Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][OH:26])=[NH:24])=[C:21]([O:29][CH3:30])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42](OC1C=CC=CC=1)=[O:43].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]2[NH:24][C:42](=[O:43])[O:26][N:25]=2)=[C:21]([O:29][CH3:30])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1C(=N)NO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1-c1noc(=O)[nH]1
Temperature: 150 °C

Procedure:
To a solution of 1.05 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-hydroxy-2-methoxy-benzamidine in 5 mL of tetrahydrofuran were added 254 μL of phenyl chloroformate and 607 μL of diisopropylethylamine. The resulting mixture was heated to 150° C. under microwave irradiation for 20 minutes. After allowing it to cool down to room temperature, the mixture was concentrated under reduced pressure and dichloromethane/water were added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Diisopropyl ether was added to the residue and the solid was collected by filtration and washed with diisopropyl ether to give 558 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([O:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:25])[CH3:24]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCCNC(=O)OCc1ccccc1
Yield: 111 %

Procedure:
In 200 ml of methylene chloride was dissolved 21 g of the 3-(benzyloxycarbonylamino)propanol, and 11 g of triethylamine was added thereto, after which 8.6 g of acetyl chloride was added thereto dropwise at -10° C. to -5° C. The resulting mixture was subjected to reaction at the same temperature for 1 hour. Subsequently, at room temperature, the reaction mixture was washed successively with 50 ml of diluted hydrochloric acid, 50 ml of a saturated aqueous sodium hydrogencarbonate solution and 50 ml of water, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 28 g of oily 1-acetoxy-3-(benzyloxycarbonylamino)propane.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]#[N:10].N.CO.[H][H]>[Ni]>[F:11][C:2]([F:1])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][NH2:10]
Reactant: [H][H]
Reactant: N#Cc1cnccc1C(F)(F)F
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cnccc1C(F)(F)F
Reaction time: 16 h
Yield: 108.4 %

Procedure:
To a mixture of 4-(trifluoromethyl)-3-pyridinecarbonitrile (9.5 g, 55 mmol, 1.0 equiv) and 5 M NH3 in methanol (600 mL, 3.0 mol, 54 equiv) was added Raney-Ni (3.0 g, 52 mmol, 0.95 equiv). The flask was fitted with a hydrogen balloon, and the mixture was stirred for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by HPLC to afford 10.5 g (47%) of the title compound as the bis-trifluoroacetate salt. MS (ES+): m/e 177.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11](O)=[O:12])=[C:7]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[C:29]([CH3:38])[CH:28]=1)[CH3:26].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:24][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[C:29]([CH3:38])[CH:28]=2)[CH3:26])=[O:12])=[C:7]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(CN2CCCCC2)c1
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C)cc2CN2CCCCC2)ccc1NS(C)(=O)=O
Reaction time: 18 h
Yield: 4.9 %

Procedure:
To a methylene dichloride (5.0 ml) solution of [4-tert-butyl-2-(piperidin-1-ylmethyl)phenoxy]acetic acid (111 mg) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (97 mg, 0.37 mmol), a portion of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (109 mg, 0.57 mmol), triethylamine (0.2 ml, 1.4 mmol), and catalytic amount of 4-(dimethylamino)pyridine were added at ambient temperature under nitrogen atmosphere. After being stirred for 18 hours, the reaction mixture was diluted with methylene dichloride and quenched with saturated aqueous solution of ammonium chloride. The organic layer was then washed with brine and dried over magnesium sulfate. After filtration to separate solvent and magnesium sulfate, the solvent was removed under reduced pressure, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=40/1 to give oil which contained 4-(dimethylamino)pyridine. This crude product was purified by HPLC gradient from 0.05% aqueous solution of ammonium formate/acetonitrile=4/96 to 96/4 to furnish 9.1 mg (5% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([CH:18]=O)[C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][OH:28])=[NH:26])=[CH:23][CH:22]=1.C([N+]#[C-])C1C=CC=CC=1>>[C:9]([O:8][C:6]([CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:16][C:15]([Cl:17])=[CH:14][C:13]=1[CH:18]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[NH:26])[NH:27][OH:28])=[CH:23][CH:22]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)COc1c(Cl)cc(Cl)cc1C=O
Reactant: N=C(NO)c1ccc(N)cc1
Agent: [C-]#[N+]Cc1ccccc1
Product: COC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(Cl)cc(Cl)c1OCC(=O)OC(C)(C)C

Procedure:
In analogy to Example 1.1., tert-butyl (2,4-dichloro-6-formyl-phenoxy)-acetate was reacted with 4-amino-N-hydroxybenzamidine and benzyl isonitrile. There was obtained methyl (RS)-(2-tert-butoxycarbonylmethoxy-3,5-dichloro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate; MS (ISP) m/z 498.2 (M+H)+, 520.2 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: BrCCOc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCOc2ccc(Br)cc2)cc1

Procedure:
A mixture of 26.4 g of ethyl p-aminobenzoate, 22.4 g of 2-bromoethyl p-bromophenyl ether and 80 ml of hexamethylphosphoramide is heated at 100°-110° C. for 20 hours. The mixture is chilled, diluted with 25 ml of water, chilled and filtered. The solid is washed with 100 ml of ethanol-water (1:1), with 25 ml of ethanol and with water to give tan crystals, mp 128°-133° C. Recrystallization from ethanol gives yellow crystals, mp 135.5°-137° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]([CH3:51])([CH3:50])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28](=[O:29])[N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)[C:26]([CH2:45][CH2:46][CH3:47])=[N:25][C:24]=2[CH2:48][CH3:49])=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH3:51][C:14]([CH3:50])([CH3:13])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:28](=[O:29])[N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)[C:26]([CH2:45][CH2:46][CH3:47])=[N:25][C:24]=2[CH2:48][CH3:49])=[CH:21][CH:22]=1
Reactant: CCCc1nc(CC)c(-c2ccc(OCC(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OCC(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.42 g), sodium hydrogen carbonate (0.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-[4-(2,2-dimethylpropoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.37 g) was added, and the mixture was stirred at 90° 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. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixture was stirred at room temperature for 2 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 (0.2 g, 65%).
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]3[C:21]([C:24]4[S:25][C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=4)=[N:22][N:23]=[C:17]3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.O.[OH-].[Li+]>O1CCCC1.CO.O>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[C:21]1[N:18]2[CH2:19][CH2:20][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=3)[CH2:16][C:17]2=[N:23][N:22]=1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCn3c(nnc3-c3nc4ccccc4s3)C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nccc(N2CCn3c(nnc3-c3nc4ccccc4s3)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (R)-1-[4-(3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 259, Step D, 220 mg, 0.49 mmol) in a 3:1:1 mixture of tetrahydrofuran/methanol/water (5 mL) was added lithium hydroxide hydrate (62 mg, 1.47 mmol). This mixture was stirred at room temperature for 3 h, concentrated, and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (5% methanol/chloroform) to give 192 mg (100%) of the title compound as a colorless solid. mp: 216.5-218.5° C.; 1H NMR (CDCl3, 300 MHz) δ8.37 (d, 1H), 8.06 (d, 1H), 7.97 (d, 1H), 7.56-7.45 (c, 2H), 6.56 (d, 1H), 5.11 (s, 2H), 4.83 (t, 2H), 4.77 (m, 1H), 4.35-4.25 (c, 2H), 4.16 (s, 1H), 1.54 (d, 3H); MS (APCI) 380 (MH+), [α]D +14.2 (c 1.0, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=S)[NH:10][C:9]=2[CH:14]=1)=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:14][C:9]=2[N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2oc(=S)[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2oc(Cl)nc2c1
Temperature: 25 °C

Procedure:
In a round bottom flask equipped with a magnetic stirrer, nitrogen inlet, reflux condenser and drying tube were placed 5-methoxycarbonylbenzoxazolthione (5.2 g, 0.025 mole), phosphorus pentachloride (5.2 g, 0,025 mole), and phosphorus oxychloride (40 mL). The reaction mixture was heated by an oil bath at 95°-100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was distilled with a short path distillation apparatus and the product was collected at 160°-163° C. at 29 mm Hg. The product solidified on standing to give a pale yellow solid, m.p. 104°-106° C. Anal Calcd. for C9H6ClNO3: C, 51.1; H, 2.9; N, 6.6; Cl, 16.8. Found: C, 50.7; H, 2.9; N, 6.6; Cl, 16.3
Reaction SMILES: [N+](=[C:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH3:17][OH:18]>C1C=CC=CC=1.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH:3]([O:18][CH3:17])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=1
Reactant: CO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(O)cc1)OC
Temperature: 25 °C

Procedure:
A solution of ethyl 2-diazo-3-(4hydroxyphenyl)propanoate (c.f. N. Takamura and T. Mizoguchi, Tetrahedron Lett., 1971, 4495) (8.8 g) in benzene (40 mL) was added over 30 minutes to a stirred, refluxing mixture of rhodium (II) acetate dimer (10 mg), methanol (7.9 mL) and benzene (50 mL). The mixture was heated at reflux for a further 30 minutes, then allowed to cool to room temperature overnight and washed with water (2×200 mL). The benzene solution was dried (MgSO4) and evaporated and the residual oil chromatographed twice on silica gel, firstly with 20% ethyl acetate in hexane as eluent and subsequently with 4% ethyl acetate in dichloromethane as eluent to afford the title compound as an oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>C(OCC)(=O)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
To a solution of 1-iodo-3-(trifluoromethyl)benzene (1.0 g, 3.6 mmol) in ethyl acetate (20 mL) was added ethynyl(trimethyl)silane (0.540 g, 5.5 mmol), copper iodide (0.042 g, 0.22 mmol), bis(triphenylphosphine) palladium(II) chloride (0.129 g, 0.18 mmol) and TEA (2.2 mL, 14.7 mmol). The reaction mass stirred at 50-60° C. for 24 h. The reaction mass was quenched in water, extracted with ethyl acetate and concentrated to afford 0.500 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.26 (s, 9H), 7.44 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.72 (s, 1H).
Reaction SMILES: COP([CH2:7][C:8](=[O:25])[CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][CH:35]=1>CN(C)C=O.C(OCC)(=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][C@H:12]1[CH2:13][C@@H:14]([CH3:15])[N:10]([CH2:9][C:8](=[O:25])[CH:7]=[CH:40][C:37]2[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[C:11]1=[O:24])([CH3:21])([CH3:22])[CH3:23]
Reactant: COP(=O)(CC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)OC
Reactant: COc1ccc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C=CC(=O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Temperature: 82.5 °C

Procedure:
A stirred suspension of 4-3 (190 mg, 0.50 mmol), potassium carbonate (104 mg, 0.75 mmol), and 6-methoxy-pyridine-3-carboxaldehyde (for preparation, see U.S. Pat. No. 6,048,861, which is incorporated by reference herein in its entirety) (69 mg, 0.50 mmol) in N,N-dimethylformamide (2 mL) was heated at 80-85° C. for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 95:5% ethyl acetate/methanol) to give 4-4 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:25][CH:26]=[CH2:27])[CH2:9][CH:8]([O:10][Si](C(C)(C)C)(C)C)[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]([C@@:5]1([CH2:25][CH:26]=[CH2:27])[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:4]
Reactant: C=CCC1(C(=O)OC)CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@]1(C(=O)OC)C[C@@H](O)CN1C(=O)OC(C)(C)C

Procedure:
3.3 g (8.27 mmol) (2R,4R)-(2-allyl-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester are dissolved in 60 mL THF, cooled below 5° C. and treated with 8.68 mL (1.05 eq) 1 M TBAF in THF under stirring. The reaction mixture is allowed to slowly reach room temperature, while being stirred another 4 h. Ice and AcOEt are added, the mixture washed with brine twice, and the organic phase evaporated to yield a crude product which is column chromatographed (silica gel, TBME/petroleum ether 1:1) to yield 1.8 g desired product as a colorless, thick oil, which is used as such in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[O:6].[CH:12](I)([CH3:14])[CH3:13]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C(C)C)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 17.6 %

Procedure:
Add sodium hydride (2.87 g, 71.7 mmol, 60% in mineral oil) portion-wise over 10 minutes to a cooled (0° C.) solution of 1H-imidazole-4-carboxylic acid methyl ester (6.03 g, 47.8 mmol) in dimethylformamide (150 ml). Remove the cooling bath and stir at room temperature for 4.5 hrs. Cool the mixture to 0° C. and add isopropyl iodide (8.94 g, 52.6 mmol) dropwise over 10 min. Remove the cooling bath and stir at room temperature for 20 hrs. Quench the mixture with saturated aqueous ammonium chloride and extract with ethyl acetate (3×). Wash the combined extracts with brine, dry over sodium sulfate, filter and concentrate under reduced pressure to give an oil. Purify the oil by flash chromatography (silica gel) eluting with 25% acetone/hexanes to provide the product as an oil (1.41 g, 8.4 mmol, 17% yield). M/S (m/z): 169 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[F:26][C:24]1[CH:25]=[C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])[CH:21]=[C:22]([F:28])[C:23]=1[O:27][CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(CCl)c(SC(C)C)n1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: Cc1ccc(COc2c(F)cc(CCC(=O)O)cc2F)c(SC(C)C)n1
Yield: 78 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine obtained in Step D of Preparation Example 9 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (236 mg, 1.02 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (278 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([OH:35])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:35][C:27]4[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([F:24])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cc(F)cc(C(F)(F)F)c4)ncnc32)CC1

Procedure:
4-[4-(3-Fluoro-5-trifluoromethyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluoro-5-(trifluoromethyl)phenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.06 (m, 4H), 2.99-3.07 (m, 2H), 4.08-4.11 (m, 2H), 4.99-5.05 (m, 1H), 7.71-7.78 (m, 3H), 8.40 (s, 1H), 8.59 (s, 1H). Mass spectrum MH+=482.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:42]([CH2:43][CH3:44])=[C:16]3[N:17]=[C:18]([C:22]4[C:23]([O:39][CH2:40][CH3:41])=[N:24][CH:25]=[C:26]([S:28]([N:31]5[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]5)(=[O:30])=[O:29])[CH:27]=4)[NH:19][C:20](=[O:21])[C:15]3=[N:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[NH3:6].[CH2:40]([O:39][C:23]1[C:22]([C:18]2[NH:19][C:20](=[O:21])[C:15]3[C:16](=[C:42]([CH2:43][CH3:44])[N:13]([C:10]4[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=4)[N:14]=3)[N:17]=2)=[CH:27][C:26]([S:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:25][N:24]=1)[CH3:41]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(-c3ccc(N)cc3)nc2c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(-c3ccc(NS(C)(=O)=O)cc3)nc2c(=O)[nH]1
Product: N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methanesulphonyl chloride (15 μl, 0.19 mmol) was added to an ice-cooled solution of the title compound from example 64 (93 mg, 0.17 mmol) in pyridine (2 ml), and the reaction allowed to warm to room temperature, and stirred for 90 minutes. Tlc analysis showed starting material remaining, so additional methanesulphonyl chloride (15 μl, 0.19 mmol) was added, and the reaction stirred for a further hour. The reaction was quenched by the addition of aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) as eluant, then repeated using dichloromethane:methanol:0.88 ammonia (95:5:1) to afford the title compound, 36 mg.