Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C[O:42][C:43]([C@@H:45]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]1[NH:52][CH2:53][CH2:54][CH:55]([CH3:57])[CH3:56])=O.[O-]CC.[Na+].C(O)C>CN(C)C=O>[OH:42][C:43]1[CH:45]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[N:52]([CH2:53][CH2:54][CH:55]([CH3:57])[CH3:56])[C:17](=[O:18])[C:16]=1[C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=2[S:13](=[O:15])(=[O:14])[N:12]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.200 g, 0.600 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.121 g, 0.630 mmol) and N-methylmorpholine (0.139 mL, 1.26 mmol) were added sequentially to a solution of cis-2-(3-methyl-butylamino)-cycloheptanecarboxylic acid methyl ester (0.144 g, 0.600 mmol) in N,N-dimethylformamide (7 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was dissolved in ethanol (5 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (0.448 mL, 1.20 mmol) was added and the reaction mixture was heated to 60° C. for 2 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×75 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 25-80% ethyl acetate in hexanes) to afford the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.186 g, 0.354 mmol, 59%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.98-1.01 (m, 6H), 1.41-2.24 (m, 15H), 2.75-3.01 (m, 1H), 3.05-3.09 (m, 1H), 3.06 (d, 3H, J=3.9 Hz), 3.41-3.52 (m, 1H), 3.96-4.09 (m, 1H), 7.16-7.23 (m, 1H), 7.62-7.66 (m, 1H), 7.69-7.71 (m, 1H). LC-MS (ESI) calcd for C23H32N4O6S2 524.18, found 525.4 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Nitrobenzyl)-benzoic acid (1.03 g, 4 mmol) was dissolved in dichloromethane (40 mL). Oxalyl chloride (0.42 mL, 1.2 eq) was added to the mixture, followed by 1 drop of N,N-dimethylformamide. The mixture was stirred for 1 hour at room temperature and the solvents evaporated to give 4-(4-chlorocarbonylbenzyl)-nitrobenzene (1.10 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([CH2:9][CH3:10])[C:7](=[O:11])[C:6]([CH3:12])=[C:5]([OH:13])[N:4]=1)[CH3:2].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:3]1[N:8]([CH2:9][CH3:10])[C:7](=[O:11])[C:6]([CH3:12])=[C:5]([O:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)c(C)c(=O)n1CC
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(OCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)c(=O)n1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 0.91 g of 2,3-diethyl-6-hydroxy-5-methyl-4(3H)-pyrimidinone and 1.66 g of 4-(4'-trifluoromethylphenoxy)benzyl bromide, and then 0.69 g of potassium carbonate was added thereto. The mixture was stirred for 18 hours at room temperature. The resulting solution was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The oil thus obtained was purified by means of column chromatography (on silica gel, eluting with benzene) to give 1.35 g of the intended product.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([CH3:21])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC>[CH2:13]([O:12][CH2:11][CH:10]([CH3:20])[CH2:9][CH2:8][CH2:7][C:6]([CH3:21])=[CH:5][CH2:4][OH:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C=C(C)CCCC(C)COCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(=CCO)CCCC(C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ethyl-8-benzyloxy-3,7-dimethyl-2-octenoate (94.6 g, 0.31 M) in ether (1.4 l) is added to a slurry of lithium aluminum hydride (47.3 g, 1.25 M) in ether (3.3 l) at 0° C. and the reaction mixture is allowed to stir at 0° C. for 4 hours. Wet ether (750 ml) is added slowly and the mixture is acidified with 1N hydrochloric acid. The organic phase is separated, the aqueous phase is extracted with ether and the combined organic extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give the crude product (77.6 g, 95%). Purification over silica gel using an ethyl acetate/hexane gradient as the eluent gives fractions of varying mixtures of isomers. A collection of fractions that gives 17.7 g of 8-benzyloxy-3,7-dimethyl-2-octenolwith an 85/15 E/Z isomer ratio by gas chromatography analysis is used in the next step:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([NH:13][CH2:12][CH:8]1[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1)=[O:27]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccccc1Cl)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 29.3 %

Procedure:
Example 16 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (2-chlorophenyl)acetic acid (0.034 g) to give the title compound (0.025 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:6])[CH2:4][OH:5].[CH3:7][C:8]1[CH:9]=[C:10]([C:25]2[S:29][C:28]([C:30](O)=[O:31])=[N:27][CH:26]=2)[CH:11]=[C:12]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O.O>[OH:6][C@@H:3]([CH2:4][OH:5])[CH2:2][NH:1][C:30]([C:28]1[S:29][C:25]([C:10]2[CH:11]=[C:12]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[CH:17][N:16]=3)[CH:13]=[C:8]([CH3:7])[CH:9]=2)=[CH:26][N:27]=1)=[O:31]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(=O)O)s2)c1
Reactant: NC[C@@H](O)CO
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(=O)NC[C@@H](O)CO)s2)c1
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
To a solution of (2R)-3-aminopropane-1,2-diol (132 mg, L446 mmol), 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxylic acid (500 mg, 1.315 mmol), and triethylamine (0.403 mL, 2.89 mmol) in N,N-dimethylformamide (8 mL) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (821 mg, 1.578 mmol). After 45 minutes, water (32 mL) was added to the reaction mixture and the resulting yellow solid was collected by filtration; the solid was then purified by trituration using a mixture of methanol (2 mL), ethyl acetate (3 mL), and dichloromethane (3 mL) followed by filtration and drying in vacuo. The mother liquor from the trituration was concentrated and additional product was purified via column chromatography on silica (Biotage 50 g SNAP column, 97.5:2.5 to 85:15 dichloromethane:methanol). The combined material afforded in N-[(2R)-2,3-dihydroxypropyl]-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxamide (487 mg 82% yield) as a yellow solid. MS ESI: [M+H]+ m/z 454.0. 1H NMR (500 MHz, d6-DMSO): δ 10.31 (s, 1H); 8.85 (d, J=4.9 Hz, 1H); 8.53 (t, J=5.9 Hz, 1H); 8.29 (s, 1H); 8.11 (s, 1H); 7.51 (s, 1H); 7.31 (s, 1H); 7.30 (d, J=4.9 Hz, 1H); 4.90 (d, J=5.1 Hz, 1H); 4.64 (t, J=5.7 Hz, 1H); 3.63 (m, 1H); 3.42 (m, 1H); 3.35 (m, 2H); 3.23 (m, 1H); 2.34 (s, 3H). rhSYK activity=+++
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:23][CH2:22][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:2]=1.O.Cl.[H][H]>O=[Pt]=O.C(O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:23][CH2:22][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2N2CCN(CCc3ccncc3)CC12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2N2CCN(CCC3CCNCC3)CC12

Procedure:
A solution of 2,3,4,4a-tetrahydro-3-[2-(4-pyridinyl)ethyl]-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one in 120 ml. water and 60 ml. ethanol containing 13 ml. conc. hydrochloric acid was placed in a Parr hydrogenation apparatus, with 1.2 g. PtO2, under 45 psi. of hydrogen and shaken till pressure drop ceased. After filtering off catalyst the solvents were removed under vacuum and the residue crystallized from hot ethanol. Product filtered off, washed (ethanol), and dried. Dissolved in hot methanol which was displaced by ethanol by boiling off lower boiling solvent. Yield: 4.0 g. of the title compound as the dihydrochloride salt, m.p. 238°-240° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CN([CH:32]=[O:33])C.Cl>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([CH:32]=[O:33])=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The reaction apparatus was dried by heating, and the reaction was carried out under argon and with stirring. 15 g (65.6 mmol) of tert-butyl(6-chloropyridin-2-yl)carbamate (Example 3A) and 19 g (164 mmol) of 1,2-bis(dimethylamino)ethane were initially charged in 270 ml of THF and cooled to −78° C. 102.5 ml (164 mmol) of butyllithium (1.6 N) were added dropwise. After the end of the dropwise addition, the reaction was slowly warmed to −10° C. and kept at −10° C. for 2 h. The mixture was then once more cooled to −78° C., and 10 ml (131 mmol) of DMF were added. The reaction was slowly warmed to RT, the reaction mixture was added to 1 l of ethyl acetate and 350 ml of 1 N hydrochloric acid and stirred for 15 min, and the organic phase was separated off. The organic phase was washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated on a rotary evaporator. Diethyl ether was added to the residue and the solid was filtered off with suction and dried. This gave 12.3 g (73% of theory) of the product as a solid.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:17][CH2:18][C@@H:19]1[O:27][CH2:26][C:22]2=[N:23][O:24][CH2:25][C@@H:21]2[CH2:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC(C)C)(C)C.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[CH2:10]([O:17][CH2:18][C@@H:19]1[O:27][CH2:26][C@:22]2([C:39]3[CH:38]=[CH:37][C:36]([F:35])=[CH:41][C:40]=3[F:42])[NH:23][O:24][CH2:25][C@@H:21]2[CH2:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1ccc(I)c(F)c1
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Fc1ccc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)c(F)c1
Temperature: -73.5 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (60.1 mL, 474 mmol) was added to a solution of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C4) (50.0 g, 202 mmol) in a 1:1 mixture of toluene and diisopropyl ether (2 L) at an internal temperature of −76° C. The reaction was stirred at this temperature for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (27.1 mL, 226 mmol). While the reaction temperature was maintained at −76 to −71° C., n-butyllithium (2.5 M in hexanes, 85.7 mL, 214 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (1 L) and partitioned between water (1 L) and ethyl acetate (750 mL). After the heterogeneous mixture warmed to room temperature, the aqueous layer was extracted with ethyl acetate (3×250 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (550 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 70% ethyl acetate in heptane) afforded the product as a yellow oil. Yield: 48.14 g, 133.2 mmol, 66%. 1H NMR (400 MHz, CDCl3) δ 7.94 (ddd, J=9, 9, 7 Hz, 1H), 7.28-7.40 (m, 5H), 6.87-6.93 (m, 1H), 6.80 (ddd, J=12.0, 8.6, 2.4 Hz, 1H), 4.60 (AB quartet, JAB=12.1 Hz, ΔνAB=21.4 Hz, 2H), 4.14 (br dd, J=12.8, 1.3 Hz, 1H), 3.82-3.90 (m, 2H), 3.72 (d, J=7.2 Hz, 1H), 3.54-3.60 (m, 2H), 3.50 (dd, half of ABX pattern, J=10.3, 4.1 Hz, 1H), 3.04-3.13 (m, 1H), 1.86 (ddd, J=14.0, 7.0, 2.0 Hz, 1H), 1.49-1.61 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CO.[CH3:12][NH2:13].CCOC(C)=O>C(O)C.CCCCCCC>[Cl:8][C:5]1[N:4]=[C:3]([NH:13][CH3:12])[C:2]([F:1])=[CH:7][N:6]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CN
Solvent: CCO
Solvent: CCCCCCC
Solvent: CO
Product: CNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL round bottom flask equipped with a stir bar was added 9.0 g 5-fluoro-2,4-dichloro-pyrimidine, 40 mL methanol and 15 mL of 8M methylamine in ethanol. The reaction heated up (mild exo-therm) and was allowed to stir at room temperature for ˜30 minutes. A check by TLC (1:1 EtOAc:heptane) and LCMS showed complete reaction. The reaction was concentrated down to give 9.77 g crude material which was purified on a silica column running a gradient of 1% to 10% MeOH in DCM over 35 minutes to give 6.77 g pure 2-chloro-5-fluoro-N-methylpyrimidin-4-amine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2.C(O)C.[H][H]>[Pd].O1CCCC1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2cc(N)ccc2[nH]1
Yield: 90 %

Procedure:
To a solution of 2.0 gm (11.4 mMol) 2-methyl-5-nitro-1H-indole in 100 mL 1:1 ethanol:tetrahydrofuran were added 0.25 gm 5% palladium on carbon. The suspension was hydrogenated at ambient temperature at an initial hydrogen pressure of 60 p.s.i. After 5 hours the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 1.5 gm of a dark brown solid. The solid was purified by flash chromatography, eluting with a gradient of dichloromethane containing 0-3% methanol, to give 1.19 gm (71.7%) of the title compound as light brown plates.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:38]=[N:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:38]=[N:37][N:36]([CH:39]([CH3:41])[CH3:40])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:27][CH2:28][N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:30][CH2:31]3)[CH2:24][CH2:25]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(S(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C4CCN(S(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 27 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(1-(methylsulfonyl)piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.06 g, 0.18 mmol) in EtOH (2 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (balloon pressure) for 3-4 hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduced pressure, finally the residue was washed with diethyl ether to provide the desired compound (27% yield). LCMS: 584.35 (M+1)+; HPLC: 96.59% (@ 254 nm) (Rt; 4.927); 1H NMR (CD3OD, 400 MHz) δ 8.28 (s, 1H), 7.43 (s, 1H), 6.13 (s, 1H), 5.27 (bs, 1H), 4.55 (s, 2H), 3.94 (d, 2H, J=10.4 Hz), 5.74 (d, 2H, J=10.8 Hz), 3.40 (m, 2H), 3.30 (m, 2H), 2.89 (s, 3H), 2.85 (m, 2H), 2.41-2.25 (m, 12H), 1.90 (m, 2H), 1.56 (d, 6H, J=4.4 Hz).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].Cl[CH2:12][CH:13]1[O:15][CH2:14]1.C(O)C.[OH-].[K+]>O>[O:15]1[CH:13]([CH2:12][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:1][CH2:2][CH3:3])[CH2:14]1
Reactant: CCCc1ccccc1O
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1ccccc1OCC1CO1

Procedure:
To a solution of 27.2 parts of 2-propylphenol and 56 parts of 1-chloro-2,3-epoxypropane in 30 parts of ethyl alcohol, heated under reflux, was added a solution of 13.2 parts of potassium hydroxide in 50 parts of ethyl alcohol and 6 parts of water over 15 minutes and the mixture obtained was heated under reflux for a further 2 hours. The mixture was poured into 1,000 parts of water and extracted with ethyl acetate. The organic phase was separated, washed with water, dried over magnesium sulphate, filtered and evaporated to yield a yellow oil. The oil was distilled at the water pump to yield 31.0 parts of 1,2-epoxy-3-(2-propylphenoxy)propane, boiling point 155°-158° at 15 mm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:22](=[O:24])[CH3:23])[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][O:15]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(Cl)[Cl:59]>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:22](=[O:24])[CH2:23][Cl:59])[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(=O)c1cc(COCCOC2CCCCO2)cc(C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(COCCO)cc(C(=O)CCl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-{3-tert-Butyl-5-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]phenyl} ethanone (O2.063; 2.0 g) was dissolved in methanol/THF (30 ml/30 ml) and admixed while stirring with phenyl-trimethylammonium tribromide (2.25 g). After stirring at RT for 3 h, the mixture was diluted with DCM and washed once with 5% sodium thiosulfate solution, and the DCM phase was dried over magnesium sulfate and concentrated by rotary evaporation. The residue was dissolved in THF (200 ml), and 3 N HCl (30 ml) was added. After standing for 1 h, EA and water were added, and the EA phase was removed. The EA phase was dried over magnesium sulfate and concentrated by rotary evaporation. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-50% within 40 min). 774 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][NH2:2].Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11]Cl)[CH:5]=1.[OH-].[Na+].[Cl-].[Na+]>>[CH3:1][NH:2][CH2:11][CH2:10][C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1
Reactant: ClCCc1cccnc1
Reactant: CN
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CNCCc1cccnc1
Temperature: 80 °C
Yield: 110.5 %

Procedure:
To 32.6 g of 40% aqueous methylamine solution was added 7.48 g (0.042 mole) of 2-(3-pyridyl)ethyl chloride hydrochloride in small portions with stirring. The mixture was transfered to a stainless steel reaction column and heated at an external temperature of 80° C. for 4 hours. After cooling, 3.36 g of NaOH was added with ice-cooling and stirring and the mixture was saturated with sodium chloride and extracted with CH2Cl2. The extract was dried over MgSO4 and the CH2Cl2 was distilled off to give 6.32 g of the title compound in crude form as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:1]1([S:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCCBr
Reactant: N#CCS(=O)(=O)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Product: N#CC1(S(=O)(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
629 mg (2.8 mmol) of benzyltriethylammonium chloride is added to 5 g (27.6 mmol) of benzenesulfonylacetonitrile and 6.55 g (30.3 mmol) of 1,4-dibromobutane in 50 ml of a 50% aqueous soda solution. The reaction mixture is stirred at room temperature for 3 h. It is then diluted with water and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over magnesium sulfate, filtered and the solvents are evaporated. The residue is purified on silica gel (heptane/ethyl acetate, 50/50, v/v). 6.35 g of 1-benzenesulfonyl-cyclopentanecarbonitrile is obtained in the form of a beige powder. (Yield=98%).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].Br[CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][O:26][CH3:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:9][O:8][C:7]1[C:2]([O:1][CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][O:26][CH3:27])=[C:3]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:4]=[CH:5][C:6]=1[O:10][CH3:11]
Reactant: COCC(C)(C)CBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Temperature: 100 °C

Procedure:
Compound 303 (0.02 g, 0.07 mmol) and 1-bromo-3-methoxy-2,2-dimethyl-propane (0.12 g, 0.56 mmol) were dissolved in dry DMF (0.8 mL). K2CO3 (0.1 g, 0.68 mmol) were added. The suspension was heated at 100° C. for 18 h. H2O was added and the mixture was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC afforded the title compound as an oil.