Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11](N)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.[OH:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].N([O-])=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([O:23][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(-c2nc(N)cc3cccnc23)c1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 8-(3-methylsulfanyl-phenyl)-[1,7]naphthyridin-6-ylamine (2.05 g, 7.68 mmol) in DMF (30 ml) at 0° C. is added triflic acid (20 ml) slowly. Sodium nitrite (1.06 g) is then added slowly over 15 minutes and the reaction mixture allowed to warm to room temperature. After stirring for 23 hours the reaction is complete by HPLC. The mixture is then diluted with ethyl acetate and washed with water, 2 N sodium carbonate and brine. The organic layer is dried over magnesium sulfate and concentrated. The product is purified by silica gel chromatography, eluting with 30% ethyl acetate in isohexane. The product is obtained as an amorphous solid. MS (ES+) 400.9948
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:45]=[CH:44][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:28][C:29]4[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:30]=4[F:38])[C:14](=[O:39])[N:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:45]=[CH:44][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:28][C:29]4[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:30]=4[F:38])[C:14](=[O:39])[N:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCCn1c(=O)n(Cc2cc([N+](=O)[O-])ccc2F)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCn1c(=O)n(Cc2cc(N)ccc2F)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Yield: 95.9 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-nitro-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (45 mg, 0.07 mmol) in methanol (30 mL) was treated with 10% palladium on carbon (45 mg). The reaction mixture was subjected to 48 psi pressure of hydrogen gas in a Parr apparatus for 2 h. At this time, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated in vacuo to afford 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-1-(5-amino-2-fluoro-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (39.8 mg, 92.9%) as an off-white solid: LR-MS for C31H37FN6O5 (M−H)+ at m/z=591.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[O:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>C1COCC1>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][CH:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: NC1CCOCC1
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(NC3CCOCC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and tetrahydro-2H-pyran-4-amine (0.19 g, 1.90 mmol) in THF (1 mL) the title compound was obtained as an off-white solid (0.094 g, 0.16 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (d, J=5.2 Hz, 1H), 7.75-7.65 (m, 1H), 7.55-7.38 (m, 1H), 7.38-7.28 (m, 1H), 7.28-7.11 (m, 3H), 7.11-6.88 (m, 2H), 6.22 (d, J=5.2 Hz, 1H), 5.06 (d, J=7.8 Hz, 1H), 4.02-3.92 (m, 4H), 3.56-3.46 (m, 2H), 3.29 (quin, J=6.9 Hz, 1H), 2.00 (d, J=13.2 Hz, 2H), 1.41 (d, J=7.0 Hz, 6H). MS (ESI): 590 [M+H]+.
Reaction SMILES: O[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15].C(O)C>P(Cl)(Cl)(Cl)=O>[Cl:15][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1nc(O)c(C#N)cc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
A suspension of the compound prepared in Example 442 (5.00 g) and phosphorus pentachloride (6.97 g) in phosphorus oxychloride (25 mL) was stirred and heated in an oil bath set to 110° C. for 30 minutes. The resulting solution was cooled to ambient temperature and concentrated. The residual liquid was cooled in an ice bath, whereupon a solid formed. This solid was carefully treated with 50% aqueous ethanol (10 mL), and then the mixture was stirred and heated in the 110° C. oil bath for 5 minutes. This redissolved the solid, and then the flask was again placed in the ice bath. The solid reappeared on cooling, and it was collected by filtration, washed with water, and air-dried. The solid was then recrystallized by stirring it with methanol (20 mL), and heating to boiling until all solid dissolved. On cooling to ambient temperature crystallization began, and the mixture was stored in the refrigerator overnight. The crystals were collected by filtration, washed with cold methanol, and dried under vacuum to provide the title compound (2.09 g) with the following physical data.
Reaction SMILES: C(=O)=O.CC(C)=O.[C:8]([S:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9].[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[C:8]([S:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:17])=[C:18]([Br:20])[CH:19]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)Sc1ccc(N)cc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)Sc1ccc(N)c(Br)c1
Reaction time: 8 h

Procedure:
To a cold (dry ice - acetone bath) stirred solution of 4-tert-butylthioaniline (25.6 g., 0.14 mole) in methylene chloride is added a slurry of N-bromosuccinimide (25.0 g., 0.14 mole) in methylene chloride in three equal portions. The reaction is allowed to come to room temperature with stirring overnight. The methylene chloride solution is washed with dilute aqueous sodium carbonate and water and then evaporated to give the desired product as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([OH:21])=O.[N:22]1([CH2:28][C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C@H:37]([NH2:41])[CH2:36][CH2:35][CH2:34]3)=[CH2:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([NH:41][C@H:37]1[C:38]2[C:33](=[CH:32][C:31]([C:29]([CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH2:30])=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36]1)=[O:21]
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCC[C@H]2N
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCC[C@H]2NC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
To a 20 mL flask equipped with stirring was added [3-oxo-1-(toluene-4-sulfonyl)-piperazin-2-yl]-acetic acid (104 mg, 0.33 mmol), 6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-ylamine (Step g, 90 mg, 0.33 mmol), EDC (Aldrich, 96 mg, 0.50 mmol), HOBt (Aldrich, 45 mg, 0.33 mmol), and CH2Cl2 (2 mL). The reaction mixture was stirred at RT overnight and diluted with CH2Cl2 (50 mL). The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by preparative TLC in 10% MeOH-CH2Cl2 to afford the title compound as a mixture of two diastereomers. MS (ESI): 565 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:35]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([CH:20]4[CH2:22][CH2:21]4)[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>CO.CCOC(C)=O>[C:24]([O:23][C@@H:17]1[C@@H:18]([CH:20]2[CH2:21][CH2:22]2)[CH2:19][N:14]([C:13]2[C:12]([NH2:35])=[CH:11][N:10]=[C:9]3[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][C:8]=23)[CH2:15][C@H:16]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:26])[CH3:25]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C2CC2)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C2CC2)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Yield: 96.8 %

Procedure:
A solution of 4-{(3R,4R,5S)-4-(acetyloxy)-3-[(tert-butoxycarbonyl)amino]-5-cyclopropylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.055 g, 0.11 mmol) in MeOH (5.0 mL) and EtOAc (1.0 mL) was deoxygenated and purged with nitrogen prior to the addition of 10% palladium (dry basis) on activated carbon (wet, Degussa type E101 NE/W) (0.025 g). The reaction mixture was stirred under an atmosphere of hydrogen, introduced via a balloon, for 2 h. The crude reaction mixture was filtered through a pad of diatomaceous earth and the solids were washed thoroughly with EtOAc and MeOH. The filtrate was concentrated under reduced pressure to afford the sub-title compound (0.052 g, 100%). LCMS (ESI) m/z calc. for C25H37N4O6 489.3 [M+H]+. found 489.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: NCCc1cccc(F)c1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)cc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (2.2 g, 10.0 mmol) and 3-fluoro-phenylethylamine (1.5 g, 11.0 mmol) in DMF (20 mL) was added K2CO3 (4.1 g, 30 mmol) at r.t. The reaction mixture was stirred at r.t. overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give ethyl 6-chloro-4-(3-fluorophenethylamino)nicotinate (1.1 mg, 34%). LRMS (M+H+) m/z 323.0.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[C:13]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:21][CH3:22])=[O:8])([OH:15])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1C(=O)O

Procedure:
A mixture of 3-nitrophthalic acid (35 g) in ethanol (300 ml) containing conc. sulfuric acid (20 ml) was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into cold water (700 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with water and shaken with an aqueous solution of potassium carbonate. The aqueous layer was made acidic with hydrochloric acid and the mixture was extracted with methylene chloride. The organic layer was washed with water, then dried, followed by evaporation of the solvent. The resultant solid (29 g, 74%) was used for the subsequent reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: COc1ccc(I)nc1
Product: COc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Yield: 33.9 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.214 g, 0.64 mmole) with 2-iodo-5-methoxypyridine (0.152 g, 0.64 mmole) using tereakis (triphenylphosphine)palladium(0) (30 mg) as catalyst in a manner as previously described for example 39b to give a yellow solid (0.060 g, 34%). 1H NMR (300 MHz, CDCl3) δ8.55 (1H, d, J=5.1 Hz), 8.43 (1H, s), 8.28 (1H, dd, J=1.3, 4.6 Hz), 7.34 (1H, m), 7.28 (1H, m), 7.24 (1H, d, J=5.8 Hz), 4.04 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([CH3:12])[CH:4]=1.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:13][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[CH3:12])=[O:11]
Reactant: CC(=O)c1ccc(CO)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: Cc1cc(CO)ccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-hydroxymethyl-2-methyl-phenyl)-ethanone (preparation 1a, 600 mg, 3.65 mmol) in CH2Cl2 (25 mL) is added tetrabutylammonium tribromide in several portions (1.76 g, 3.65 mmol). The reaction mixture is stirred for 30 min at room temperature. After washing with water, the organic layer is dried over MgSO4 and concentrated under reduced pressure. The remaining residue is dissolved in hexanes/EtOAc 3:7 and filtered over silica gel.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([F:18])[CH2:4]1)[CH3:2].ClCCl.[H][H]>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:5]([F:18])[CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCC(NC(=O)c2ccccc2)=C(F)C1
Solvent: ClCCl
Solvent: CO
Product: CCN1CC[C@@H](NC(=O)c2ccccc2)[C@@H](F)C1
Temperature: 40 °C
Reaction time: 20 h
Yield: 108.8 %

Procedure:
A 50 L autoclave was purged with nitrogen. N-(1-ethyl-3-fluoro-1,2,5,6-tetrahydro-pyridin-4-yl)benzamide (6.00 kg, 24.16 mol) was dissolved in methanol (19 L) and dichloromethane (1 L) and transferred to the inert autoclave. After four high vacuum—nitrogen fill cycles the prepared catalyst solution (6.5 L) was added to the autoclave. The reaction was pressurized with hydrogen gas to 20 bar and left to stand at 1000 rpm for 20 h at room temperature, was heated to 40° C. for 7 h, and then cooled to 25° C. Following a nitrogen purge the contents of autoclave were transferred into a 60 L reactor with methanol (2.0 L). Deloxan THPII (2.4 kg, 40 mass %) was added, and stirred at 500 rpm for 3 days at room temperature. The suspension was filtered over Arbocel (0.7 kg) applying high vacuum, the filter cake was washed with methanol (5.0 L), and solvent evaporated at 20 mbar and 45° C. Obtained 6.58 kg of N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)benzamide which was used without further purification. 1H NMR (400 MHz, MeOD) δ 7.83 (2H, t, J=9.1 Hz), 7.53 (1H, t, J=7.3 Hz), 7.45 (2H, t, J=7.6 Hz), 4.84 (1H, d, J=49.28 Hz), 4.25-3.91 (1H, m), 3.37-3.22 (2H, m), 3.10-2.95 (1H, m), 2.60-2.39 (2H, m), 2.32-2.02 (3H, m), 1.79 (1H, d, J=12.3 Hz), 1.11 (3H, t, J=7.2 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@H:24]4[CH2:26][O:25]4)=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH3:32][O-:33].[Na+]>CO.CC(=O)OCC>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@H:24]([OH:25])[CH2:26][O:33][CH3:32])=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:31]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)COC

Procedure:
A solution of diethyl-{4-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (100 mg, 0.229 mmol) in 5.4 M NaOMe in methanol (5 mL) is stirred at 70° C. for 72 h. The mixture is diluted with EA and washed with water and brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give the title compound (91 mg) as a yellow solid; LC-MS*: tR=1.21 min, [M+1]+=455.09; 1H NMR (CDCl3): δ 1.25 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.50 (s, 3H), 2.58 (d, J=5.0 Hz, 1H), 2.77 (q, J=7.8 Hz, 2H), 3.47 (s, 3H), 3.59-3.70 (m, 6H), 3.92 (d, J=5.3 Hz, 2H), 4.19-4.27 (m, 1H), 7.01 (s, 1H), 7.10 (s, 1H), 7.87 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: O=[O+][O-].[CH2:4]([O:11][C:12](=[O:47])[CH2:13][CH:14]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:15](=[O:38])C(C#N)=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:48]([NH2:56])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[NH:39]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[C@H:14]([C:15]([NH:56][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:38])[CH2:13][C:12](=[O:47])[O:11][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)OCc1ccccc1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccccc1
Agent: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Ozone gas was bubbled through a solution of 5 (606 mg, 1 mmol) in CH2Cl2 (20 mL) cooled to −78° C. until its blue color persists within the solution. The excess ozone was purged using argon and phenethylamine (181 mg, 189 μL, 1.5 mmol) was added. The resulting solution was stirred at −78° C. for 1 h and then allowed to warm to r.t. The solvent was removed under reduced pressure and the residue chromatographed on silica gel (0-30% ethyl acetate in hexane) to yield the product as a clear oil which was then recrystallized from ether/hexane (145 mg, 32%): mp 132-134° C.; 1H NMR (CDCl3) δ1.43 (s, 9H, Boc CH3's), 2.81 (t, 2H, NHCH2—CH2—Ph), 3.12 (dd, 1H, 1 of CH2—CO2Bzl), 3.44 (dd, 1H, 1 of CH2—CO2Bzl), 3.55 (t, 2H, NH—CH2—CH2Ph), 5.10 (s, 2H, benzyl CH2), 5.13 (m, 1H, α-CH), 5.51 (d, 1H, urethane NH), 6.92 (br, 1H, amide NH), 7.20 (m, 5H, phenethyl aromatic CH's), 7.30 (m, 5H, benzyl aromatic CH's); FABMS (calculated for C25H31N2O6, 455.2182) m/e 455.2146 (M++1).
Reaction SMILES: FC1C=C(S(C)(=O)=O)C=CC=1OC1N=CN=C2N(C3CCC(C4ON=C(C(C)C)N=4)CC3)N=CC=12.[CH:36]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([N:48]2[C:52]3=[N:53][CH:54]=[N:55][C:56](Cl)=[C:51]3[CH:50]=[N:49]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])[CH3:37].[F:58][C:59]1[CH:60]=[C:61]([OH:69])[CH:62]=[CH:63][C:64]=1[S:65]([CH3:68])(=[O:67])=[O:66]>CN(C)C=O>[CH:36]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([N:48]2[C:52]3=[N:53][CH:54]=[N:55][C:56]([O:69][C:61]4[CH:62]=[CH:63][C:64]([S:65]([CH3:68])(=[O:67])=[O:66])=[C:59]([F:58])[CH:60]=4)=[C:51]3[CH:50]=[N:49]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])[CH3:37]
Reactant: CS(=O)(=O)c1ccc(O)cc1F
Reactant: CC(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: CC(C)c1noc(C2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)c(F)c4)ncnc32)CC1
Yield: 40 %

Procedure:
4-[4-(3-Fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester was prepared using the procedure described above for the preparation of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Example 129) by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester (Intermediate 20) with 3-fluoro-4-methanesulfonyl-phenol (Intermediate 2) in dimethylformamide. The product was purified by flash chromatography, eluting with 5% methanol/dichloromethane to give 4-[4-(3-fluoro-4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (70 mg, 40%) as a white solid. Mass spectrum (ES) MH+=478.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:23]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([OH:14])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: C=CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 60 °C
Yield: 23.1 %

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.29 g, 1.45 mmol), acetonitrile (15 mL), potassium carbonate (0.4 g, 2.9 mmol) and allylbromide (0.13 mL, 1.59 mmol) was heated at 60° C. for 2 h. Aqueous sodium carbonate (10%, 5 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 7:1) gave the title compound (0.08 g). [α]D=−20.3° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 102-103° C.; MS m/z (relative intensity, 70 eV) 239 (M+, 22), 83 (bp), 198 (52), 82 (33), 84 (29), 113 (27).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([Cl:14])[CH:13]=[CH:12][CH:11]=[N:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[N:7]([CH2:18][CH:17]=[CH2:16])[C:8]1([Cl:14])[CH:13]=[CH:12][CH:11]=[N:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(Cl)C=CC=NC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)C1(Cl)C=CC=NC1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A mixture of (3-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (8.4 g, 36.8 mmol), allyl bromide (7.46 g, 39.1 mmol) and cesium carbonate (24.9 g, 76.4 mmol) in DMF (100 mL) is heated at 600 C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-40% EtOAc in heptane to afford allyl-(3-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (8.4 g, 85%). MS: 269 (M+H); 1H NMR (300 MHz, CDCl3): δ=8.66 (s, 1H), 8.49 (d, 1H), 7.18 (d, 1H), 5.80-5.96 (m, 1H) 5.15 (s, 1H), 5.10(d, 1H), 4.2 (broad s, 1H), 1.43 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>CC(O)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:26]2[CH2:27][CH2:28][CH:23]([C:19]3[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=3)[CH2:24][CH2:25]2)[CH:3]=[CH:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cccc2cc[nH]c12
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 1H-indole-7-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 376.2 (M+H)+.