Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH2:13][CH:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7][C@@H:6]3[CH2:27][O:28][CH2:29][CH2:30][N:5]3[C:4]=2[N:3]=1.[NH:31]1[C:39]2[C:34](=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[NH:31]1[C:39]2[C:34](=[C:35]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][CH2:13][CH:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7][C@@H:6]5[CH2:27][O:28][CH2:29][CH2:30][N:5]5[C:4]=4[N:3]=3)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1
Reactant: CC(C)(C)OC(=O)NC(CCN1C[C@@H]2COCCN2c2nc(Cl)ncc21)C(C)(C)C
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(CCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21)C(C)(C)C

Procedure:
The title compound was prepared in a manner similar to Example 2 using tert-butyl (1-((R)-2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-4,4-dimethylpentan-3-yl)carbamate (PREPARATION x77, 53 mg, 0.120 mmol), 1H-indol-4-ylboronic acid (38.8 mg, 0.241 mmol) and PdCl2(dppf) (4.41 mg, 0.006 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL) (19 mg, 30%). ESI-MS m/z [M+H]+ calc'd for C29H40N6O3, 521.32. found 521.5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCOCCO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OCCOCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 50 g (475.56 mmol) of 2-(2-amino-ethoxy)ethanol and 144.6 g (1.046 mol) of potassium carbonate in 600 ml of EtOH/60 ml of water is heated to 60° C. To this mixture is added dropwise within one hour 178.95 g (1.046 mol) of benzyl bromide and then the mixture is refluxed for 2 hours, evaporated under vacuum, the residue taken up with 1 liter of methylene chloride, and filtered off from the salts. The filtrate is concentrated under vacuum and purified by flash chromatography (silica gel/mobile phase: methylene chloride/hexane/acetone: 10/5/1).
Reaction SMILES: [C:1]1(CO)CCCCC=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16]([CH2:19][OH:20])=[CH:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[O:9]1[CH2:10][CH2:11][O:12][C:13]21[CH2:18][CH2:17][C:16]1([CH2:19][OH:20])[CH:15]([CH2:1]1)[CH2:14]2
Reactant: OCC1=CCCCC1
Reactant: OCC1=CCC2(CC1)OCCO2
Product: OCC12CCC3(CC1C2)OCCO3

Procedure:
Following the procedure as described in Example 342 Step 2 and making non-critical variations to replace cyclohexenylmethanol with 1,4-dioxaspiro[4.5]dec-7-en-8-ylmethanol, the title compound was obtained as a colourless liquid (4.0 g, 96%): 1H NMR (300 MHz, CDCl3) δ 3.92-3.84 (m, 4H), 3.48 (d, J=10.8 Hz, 1H), 3.26 (d, J=10.9 Hz, 1H), 2.21-2.0 (m, 2H), 1.94-1.86 (m 1H), 1.77-1.65 (m, 1H), 1.60-1.51 (m, 1H), 1.40-1.30 (m, 1H), 0.58 (dd, J=9.2, 4.8 Hz, 1H), 0.40 (t, J=5.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:12])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: Nc1ccccc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(=O)Nc2ccccc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 86 %

Procedure:
To 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 0.98 mmol) in 5 mL of dry tetrahydrofuran is added oxalyl chloride (0.10 mL, 1.18 mmol) followed by dimethylformamide (0.02 mL). The solution is stirred at room temperature for 1.75 hours, then aniline (0.54 mL, 5.88 mmol) is added. The solution is stirred at room temperature overnight then partitioned between ethyl acetate and 1N HCl . The organic layer is washed with saturated aqueous NaHCO3, followed by brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 3:1 hexane:ethyl acetate to provide 5-chloro-3-(1-methylethoxy)-N-phenyl-2-benzofurancarboxamide, 86% yield; mp=147°-149° C.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[C:48]#[N:49]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=3)[C:48]#[N:49])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1cccc(N)c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cccc(C#N)c3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 3-amino-benzonitrile according to procedure B followed by deprotection yielded the title compound as a pale yellow foam. MS (ESI): m/z=380.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:15])=[C:6]([O:12][CH2:13][CH3:14])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:13]([O:12][C:6]1[CH:7]=[C:8]([CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[O:15][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([O:17][CH3:16])[CH:19]=1)[CH:9]=[O:10])[CH3:14]
Reactant: COc1cccc(CBr)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1OCc1cccc(OC)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-nitro-3-ethoxy-4-hydroxybenzaldehyde (100 mg), 3-methoxybenzyl bromide (73 μl), potassium carbonate (144 mg) and tetrabutylammonium iodide (10 mg) in DMF (5 ml) was stirred at 60° C. for 90 min. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 2/1 (v/v) as eluent.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:20](/[CH:19]=[CH:18]/[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[F:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccccc3F)nc2n(CC)c1=O
Yield: 40.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.70 g (13.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.49 g (15.0 mmol) of 2-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.81 g (yield 41%) of Compound 160 as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.C[O-].[Na+].Cl>CO>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=[CH:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: O=Cc1ccco1
Reactant: COc1ccc(C(C)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2ccco2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.3 %

Procedure:
To a solution of 1-(4-methoxyphenyl)ethanone (17.0 g, 113.0 mmol) in methanol (240 mL) was added a solution of 2-furaldehyde (12.0 g, 125.0 mmol) in methanol (240 mL) followed by the addition of sodium methoxide (6.10 g, 113.0 mmol). The reaction mixture was stirred at room temperature for 24 h, and then was neutralized with HCl aq. (6.0 M, 18.8 mL). The volatile was removed in vacuum. The residue was dissolved in ethyl acetate (500 mL), washed with water (250 mL) and brine (250 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=5:1˜3:1) to afford 3-(furan-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (25B) as a yellow solid (23.80 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH2:14])=[O:13].C[O:16][C:17](=O)[C:18](=O)[C:19]1[CH:20]=[C:21]2[C:26]3=[C:27]([CH2:29][CH2:30][N:25]3[CH2:24][CH2:23][CH2:22]2)[CH:28]=1.CC(C)([O-])C.[K+].N1CCCCC1.C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12](=[O:13])[NH:14][C:17](=[O:16])[C:18]=1[C:19]1[CH:20]=[C:21]2[C:26]3=[C:27]([CH2:29][CH2:30][N:25]3[CH2:24][CH2:23][CH2:22]2)[CH:28]=1
Reactant: COC(=O)C(=O)c1cc2c3c(c1)CCN3CCC2
Reactant: NC(=O)Cc1c[nH]c2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(c2c[nH]c3ccc(Br)cc23)=C1c1cc2c3c(c1)CCN3CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of 2-(5-bromo-1H-indol-3-yl)-acetamide (500 mg, 1.98 mmol) and oxo-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-acetic acid methyl ester (404 mg, 1.65 mmol) in anhydrous tetrahydrofuran at 0° C. was added a solution of potassium tert-butoxide (4.95 ml, 4.95 mmol; 1M solution in tetrahydrofuran) dropwise over 5 minutes. The reaction was stirred for a further 30 minutes then cooled to 0° C. and quenched with water (50 ml) and acidified to pH6 with aqueous 2M hydrochloric acid. The mixture was extracted with dichloromethane (3×50 ml) and the combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in N,N-dimethylformamide (4 ml) and treated with piperidine (99 μl, 1.00 mmol) and acetic acid (57 μl, 1.00 mmol). The mixture was heated to 150° C. for 5 minutes under microwave conditions then partitioned between ethyl acetate (50 ml) and water (30 ml). The aqueous layer was removed and the organic layer was washed with water (2×30 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (SiO2, 1% methanol to 10% methanol in dichloromethane) to provide 3-(5-bromo-1H-indol-3-yl)-4-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrole-2,5-dione as a red solid (340 mg). 400 MHz 1H NMR (CDCl3) δ: 8.71 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.27 (m, 2H), 7.08 (s, 1H), 6.94 (s, 1H), 6.56 (s, 1H), 3.36 (t, J=8.0 Hz, 2H), 3.07 (m, 2H), 3.83 (t, J=8.0 Hz, 2H), 2.47 (t, J=6.8 Hz, 2H), 2.04 (m, 2H); LCMS: 448 and 450 [M+H].
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:9]=2)C(C)=CC=1.Cl.NO.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(O)C.O>[NH2:3][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:9]=1
Reactant: Cc1cc(-n2c(C)ccc2C)nc(CCCCCCCCCCOCc2ccccc2)c1OCc1ccccc1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1cc(N)nc(CCCCCCCCCCOCc2ccccc2)c1OCc1ccccc1

Procedure:
To stirred solution containing 1.22 g (2.26 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-benzyloxy-4-methyl-6-(10-benzyloxydecyl)-pyridine (17) in 40 mL of ethanol-water 4:1 were added 5.44 g (90.40 mmol) of hydroxylamine hydrochloride followed by 6.00 mL (45.20 mmol) of triethylamine. The reaction mixture was then stirred at reflux under argon atmosphere overnight. The reaction mixture was then poured into 100 mL of saturated aqueous NaHCO3 and extracted with two portions of 100 mL of dichloromethane. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with dichloromethane-methanol 9:1 gave the expected product as a yellowish oil: yield 722 mg (69%). 1H-NMR (CDCl3) δ 7.38-7.24 (m, 10H), 6.24 (s, 1H), 4.72 (s, 2H), 4.48 (s, 2H), 3.44 (t, 2H, J=8.0), 2.63 (t, 2H, J=8.0), 2.19 (s, 3H), 2.04 (s, 3H), 1.63-1.53 (m, 4H), 1.27 (m, 12H); 13C-NMR (CDCl3) δ 176.95, 153.85, 149.42, 146.90, 143.66, 138.66, 136.73, 128.62, 128.30, 127.77, 127.61, 127.44, 109.71, 75.86, 72.81, 70.50, 29.73, 29.58, 29.55, 29.52, 29.44, 29.42, 29.26, 26.16, 22.14, 16.73.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([OH:19])[CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([O:19][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1
Product: CC(C)c1cc(OCc2ccc(C(F)(F)F)cc2)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 6-isopropyl-2-(3-nitro-phenyl)-pyrimidin-4-ol (which was obtained in Intermediate 8) and 4-(trifluoromethyl)benzyl bromide according to Method A; 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (d, J=6.8 Hz, 6H), 3.00-3.10 (m, 1H), 5.69 (s, 2H), 6.95 (s, 1H), 7.75-7.85 (m, 4H), 7.84 (t, J=8.1 Hz, 1H), 8.38 (t, J=8.1 Hz, 1H), 8.80 (d, J=7.8 Hz, 1H), 9.08 (s, 1H); LC retention 4.18 min; MS: m/z (ESI) 418 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:13]=[N+:14]=[N-:15].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[NH:15][N:14]=[N:13][N:6]=1
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccccc1-c1nnn[nH]1
Temperature: 110 °C

Procedure:
A vigorously stirred suspension of 2-(trifluoromethyl)benzonitrile (2-A) (6.34 g, 37 mmol), sodium azide (4.81 g, 74 mmol) and triethylamine hydrochloride (10.19 g, 74 mmol) in toluene (70 mL) was heated at 110° C. for 48 h. The mixture was cooled and extracted twice with water. The combined extracts were washed with hexane and brought to pH about 1 with concentrated HCl. The precipitate which formed was filtered, washed with water and dried to give 5-[2-(trifluoromethyl)phenyl]-1H-tetrazole (2-B).
Reaction SMILES: C(O[C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])=[O:5])C.[OH-].[Na+].[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH2:34])[CH2:29][O:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C.CO>[CH3:26][C:27]1([CH3:35])[O:31][C@@H:30]([CH2:32][O:33][NH:34][C:4]([C:6]2[S:14][C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[C:7]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[O:5])[CH2:29][O:28]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: CCOC(=O)c1sc2ccncc2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)OC[C@H](CONC(=O)c2sc3ccncc3c2Nc2ccc(Br)cc2F)O1
Temperature: 65 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of 3-(4-bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (36 mg, 0.09 mmol), 1N aqueous NaOH solution (0.10 ml, 0.10 mmol) and methanol (2 ml) was heated at 65° C. for 45 minutes. The reaction mixture was concentrated in vacuo then azeotroped with toluene (2×2 ml) to give a solid residue. The solid residue was dissolved in anhydrous THF (2 ml) and O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (22 mg, 0.18 mmol), EDCI (22 mg, 0.12 mmol), HOBt (17 mg, 0.13 mmol) and DIPEA (48 μl, 0.28 mmol) were added. After stirring overnight at ambient temperature, the reaction mixture was concentrated in vacuo to afford a yellow residue. The resultant residue was dissolved in ethyl acetate (30 ml), washed with water (20 ml) followed by brine (10 ml) before the organic layer was isolated then dried over sodium sulfate and concentrated in vacuo to afford a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane:ethyl acetate, gradient 90:10 to 50:50) to afford the title compound as a yellow oil (18 mg, 41%). LCMS (method B): RT=3.03 min, M+H+=496/498.
Reaction SMILES: [CH:1]([C:4]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[O:25])=[CH:17][CH:16]=2)[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)(C)[CH3:2].[C:37](Cl)(=O)[CH2:38]CCC>>[CH2:1]([C:4]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24]([NH:26][S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)(=[O:29])=[O:28])=[O:25])=[CH:17][CH:16]=2)[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH2:2][CH2:37][CH3:38]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(C(C)C)nc4c(C)cc(C)nc43)cc2)cc1
Reactant: CCCCC(=O)Cl
Product: CCCCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 9) and pentanoyl chloride.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=2[OH:19])=[N:7][C:6]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CO>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([OH:19])=[C:12]([CH:17]=1)[C:11]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]([OH:27])=[O:2])=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1)=[O:20]
Reactant: COC(=O)Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
{2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid methyl ester (75 mg, 0.17 mmol) was dissolved in methanol (5 mL). 2 N sodium hydroxide (0.5 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-ethyl acetate under heating at reflux to give the title compound (56 mg, 77.3%) as a light yellow white crystal.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][Si](C(C)(C)C)(C)C)=[C:13]([O:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[F-].C([NH3+])CCC>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:20])=[C:13]([O:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CN(C(=O)OC(C)(C)C)CC2
Agent: CCCC[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1O)CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C

Procedure:
A 6.0 g portion of 3,4-dihydro-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-methoxy-2(1H)-isoquinolinecarboxylic acid-1,1-dimethylethyl ester is dissolved in 30 mL tetrahydrofuran and cooled to 0° C. To this is added 22.8 mL of a 1.0M solution of tetra, butylammonium fluoride, while stirring. The reaction mixture is brought to room temperature, and stirred for three hours. The reaction is quenched with 10 mL saturated sodium bicarbonate solution and 10 mL water, followed by the addition of 20 mL diethyl ether. After separating the layers, the aqueous phase is extracted with 2×20 mL diethyl ether. The combined organic layers are washed with 20 mL brine, and dried over magnesium sulfate. Following removal of the solvent, the product is purified by silica gel chromatography (eluting with 2:1 hexane/ethyl acetate) to produce 4.15 g of the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][CH3:15])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]1=2)[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=[O:23])C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)(Cl)Cl>[CH2:14]([C:3]1([CH2:1][CH3:2])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=[O:23])=[CH:12][C:4]1=2)[CH3:15]
Reactant: CCC1(CC)OB(O)c2ccc(C)cc21
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(CC)OB(O)c2ccc(C=O)cc21
Temperature: 25 °C
Yield: 561.5 %

Procedure:
To a solution of 3,3-diethyl-5-methylbenzo[c][1,2]oxaborol-1(3H)-ol (2.0 g, 9.8 mmol) in CCl4 (25 ml) at rt was added benzoyl peroxide (237 mg, 0.98 mmol) followed by NBS (3.489 g, 19.6 mmol). The reaction mixture was refluxed for 16 h, cooled to rt and treated with aqueous Na2CO3. The aqueous layer was acidified with 3N HCl to pH=3 and extracted with EA (50 ml×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (1.2 g, yield 56%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.30 (s, 1H), 7.85 (m, 3H), 1.86 (m, 4H), 0.55 (m, 6H). MS: m/z=219 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CCCCCCCCI
Reactant: COc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1c(C)cc(Br)cc1OC
Temperature: 85 °C
Reaction time: 19 h
Yield: 4.8 %

Procedure:
A solution of 5.89 g (27 mmol) of 1-bromo-4-hydroxy-3-methoxy-5-methylbenzene (Syn. Lett. 1997, 1351-1352) in 100 mL of acetonitrile was treated with 5.33 g (38.5 mmol) of powdered K2CO3 and 5.75 mL (31.8 mmol) of 1-iodooctane. After stirring at 85° C. for 19 h, the reaction was cooled and concentrated. The residue was dissolved in 100 mL of H2O and extracted with 100 mL of Et2O. After separating phases, the organic layer was washed with 100 mL of 10% Na2S2O3, dried over MgSO4 and concentrated. The residue was purified on a Biotage 40L column using a gradient of hexane, 99/1 v/v hexane/EtOAc and 98/2 v/v hexane/EtOAc to afford 0.43 g of the title compound as a colorless oil. Several mixed column fractions were rechromatographed to yield an additional 703 mg of the title compound. RF: 0.63 (19/1 v/v hexane/EtOAc); 1H-NMR (500 MHz) δ 0.93 (t, J=6.8, 3H), 1.33-1.39 (m, 8H), 1.46-1.52 (m, 2H), 1.75-1.81 (m, 2H), 2.27 (s, 3H), 3.85 (s, 3H), 3.91 (t, J=6.6, 2H), 6.90 (d, J=2.3, 11H), 6.95 (d, J=2.3, 11H).