Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CN.[BH4-].[Na+].ClCCl>CO>[NH3:11].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH:24]([OH:26])[CH3:25])=[CH:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Agent: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(O)c1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Product: N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the suspension of 1-{4-[2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-pyridin-4-yl]-phenyl}-ethanone (Example 7, 0.19 g, 0.55 mmol) in 2 mL of MeOH was added a solution of methylamine in MeOH (Aldrich Chemical Company) (2N, 0.55 mL, 1.1 mmol). The reaction was stirred at room temperature under nitrogen overnight. NaBH4 (Aldrich Chemical Company) (25 mg, 0.66 mmol) was then added to the reaction and it was stirred for another 5 hrs. The solvent was dichloromethane:2N NH3 in MeOH) to give the title compound as an off-white foam. MS (ESI, pos. ion) m/z: 349 (M+1). Mp: 55.9-61.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:39])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([I:39])=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1Sc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(I)nc(-c2ccc(S(C)(=O)=O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To the solution of Step 2 product (200 mg, 0.528 mmol) in CH2Cl2 (0.5 ml) was added TFA (3 ml) and NIS (238 mg, 1.06 mmol) at rt, and then reaction mixture was heated to reflux overnight. Reaction mixture was cooled to rt and concentrated. To the residue was added CH2Cl2, quenched with NaHCO3 (aq), washed with aq Na2S2O3, water and brine. Dried over Na2SO4, filtered and concentrated. Separated by prep TLC (hex:EtOAc=1:1) to give 5-[(4-chlorophenyl)sulfanyl]-2-iodo-1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole as light yellow solid (180 mg). LCMS: [M+1]+=505.0 Human FAAH lysate assay: IC50=15.6 nM.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CC(C)=O>CC(C)=O>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:28]3[CH2:29][CH2:30][CH:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CN1C(=O)CCc2c(OCC3CO3)cccc21
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: CN1C(=O)CCc2c(OCC(O)CN3CCC(Cc4ccccc4)CC3)cccc21
Temperature: 25 °C
Yield: 78 %

Procedure:
2.4 Grams of 1-methyl-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 2.0 g of 4-benzylpiperidine were mixed with 30 ml of methanol and the mixture was heated under refluxing condition for 3 hours. The reaction mixture was concentrated under a reduced pressure and the residue thus obtained was dissolved in 30 ml of acetone and a 5%-oxalic acid-acetone solution was added under stirring at a room temperature to adjust the pH to 4.5 and allowed to stand. The precipitates thus formed were collected by filtration, washed with acetone and recrystallized from ethanol-ether to obtain 3.9 g (yield: 78%) of 1-methyl-5-[2-hydroxy-3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril monooxalate as in the form of colorless powder. Melting point: 150°-152° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:22])[CH3:21]
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Fluorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.[CH3:23][N:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]([CH3:32])=[N:25]1.O>CN(C)C(=O)C>[C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:19]=[CH:20][C:21]([F:22])=[C:2]([NH:1][C:29]([C:28]4[N:24]([CH3:23])[N:25]=[C:26]([CH3:32])[CH:27]=4)=[O:30])[CH:3]=3)=[N:11][N:10]2[CH:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cn2nc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (5.6 g, 18.6 mmol) in N,N-dimethylacetamide (44.8 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (3.25 g, 20.4 mmol). After stirring at room temperature for 2 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/ethanol to give the title compound (6.1 g, 78%) as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[CH:10]([OH:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[CH:10]([O:28][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(Cc2ccccc2)CCC1c1cccc(OCc2ccccc2)c1
Reactant: BrCc1ccc2ccccc2c1
Product: c1ccc(COc2cccc(C3CCN(Cc4ccccc4)CC3OCc3ccc4ccccc4c3)c2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-piperidin-3-ol with 2-bromomethylnaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless resin; MS: 514 (M+H)+.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)=[CH:7][CH:6]=1.[NH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:26]([C:27]([NH2:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>O1CCOCC1>[C:27]([C:26]1[CH:30]=[C:22]([CH:23]=[CH:24][C:25]=1[OH:31])[O:21][CH2:20][CH2:19][NH:18][CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)=[CH:7][CH:6]=1)(=[O:28])[NH2:29]
Reactant: Cn1nnc(-c2ccc(OCC3CO3)cc2)n1
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Solvent: C1COCCO1
Product: Cn1nnc(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)n1

Procedure:
Analogously to the procedure described in Example 12, by reacting 2.3 g of 5-[4-(2,3-epoxypropoxy)-phenyl]-2-methyl-2H-tetrazole with 1.5 g of 5-(2-aminoethoxy)-salicylamide there is obtained 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(2-methyl-2H-tetrazol-5-yl)-phenoxy]-2-propanol having a melting point of 174°-175° (from dioxan).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:19])=[C:10]([OH:18])[C:11]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:20][C:21]1[CH:22]=[N:23][C:24]([O:18][C:10]2[C:9]([F:19])=[C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)[CH:13]=[CH:12][C:11]=2[CH:14]2[CH2:15][CH2:16][CH2:17]2)=[N:25][CH:26]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(O)c2F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1cnc(-c2ccc(C3CCC3)c(Oc3ncc(Br)cn3)c2F)cn1
Temperature: 120 °C

Procedure:
To a microwave vial containing a stir-bar was added 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (100 mg, 0.386 mmol), 5-bromo-2-chloropyrimidine (74 mg, 0.39 mmol), cesium carbonate (188 mg, 0.580), and DMSO (2 mL). The vial was sealed and heated in the microwave for 30 minutes at 120° Celsius. The mixture was cooled to rt then passed through a syringe filter and the filtrate subjected to HPLC purification to give the title compound. 1H NMR (500 MHz, 2 mL) δ 8.69 (d, J=1.5, 2H), 8.24 (s, 1H), 8.10 (s, 1H), 7.79-7.69 (m, 1H), 7.27 (d, J=8.3, 1H), 3.72-3.58 (m, 1H), 2.23-2.10 (m, 3H), 2.02-1.94 (m, 1H), 1.89-1.75 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:7]=1Br.CCO[C:23]([S-:25])=[S:24].[K+].[C:27](O)(=O)C.IC>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:27][S:25][C:23]1[S:24][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=2
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)c1cccc(-c2ccc(N)c(Br)n2)c1
Reactant: CC(=O)O
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2ccc3nc(SC)sc3n2)c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of ethyl 3-(5-amino-6-bromopyridin-2-yl)benzoate (10.44 g, 32.60 mmol) in NMP (150 mL) was added potassium ethyl xanthogenate (26.14 g, 163.11 mmol) and acetic acid (9.4 mL, 163.11 mmol). The reaction mixture was heated at 150° C. for 16 hours. The mixture was cooled to 50° C. and iodomethane (20.3 mL, 326 mmol) was added. The reaction mixture was further stirred for 30 minutes and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 85:15 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(2-(methylthio)thiazolo[5,4-b]pyridin-5-yl)benzoate (7.6 g, 70% yield) as a bright brown solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4]O.[C:9]([O:13][CH3:14])(=O)[CH:10]=C.S(=O)(=O)(O)[OH:16]>O1CCCC1.CS(C)=O>[O:16]=[C:10]1[CH2:9][O:13][CH2:14][CH:4]1[C:3]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CO
Reactant: C=CC(=O)OC
Reactant: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1COCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
55% Sodium hydride (1.9 g) was suspended in tetrahydrofuran (30 ml), and a solution of methyl glycolate (3.6 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes. After stirring at room temperature for 30 minutes, the solvent was evaporated to give a colorless solid. This was suspended in dimethyl sulfoxide (20 ml), and methyl acrylate (4.3 ml) was added under ice-cooling. The mixture was stirred at the same temperature for 15 minutes and then stirred at room temperature for 45 minutes. The reaction solution was poured into a 5% aqueous sulfuric acid solution (50 ml), followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (3.0 g) as a colorless solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:27])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: O=C(c1cncc(Cl)n1)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: O=C(c1cncc(-c2cnc3[nH]ccc3c2)n1)N1CCCCC1
Temperature: 90 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and (6-chloropyrazin-2-yl)(piperidin-1-yl)methanone (75) (41 mg, 0.184 mmol, 0.9 eq) in DME (8 mL) was degassed and purged under argon atmosphere for min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.410 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound (6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)(piperidin-1-yl)methanone 138 in 10 mg quantity. The compound 138 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.61 (s, 1H), 9.12 (s, 1H), 9.02 (s, 1H), 8.80 (m, J=87.55 1H), 8.60 (d, J=1.82, 1H), 7.42 (m, J=3.17, 1H), 6.64 (m, J=1.58, 1H), 3.87 (s, 2H), 3.59 (m, J=88.29, 1H), 1.75 (s, 4H), 1.69 (m, J=24.99, 2H); MS m/z 307.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]I>C(#N)C.[Ag]=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH3:17])[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1nc(CO)cs1
Agent: O=[Ag]
Solvent: CC#N
Product: COCc1csc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
0.412 g of 2-(tert-butoxycarbonylamino)methyl-4-hydroxymethylthiazole was dissolved in 8 ml of acetonitrile. To this solution were added 0.98 g of silver oxide and 0.5 ml of methyl iodide, and the mixture was stirred at room temperature for 6 hours. The reaction solution was filtered, and then concentrated to dryness to give 0.385 g (yield 89%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[C:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)#[N:20].C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:24]3[CH2:25][CH2:26][CH:21]([C:19]#[N:20])[CH2:22][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: N#CC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1c(-c2ccc(C(=O)N3CCC(C#N)CC3)s2)noc1C(F)(F)F
Yield: 61 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-cyanopiperdine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on a short column of silica gel with EtOAc as eluant to afford product as a colorless solid (91 mg, 61%). 1H NMR (CDCl3) 1.91-2.06 (m, 4 H), 2.37 (d, J=1.3, 3 H), 2.97-3.03 (m, 1 H), 3.71-3.79 (m, 2 H), 3.90-3.98 (m, 2 H), 7.34 (d, J=4.0, 1 H), 7.47 (d, J=4.0, 1 H). 13C NMR 7.9, 26.5, 28.9, 43.6, 114.8, 118.7 (q, J=271), 120.8, 128.1, 129.5, 131.7, 139.4, 155.2 (q, J=40), 157.8, 162.9. 19F NMR −63.2. LC/MS 6.18 min, [M+1]+ 370.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[CH3:12].[N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]=S.[NH:26]1[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:28]=[N:27]1.CC(C)N=C=NC(C)C>C(Cl)Cl>[CH2:34]([O:33][C:31]([C:29]1[CH:30]=[N:26][N:27]([C:19]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][C:3]3[C:2]([CH3:1])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:17])=[C:6]([CH3:12])[CH:7]=2)=[N:18][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:28]=1)=[O:32])[CH3:35]
Reactant: Cc1cc(N)ccc1Oc1c(C)cccc1C
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CCOC(=O)N=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)N=C(Nc1ccc(Oc2c(C)cccc2C)c(C)c1)n1cc(C(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
A solution of 4-(2,6-dimethyl-phenoxy)-3-methyl-aniline (0.80 g, 3.5 mmol), ethyl isothiocyanatoformate (0.40 mL, 3.5 mmol) and DCM (30 mL) was stirred at room temperature for 1 h. Ethyl pyrazole-4-carboxylate (0.54 g, 3.9 mmol) and DIC (0.54 mL, 3.5 mmol) were added, and the solution was stirred at room temperature for 16 h. The mixture was concentrated and purified by FCC (EtOAc/hexanes 0:100 to 50:50) to provide the titled compound (0.97 g, 60%). MS (ESI): mass calcd. for C25H28N4O5, 464.5; m/z found, 465.1 [M+H]+.
Reaction SMILES: [N:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[OH:8].C([O:11][C:12](=O)[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[C:14](=O)[CH3:15])C.O>CO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[OH:7][C:6]1[N:1]=[C:2]2[O:8][C:12](=[O:11])[C:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[C:14]([CH3:15])[C:3]2=[CH:4][CH:5]=1
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: Oc1cccc(O)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: O
Solvent: CO
Product: Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2nc(O)ccc12
Temperature: 75 °C
Reaction time: 30 h
Yield: 57.4 %

Procedure:
Zn(OTf)2 (669 mg, 1.84 mmol) was added to a suspension of pyridine-2,6-diol (204 mg, 1.84 mmol) and 2-(3-nitrobenzyl)-3-oxobutyric acid ethyl ester (488 mg, 1.84 mmol) in methanol (10 mL), and the mixture was stirred at 75° C. for 30 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. It was then concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (330 mg, 57%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43]([OH:45])=O)=[C:35]2[CH:34]=[N:33]1.[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([NH2:58])=[N:56][CH:57]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43]([NH:58][C:55]3[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=3)=[O:45])=[C:35]2[CH:34]=[N:33]1
Reactant: CC(C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)O
Reactant: Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (333 mg, 0.88 mmol) was added to (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoic acid D2 (300 mg, 0.80 mmol), 5-methylpyridin-2-amine (95 mg, 0.88 mmol) and N-ethyldiisopropylamine (0.153 mL, 0.88 mmol) in DCM (15 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM (25 mL) and washed with saturated brine (20 mL). The aqueous layer was re-extracted with DCM (30 mL). The combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (175 mg, 47.1%), 10% ee. 143 mg of this material was further purified by chiral preparative HPLC on Chiralcel OJ (50 mm×20 μm), eluent isohexane/EtOH/MeOH 70/15/15 to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (56 mg, >99% ee which eluted after the R enantiomer).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([O-:11])(=[S:10])[CH3:9].[CH2:12](Cl)Cl>CN(C)C1C=CN=CC=1>[C:8]([OH:11])(=[S:10])[CH3:9].[CH2:5]([O:4][C:1](=[O:3])[CH2:2][CH2:8][SH:10])[CH:6]=[CH2:12]
Reactant: CC([O-])=S
Reactant: CC(=O)OC(C)=O
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Product: C=CCOC(=O)CCS
Product: CC(O)=S
Reaction time: 1 h

Procedure:
The reaction mixture from step 1 was cooled under nitrogen and then diluted with 200 g. of methylene chloride. Then, 289 g. of acetic anhydride, along with a catalyst of 0.5 g. of 4-dimethylaminopyridine, were added to the reaction mixture. The reaction mixture was stirred for 1 hour at which time NMR analysis of a vacuum stripped aliquot indicated complete conversion to the desired thioacetate. The product was distilled at 132°-134° C. at 20 mm Hg to yield 355 g. of product (80%).
Reaction SMILES: S1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[C:13](O)(C(F)(F)F)=O>C(Cl)Cl>[CH:5]1[CH:6]=[C:2]([CH2:13][C:12]2[NH:8][CH:9]=[CH:10][CH:11]=2)[NH:3][CH:4]=1
Reactant: O=Cc1nccs1
Reactant: O=C(O)C(F)(F)F
Reactant: c1cc[nH]c1
Solvent: ClCCl
Product: c1c[nH]c(Cc2ccc[nH]2)c1
Reaction time: 0.17 h
Yield: 245.5 %

Procedure:
In a foil-covered 250-mL three-necked flask, equipped with a magnetic stirrer and a N2 inlet, was placed 2-thiazolecarboxaldehyde (13, 0.97 g, 8.6 mmol) (Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. Synthesis 1987, 998-1001), CH2Cl2 (35 mL), and pyrrole (7.2 mL, 104 mmol). The reaction mixture was stirred for 10 min, then TFA (0.26 mL, 3.4 mmol) was added. After a stirring period of 1 h at room temperature, the reaction mixture was transferred to a separatory funnel and washed with saturated aqueous NaHCO3 (50 mL), H2O (50 mL), and brine (50 mL) The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), and adsorbed onto silica gel (3 g). Purification by column chromatography (1:1 ether/hexanes) provided dipyrromethane 14 (1.22 g, 62%) as a solid: 1H NMR (300 MHz, CDCl3) δ 5.78 (s, 1H), 6.04 (s, 2H), 6.15 (m, 2H), 6.71 (m, 2H), 7.20 (d, 1H), 7.74 (d, 1H), 8.81 (br s, 1H).