Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9][C@@H:5]2[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:3][CH2:4][C@@H:5]1[NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9]1
Reactant: CC1(C)C[C@@H]2COC(C)(C)N2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC1(C)C[C@H](CO)NC1=O
Yield: 90.1 %

Procedure:
Prepared according to WO patent: 2013004290. To a solution of (R)-3,3,6,6-tetramethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4.13 g, 22.54 mmol) in MeOH (90 mL) was added p-toluenesulfonic acid monohydrate (0.429 g, 2.254 mmol). The resulting mixture was heated at reflux for 2 h. The solvent was removed under reduced pressure (rotary evaporator) and the crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-20% MeOH in DCM) affording (R)-5-(hydroxymethyl)-3,3-dimethylpyrrolidin-2-one (2.91 g, 20.31 mmol, 90% yield) as a white semi-solid. MS (ESI) 144.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:23]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.CI>O1CCCC1.O>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)[N-]C(C)C
Reactant: c1ccc2c(c1)CCc1ccccc1C2Nc1ccncc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CN(c1ccncc1)C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.01 mole of N-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-pyridinamine in 100 milliliters of dry tetrahydrofuran is added at -10° C. to a solution of lithium diisopropylamide (prepared from 1.5 milliliters (0.01 mole) of diisopropylamine and butyl lithium in hexane (7.7 milliliters; 0.01 mole) at -20° C.) in 100 milliliters of tetrahydrofuran, in an atmosphere of nitrogen. The solution is stirred at room temperature for 30 minutes and then treated with 0.63 milliliters (0.01 mole) of methyl iodide and stirred at room temperature overnight. The solution is decomposed with 5 milliliters of water and evaporated and the residue is dissolved in propan-2-ol. Acidification with ethereal hydrogen chloride followed by careful addition of ether gives the title compound in hydrochloride form.
Reaction SMILES: Cl[C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5](C(O)=O)=[C:4](C)[CH:3]=1.[C:16](OC)([O:20][CH3:21])([O:18]C)[CH3:17].C1(C)C=CC=CC=1>O1CCOCC1>[CH3:14][S:11]([C:10]1[C:9]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:5][C:17]([C:16]([O:20][CH3:21])=[O:18])=[C:3]([CH3:4])[CH:2]=1)(=[O:13])=[O:12]
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reactant: COC(C)(OC)OC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 29.5 g of 4-chloro-5-methanesulfonyl-2-methylbenzoic acid and 18.39 g of trimethyl orthoacetate in 100 ml of dioxane was refluxed until the acid had reacted completely. 150 ml of toluene were added, and the solvent was removed to the extent that the mixture still remained stirrable. 150 ml of 1-methyl-2-pyrrolidone (NMP) and 15.8 g of sodium methanesulfinate were subsequently added, and the mixture was stirred at 80° C. for 5 h. After addition of a further 5.3 g of sodium methanesulfinate, the mixture was stirred for 25 h. Conventional work-up gave methyl 4,5-bismethanesulfonyl-2-methylbenzoate.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C@@H:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)[C:31]([OH:33])=O)=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:43][NH:44][O:45][CH3:46].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C@H:30]([NH:29][C:27]([C:24]2[CH:25]=[CH:26][C:8]3[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[C:16]4[N:10]([CH2:11][CH2:12][O:13][C:14]5[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=54)[C:9]=3[CH:23]=2)=[O:28])[C:31](=[O:33])[N:44]([O:45][CH3:46])[CH3:43])=[CH:36][CH:37]=1
Reactant: CNOC
Reactant: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N(C)OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of (S)-2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionic acid (50.0 mg, 0.090 mmol) synthesized in the same manner as in Examples 2-175 and 2-180, N,O -dimethylhydroxylamine hydrochloride (10.5 mg, 0.180 mmol), 1-hydroxybenzotriazole monohydrate (15.2 mg, 0.38 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (20.7 mg, 0.108 mmol) in N,N-dimethylformamide (1 ml) was added triethylamine (25.1 μl, 0.180 mmol), and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The precipitated solid was collected by filtration, further washed with water and dried in vacuo. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:4). To the obtained residue was added a mixed solvent of hexane:ethyl acetate (5:1), and the precipitated solid was collected by filtration and washed with a mixed solvent of hexane:ethyl acetate (5:1). The obtained solid was dried in vacuo to give N- [(S)-2-(4-hydroxyphenyl)-1-(N-methoxy-N-methylcarbamoyl)ethyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (30.0 mg, yield 54.1%).
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].[SH:29][CH2:30][C:31]([NH2:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[NH2:33][C:31](=[O:32])[CH2:30][S:29][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=1[C:11](/[N:10]=[C:9]1/[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH3:28])[C:7]([C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:8]/1)=[O:23]
Reactant: NC(=O)CS
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2SCC(N)=O)cc(C(C)(C)C)n1C
Yield: 49.9 %

Procedure:
A mixture of Example 81C (400 mg, 1 mmol), 2-mercaptoacetamide (183 mg, 2 mmol) and potassium carbonate (277 mg, 2 mmol) in DMA (10 mL) was heated at 50° C. for 14 hours. The mixture was then poured into water and extracted with ethyl acetate. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, EtOAc-MeOH: 9:1) afforded 235 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-1.02 (m, 3H), 1.27-1.44 (m, 11H), 1.56-1.78 (m, 2H), 3.55 (s, 2H), 3.88 (s, 3H), 4.27-4.50 (m, 2H), 6.83 (s, 1H), 7.12 (s, 1H), 7.41-7.73 (m, 3H), 8.32 (d, J=2.0 Hz, 1H). MS (ESI+) m/z 471 (M+H)+. Anal. calculated for C22H29F3N4O2S.0.25H2O: C, 55.62 H, 6.26 N, 11.79. Found: C, 55.46 H, 6.32 N, 11.50.
Reaction SMILES: Cl.[CH3:2][NH2:3].O=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)[CH:15]=2)=[O:12])[CH2:7][CH2:6]1>C1COCC1.CO>[CH3:2][NH:3][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:31][CH2:32]4)[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]3)[CH:15]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CN
Reactant: CC1CCC(c2cccc(NC(=O)N3CCC(=O)CC3)c2)(N2CCN(c3ccccc3)CC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNC1CCN(C(=O)Nc2cccc(C3(N4CCN(c5ccccc5)CC4)CCC(C)CC3)c2)CC1
Temperature: 25 °C

Procedure:
Methylamine hydrochloride (37 mg, 0.546 mmol) was added to a solution of 4-(oxo)-N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer) (43 mg, 0.091 mmol) in THF/MeOH (1:1) and stirred at room temperature. When all the methylamine hydrochloride had dissolved, NaCNBH4 (6 mg, 0.091 mmol) was added and the reaction allowed to stir overnight at room temperature. The reaction mixture was concentrated, dissolved in an excess of 3N HCl, and the aqueous solution washed with ether (3×). The aqueous solution was made basic with 10N NaOH, extracted with EtOAc (4×), dried (Na2SO4), and concentrated to give 4-(methylamino)-N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)-cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer) as a clear oil. The HCl salt was prepared by adding excess saturated EtOAc/HCl solution to the free base in dry MeOH. Concentration of the homogeneous solution yielded a white solid which was washed with EtOAc. mp=154-155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:17])[CH3:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:17])[CH3:16])[CH2:10]1
Reactant: CC(=O)N1CCCC(=Cc2cccc(F)c2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCCC(Cc2cccc(F)c2)C1
Reaction time: 21.5 h
Yield: 93.5 %

Procedure:
A mixture of 1-{3-[1-(3-fluorophenyl)methylidene]piperidin-1-yl}ethanone (Intermediate 225, 0.7 g), palladium hydroxide (20% on carbon, 0.07 g) in ethyl acetate (20 mL) and IMS (1 mL) was degassed by nitrogen/vacuum purging. The mixture was stirred under an atmosphere of hydrogen for 21.5 hours. The mixture was filtered the filtrate was evaporated to dryness to give 1-[3-(3-fluorobenzyl)piperidin-1-yl]ethanone (0.66 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:6][CH2:5]2
Reactant: OC1CCc2cc(Br)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 5-bromoindan-1-ol (4.00 g, 18.8 mmol) in N,N-dimethylformamide (25.00 mL) were added triethylamine (5.23 mL, 37.5 mmol), tert-butyldimethylsilyl chloride (4.244 g, 28.16 mmol) and 4-dimethylaminopyridine (115 mg, 0.939 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with ether (100 mL) and quenched with water. The aqueous phase was extracted with ether (4×40 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. Chromatography on silica gel with 5% EtOAc/hexane afforded the desired product (6.05 g, 98%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](CO)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.7 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide (41 mg, 0.080 mmol) and TFA (0.6 ml, 7.8 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at room temperature until the consumption of starting material (2.5 h). The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (2 mL) and ethylenediamine (400 μl, 5.9 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (9:1 dichloromethane/MeOH) to afford 11 mg (36%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=385; 1H NMR (300 MHz, DMSO-d6) δ: 12.84 (br. s., 1H), 9.13 (s, 1H), 8.66 (d, J=8.7 Hz, 1H), 8.43 (s, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.91-8.04 (m, 1H), 7.32 (dd, J=8.7, 1.5 Hz, 1H), 5.09 (t, J=5.1 Hz, 1H), 4.18 (s, 3H), 4.08-4.33 (m, 1H), 3.58 (t, J=4.7 Hz, 2H), 1.28 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([C:11](C)=[O:12])[CH2:7][CH2:8]CC>>[CH2:3]([CH:2]([CH2:11][CH2:6][CH2:7][CH3:8])[CH:1]=[O:5])[CH3:4].[CH:11](=[O:12])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(C)=O
Solvent: CCCC=O
Product: CCCCC(C=O)CC

Procedure:
The processes according to the invention may be carried out by passing the aldehyde and ketone reactant mixture, and the aldol catalyst solution, through a stationary bed of pelleted or supported hydrogenation catalysts, enclosed in a tubular reactor. This is typical of continuous fixed-bed plug-flow reactor processes, where the reactants are continually consumed as they flow down the length of the reactor. However, as seen in Example 2 (Comparative), when this continuous plug-flow fixed-bed concept is applied to the cross-aldol condensation of acetone and n-butyraldehyde, the selectivity of n-butyraldehyde to methyl amyl ketone is very low, only 38%. The main-by-product, 2-ethylhexaldehyde, the result of the self-aldol condensation of n-butyraldehyde, cannot be easily separated from the methyl amyl ketone by distillation.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:21])[CH2:17][CH2:18][CH2:19][CH3:20]>O1CCOCC1>[NH2:14][C:11]1[N:10]=[C:9]([NH:21][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][N:12]=1
Reactant: Nc1ncc(Cc2ccccc2)c(Cl)n1
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)ncc1Cc1ccccc1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A mixture of 5-benzyl-4-chloropyrimidine-2-ylamine (350 mg, 0.74 mmol), amylamine (0.74 ml) and dioxane (4 ml) was kept at 90-100° C. for 8 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with ether and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH:CHCl3=70:1) to give the object compound (355 mg, 82.2%).
Reaction SMILES: FC1C(O[C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=2)=C(F)C(F)=C(F)C=1F.[C:25]1([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1>C(OCC)(=O)C>[C:25]1([C:31]2[CH:32]=[C:33]([NH:34][C:9](=[O:20])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[CH:35]=[CH:36][CH:37]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1O
Reactant: Nc1cccc(C2=CCCCC2)c1
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)Nc2cccc(C3=CCCCC3)c2)ccc1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
4-Hydroxy-3-methoxyphenylacetic acid pentafluorophenyl ester (60 mg) and Intermediate 2 (60 mg) are dissolved in ethyl acetate, and the mixture is stirred at 60° C. for 18 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the title compound (50 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]2[CH2:18][CH2:17][N:16](CCC3C=NC=CC=3)[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.N1C=CC=C(CCCl)C=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[CH2:42][CH2:43]Cl>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH2:42][CH2:43][N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=3)[CH2:14][CH2:15]2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]
Reactant: COc1ccc(CCCl)cc1OC
Reactant: CS(=O)(=O)Nc1ccc(SC2CCN(CCc3cccnc3)CC2)cc1
Agent: Cl
Agent: ClCCc1cccnc1
Product: COc1ccc(CCN2CCC(Sc3ccc(NS(C)(=O)=O)cc3)CC2)cc1OC

Procedure:
The same procedure as that of Example 1 (1) to (8) was repeated except that 2-(3-pyridyl)ethyl chloride hydrochloride was replaced with 3,4-dimethoxyphenethyl chloride to prepare the intended compound.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:10]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:9][C:3]=1[CH:4]=[CH:5]C([O-])=O.[H-].C([Al+]CC(C)C)C(C)C>CCCCCC>[F:1][C:2]1[C:12]([F:13])=[C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:10]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:9][C:3]=1[CH:4]=[CH2:5]
Reactant: COCCOCOc1cc(C=CC(=O)[O-])c(F)c(F)c1OCOCCOC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: C=Cc1cc(OCOCCOC)c(OCOCCOC)c(F)c1F
Yield: 81.2 %

Procedure:
Using the procedure of Stage C of Example 40, 44.3 g of the ester of Stage D and 230 ml of a molar solution of diisobutyl-aluminum hydride in hexane were reacted to obtain 32 g of the expected product.
Reaction SMILES: C(C1C(O[SiH](C)C)=CC=CC=1C=O)(C)(C)C.[C:17]([C:21]1[CH:32]=[C:31](Br)[C:30](OC)=[CH:29][C:22]=1[CH:23]([OH:28])[O:24][SiH:25]([CH3:27])[CH3:26])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=1[CH:23]([OH:28])[O:24][SiH:25]([CH3:26])[CH3:27])([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cc(C(O)O[SiH](C)C)c(C(C)(C)C)cc1Br
Agent: C[SiH](C)Oc1cccc(C=O)c1C(C)(C)C
Product: C[SiH](C)OC(O)c1ccccc1C(C)(C)C
Yield: 66 %

Procedure:
This compound was prepared from 2-(tert-butyl)dimethylsilyloxybenzaldehyde (7) (4.23 g, 17.9 mmol) in the manner previously described for the synthesis of benzyl alcohol 5, affording 2.81 g (66%) of the silyloxybenzyl alcohol as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ0.26 [s, 6H, Si(CH3)2 ], 1.02 [s, 9H, SiC(CH3)3 ], 4.68 (d, 2H, J=6.3 Hz, CH2OH), 6.81 (d, 1H, J=6.3 Hz, Ar--H), 6.95 (dd, 1H, J=7.1, 7.1 Hz, Ar--H), 7.17 (ddd, 1H, J=9.5, 7.8 1.7 Hz, Ar--H), 7.30 ppm (dd, 1H, J=5.8, 1.6 Hz, Ar--H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:15]=1>N1C=CC=CC=1>[C:1]([O:8][CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCC(O)/C=C/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCC(/C=C/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1)OC(C)=O
Temperature: 23 °C
Reaction time: 15 h

Procedure:
For acetylation, 31 ml of acetic anhydride is added to a solution of 11 g of the above-produced alcohol in 120 ml of pyridine and stirred for 15 hours at 23° C. Then, it is concentrated by evaporation in a vacuum with adding toluene and the residue is chromatographed on silica gel. With hexane/0-3% ethyl acetate, 8.9 g of the title compound is obtained as colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([O:19][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Reactant: N#CCCCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#CCCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure of Example 4 is followed using 4,6-diphenyl-2-pyridone (6.18 g) and 6-bromohexanonitrile (6.60 g) in place of 6-bromohexanoate, silver carbonate (6.89 g) and toluene (300 cc) and the reaction mixture is refluxed for 72 hours. The material formed is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9.5-0.5) to obtain 6-[(4,6-diphenyl-2-pyridyl)oxy]hexanonitrile as a white solid which is used directly in subsequent reactions.
Reaction SMILES: CC1C=CN=C(NC2N=C(C3OC(NCC4C=CN=CC=4)=NC=3)C=CC=2)C=1.Cl[C:29]1[O:30][C:31]([C:34]2[N:39]=[C:38]([NH:40][C:41]3[S:42][C:43]([CH3:46])=[CH:44][N:45]=3)[CH:37]=[CH:36][CH:35]=2)=[CH:32][N:33]=1.[O:47]=[C:48]1[CH2:53][NH:52][CH2:51][CH2:50][NH:49]1>CC(O)C>[CH3:46][C:43]1[S:42][C:41]([NH:40][C:38]2[N:39]=[C:34]([C:31]3[O:30][C:29]([N:52]4[CH2:51][CH2:50][NH:49][C:48](=[O:47])[CH2:53]4)=[N:33][CH:32]=3)[CH:35]=[CH:36][CH:37]=2)=[N:45][CH:44]=1
Reactant: Cc1cnc(Nc2cccc(-c3cnc(Cl)o3)n2)s1
Reactant: O=C1CNCCN1
Agent: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Solvent: CC(C)O
Product: Cc1cnc(Nc2cccc(-c3cnc(N4CCNC(=O)C4)o3)n2)s1

Procedure:
Prepared as for 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]-N-(pyridin-4-ylmethyl)oxazol-2-amine above from [6-(2-Chloro-oxazol-5-yl)-pyridin-2-yl]-(5-methyl-thiazol-2-yl)-amine and 2-oxopiperazine in iPrOH. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.14 (s, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.16-6.97 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 4.11 (s, 2H), 3.86-3.63 (m, 2H), 3.43-3.32 (m, 2H), 2.37 (s, 3H). (ESI+) m/z 357 (M+H)+. Retention time=1.91 mins (method 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29]C)=O)=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.[CH3:31][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:31])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: C[Mg]Br
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylate (prepared in an analogous manner to Example 279, 1.00 g, 2.47 mmol) in anhydrous THF (30 mL) at −78 C was added methyl magnesium bromide (3M sol. in ether, 907 μL, 2.72 mmol) drop wise under an inert atmosphere. The resulting solution was stirred at −78 C for 1 h and then allowed to warm to room temperature where upon stirring was continued for a further 1 h. The reaction mixture was cooled again and quenched with acetone (1 mL) and a 10% citric acid aq. solution (5 mL). The reaction mixture was extracted with EtOAc (3×50 mL) and the resultant organics washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. 50 milligrams of the resulting crude material was purified by preparative HPLC-MS (Method C) to afford the title compound as an off white solid (21 mg).