Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=1)(=[O:19])=[O:18].C(OCC)(=O)C>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:17]([N:20]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=1)[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:18])=[O:19]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cnccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1Cl
Temperature: -5 °C

Procedure:
2-(Trimethylsilyl)ethoxymethyl chloride (0.22 ml) was added dropwise over 5 minutes to a stirred solution of 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.306 g) and N,N-diisopropylethylaminc (0.21 ml) in dry DMF (1 ml) at -15° C. The resultant solution was allowed to warm to -5° C. over 40 minutes then ethyl acetate (30 ml) was added and the mixture was washed with 2M hydrochloric acid (30 ml), water (30 ml) and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 30-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.266 g) as an oil; 1H NMR (d6 -DMSO): -0.1 (s, 9 H), 0.7 (t, 2 H), 2.45 (s, 3 H), 3.6 (t, 2 H), 3.85 (s, 3 H), 5.2 (s, 2 H), 7.8 (d, 1 H), 8.0 (s, 1 H), 8.8 (d, 1 H), 9.1 (s, 1 H); mass spectrum (+ve FAB, DMSO/Glycerol): 445 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9]C)=O.[OH:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:7](=[O:9])/[CH:22]=[C:21](\[OH:23])/[CH:20]=[CH:19]/[C:18]2[CH:17]=[CH:16][C:15]([OH:14])=[CH:25][CH:24]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)C=Cc1ccc(O)cc1
Reactant: COC(=O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(/C=C(O)/C=C/c1ccc(O)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
NaH (60% dispersion, 0.477 g, 11.9 mmol) was added to a solution of methyl 3-chlorobenzoate (0.677 g, 3.97 mmol) and 4-hydroxybenzylideneacetone (0.644 g, 3.97 mmol) in anhydrous DMF (20 mL) at 0° C. The reaction was allowed to warm to room temperature overnight and quenched with saturated aqueous NH4Cl and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 mL) and the organic layer washed successively with saturated aqueous NaHCO3 and brine. The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo to provide the condensation product as a yellow oil (0.717 g, 60% yield).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.C(C1C=CC(C([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[O:29][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])O)=CC=1)C.O>CS(C)=O.O1CCCC1>[CH3:35][Si:34]([CH3:37])([CH3:36])[CH2:33][CH2:32][O:31][CH2:30][O:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:23]=1
Reactant: CCc1ccc(C(O)c2ccncc2OCOCC[Si](C)(C)C)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cccnc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 180.9 %

Procedure:
To a solution of o-iodoxybenzoic acid (IBX) in dimethyl sulfoxide (15 mL), a solution of (4-ethylphenyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridin-4-yl]-methanol (synthesized in Reference Example 6; 3.0 g, 8.34 mmol) in tetrahydrofuran (20 mL) was added and the reaction mixture was stirred at room temperature for 17.5 hours. Water was added to the reaction mixture and the resulting precipitate was filtered and washed with ethyl acetate. The filtrate was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 4-(4-ethylbenzoyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (3.4 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([NH2:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C@H:23]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:24](O)=[O:25].S([O-])([O-])(=O)=O.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(=O)([O-])O.[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([NH:21][C:24](=[O:25])[C@H:23]([OH:22])[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Reactant: O=C(O)[C@H](O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC(=O)[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a solution of (1R)-2-(7-(benzyloxy)-1H-indol-3-yl)-1-methyl-ethylamine (5.0 g, 17.8 mmol) in tetrahydrofuran (100 mL) are added successively with stirring (R)-2-hydroxy-2-(3-pyridyl)acetic acid.sulfate (4.68 g, 11.6 mmol), triethylamine (3.22 mL, 23.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride (4.78 g, 24.9 mmol), and 1-hydroxybenzotriazole (3.36 g, 24.9 mmol) under ice-cooling, and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is diluted with a mixture of a saturated aqueous sodium hydrogen carbonate solution and water (1:1, 100 mL), and extracted with ethyl acetate (2×100 mL). The organic layers are combined and washed with a mixture of a saturated brine and water (1:1, 100 mL), dried over magnesium sulfate, and separated by filtration. The filtrate is concentrated under reduced pressure, and the obtained pale brown solid is dispersed into chloroform (80 mL). The insoluble white solid is collected by filtration, washed with chloroform (40 mL), and dried under reduced pressure to give the title compound (6.38 g, yield: 86%).
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O-:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[C:18]1([CH2:24][CH2:25][CH2:26]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][C:4]([CH3:7])([CH2:5][CH3:6])[C:3](=[O:9])[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])=[O:1]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)[O-]
Reactant: OCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OCCCc1ccccc1
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylate acid (600 mg; 2.49 mmol), 3-phenyl-1-propanol (508 mg; 3.73 mmol), dicyclohexylcarbodiimide (822 mg; 3.98 mmol), camphorsulfonic acid (190 mg; 0.8 mmol) and 4-dimethylaminopyridine (100 mg; 0.8 mmol) in methylene chloride (20 ml) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo, and the crude material was purified on a flash column (25% ethyl acetate in hexane) to obtain 720 mg (80%) of Example 1 as a colorless oil. 1H NMR (CDCl3): d 0.84 (t, 3H); 1.19 (s, 3H); 1.23 (s, 3H); 1.70 (dm, 2H); 1.98 (m, 5H); 2.22 (m, 1H); 2.64 (m, 2H); 3.47 (m, 2H); 4.14 (m, 2); 4.51 (d, 1H); 7.16 (m, 3H); 7.26 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:20]2[S:21][CH:22]=[N:23][C:19]=2[CH2:18][CH2:17][NH:16]1)[CH3:3].[CH2:25]1COCC1>CCO.[OH-].[Na+]>[CH:2]([O:4][C:5](=[O:24])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:20]2[S:21][CH:22]=[N:23][C:19]=2[CH2:18][CH2:17][NH:16]1)([CH3:25])[CH3:3]
Reactant: C1CCOC1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ncsc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)OC(=O)COc1ccc(Cl)cc1C1NCCc2ncsc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (1.70 g, 4.37 mmol, 1 eq.) in THF (50 mL) and EtOH (25 mL), 1M aq. NaOH (50 mL) was added. The pale yellow solution was stirred at r.t. for 18 hours, then concentrated in vacuo. The resulting aq. layer was carefully acidified with 2N aq. HCl. The mixture was extracted with DCM (3×100 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in 5-6N HCl in 2-propanol (150 mL). The reaction mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The reaction was diluted with sat. aq. NaHCO3 (250 mL). The mixture was extracted with DCM (3×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow solid. The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10](Br)[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2C=1C(C#N)=C[NH:29]2)C1C=CC=CC=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][NH:7]2)=[C:3]([O:2][CH3:1])[CH:11]=1)[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:14]
Reactant: COc1cc(Br)cc2[nH]ccc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1cc(OC)c2cc[nH]c2c1)c1ccccn1

Procedure:
3-(4-Methoxy-1H-indol-6-yl)-3-pyridin-2-yl-acrylic acid ethyl ester CLXXIV was prepared from 4-methoxy-6-bromo-1H-indole and 3-pyridin-2-yl-acrylic acid ethyl este using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccccc1CBr
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(bromomethyl)-2-(trifluoromethyl)benzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, (8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (87%) as a colorless solid: mp 137-138° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) 7.72 (d, J=7.6 Hz, 1H), 7.52-7.33 (m, 2H), 7.22-7.13 (m, 3H), 7.07-7.00 (m, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.08 (d, J=17.1 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 127.9 (q, 2JC-F=30.8 Hz), 127.6, 126.8, 126.4 (q, 5JC-F=5.8 Hz), 124.4 (q, 1JC-F=273.8 Hz), 124.1, 123.8, 120.8, 111.6, 109.2, 99.6, 80.3, 64.5, 64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+) m/z 454.0 (M+1). Anal. Calcd. for C26H18F3NO4: C, 66.22; H, 4.00; N, 3.09. Found: C, 66.16; H, 4.11; N, 3.07.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[CH2:9]([O:12][C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18](F)=[CH:19][CH:20]=2)[N:15]([CH3:25])[CH:14]=1)[CH:10]=[CH2:11]>O1CCOCC1>[CH2:9]([O:12][C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:19][CH:20]=2)[N:15]([CH3:25])[CH:14]=1)[CH:10]=[CH2:11]
Reactant: C=CCOc1cn(C)c2cc(F)ccc2c1=O
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOc1cn(C)c2cc(OCC(F)(F)F)ccc2c1=O

Procedure:
2,2,2-Trifluoroethanol (7.0 ml) was added to a stirred suspension of sodium hydride (4.0 g of a 50% dispersion in mineral oil) in dioxan (60 ml). After 30 minutes 3-allyloxy-7-fluoro-1-methyl-4-quinolone (2.8 g) was added and the mixture heated under reflux for 24 hours. The solvent was removed by evaporation under reduced pressure at 40°. The residue was dissolved in water (150 ml) and the solution extracted with dichloromethane (3×150 ml). The combined extracts were dried over magnesium sulphate and evaporated to give the novel compound 3-allyloxy-1-methyl-7-(2,2,2-trifluoroethoxy)-4-quinolone, m.p. 120°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1ccn2c(I)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Yield: 97 %

Procedure:
To a round bottomed flask add 7-chloro-3-iodo-imidazo[1,2-a]pyridine (3.0 g, 0.011 mol), add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.6 g, 1.1 equiv.), potassium carbonate (4.5 g, 3 equiv.), dioxane (40 mL), and water (20 mL). Deoxygenate this mixture thoroughly with N2 then add dichlorobis(triphenylphosphine)palladium (II) (0.23 g, 0.03 equiv.) and reflux the reaction overnight under N2. Concentrate the reaction to dryness and slurry in DCM. Filter this slurry thru Celite® and wash with DCM. Concentrate the filtrate then purify by silica plug (EtOAc to 5% MeOH: DCM to 10% MeOH: DCM) to give a pale grey solid (2.6 g, 100%). MS (ES), m/z 244 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[N:5]2[CH:22]=1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:6]2[N:5]3[CH:22]=[C:2]([CH3:1])[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC=O
Reactant: Cc1cn2c(SCCCCN3C(=O)CSC3=O)cccc2n1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3nc(C)cn23)C1=O

Procedure:
To a solution of 0.67 g (2.0 mmol) of 3-[4-(2-methylimidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.18 ml (2.0 mmol) of n-butyraldehyde in 10 ml of ethanol, 0.02 ml (0.2 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 0.794 g (quant, light yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:17]1[CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:13]([CH3:12])[CH2:18]1
Reactant: CNc1ccc(C=O)c(C)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 2-methyl-4-(methylamino)benzaldehyde (D93) (0.397 g) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.533 g, 2.66 mmol) in 1,2-DCE (35 mL) was added sodium tri(acetoxy)borohydride (0.847 g, 4.00 mmol) and the reaction stirred at room temperature overnight. Saturated aqueous NaHCO3 (30 mL) was added and the mixture was stirred for 4 h. The reaction mixture was extracted with DCM and the organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with ether/petroleum ether gave the title compound as a colourless oil (0.328 g).
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F-].[K+]>CN(C)C=O>[O:4]([CH2:8][C:7]([CH2:12][O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:13])[C:3]1[CH:5]=[CH:11][CH:10]=[CH:9][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(CBr)CBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)COc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
Thus obtained bromomethyl ketone derivative (X, 12.9 g, 31.0 mmol) and phenol (3.23 g, 1.2 Eq) were dissolved in dimethylformamide (30 ml), KF(4.53 g, 2.5 Eq) was added, and the mixture was stirred for two hours to give phenoxymethyl ketone derivative (XIb). This compound was dissolved in methanol (40 ml)-THF (100 ml) and was reacted by adding NaBH4 (2.35 g)-methanol solution (40 ml) (−10□-room temperature, two hours). The reaction was stopped by acetic acid, and the reaction mixture was distilled under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (50 ml×2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na2SO4), concentrated under reduced pressure, and separated-purified by column chromatography (ethyl acetate-hexane, 1:7) to give a compound (XIIb, 6.50 g, Yield 50%) in a diastereomeric form of which amino group is protected by benzyloxycarbonyl.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].CCCCCC.C([Li])CCC.[F:18][C:19](=[CH2:22])[CH:20]=[O:21]>O1CCCC1>[F:18][C:19]([CH:20]([OH:21])[C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[CH2:22]
Reactant: C#CC(C)(C)C
Reactant: C=C(F)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(F)C(O)C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
Ten grams (0.122 mole) of 3,3-dimethyl-1-butyne was dissolved in 100 ml of anhydrous tetrahydrofuran, and the resulting solution was cooled to -40° C. or less in a dry ice-acetone bath. Under a stream of a nitrogen gas, 81.13 ml of a 1.5M hexane solution of n-butyllithium was added dropwise at -40° C. or less with stirring. After aging the reaction solution at -50° C. for 30 minutes, 9.01 g (0.122 mole) of 2-fluoroacrolein was added dropwise at -50° C. or less. After the reaction mixture was allowed to stand overnight at room temperature, it was poured into 200 ml of ice water and extracted with two 100-ml portions of ethyl acetate. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 11 g of 2-fluoro-3-hydroxy-6,6-dimethylhept-1 -ene-4-yne (bp20, 86° C.).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)O)[CH:17]=[CH:18][C:19]=1[F:20].FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: OC(c1ccc(Cl)cc1)c1ccc(F)c(Cl)c1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(F)c(Cl)c3)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.15 g (4.23 mmol) of the compound from Example 177A in analogy to the synthesis of the compound from Example 278. 483 mg (26% of theory) of the target compound were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[N:13]=2.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:38][CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)(=O)=O>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:38][CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[N:13]=2
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: COc1nc2c(N)nc(OCC3CCCO3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCC3CCCO3)nc2n1CC1CCOCC1
Temperature: 60 °C
Yield: 54.3 %

Procedure:
8-(Methoxy)-2-[(tetrahydro-2-furanylmethyl)oxy]-9H-purin-6-amine trifluoroacetate salt (0.30 g) was dissolved in dry DMF (5 mL). To this solution was added anhydrous potassium carbonate (0.4376 g) and then the reaction mixture was heated to 60° C. under nitrogen for 1 hour. The reaction mixture was then cooled to room temperature before adding tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.1690 g) and then the resultant reaction mixture was heated to 90° C. for 2.5 hours. The reaction mixture was cooled and then quenched with water (50 mL), followed by extraction into ethyl acetate (50 mL, 3 times). After separating, the organic layers were combined and dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave mobile oil which was then purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (10-45%). This gave the title compound as a white solid (0.1560 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[NH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][NH:11][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: NCCO
Reactant: COC(=O)c1ccccn1
Product: O=C(NCCO)c1ccccn1

Procedure:
A mixture of 72 parts of methyl 2-pyridinecarboxylate and 32 parts of 2-aminoethanol is stirred and refluxed carefully for 2 hours. The reaction mixture is cooled and poured onto water. The product is extracted five times with trichloromethane. The combined extracts are dried, filtered and evaporated, yielding 49 parts of N-(2-hydroxyethyl)-2-pyridinecarboxamide as a residue.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:13][C:9]=2[N:10]=[CH:11][N:12]=1)C.Br.[CH:32]12[CH2:38][CH:35]([NH:36][CH2:37]1)[CH2:34][NH:33]2.C([BH3-])#N.[Na+]>C(O)(=O)C.ClCCCl>[CH:32]12[CH2:38][CH:35]([NH:36][CH2:37]1)[CH2:34][N:33]2[CH2:4][CH2:5][NH:6][C:7]1[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: C1NC2CNC1C2
Reactant: CCOC(CNc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12)OCC
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(-c2oc3ncnc(NCCN4CC5CC4CN5)c3c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 109 (10 mg, crude, 0.03 mmol for aldehyde) (made from compound 108 as in the preparation for 110) and 2,5-diaza-bicyclo[2.2.1]heptane hydrobromide (10 mg, 0.056 mmol) in 5% acetic acid solution in DCE (1 mL) was stirred at rt for 20 min. Sodium cyanoborohydride (20 mg, 0.32 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was directly purified by HPLC, providing 136. MS: 412.2 (M+1).