Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[C:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[CH3:9]
Reactant: CC(C)CCCCCC(=O)O
Reactant: CC(C)CCCCCCCO
Product: CC(C)CCCCCCCOC(=O)CCCCCC(C)C
Yield: 46.7 %

Procedure:
A reaction between 160 g of isononanoic acid and 160 g of isodecyl alcohol was carried out as in Example 1, obtaining 141 g of the desired ester.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:18][CH:19]([CH2:23][CH2:24][Cl:25])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:25][CH2:24][CH2:23][CH:19]([CH3:18])[C:20]([NH:10][C:8]1[O:7][N:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=1)=[O:21]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: CC(CCCl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)no1

Procedure:
To a stirred solution of 7 g of 3-(1,1-dimethylethyl)-5-aminoisoxazole dissolved in 50 ml ethyl acetate was added 5.05 g of triethylamine at room temperature. As the solution continued to stir, 8 g of 2-methyl-4-chlorobutyric acid chloride was added to the reaction mixture over a 15 minute period. The reaction was allowed to stir for about 3 days and the precipitated triethylamine hydrochloride salt was collected by filtration and washed with ethyl acetate. The solvent was evaporated from the filtrate under reduced pressure and the residue was recrystallized from diethyl ether to afford 4-chloro-N-[3-(1,1-dimethylethyl)-5-isoxazolyl]-2-methylbutanamide as a solid. mp 135°-137° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:20])[C:8]2[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])[CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:20][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=1[O:18][CH3:19])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)c(OC)c(C)c1C(O)c1cccnc1
Solvent: c1ccncc1
Product: COc1cc(C)c(OC)c(C)c1C(OC(C)=O)c1cccnc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture comprising 3.2 g of α-(3-pyridyl)-2,5-dimethoxy-4,6-dimethylbenzyl alcohol obtained by the method described in any of the Production Examples 1, 2 and 3, 5 ml of pyridine and 5 ml of acetic anhydride was heated and stirred at 80° C. for 1 hour. Then the pyridine and acetic anhydride were distilled off and the residue was purified by silica gel column chromatography. Thus 2.9 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:28](OCC)=[O:29].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[C:9]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:28]=[O:29])=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: Cn1nnnc1C=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -80 °C
Reaction time: 0.67 h
Yield: 71.5 %

Procedure:
To a finely divided suspension of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.0 g, 3.3 mmoles) [prepared in Step B] in tetrahydrofuran (10 mL) at -80° C. was added n-butyl lithium (1.54 mL of 2.14 M solution), 3.3 mmoles) with the formation of a dark violet color. After stirring for 40 minutes at -80° C., ethyl formate (0.32 g, 4.3 mmoles) was added and the mixture stirred for 2.5 hours at -80° C. The mixture was hydrolyzed with 1N hydrochloric acid and extracted with methylene chloride. The extracts were dried (MgSO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give 0.77 g of yellow solid, m.p. 128°-131° C. The solid was crystallized from isopropyl acetate-hexane to give 0.55 g of the title compound; m.p.=130°-132° C.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[CH:13]=[C:12](I)[CH:11]=[CH:10][C:8]=1[NH2:9]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:2]([C:12]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([F:6])[CH:13]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccc(I)cc1F
Reactant: [Li]CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCCCc1ccc(N)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
ZnCl2 (5. 17 g, 38.0 mmol) was weighed into a flask, which was then flame dried and flushed with N2. Anhydrous THF (20 ml) was then added at 0° C., followed by 2.5 M nBuLi (15.2 ml, 38.0 mmol). The reaction mixture was stirred at 0° C. for 15 min, after which 2-fluoro-4-iodoaniline (3.00 g, 12.7 mmol) in anhydrous THF (10 ml) and Pd(PPh3)4 (0.74 g, 0.64 mmol) were added sequentially. The mixture was allowed to warm to RT and stirred for a further 6 h. The mixture was poured into ice/Et2O, the organic layer separated and the aqueous layer further extracted with Et2O. The combined organic fractions were washed with sat. NaHCO3, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid was removed from the mixture by filtration and the filtrate purified by flash chromatography on silica (12.5% EtOAc/Hexane as eluant) to give the desired product (30%, 3.7 mmol). 1H NMR [400 MHz, CDCl3]δ 6.80 (dd, J=12.1, 1.8 Hz, 1 H), 6.76-6.65 (m, 2 H), 3.65 (br s, 2 H), 2.49 (t, J=7.7 Hz, 2 H), 1.57-1.49 (m, 2 H), 1.32 (sextet, J=7.3 Hz, 2 H), 0.91 (t, J=7.3 Hz, 3 H). LCMS (ACPI+) 168 (100%). Step B: Preparation of 2-(4-butyl-2-fluoroanilino)-3,4-difluorobenzoic acid
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH3:25])[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1ccccc1C)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccccc1C
Yield: 86.8 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.32 g, 0.88 mmol) prepared in example 4b was reacted with 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.4 g, 1.71 mmol) prepared in example 17a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (Yield 0.4 g, 87%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=1)([O-])=O>C(O)C.[Pd]>[NH:16]1[CH:17]=[C:13]([CH2:12][CH2:11][C:7]2[CH:6]=[C:5]([NH2:2])[CH:10]=[CH:9][CH:8]=2)[N:14]=[CH:15]1
Reactant: O=[N+]([O-])c1cccc(C=Cc2c[nH]cn2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(CCc2c[nH]cn2)c1

Procedure:
The hydrochloride of the product obtained in Step 4 is stirred under a hydrogen atmosphere in the presence of a 90% solution of 10% palladium-on-carbon in ethanol. After filtration and concentration of the solvent, the product is used as it is in the following Step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[C:26]([O:28][CH3:29])=[N:27][C:22]([O:21][CH3:20])=[N:23][CH:24]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cnc(OC)nc3OC)c(F)ccc2c1N

Procedure:
The title compound was prepared from 4-amino-7-flouro-8-iodo-N-propylcinnoline-3-carboxamide (220 mg, 58.8 mmol) and 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (312 mg, 1.62 mmol) according to Method B to afford a white solid (123 mg, 54%). 1H NMR (300.132 MHz, CDCl3) δ 8.47 (t, J=5.4 Hz, 1H), 8.32 (s, 1H), 7.93 (dd, J=9.1, 5.2 Hz, 1H), 7.53 (dd, J=9.2, 8.4 Hz, 1H), 4.07 (s, 3H), 3.94 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), 1.66 (sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=387 (M+H). HPLC 1.87 min.
Reaction SMILES: P(O)(O)(O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][O:12][NH2:13])=[CH:9][C:8]=1[OH:16].C(=O)(O)[O-].[Na+].[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=O)[C:31]([OH:33])=[O:32])[N:29]=1)=[O:23]>O.C(O)C>[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:13][O:12][CH2:11][C:10]2[CH:14]=[CH:15][C:7]([Br:6])=[C:8]([OH:16])[CH:9]=2)[C:31]([OH:33])=[O:32])[N:29]=1)=[O:23]
Reactant: NOCc1ccc(Br)c(O)c1
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=CNc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The solution of 4-bromo-3-hydroxybenzyloxyamine phosphate (17.4 g.) in water (200 ml.) and ethanol (200 ml.) was stirred at room temperature and adjusted to pH 7.0 with sodium bicarbonate. 2-(2-Formamidothiazol-4-yl)glyoxylic acid (10.0 g.) was added to the solution and the resulting suspension was adjusted to pH 4.0 to 4.5. After stirring the solution at room temperature for 2 hours, ethanol was removed from the resultant solution in vacuo. Ethyl acetate was added to aqueous residue and adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. The solution was concentrated in vacuo to give 2-(2-formamidothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetic acid (syn isomer, 14.8 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][C:35]=2[CH3:37])[N:30]=[CH:29][CH:28]=1.S(Cl)(Cl)(=O)=O>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:40])=[CH:34][C:35]=2[CH3:37])[N:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(S(=O)(=O)Cl)cc2nccc(Cl)c12
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(C)c3c(Cl)ccnc3c2)cc1
Reaction time: 0.25 h

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (25.1 mg, 0.114 mmol) in THF (418 μl) was added lithium bis(trimethylsilyl)amide (1M in THF) (120 μl, 0.120 mmol) dropwise over 10 min. The mixture was stirred for 15 min prior to the drop wise addition of a solution of 4-chloro-5-methylquinoline-7-sulfonyl chloride (30 mg, 0.109 mmol) in THF (0.6 ml). After 30 min LC/MS indicated desired product and methanolysis of the sulfonyl chloride (about 1:1). Additional solid N-(4-methoxybenzyl)thiazol-2-amine (25.1 mg, 0.114 mmol) was added with stirring at room temperature. After 15 min, no further conversion had occurred. Additional LHMDS (0.5 eq) was added after cooling back to 0° C. and stirring continued. After 20 min, LC/MS indicated consumption of sulfonyl chloride (methanolysis) with product visible as a minor species. To the orange/brown solution was added acetic acid (300 μl) and the mixture dried under reduced pressure. The crude material was purified with a 25 g (25 μm spherical) silica column ramping EtOAc in heptane (0-50%, 5% DCM throughout) to provide 4-chloro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (6 mg, 0.013 mmol, 12.01% yield) as a white solid. m/z (ESI) 460.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1.O>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(OC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
Oxan-4-ol (0.302 g, 2.96 mmol) was dissolved in THF (5 mL) and cooled to 0 C under nitrogen. Potassium tert-butoxide (0.332 g, 2.96 mmol) was added and the mixture stirred for 5 min. Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h. Water (5 mL) was added and the mixture extracted with EtOAc (2×10 mL). The organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 5-20% EtOAc in heptane to afford the title compound as a colourless oil (0.239 g, 35%). 1H NMR (250 MHZ, CDCl3) δ ppm 8.80 (1H, dd), 8.14 (1H, m), 6.73 (1H, dd), 5.25 (1H, m), 4.39 (2H, dq), 3.96 (2H, m), 3.60 (2H, m), 2.05 (2H, m), 1.81 (2H, m) and 1.40 (3H, dt).
Reaction SMILES: P([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(O)(O)=O.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>O1CCCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)CP(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C\c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To a 500 mL RB flask fitted with magnetic stirrer was charged with 160 mL of tetrahydrofuran. To the stirred solvent was added ethyl phosphonoacetate (16.5 g, 73.6 mmol) under argon atmosphere. The reaction mixture was cooled to 0° C. and sodium hydride (2.65 g, 110 mmol) was added portion wise, stirred for 15 minutes at the same temperature. Then 4-methoxybenzaldehyde (5 g, 36.0 mmol) in tetrahydrofuran (30 mL) was added drop wise. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with water at 0° C. by slow addition, stirred for 10 minutes. The layers were separated; ethyl acetate (50 mL) was added to the aqueous layer and extracted the layers. The organic layer was washed with brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow semi-solid (7.4 g, yield: 98.76%). 1H NMR (300 MHz, CDCl3): δ 7.54-7.60 (d, 1H), 7.39-7.42 (d, 2H), 6.82-6.85 (d, 2H), 6.21-6.26 (d, 1H), 4.15-4.22 (q, 2H), 3.76 (s, 3H), 1.24-1.28 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][N:4]2[CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]2)=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (450 mg) was dissolved in 20 mL of dichloroethane, N-boc-4-formylpiperidine (750 mg) was added to the mixture, followed by 2 g NaHB(OAc)3 and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (20 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 Hexane:EtOAc to afford an orange oil. MS: 290 (M−99). Calc'd. for C21H31N3O4—389.5.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]5[CH2:35][CH2:34][NH:33][CH2:32]5)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[CH:53]1([CH2:56][C:57](Cl)=[O:58])[CH2:55][CH2:54]1>ClCCl>[CH:53]1([CH2:56][C:57]([N:33]2[CH2:34][CH2:35][CH:31]([O:30][C:27]3[CH:28]=[CH:29][C:24]([CH:23]4[CH2:22][CH2:21][N:20]([C:36]([O:38][CH2:39][C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[O:37])[CH2:19][CH:18]4[O:17][CH2:16][C:13]4[CH:14]=[CH:15][C:10]5[O:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=5[CH:12]=4)=[CH:25][CH:26]=3)[CH2:32]2)=[O:58])[CH2:55][CH2:54]1
Reactant: O=C(Cl)CC1CC1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CCNC4)cc3)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CCN(C(=O)CC5CC5)C4)cc3)cc21

Procedure:
The solution of 0.120 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(pyrrolidin-3-yloxy)phenyl]piperidine-1-carboxylate in 4.0 ml of dichloromethane is cooled to 0° C. with stirring and admixed with 0.032 ml of triethylamine. 0.031 ml of cyclopropylacetyl chloride in 0.40 ml of dichloromethane is slowly added dropwise. Subsequently, the mixture is stirred at 0° C. over 1 hour. The reaction mixture is poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a pink oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.18.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cccc(O)c1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a mixture of 5 g of 3-tert-butylphenol and 30 ml of acetic acid, a mixture of 3.0 g of 70% nitric acid and 10 ml of acetic acid was added dropwise with the temperature kept at 10-15° C. and stirred for two hours. The reaction mixture was poured into ice water and extracted with ethyl acetate twice. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.82 g of 5-tert-butyl-2-nitrophenol.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:31][O:30][C:27]1[N:26]=[CH:25][C:24]([NH:23][C:2]2[C:7]([C:8]3[N:16]=[CH:15][N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(N)cn1
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)cn1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (196.6 mg, 657 μmol) and 3-amino-6-methoxypyridine (Aldrich, St. Louis, Mo.) (101.9 mg, 821 μmol) in THF (2.0 mL) was cooled in an ice bath and treated with LiHMDS (3.0 mL, 3.0 mmol). A blood-red solution was obtained. The mixture was stirred for 1 h, and then quenched with water (0.1 mL). The mixture was extracted into EtOAc from saturated aqueous NaHCO3, concentrated and purified by flash chromatography on silica (50% EtOAc/hexane; yellow band from column) to give 6-methoxy-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)pyridin-3-amine (190 mg, 71.7% yield) as a yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H); 9.68 (dd, J=7.82, 1.76 Hz, 1H); 8.99 (s, 1H); 8.44 (d, J=2.54 Hz, 1H); 8.28 (dd, J=4.69, 1.76 Hz, 1H) 8.34 (s, 1H); 8.05 (dd, J=8.90, 2.64 Hz, 1H); 6.88 (dd, J=7.82, 4.69 Hz, 1H); 6.77 (d, J=8.80 Hz, 1H); 5.86 (dd, J=10.37, 2.35 Hz, 1H); 4.16-4.25 (m, 1H); 3.95 (s, 3H); 3.82 (s, 1H); 1.98-2.24 (m, 3H); 1.61-1.89 (m, 3H). m/z (ESI, +ve) 404.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:28]=[O:29])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C=O)ccc2c1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (4 g, 0.01 mol, 1.0 equiv) in dry THF (30 mL) at −78° C. under N2 atmosphere was added n-BuLi (2.5 M, 12 mL, 3.0 equiv) dropwise and stirred for 30 min. Then DMF (7.3 g, 0.1 mol, 10 equiv) was added and stirred for another 1 h, then quenched with water, extracted with ethyl acetate and washed with brine, dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by silica gel chromatography (PE:EA=20:1) to give compound the title compound (2.2 g, 64%) as a yellow liquid. ESI-MS (M+1)+: 287.0. 1H NMR (400 MHz, CDCl3) δ: 10.10 (s, 1H), 8.26 (s, 1H), 7.91-7.88 (m, 2H), 7.78-7.76 (m, 1H), 7.24-7.167 (m, 2H), 1.03 (s, 9H), 0.28 (s, 6H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>O.CN(C)C(=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 150 °C
Yield: 90 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in an oven-dried flask with 3-(S)-amino-3-o-tolyl-propionic acid (84 mg, 0.468 mmol) (commercially available from Combi-Blocks SS-1801) and N,N-dimethylacetamide (1.5 mL) was added with stirring. Solid sodium methoxide (25 mg, 0.468 mmol) was added and the reaction was heated to 150° C. in an oil bath for approximately five hours. The reaction was cooled and the solution diluted with five volumes of water. The solution was acidified to pH 3 with 1M hydrochloric acid to induce precipitation. Filtration of the solid followed by vacuum drying provided the desired product in 90% yield. LC-MS ESI−: 466 (M−1)−.