Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]1[CH2:24][CH2:23][O:22][CH2:21]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCOC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCC3CCOC3)c2n1
Yield: 53 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-{3-[(tetrahydro-3-furanylmethyl)amino]propyl}-9H-purin-6-amine (11 mg, 0.029 mmol) and 4M HCl in 1,4 dioxane (0.160 ml, 0.639 mmol) were stirred at 20° C. for 16 hours in methanol (1 ml). The solvent was removed by N2 blowdown. The sample was loaded in methanol and purified by SPE on an aminopropyl (NH2) cartridge (2 g) using methanol. The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product as a white solid. The sample were dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as a white solid (5.6 mg).
Reaction SMILES: [C:1](O)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:2]1([CH2:1][OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccccc1CO
Yield: 101.3 %

Procedure:
A solution of phthalic acid (9 g, 0.05 mol) in anhydrous THF (200 mL) was added to LAH (7.6 g, 0.2 mol) in THF (250 mL) dropwise, and the mixture was refluxed for 18 hours. The mixture was cooled in ice bath and carefully added water dropwise, followed by 50% NaOH (150 mL), and then removed the ice bath added water slowly with stirring until the gray precipitate turns white. The mixture was filtrated and the filtrate was concentrated to give crude 1,2-phenylenedimethanol (7 g, 92%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.N.[Ni]>[NH2:19][CH2:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccccc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
tert-Butyl 1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (1.787 g, 4.93 mmol) was dissolved in THF (40 mL) and 7 N methanolic ammonia (40 mL). Raney nickel (0.422 g, 4.93 mmol) was added. The vessel was evacuated and filled with Hydrogen at atmospheric pressure. The mixture was stirred overnight at room temperature. The catalyst was filtered off on a celite pad and washed with 500 mL MeOH. Product was obtained as a crimson powder (1.813 g, 4.95 mmol, 100%) after evaporating the solvent.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]([C:11]1[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.CCOC(C)=O>[CH:8]([C:11]1[CH:12]=[C:13]([CH3:16])[N:14]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(C)C)[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(C(C)C)cc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 34 %

Procedure:
Ethyl bromoacetate (1.00 mL, 9.03 mmol) was added to 5-isopropyl-3-methyl-1H-pyrazole (1.07 g, 8.60 mmol) and potassium carbonate (3.57 g, 25.9 mol) in DMF (10 mL). The mixture was stirred at room temperature for 17 hours then EtOAc (20 mL) and aqueous HCl (20 mL, 1 M) were added. The organic phase was dried over magnesium sulphate then evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 4:1) to afford the title compound as a yellow oil in 34% yield, 607 mg.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C[O:9][C:10](=O)[CH:11]([Cl:13])[CH3:12]>>[Cl:13][CH:11]([CH3:12])[C:10]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:9]
Reactant: COC(=O)C(C)Cl
Reactant: OCCNCCO
Product: CC(Cl)C(=O)N(CCO)CCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Diethanolamine (10.51 g, 0.1 mol) is added to 12.25 (0.1 mol) of 2-chloropropionic acid methylester. The mixture is stirred for 24 h at room temperature. The formed methanol is evaporated to afford 18.8 g of the title compound as slightly yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][C:15](=O)[CH2:16][CH2:17][CH3:18])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.CO.O>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:13][CH:12]=1)[NH:1][C:15]([CH2:16][CH2:17][CH3:18])=[CH:14]2)=[O:9]
Reactant: CCCC(=O)Cc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc2cc(C(=O)OC)ccc2[nH]1
Yield: 71.2 %

Procedure:
Methyl 4-nitro-3-(2-oxopentyl)benzoate (5.42 g) is dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (20 ml), to which is added a suspension of sodium hydrosulfite (52.2 g) in water (60 ml). After having been refluxed for 2 hours, this is subjected to liquid-liquid separation by adding ethyl acetate (300 ml) and water (200 ml) thereto. The organic layer is washed with a saline solution, dried and concentrated. The resulting residue is purified through silica gel column chromatography to obtain 5-(methoxycarbonyl)-2-propylindole (3.16 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]#[CH:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)Cl>[Br:14][C:3]1[C:4]([NH:10][CH2:11][C:12]#[CH:13])=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: C#CCNc1cc(Cl)nc(SC)n1
Solvent: ClCCl
Product: C#CCNc1nc(SC)nc(Cl)c1Br
Reaction time: 4 h

Procedure:
To a stirring solution of 1.16 g (5.45 mmol) of 6-chloro-2-(methylthio)-N-(prop-2-ynyl)pyrimidine-4-amine (intermediate 27) in 6 ml of DCM, 1.07 g (6.0 mmol) of N-bromosuccinimide were added, and stirring was continued for 4 hours at room temperature to give 5-bromo-6-chloro-2-(methylthio)-N-(prop-2-ynyl)pyrimidine-4-amine, which was used without further purification in the next step (see intermediate 31). The completion of the reaction is monitored by thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][NH:28][CH:29]3[CH3:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][C:22]([C:19]5[CH:20]=[N:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=5)=[CH:23][CH:24]=4)[CH:29]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ccc(-c2ccc3c(c2)C(C)NCC3)cn1
Product: COc1ccc(-c2ccc3c(c2)C(C)N(C(=O)c2cc4ncc(Cl)cn4n2)CC3)cn1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(6-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][OH:11])[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[OH:11][CH2:10][C@H:9]([NH:8][C:6]1[N:7]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([OH:35])=[C:20]([O:19][CH3:18])[CH:25]=2)[CH:3]=[N:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: OC[C@H](Nc1cncc(Cl)n1)c1ccccc1
Product: COc1cc(-c2cncc(N[C@@H](CO)c3ccccc3)n2)ccc1O
Yield: 37.7 %

Procedure:
In a procedure analogous to Example 2, reaction of (2R)-2-[(6-chloropyrazin-2-yl)amino]-2-phenylethanol (137 mg, 0.55 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (151 mg, 0.60 mmol) furnished the product (70 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].[CH3:20]I>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([O:18][CH3:20])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(Oc2cc(Cl)cc(C#N)c2)c(Cl)c(=O)[nH]1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1nc(C)cc(Oc2cc(Cl)cc(C#N)c2)c1Cl
Temperature: 50 °C

Procedure:
Compound 3-4 (2.45 g; 8.32 mmol), methyl iodide (1.573 mL; 25.2 mmol), silver carbonate (3.28 g; 11.89 mmol) and chloroform (100 mL) were added to a sealed vessel. The contents of the sealed vessel were heated at 50° C. for 3 hours in the absence of light. The reaction was cooled to room temperature, the insoluble material filtered off, and the filtrate concentrated in vacuo. The crude material was purified via silica gel chromatography (0-10% EtOAc in hexane) to give the title compound. MS M+1=308.9. 1H NMR (CDCl3): 2.42 (s, 3H), 4.05 (s, 3H), 6.36 (s, 1), 7.16 (m, 1H), 7.24 (m, 1H), 7.44 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[OH-:26].[Na+].[O-]Cl.[Na+].Cl>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O.C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:26])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: [OH-]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
A 1 L flat bottom flask equipped with a stirrer is charged with acetonitrile (0.6 L). Under mixing compound VI (200 g) is added, followed by water (0.2 L), and NaOH pellets (88 g, 4.0 eq.). The flask is cooled to 5° C. Aqueous 9.4% active NaOCl (540 g, d=1.16, 1.25 eq.) is added dropwise over 40 min. The two-phase mixture is then stirred at room temperature for 40 min at 10° C. Solid Na2S2O5 (6.6 g) is then added, and the mixture is stirred for another 0.5 h. The work up is finished by adjusting the pH to 8.5 with 32% HCl. A precipitate forms in the reaction mixture and is separated by filtration, washed with water, and dried to obtain pantoprazole (137.8 g, yield 66%) containing 0.02% sulfone and 0.01% compound VI within the limit of UV detection.
Reaction SMILES: [CH3:1][C:2]1[C:16]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3([CH2:14][C:4]=2[CH:3]=1)[O:13][CH2:12][CH2:11][O:10]3.CC([O-])=O.[K+].CC(O)=O.C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:61]=O)CC(C)C.C([O-])(O)=O.[Na+]>FC1C=CC(N2C3C(=CC=C(CCCC(O)=O)C=3)C=N2)=CC=1.C(Cl)(Cl)Cl>[O:10]1[CH2:11][CH2:12][O:13][C:9]21[CH2:14][C:4]1[CH:3]=[C:2]3[C:16](=[CH:15][C:5]=1[CH2:6][CH2:7][CH2:8]2)[N:17]([C:18](=[O:20])[CH3:19])[N:61]=[CH:1]3
Reactant: CC(=O)Nc1cc2c(cc1C)CC1(CCC2)OCCO1
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: O=C(O)CCCc1ccc2cnn(-c3ccc(F)cc3)c2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1ncc2cc3c(cc21)CCCC1(C3)OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
In a 20 L 3 necked flask, N-(3-Methyl-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-[1,3]dioxolan]-2-yl)acetamide (78) (900 g, 3.27 mol) was dissolved in chloroform (10 L). KOAc (634 g, 6.54 mol), HOAc (382 mL, 6.54 mol), acetic anhydride (655 mL, 6.54 mol), 18-crown-6 (130 g, 523 mmol) and isoamylnitrite (1.30 L, 13.4 mol) were respectively added. The mixture was heated to reflux for about 3 h. Acetic anhydride (900 mL, 9.54 mol) and isoamylnitrite (1.80 L, 13.4 mol) were added and the mixture was heated to reflux overnight. The reaction mixture was cooled to rt and then carefully poured into sat. aq. NaHCO3 (80 L). The pH was carefully adjusted to basic with NaHCO3. The layers were separated and the aq. phase was extracted with DCM (2×15 L). The combined organic layers were concentrated under reduced pressure. tert-Butyl methyl ether (1500 mL) was added and the resulting slurry was stirred for about 1 h. The precipitate was collected by filtration to afford 1-(5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolan]-1-yl)ethanone (79) (450 g, 48% yield) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 8.38 (s, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 3.95 (m, 2H), 3.82 (m, 2H), 3.16 (s, 2H), 2.96 (m, 2H), 2.64 (s, 3H), 1.84 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=3[N:22]=[C:23]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)nc(-c1ccccc1)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
In a small pressure bottle was placed 4-(2-amino-4-methyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester, benzaldehyde (92 μL, 0.90 mmol), sodium hydrogensulfite (147 mg, 1.48 mmol) in DMF (5 mL). The bottle was sealed and heated at 100° C. for two hours and then stirred at 25° C. overnight for 16 hours. The reaction mixture was then concentrated in vacuo and partitioned between ethyl acetate (15 mL) and brine/water (1:1, 15 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. Flash chromatography (Biotage 40S column, 40/60 ethyl acetate/hexanes) afforded 4-(5-methyl-2-phenyl-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (339 mg, quantitative) as a light purple foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]=1.C([Li])(C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:32])(=O)=O)=CC=1.C(O)(=O)C>O1CCCC1.CCCCC.O.CCOCC>[F:32][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: COc1ncccc1NC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: CC(=O)O
Product: COc1nccc(F)c1NC(=O)OC(C)(C)C
Temperature: -60 °C

Procedure:
To a solution of 8 g (35.7 mmol) of t-butyl N-(2-methoxy-3-pyridyl)carbamate in 200 mL of dry tetrahydrofuran was added with stirring at -60° C., 46.2 mL (78.5 mmol) of 1.7M t-butyl lithium in pentane. The resulting solution was allowed to warm slowly with stirring to -20° C. over a 20 to 30 min period. It was then cooled to about -60° C. and 12.2 g (38.7 mmol) of N-fluorodibenzenesulfonimide was added with stirring all at once. The mixture was allowed to warm to -20° C. and was poured into 500 mL of ether. The resulting ethereal solution was washed with a mixture of 2.5 g (41.7 mmol) of acetic acid and 150 mL of water. The aqueous phase was extracted with 200 mL of ether. The ethereal extracts were combined, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by flash chromatography to obtain 6.7 g (77 percent of theory) of the title compound as a colorless solid melting at 75°-77° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]([CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1.Br[CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[I].[K].[ClH:36]>CN(C=O)C.CCOC(C)=O.C(OCC)C>[ClH:36].[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]([CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CN(C)C(=O)CN(CCc1cccc(O)c1)CC1CCOC1
Reactant: CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCOc1cccc(CCN(CC(=O)N(C)C)CC2CCOC2)c1
Yield: 50 %

Procedure:
A solution of 2-[[2-(3-hydroxy-phenyl)-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide (1.0 g 3.3 mmol), 1-bromobutane (0.43 ml, 4 mmol), potassium carbonate (680 mg 5 mmol), potassium iodine (50 mg, 0.3 mmol), in DMF (30 ml) was refluxed for 16 h. After filtration over celite pad, the solution was evaporated from the solvent and the crude oil obtained purified by preparative HPLC. The hydrochloride salt was prepared by adding HCl N in AcOEt to the free amine dissolved in ethyl ether. After filtration, 690 mg (50% yield) the title compound was obtained as a white solid of 99% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:28]3[CH2:27][CH2:26][N:25]([CH2:24][C:23]4[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=4[C:21]([F:35])([F:36])[F:20])[CH2:30][CH2:29]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4C(F)(F)F)CC3)on2)cc1OC
Yield: 62.8 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-[2-(trifluoromethyl)benzyl]piperazine (8.0, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22.5 hr and followed the same processes as in Example 1 to obtain 12.3 mg (65.6%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:31])[CH2:20][O:21][C:22]1[N:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[N:23][C:22]([O:21][CH2:20][CH:19]([F:31])[F:18])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1cnc(OCC(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2-difluoro-ethoxy)-pyrazine-2-carboxylic acid (CAS 1174323-38-6; WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=428.2 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[C:19]([Cu])#[N:20]>CN1C(=O)CCC1>[C:19]([C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16])#[N:20]
Reactant: CCc1c(C)nc2sc(C(=O)OC)c(I)c2c1C
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCc1c(C)nc2sc(C(=O)OC)c(C#N)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To the solution of methyl 3-iodo-5-ethyl-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate prepared above (5.18 g, 13.8 mmol) in NMP (100 mL), was added CuCN (2.47 g, 27.6 mmol). The mixture was stirred at room temperature overnight. Work-up was conducted as above and the crude product was chromatographed (EtOAc/CH2Cl2, 2.5/97.5) to give pure methyl 3-cyano-5-ethyl-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate (2.70 g, 71%). MS (ES+) m/z: 275.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([CH:20]=[O:21])[CH:9]1[CH2:22][CH2:23][CH:24](OC1CCCCO1)[CH2:25][CH2:26][CH2:27][CH2:28]C.C(OCCCCCCCC1C(C#N)CC(OC2CCCCO2)C1=O)(=[O:39])C.O1CCCCC1OC1C(OC2CCCCO2)CC(C#N)C1CCC(OC1CCCCO1)CCCCC.O1CCCCC1OC1C(O)CCC1>>[CH:20]([CH:10]1[CH2:11][CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:8]([OH:7])[CH:9]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:39])=[O:21]
Reactant: CCCCCC(CCC1C(C=O)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Reactant: CC(=O)OCCCCCCCC1C(=O)C(OC2CCCCO2)CC1C#N
Agent: CCCCCC(CCC1C(C#N)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Agent: OC1CCCC1OC1CCCCO1
Product: O=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO

Procedure:
By proceeding in a similar manner to that described above in Example 1(m) for the preparation of 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbaldehyde, but substituting the appropriate quantity of 2-(7-acetoxyheptyl)-3-cyano-5-(2-tetrahydropyranyloxy)cyclopentanone [prepared as described above in Example 2(d)] for the 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbonitrile used as starting material, there was prepared 3-formyl-2-(7-hydroxyheptyl(-5-(2 -tetrahydropyranyloxy)cyclopentanol, νmax 3400 cm-1, 1710 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:3]=1[CH2:4][C@@H:5]([NH:23][C:24](=[O:26])[CH3:25])[CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][C:14]3[N:15]([N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)[C:10]2=[N:9][N:8]=1.[H][H]>[Pd].COCCO>[F:1][C:2]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:3]=1[CH2:4][C@@H:5]([NH:23][C:24](=[O:26])[CH3:25])[CH2:6][C:7]1[N:11]2[CH2:12][CH2:13][C:14]3[N:15]([N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)[C:10]2=[N:9][N:8]=1
Reactant: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1ccc1nc(C(F)(F)F)nn12
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCc1nc(C(F)(F)F)nn1-2

Procedure:
A mixture of 52.1 mg (0.114 mmol) of N-{(1R)-1-(2,4,5-trifluorobenzyl)-2-[8-(trifluoromethyl)bis[1,2,4]triazolo[1,5-c:4′,3′-a]pyrimidin-3-yl]ethyl}acetamide, 52 mg of 10% palladium on carbon, and 5 mL of 2-methoxyethanol was shaken with hydrogen (52 psi) for 26 h. The catalyst was removed by filtration through Celite, and the filtrate was concentrated to dryness. The residue was purified by preparative thin-layer chromatography on silica gel (three successive developments in 92.5:7.5 dichloromethane:methanol) to provide the title compound. LC-MS 460 (M+1).