3cc(F)cc(Cl)c3)ccc2OC12CCc1ccccc1CC2
Temperature: 110 °C
Yield: 92.5 %

Procedure:
A 10 mL microwave tube was charged with 5′-bromo-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one (0.0573 g, 0.167 mmol), 3-chloro-5-fluorophenylboronic acid (0.0930 g, 0.53 mmol), Cs2CO3 (0.2537 g, 0.78 mmol), 1,4-dioxane (4 mL), water (1 mL), and PdCl2(PPh3)2 (0.0118 g, 0.0168 mmol). The tube was heated in a CEM microwave reactor at 110° C. for 30 min. The reaction mixture was diluted with CH2Cl2 and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.0607 g (92%) of 5′-(3-chloro-5-fluorophenyl)-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one. LC-MS tR=2.55 min in 3 min chromatography, m/z 393, 395 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:30][CH:31]([O:34][CH3:35])[O:32][CH3:33])[CH:11]=[C:12]([CH:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:30][CH:31]([O:34][CH3:35])[O:32][CH3:33])[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: COC(Cn1cc(C(O)C(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(Cn1cc(C(=O)C(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (120 mg) obtained in Example 118, Step 2 in dimethyl sulfoxide (5 ml) were added triethylamine (1.1 ml) and sulfur trioxide pyridine complex (450 mg) and the mixture was stirred at room temperature for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted twice with ethyl acetate (30 ml). The combined ethyl acetate layer washed with water, dried, concentrated and purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (104 mg).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[C:6]=1[CH3:7].[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:7][C:6]1[N:5]([C:8]2[N:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:11]=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:4]=[N:3][C:2]=1[C:32]1[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=1
Reactant: Cc1c(I)ncn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1c(-c2ccc(N)nc2)ncn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-(4-iodo-5-methyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.67) (0.25 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.12 g, 50%). MS (ISP) 465.1 [(M+H)+]; mp 252° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][C:18](=[O:25])[C@@H:19]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH2:20].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH3:16][O:17][C:18](=[O:25])[C@H:19]([NH:20][C:10](=[O:12])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:14])[CH3:13])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COC(=O)[C@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC(C)C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
2-(tert-Butoxycarbonylamino)-2-methylpropanoic acid (22.4 g) and D-leucine methyl ester hydrochloride (20.0 g) were dissolved in N,N-dimethylformamide (224 mL), and triethylamine (11.1 g) was added dropwise thereto under cooling on ice. To the mixture were sequentially added 1-hydroxybenzotriazole (14.9 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.1 g), and stirring was performed for two hours. Water (224 mL) was added to the reaction mixture, and the formed precipitates were recovered through filtration, whereby the title compound (57.8 g) was yielded as wet crystals.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH2:30]1[N:35]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:34][CH2:33][O:32][CH2:31]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:42][C:39]3[CH:38]=[CH:37][C:36]([N:35]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:41][CH:40]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Yield: 7.2 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 4-(4-morpholino)aniline (0.155 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and The reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 12.51 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine as a lyophilized powder. (M+H)=402.8. 1H NMR (400 MHz, DMSO, d6) δ 9.23 (m, 1H), 8.91 (s, 1H), 7.81 (dd, 1H, J=1.60, 6.01 Hz), 7.62 (d, 2H, J=8.88 Hz), 7.45 (m, 1H), 7.21 (d, 1H, J=8.13 Hz), 7.12 (t, 1H, J=7.60 Hz), 6.91 (m, 4H), 3.80 (s, 3H), 3.75 (m, 4H), 3.09 (m, 4H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH3:12])[CH2:6]1)(=[O:4])=[O:3].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C@H:8]1[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C@H:7]1[CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CC1CN(S(C)(=O)=O)CCC1=O
Product: C[C@@H]1CN(S(C)(=O)=O)CC[C@@H]1NCc1ccccc1

Procedure:
Racemic cis benzyl-(1-methanesulfonyl-3-methyl-piperidin-4-yl)-amine was prepared in the same manner from racemic 1-methanesulfonyl-3-methyl-piperidin-4-one. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:17][CH2:18][CH2:19][CH2:20][OH:21])(=[O:12])=[O:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:17][CH2:18][CH2:19][CH:20]=[O:21])(=[O:12])=[O:11]
Reactant: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a cooled (0° C.), stirred solution of 528 mg (1.44 mmol) of 3-[3-(2-methoxy-5-methylphenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 527 μL (3.02 mmol) of N,N-diisopropylethylamine and 307 μL (4.32 mmol) of anhydrous dimethyl sulfoxide in 6.0 mL of anhydrous dichloromethane was added 459 mg (2.88 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 16 h. The mixture was poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated. The resulting material was chromatographed on 35 g of silica gel with dichloromethane followed by 3% ethyl acetate-dichlorometharie to afford 320 mg (61%) of the title compound as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 9.83 (t, 1 H, J=1.4 Hz), 7.63 (d, 1 H, J=2.3 Hz), 7.40 (dd, 1 H, J=8.5, 2.3 Hz), 6.98 (d, 1 H, J=8.5 Hz), 6.59 (br s, 1 H), 6.55 (br s, 1 H), 6.46 (t, 1 H, J=2.1 Hz), 4.19 (t, 2 H, J=6.1 Hz), 3.98 (s, 3 H), 2.85 (td, 2 H, J=6.1, 1.4 Hz), 2.29 (s, 3 H) and 2.25 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CO)c(C)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cnc(C=O)c(C)c1

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-yl)-methanol (2.12 g, 15.45 mmol) (Weidmann, K., et al., J. Med. Chem. (1992) 35:438-450) in CH2Cl2 (50 mL) was added MnO2 (9.41 g, 108.18 mmol) and the reaction mixture was refluxed overnight. Then it was cooled and the mixture was filtered through a layer of celite. The filtrate was concentrated to afford a brown/yellow oil. Purification by flash column chromatography on silica gel using 30% EtOAc/hexane afforded 3,5-dimethyl-pyridine-2-carbaldehyde as a yellow oil (960 mg, 31% over 3 steps). 1H NMR (CDCl3) δ 2.39 (s, 3H), 2.62 (s, 3H), 7.41 (s, 1H), 8.47 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1C=C(OC2COC(C3C=CC=CC=3)OC2)N=C(SCC2C=CC=C(F)C=2F)N=1.Cl[C:80]1[CH:85]=[C:84]([O:86][C@@H:87]([C@H:89]2[CH2:93][O:92][C:91]([CH3:95])([CH3:94])[O:90]2)[CH3:88])[N:83]=[C:82]([S:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[C:100]([F:104])[C:99]=2[F:105])[N:81]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:105][C:99]1[C:100]([F:104])=[CH:101][CH:102]=[CH:103][C:98]=1[CH2:97][S:96][C:82]1[N:81]=[C:80]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:85]=[C:84]([O:86][C@@H:87]([C@H:89]2[CH2:93][O:92][C:91]([CH3:94])([CH3:95])[O:90]2)[CH3:88])[N:83]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Fc1cccc(CSc2nc(Cl)cc(OC3COC(c4ccccc4)OC3)n2)c1F
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulphonamide (prepared according to patent WO 2004/011443, 0.20 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.18 g) and 4-chloro-2-[[(2,3-difluorophenyl)-methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)oxy]-pyrimidine (the product of step v) (0.15 g) in dioxane (5 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 25 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:19 to 3:7 gradient) as eluent to give the subtitle compound as a yellow oil. Yield: 0.14 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:39])C(=O)C1>ClC(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]3[C:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:23]([Br:39])[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Oc2ncnc3occ(-c4ccccc4)c23)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Oc2ncnc3oc(Br)c(-c4ccccc4)c23)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Suspend 100 mg (0.236 mmol) of (+/−)-cis-({3-[(5-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetic acid tert-butyl ester in 0.2 ml of tetrachloromethane and add 46.1 mg (0.259 mmol) of NBS. Stir the reaction mixture at 60° C. for a total of 2 h, and add a further 23 mg of NBS after 1 h. After cooling, remove the tetrachloromethane under reduced pressure and purify the residue by preparative RP-HPLC (eluent: acetonitrile/water). 43.6 mg (36.8% of theory) of the target product are obtained.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([OH:37])[CH:31]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([O:37][C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=2[CH2:27][CH3:28])[CH:31]=1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1cc(C)nc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cc(C)cc(C)n2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 4,6-dimethylpyridin-2-ol (0.19 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.24 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Yield: 78.9 %

Procedure:
A solution of tert-butyl (3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate (109 mg, 0.202 mmol) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 16 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 70 mg (79%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43-1.82 (m, 4 H) 1.91-2.03 (m, 1 H) 2.67 (dt, J=11.68, 7.16 Hz, 2 H) 2.76-2.94 (m, 1 H) 3.21 (dd, J=11.82, 2.87 Hz, 1 H) 4.28 (br. s., 1 H) 6.11 (d, J=6.12 Hz, 1 H) 6.98-7.57 (m, 8 H) 8.36 (s, 1 H), [M+H]+ 439.6.