Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=[O:4].Cl.[CH3:22][NH:23][O:24][CH3:25].C([Mg]Cl)(C)C>O1CCCC1>[CH3:25][O:24][N:23]([CH3:22])[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: -30 °C
Yield: 40 %

Procedure:
2-(4-Trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester (5.6 g, 19.84 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (100 mL) and then cooled to −30° C. while stirring under nitrogen. N,O-dimethylhydroxylamine hydrochloride (3.12 g, 32.0 mmol) is then added to the solution in one portion. Isopropyl magnesium chloride (30 mL, 2M in THF, 60 mmol) is slowly added to the cooled suspension over 1 h. After complete consumption of starting material, then 30% solution of ammonium chloride is added with stirring: The reaction is diluted with diethyl ether and extracted. The organic layer is collected and washed with cold water (2×) and brine. The solution is then dried over anhydrous sodium sulfate, filtered, and concentrated. The 2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methoxy-methyl-amide (2.46 g, 7.936 mmol) is obtained in pure form after flash column chromatography.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([CH2:14][CH2:15][CH3:16])[C:7]([OH:13])=[CH:8][CH:9]=2)[O:4]1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([CH2:14][CH2:15][CH3:16])[C:7]([O:13][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:8][CH:9]=2)[O:4]1
Reactant: CCCc1c(O)ccc2c1OC(CO)CC2
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCBr)ccc2c1OC(CO)CC2
Yield: 59.6 %

Procedure:
A 250 ml single neck round bottom flask was charged with 2.70 g (12.15 mmole) of the compound from Example 34, 42 g or 25 ml (182 mmole) of 1,5-dibromopentane, 2.07 g (15 mmole) of anhydrous potassium carbonate, 750 mg (5 mmole) of sodium iodide, and 150 ml of methyl ethyl ketone. The flask was fitted with a magnetic stirring bar and a condenser topped with a calcium chloride drying tube and the reaction was refluxed for 5 days. The undissolved solids were removed by filtration and the filtrate was concentrated in vacuo on a rotary evaporator. The crude liquid residue was purified by high pressure liquid chromatography (20% ethyl acetate-hexane) to give 2.69 g (82%) of the title compound as a light yellow oil. Calc: C, 58.22; H, 7.33; Found: C, 58.10; H, 7.24.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16](OCC)=[O:17])=[CH:10][CH:9]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH2:16][OH:17])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC/C=C/c1ccc(Cc2cccnc2)cc1
Reaction time: 1 h
Yield: 52 %

Procedure:
In 200 ml of anhydrous diethyl ether was dissolved 24.0 g of ethyl (E)-3-[4-(pyridin-3-ylmethyl)phenyl]acrylate, and thereto was added in small portions 2.4 g of lithium aluminum hydride with ice-cooling over one hour. The resulting mixture was subjected to reaction for one hour with ice-cooling and then for a further one hour at room temperature, after which 91 ml of hydrous tetrahyrofuran (water content: 10% by volume) was added in small portions. Insolubles were removed by filtration and the solvent was removed by distillation under reduced pressure. The resulting oily product was dissolved in 200 ml of chloroform, and 40 ml of water was added to the resulting solution, after which the pH thereof was adjusted to 7 with 2N hydrochloric acid. The organic layer was separated, washed successively with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 10.5 g (yield 52.0%) of colorless, oily (E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyl alcohol. This was crystallized from a mixed solvent of chloroform and diethyl ether to obtain colorless needle crystals having a melting point of 81°-82° C.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[Cl:13].C([Mg]Br)(C)C.CN(C)[CH:21]=[O:22]>O1CCCC1>[Cl:13][C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:7]([Cl:8])[C:2]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-3,5-dichlorobenzotrifluoride (1 g, 3.4 mmol) in 1.2 mL tetrahydrofurane was slowly added to isopropylmagnesium bromide (15% in THF, 3.3 g, 3.4 mmol) at max. −10° C. After complete addition the reaction mixture was stirred for 30 min at −10° C. Dimethylformamide (0.275 g, 3.7 mmol) was added and the mixture was slowly warmed up. The mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was used without any further purification, brown oil (741 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[N+:16]([O-])=O.O.NN>[Pd].C(O)C>[NH2:16][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][C:13]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2C
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1c(N)ccc2c1CCCC(=O)N2C
Temperature: 60 °C
Yield: 92.5 %

Procedure:
6-Methoxy-1-methyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (530 mg, 2.12 mmol) in a 4:1 mixture of ethanol (17 mL) and hydrazine hydrate (4.5 mL) was heated to 60° C. and to it was added a ¼ mass equivalent of 10% Palladium/Carbon (50% H2O) (135 mg). The reaction was monitored by LC/MS to ensure that complete reduction occurred, and upon completion was cooled to room temperature. The Pd/C was filtered through celite, and the resulting filtrate concentrated to a minimal volume. This was then brought up in ˜120 mL of CH2Cl2 and washed with ˜25 mL of brine to remove excess hydrazine. The organic layer was then dried with MgSO4 and concentrated to give 7-Amino-6-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a yellow gummy solid (432 mg, 93%). 1H-NMR (CDCl3) δ 6.78 (d, J=8.6 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 3.81 (br s, 2H), 3.75 (s, 3H), 3.28 (s, 3H), 2.35-2.75 (br pk, 2H), 2.30 (t, J=6.9 Hz, 2H), 2.15 (m, 2H); LC/MS (ESI-pos) m/z 221.13 (M+H).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C>C1COCC1>[C:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:47])[NH:20][CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9](=[O:8])[NH:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65])([CH3:46])([CH3:44])[CH3:45]
Reactant: NCCOCCOCCOCCOCCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)NCCOCCOCCOCCOCCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl) ester (0.56 g, 0.822 mmol) was dissolved in THF (20 mL), 3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]ethoxy}ethoxy)propionic acid (0.22 g, 0.82 mmol) in THF (20 mL) was added and the mixture stirred at RT for 3 h. LCMS indicated the reaction was finished (MS: m/z 831 (M+1)) and the reaction mixture was used directly for the following reaction with TSTU.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Br:13]Br.O>C(O)(=O)C>[Br:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc2ccccc2c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2ccccc2c1Br

Procedure:
A stirred solution of 2-methoxynaphthalene (5 g.) in acetic acid (100 ml.) is treated dropwise with a solution of 1.1 molar equivalents of bromine in acetic acid (50 ml.). Upon disappearance of the bromine color, water is added. The solid which forms is collected by filtration, washed with water until neutral, recrystallized, rewashed, and dried to yield 1-bromo-2-methoxynaphthalene.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]1[CH:72]=[CH:71][C:18]([C:19]([NH:32][C:33]2[N:41]=[CH:40][N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3[C@H:42]2[O:47][C@@H:46]([CH2:48][O:49][C:50]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[C@@H:44]([OH:45])[CH2:43]2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:92](O)(=[O:99])[C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1>O1CCCC1.CO>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:32][C:33]2[N:41]=[CH:40][N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3[C@H:42]2[O:47][C@@H:46]([CH2:48][O:49][C:50]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:51]3[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=3)[C@H:44]([O:45][C:92](=[O:99])[C:93]3[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=3)[CH2:43]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:71][CH:72]=1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](OC(=O)c3ccccc3)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of diethylazodicarboxylate (0.38 mL, 2.49 mmol) in dry tetrahydrofuran (20 mL) was added dropwise to a cooled solution (0° C.) of nucleoside 7 (0.66 g, 0.83 mmol), triphenylphosphine (0.66 g, 2.49 mmol) and benzoic acid (0.30 g, 2.49 mmol) in dry THF (20 mL). The mixture was stirred at room temperature for 18 h and methanol (1 mL) was added. The solvents were removed under reduced pressure and the crude material was purified by silica gel column chromatography (0-5% ethyl acetate in dichloromethane) to give compound 8 slightly contaminated by triphenylphosphine oxide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C)C=O>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:24])=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(O)Cn1cnc2c(N)nc3cc(CCC(=O)O)ccc3c21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c21
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (500 mg, 1.5 mmol), anhydrous N,N-dimethylformamide (25 mL), and 1-hydroxybenzotriazole (250 mg, 1.8 mmol) were combined and the reaction was stirred for 15 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (350 mg, 1.8 mmol) was added and the reaction mixture was stirred for an additional 30 minutes. Morpholine (400 mg, 2.3 mmol) was added to the reaction slurry. After five hours 1-hydroxybenzotriazole (250 mg, 1.8 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (350 mg, 1.8 mmol), and morpholine (400 mg, 2.3 mmol) were added and the mixture was heated at 70° C. for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure and the residue was partitioned between chloroform (100 ml) and 1% aqueous sodium carbonate (50 mL). The fractions were separated and organic fraction was washed 1% aqueous sodium carbonate (2×50 mL). The combined aqueous fractions were back extracted with chloroform (50 mL). The combined organic fractions were dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-5% CMA over 75 mL, 5-35% over 1500 mL, and 35% for 600 mL) followed by recrystallization from acetonitrile to provide 335 mg of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-1-(morpholin-4-yl)propan-1-one as an off-white solid, mp 217-218° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]=[O:27])=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:28][Mg]Br>C1COCC1.[Cl-].[NH4+]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]([OH:27])[CH3:28])=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CCc1c(C=O)nc2c(cnn2CC)c1-c1cncc(C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(C(C)O)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (42 mg) in THF (1 ml) was added 0.93M methylmagnesium bromide in THF (0.18 ml) at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour. Another 0.93M methylmagnesium bromide in THF (0.18 ml) was added at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (3:1) to give ethyl 3-[1-ethyl-6-(1-hydroxyethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (34 mg) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:5].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH3:10][O:9][C:7](=[O:8])[CH:6]([C:4](=[O:5])[CH3:3])[C:18](=[O:19])[CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C(C(C)=O)C(=O)Cc1ccccc1
Reaction time: 14 h

Procedure:
NaOH (10 N, 4.4 mL, 44 mmol) in H2O is added to a solution of MeCOCH2COOMe (5 g, 43.1 mmol) in THE at RT. PhCH2COCl is added dropwise to the mixture and the mixture is stirred for 14 h. The mixture is extracted with EtOAc (2×30 mL). The organic phase is dried. The product is purified by silica gel column chromatography using 3-5% EtOAc in hexane to afford the title compound.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][OH:20])=[CH:14][CH:15]=2)[O:10][C:9]([C:21]2[N:22]=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8]1)(C)(C)C.Br[CH2:32][CH2:33][O:34][CH3:35]>>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:21]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:17]#[C:18][CH2:19][O:20][CH2:32][CH2:33][O:34][CH3:35])[CH:12]=3)[N:22]=1
Reactant: COCCBr
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#CCO)ccc12
Product: COCCOCC#Cc1ccc2c(=NO)cc(-c3cc4ccccc4cn3)oc2c1

Procedure:
2-Isoquinolin-3-yl-7-[3-(2-methoxy-ethoxy)-prop-1-ynyl]-chromen-4-one oxime was prepared in 7% overall yield using the methods described in examples 42 and 42A, starting from 7-(3-hydroxy-prop-1-ynyl)-2-Isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 54A) and bromoethylmethylether. The title compound was isolated as a beige solid and as a 90/10 mixture of Z/E oxime isomers after triturating in diethyl ether.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])OC3C=CC=CC=3)=[CH:21][CH:20]=2)[N:9]=1.C(N(CC)CC)C.[NH2:42][CH:43]([CH3:46])[CH2:44][OH:45]>CN(C=O)C>[OH:45][CH2:44][CH:43]([NH:42][C:26](=[O:34])[NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[N:9]=[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:11]=2)=[CH:24][CH:23]=1)[CH3:46]
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: CC(N)CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CO)NC(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
A solution of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamate (110 mg, 0.23 mmol) and triethylamine (0.079 mL, 0.68 mmol) in DMF (2 mL) was added to 2-aminopropan-1-ol (1.14 mmol). The reaction was stirred at 40° C. for 2 hours then purified by prep-HPLC (basic) to give the desired material as a solid (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CNCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A solution of 3-Benzyl-imidazolidine-1,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester (1.0 g, 3.12 mmol) in MeOH (20 mL) was added Pd/C (0.20 g) and stirred at room temperature under H2 for two hours. The reaction mixture was filtered through celite. The filtrate was concentrated to afford Imidazolidine-1,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester (0.72 g, xx % yield) which was used for the next step directly.
Reaction SMILES: Br[C:2]1[S:30][C:5]2[C:6](=[O:29])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([O:27][CH3:28])[CH:11]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1.CCO.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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.O>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[S:30][C:5]3[C:6](=[O:29])[N:7]([C:10]4[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([O:27][CH3:28])[CH:11]=4)[CH2:8][CH2:9][C:4]=3[CH:3]=2)=[CH:37][CH:36]=1
Reactant: COc1cc(N2CCc3cc(Br)sc3C2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
Dissolve 2-bromo-6-(3-methoxy-4-triisopropylsilanyloxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (2.87 g, 5.46 mmol) in dimethoxyethane (28 mL) followed by addition of EtOH (4 mL) and water (8 mL). Add 4-chlorophenylboronic acid (1.28 g, 8.19 mmol) followed by 2M Na2CO3 (4 mL, 8.19 mmol). Allow dry argon gas to bubble through the reaction mixture for 15-20 min. Add Pd(PPh3)4 (315 mg, 0.27 mmol) and then warm to 90° C. under an argon atmosphere. After 3 h, filter the reaction through Celite® and elute with CH2Cl2. Concentrate and purify via silica gel chromatography using a 0-25% gradient of EtOAc/hexanes to give 2.37 g (80% yield) of the desired product. MS/ES m/z (35Cl) 542.1 [M+H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[C:48]1[CH:53]=[C:52]([O:54][C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])[CH:51]=[CH:50][N:49]=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:58][C:57]1[CH:59]=[CH:60][CH:61]=[C:55]([O:54][C:52]2[CH:51]=[CH:50][N:49]=[C:48]([C:44]3[NH:43][CH:47]=[CH:46][CH:45]=3)[CH:53]=2)[CH:56]=1)=[O:9]
Reactant: Cc1ccoc1C(=O)O
Reactant: Nc1cccc(Oc2ccnc(-c3ccc[nH]3)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3ccc[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methyl-2-furoic acid (60 mg, 0.48 mmol), HBTU (198 mg, 0.52 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of 3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}aniline (100 mg, 0.40 mmol). The mixture was stirred at 70° C. for 3 hours and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3-5% MeOH/CHCl3 to give 3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide as white solid. Yield: 52 mg, 36%.