Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([S:12][C:13]1[C:17]([C:18]2[CH2:19][N:20]([CH3:24])[CH2:21][CH2:22][CH:23]=2)=[N:16][O:15][N:14]=1)[CH2:8]CC#C.Cl[C:26]1[C:30]([C:31]2C=N[CH:34]=[CH:35][CH:36]=2)=NON=1.S.[Na].BrCCCC#C>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[O:3]([CH2:8][CH2:7][S:12][C:13]1[C:17]([C:18]2[CH2:19][N:20]([CH3:24])[CH2:21][CH2:22][CH:23]=2)=[N:16][O:15][N:14]=1)[C:26]1[CH:30]=[CH:31][CH:36]=[CH:35][CH:34]=1
Reactant: Clc1nonc1-c1cccnc1
Reactant: C#CCCCSc1nonc1C1=CCCN(C)C1
Agent: C#CCCCBr
Agent: O=C(O)C(=O)O
Agent: S
Product: CN1CCC=C(c2nonc2SCCOc2ccccc2)C1

Procedure:
3-(3-(4-Pentynylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate from 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine, sodium hydrogen-sulfide and 1-bromo-4-pentyne. M.p. 119°-120° C. Compound 214.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.O.NN>CCO>[NH2:3][CH:12]1[CH2:13][CH2:14][C:15]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C)CCC(N)CC1
Temperature: 80 °C
Yield: 102.3 %

Procedure:
To an ice-cold solution of ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexanecarboxylate (0.30 g, 0.95 mmol) in EtOH (20 mL) was added hydrazine hydrate (0.115 mL, 2.38 mmol) and the resulting mixture heated up to 80° C. for 2-3 h. After the completion of reaction (by TLC), solvent was evaporated under reduced pressure, water added (20 mL), extracted with EtOAc (3×50 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product as a viscous liquid (0.18 g, crude). MS: 186.20 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([C:22]2[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1.[CH3:30][C@@H:31]1[C@@H:36]([O:37]C(=O)C(C)(C)C)[CH2:35][CH2:34][NH:33][CH2:32]1>>[OH:37][C@H:36]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:6][CH2:5]2)[CH2:32][C@@H:31]1[CH3:30]
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCO)CC4)cc23)cn1
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)cn1

Procedure:
This compound is synthesized from 4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (184, preparation see below) and 2,2-Dimethyl-propionic acid (3S,4S)-3-methyl-piperidin-4-yl ester (17) analogously to the method described in example 150, followed by cleavage of the protecting group.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH2:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[CH3:11].CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:15]1[CH:16]=[CH:17][C:12]([CH2:10][CH3:11])=[CH:13][CH:14]=1
Reactant: CCc1ccc(Br)cc1
Reactant: Cc1cccc(Cl)c1N
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(Nc2c(C)cccc2Cl)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of 5.2 g (37 mmol) of 2-chloro-6-methylaniline and 6.95 g (37.6 mmol) of 4-ethyl bromobenzene in 50 ml of toluene is added 6.5 g (68 mmol) sodium tert-butoxide, 180 mg (0.89 mmol) tri-tert-butylphosphine (dissolved in 2 ml of toluene) and 300 mg (0.52 mmol) of bis-dibenzylideneacetone palladium(0). The mixture is heated under nitrogen to 90° C. for 3 hours and then cooled to room temperature. Hyflo (1 g), water (30 ml) and cone, hydrochloric acid (10 ml) are added and after stirring for 30 minutes the mixture is filtered. The organic phase is washed with water (30 ml) twice and evaporated. The residue is subjected to flash-chromatography on silica (75 g) during with heptane to afford 5.3 g (21.6 mmol. 58%) of N-(2′-chloro-6′-methylphenyl)-4-ethylaniline as an almost colourless liquid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH3:6].O.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16]>CN(C)C=O>[CH3:6][O:5][CH2:4][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16]
Reactant: COCCl
Reactant: CC(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C(C)=O
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
In N,N-dimethylformamide (25 mL) was dissolved 3.39 g (24.9 mmol) of commercially available 1-(2-hydroxyphenyl)-ethanone, 1.52 g (38.0 mmol) of 60% sodium hydride was added to the solution in an ice bath, and the resulting mixture was stirred in an ice bath for 20 minutes. To the mixture was gradually added dropwise 3.00 mL (39.5 mmol) of chloro(methoxy)methane, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 4.33 g (24.1 mmol, Yield: 96.8%) of 1-[2-(methoxymethoxy)phenyl]ethanone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH:23]([C:24]([OH:26])=[O:25])[CH2:22][CH:21]4[CH2:27][CH2:28][CH2:29][CH:20]34)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]3[CH:23]([C:24]([OH:26])=[O:25])[CH2:22][CH:21]4[CH2:27][CH2:28][CH2:29][CH:20]34)(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)C1CC2CCCC2N1S(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reaction time: 2 h

Procedure:
1 g of 1-(4′-nitrobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (27) was dissolved in 15 ml of DMF, after which 0.1 g of hydrogenation catalyst (10% Pd on active charcoal) was added and the starting compound was quantitatively hydrogenated within 2 h. After the solvent had been removed, the crude product was purified chromatographically.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14]O.O=S(Cl)[Cl:18]>C(Cl)Cl>[Cl:18][CH2:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: OCc1ccc2oc3ccccc3c2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc2oc3ccccc3c2c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Dibenzo[b,d]furan-2-ylmethanol CCH 34116 (174 mg, 878 μmol) was immediately dissolved in dry CH2Cl2 (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer before slow addition of SOCl2 (1.0 mL, 13.78 mmol) and the reaction mixture was stirred for 20 min at 80° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum. The residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 as a grey solid (189 mg, 99% yield).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)(=O)=O)=CC=1.FC(F)(F)C(O)=O.[NH2:30][C:31]1[C:36]([C:37]([NH:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)/C=C\C(O)=O>C(#N)C>[NH2:30][C:31]1[C:36]([C:37]([NH:39][CH2:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:11][CH:12]3[O:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[O:14][CH2:13]3)[CH2:43][CH2:42]2)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: Nc1ncccc1C(=O)NCC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C(=O)NCC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
A stirred mixture of 1,4-benzodioxan-2-ylmethyl toluene4-sulphonate (0.82 g), 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate (0.905 g; prepared in a similar manner to that described in Example 2) and potassium carbonate (1.4 g) in acetonitrile (50 ml) was heated under reflux for 6 hours. After cooling, the solvent was removed in vacuo, water (60 ml) was added to the residue, and the product was extracted with dichloromethane (2×30 ml). The extracts were dried over magnesium sulphate and the solvent was removed in vacuo to give an oil. The oil was purified by flash chromatography on silica eluting with a 9:1 then 1:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvents removed in vacuo to give an oil. Ethereal maleic acid (20 ml) was added to yield a white solid. The solid was collected by filtration, washed with ether and the solvent removed in vacuo to yield 2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide 0.5 maleate (95 mg) m.p. 104-106° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:20][CH2:21][OH:22])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.[N+:23]([C:26]1[CH:36]=[CH:35][C:29]([C:30]([N:32]=[C:33]=S)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(Cl)CCl.O>C1COCC1>[Br:19][C:5]1[CH:4]=[C:3]2[C:8]([O:9][C:10]3[C:11]([F:18])=[CH:12][C:13]([O:16][CH3:17])=[CH:14][C:15]=3[C:2]32[CH2:20][CH2:21][O:22][C:33]([NH:32][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:36][CH:35]=2)=[N:1]3)=[CH:7][CH:6]=1
Reactant: COc1cc(F)c2c(c1)C(N)(CCO)c1cc(Br)ccc1O2
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1cc(F)c2c(c1)C1(CCOC(NC(=O)c3ccc([N+](=O)[O-])cc3)=N1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 2-(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)ethanol (7.17 g, 19.47 mmol) in THF (100 mL) was added 4-nitrobenzoyl isothiocyanate (4.26 g, 20.45 mmol). The reaction mixture was stirred for 30 min at RT. EDC (5.60 g, 29.2 mmol) and TEA (0.543 ml, 3.89 mmol) were added sequentially and the reaction mixture was heated to 70° C. for 1 hr. The reaction mixture was cooled to RT and water (50 ml) was added. The reaction mixture was stirred for 1 hr, upon which a precipitate formed, which was filtered off and washed with water and MeOH. The solid was dried to afford N-(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2-yl)-4-nitrobenzamide (6.0 g, 11.06 mmol, 56.8% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9]CC(C)(OC2CCCCO2)C)=[CH:4][N:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH:23]1[C:28]([OH:30])=O.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:3]1[C:4]2[N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH:23]3[C:28](=[O:30])[NH:9][C:5]=2[CH:6]=[N:7][CH:2]=1
Reactant: CC(C)(CNc1cnc(Cl)nc1Cl)OC1CCCCO1
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1Nc2cncnc2N2CCOCC12
Temperature: 95 °C
Reaction time: 4 h
Yield: 24.6 %

Procedure:
To a mixture of 2,4-dichloro-N-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrimidin-5-amine (315 mg, 0.982 mmol) and morpholine-3-carboxylic acid hydrochloride (247 mg, 1.47 mmol) in DMSO (6 ml) was added diisopropylethylamine (0.686 ml, 3.93 mmol), and the reaction mixture was stirred at 95° C. for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude residue was chromatographed by silica gel (hexane/ethyl acetate, 19:1 to 1:1) to afford 2-chloro-5-2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (96.2 mg, 0.242 mmol, 25% yield) as a pale yellow oil which was used in the next reaction without further purification. MS [M+H] found 397.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[CH3:9]N(C=O)C.C(N(C(C)C)C(C)C)C.CI>O.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CN(C)C=O
Solvent: CI
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To pyrrole-2-carboxylic acid (1.11 g., 0.010 mol) in 5 ml. DMF at 0° was added N-(ethyl)diisopropylamine (1.806 ml., 0.0105 mol) followed by methyl iodide (0.654 ml., 0.0105 mol). The mixture was stirred 18 hours at room temperature, diluted with 10 ml. ethyl acetate and 10 ml. H2O, the pH adjusted to 8.5, and the organic layer separated, washed 1×10 ml. H2O, dried over Na2SO4, and stripped with CHCl3 chase to yield title product as a gummy solid containing 10% DMF, 0.93 g.; 1H-nmr (CDCl3 ) delta (narrow product peaks only): 3.80 (s, 3H), 6.15 (m, 1H), 6.83 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:35][O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][CH:37]([O:36][CH3:35])[CH2:38][CH2:39]4)[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: COC1CCNCC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: COC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5cccc(F)c5)c(C)c4)c23)CC1
Yield: 27 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy}ethyl methanesulfonate (prepared as described in Example 21) and 4-methoxypiperidine to give the title compound in 27% yield; NMR Spectrum: 1.36-1.41 (m, 2H), 1.78-1.80 (m, 2H), 2.18-2.23 (m, 2H), 2.23 (s, 3H), 2.76-2.78 (m, 4H), 3.12-3.15 (m, 1H), 3.19 (s, 3H), 4.39 (t, 2H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.28-7.32 (m, 2H), 7.42-7.47 (m, 3H), 8.21 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 507 (MH+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C:10]1([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH2:48][O:49][Si:50]([CH:57]([CH3:59])[CH3:58])([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])[CH:42]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([CH:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:11]2)=[CH:42][C:43]=1[CH2:48][O:49][Si:50]([CH:57]([CH3:59])[CH3:58])([CH:51]([CH3:53])[CH3:52])[CH:54]([CH3:56])[CH3:55]
Reactant: CC(C)[Si](OCc1cc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)(C(C)C)C(C)C
Temperature: -10 °C

Procedure:
To a stirred −50° C. solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-((triisopropylsilyloxy)methyl)phenyl)tetra-hydro-2H-pyran-2-ol (198 mmol) from Step 4 in dichloromethane (500 mL) was added triethylsilane (63 mL, 396 mmol) followed by boron trifluoride diethyl etherate (50 mL, 396 mmol) at a rate such that the reaction temperature was maintained between −40 and −50° C. The solution was allowed to warm to −10° C. over 2 h prior to quenching with saturated potassium carbonate solution. After removal of organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and water. Following extraction of the aqueous layer with ethyl acetate, the combined organic layers were washed with water prior to drying over magnesium sulfate. Filtration and concentration under reduced pressure yielded the title compound as a yellow oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][N:19]([CH:21]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]2)[CH:20]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:51]>O1CCOCC1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:27].[ClH:51].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]3)[CH:20]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnn(C2CCN(C)C2)c1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1cnn(C2CCN(C)C2)c1
Temperature: 80 °C
Yield: 101 %

Procedure:
To a suspension of 1-(6-bromo-4-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone (80 mg, 0.19 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 mg, 0.25 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a residue that was dissolved in methanol (8 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (69.8 mg, 65%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 8.26-8.17 (m, 2H), 8.12 (s, 1H), 8.05-7.99 (d, J=8.8 Hz, 1H), 7.82-7.77 (m, 1H), 7.25 (s, 1H), 7.13 (d, J=11.3 Hz, 1H), 5.46-5.34 (m, 1H), 4.28-3.96 (m, 2H), 3.88-3.55 (m, 1H), 3.41-3.32 (m, 1H), 3.15 (s, 1H), 3.05 (s, 2H), 2.93-2.81 (m, 1H), 2.80 (s, 3H), 2.68-2.33 (m, 1H). ESI MS m/z 480 [C25H23ClFN5O2+H]+; HPLC>99% (AUC), tR=9.44 min.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[CH:7]=[CH:8][C@H:9]2[CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[CH:7]=[CH:8][C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C=C[C@H]2CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON1C(=O)N2C[C@H]1C=C[C@H]2CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of (2S,5R)-6-(allyloxy)-2-((tert-butyldimethylsilyloxy)methyl)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 129, 1.64 g, 5.05 mmol) in THF (40 mL), tetrabutylammonium fluoride (6.06 ml, 6.06 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. The mixture was concentrated and purified by silica gel column (40 g, 50-100% Hex/EA) to give the desired product (1.03 g) as an yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CCOCC2)c2nn[nH]c2n1
Yield: 13.1 %

Procedure:
A mixture of 4-(5-tert-butyl-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (10.0 mg, 26.1 μmol) and TFA (250 μL) was refluxed for 5 h under N2 atmosphere. Then, the reaction mixture was concentrated in vacuo and purified by preparative HPLC (column: Gemini 5 um C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 85:15% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as white solid (0.9 mg, 13%). MS(m/c): 263.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[N+](C1C=CC([O:17][C:18]([O:20][CH:21]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:25][C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23][CH2:22]2)=O)=CC=1)([O-])=O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:18]([O:20][CH:21]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:25][C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23][CH2:22]2)=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Reactant: COc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)OC2CN=C(c3ccccc3)OC2c2ccccc2)c1
Temperature: 70 °C
Yield: 62.4 %

Procedure:
meta-Anisidine (1.72 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-5-(4-nitrophenoxycarbonyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (3 g) and 4-(dimethylamino)pyridine (0.3 g) in anhydrous N,N-dimethylformamide (50 cc). The solution obtained is heated to a temperature in the region of 70° C. for 6 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate/triethylamine (65:30:5 by volume)], collecting 25-cc fractions. Fractions 2 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(3-methoxyphenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.8 g), m.p. 110° C. is obtained.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH:3]=[C:4](Br)Br.C1(O[C:23]#[N:24])C=CC=CC=1.CC(C1C=CC(OC)=CC=1)(C)C#CC>>[C:23]([C:4]#[C:3][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:1])#[N:24]
Reactant: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Reactant: N#COc1ccccc1
Agent: CC#CC(C)(C)c1ccc(OC)cc1
Product: COc1ccc(C(C)(C)C#CC#N)cc1

Procedure:
This compound was prepared from Compound 53 and Compound 62 in the same manner of Compound 54.