Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH3:11])[CH2:3][CH2:4][CH2:5][C:6](=[O:9])[CH:7]=[CH2:8].[C:12]1([CH:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[C:12]1([CH:18]([NH:20][CH2:11][CH2:10][C:2]2([OH:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH2:7][CH3:8])[O:9]2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC(=O)CCCC(O)CC
Reactant: CC(N)c1ccccc1
Solvent: CCCCCC
Product: CCC1CCCC(O)(CCNC(C)c2ccccc2)O1

Procedure:
A solution of racemic 7-hydroxy-1-nonen-3-one [21.3 g.; crude obtained as in Example 1(d)] in hexane (200 ml.) was treated for 15 hours at 25°C. with a solution of (-)-α-phenylethylamine (11.5 g.) in hexane (115 ml.). The reaction mixture was then purified by chromatography on alumina (660 g.). Elution with hexane first gave unpolar by-products. Hexane-ether-(4:1)-, (1:1), and straight ether then eluted 2-[2-(1-phenylethylamino)-ethyl]-6-ethyl-2-tetrahydropyranol obtained in solid form after evaporation of the solvents.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5]>C(Cl)(=O)C1C=CC=CC=1>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][CH:3]([NH:2][C:7](=[O:6])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[O:5])=[CH:18]1
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Agent: Cl
Solvent: O=C(Cl)c1ccccc1
Product: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NC(=O)c2ccccc2)c1

Procedure:
Following the method of Example 4b), benzoyl chloride (500 μL) and 3,5-dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride (500 mg) gave the title compound after chromatography on silica using ethyl acetate/petroleum ether (3:2) (0.21 g), m.p. 133°-134° C. 1H NMR (360 MHz, CDCl3) δ8.10 (1H, s), 7.67 (1H, d, J=7 Hz), 7.53 (1H, d, J=7 Hz), 7.49-7.25 (4H, m), 7.17 (1H, t, J=7 Hz), 7.05 (1H, t, J=7 Hz), 6.97 (1H, s), 6.89 (2H, s), 6.82 (1H, d, J=2 Hz), 6.68 (1H, d, J=8 Hz), 5.18 (1H, m), 5.06 (2H, s), 3.45 (2H, m), 2.3 (6H, s). Found: C, 75.24; H, 6.20; N, 6.50; C27H26N2O3. 0.25(H2O) requires C, 74.90; H, 6.22; N, 6.51%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].N1C=CC=CC=1.Cl[C:43]([O:45][CH3:46])=[O:44].Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH:21][C:43](=[O:44])[O:45][CH3:46])(=[O:19])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: COC(=O)Cl
Reactant: NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 39.8 %

Procedure:
7-(2-Chlorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.070 g, 0.137 mmol) obtained in Example 6 step 5 was dissolved in dichloromethane (0.7 mL), and the solution was cooled to 0° C. Pyridine (0.325 g, 4.110 mmol) and methyl chloroformate (0.350 g, 3.699 mmol) were added, the mixture was stirred at room temperature for 48 hr, and 1 mol/L hydrochloric acid was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=99/1) to give the title compound (0.031 g, 40%).
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)(C)C.Cl>CO>[C:13]1([C:12]2[N:8]([NH2:7])[C:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nn1c(-c2ccccc2)ccc1-c1ccccc1
Agent: Cl
Solvent: CO
Product: Nn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
A suspension of (2,5-Diphenyl-pyrrol-1-yl)-carbamic acid tert-butyl ester (3.7 g, 11.06 mmol) in anhydrous methanol (25 mL) was cooled to 0° C. in an ice water bath, then treated with conc. HCl (9.86 mL). The ice bath was removed, and the resulting suspension was heated to reflux in an oil bath for 1.5 h. Upon cooling to rt, a white solid precipitated, which was filtered, washed with water and dried in vacuo to afford 2,5-Diphenyl-pyrrol-1-ylamine (2.32 g, 90%): 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 3.64 (bs, 2H), 6.28 (s, 2H), 7.28-7.33 (m, 2H), 7.42 (t, 4H, J=8.0 Hz), 7.58 (d, 4H, J=8.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.Br[C:20]1[C:21]([CH3:39])=[C:22]([NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[CH:23]=[CH:24][CH:25]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:9][C:8]1[CH:7]=[C:6]([C:20]2[C:21]([CH3:39])=[C:22]([NH:26][C:27](=[O:38])[C:28]3[CH:29]=[CH:30][C:31]([C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:32][CH:33]=3)[CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: Cc1c(Br)cccc1NC(=O)c1ccc(C(C)(C)C)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: COCCOC
Product: COc1ncc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cc1N
Temperature: 95 °C
Yield: 64.2 %

Procedure:
A 48-mL seal tube equipped with a magnetic stirring bar was charged with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (5) (1.0 g, 4.0 mmol), N-(3-bromo-2-methylphenyl)-4-tert-butylbenzamide (1.8 g, 5.0 mmol), and tetrakis(triphenylphosphine)palladium (0.20 g, 0.20 mmol) in DME (10 mL) and 1 N sodium carbonate (10 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (20 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10%, MeOH in dichloromethane, to afford 1.0 g (64%) of N-(3-(5-amino-6-methoxypyridin-3-yl)-2-methylphenyl)-4-tert-butylbenzamide (6) as a solid.
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:10]=[C:9]([Cl:19])[CH:8]=1.C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[Br:1][C:2]1[CH2:14][C:13]([C:11]2[CH:10]=[C:9]([Cl:19])[CH:8]=[C:7]([Cl:6])[CH:12]=2)([C:15]([F:16])([F:18])[F:17])[O:4][N:3]=1
Reactant: ON=C(Br)Br
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(Br)=NO1
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.7 %

Procedure:
To a solution of dibromoformaldoxime (6.23 g, Tetrahedron Lett., 1984, 487) in ethyl acetate (150 ml) was added 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (6.3 g, prepared according to WO 2005/085216) and sodium bicarbonate (9.5 g). The reaction was stirred at room temperature for 96 h. Water was added, then the two layers were then separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated to afford a white solid (6.23 g). 1H-NMR (CDCl3, 400 MHz): 7.47-7.43 (m, 3H), 3.95 (d, 1H), 3.58 (d, 1H)
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19]C([O-])=O>O1CCCC1>[O:16]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][N:12]=1)[CH2:19][C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C(O)c1ccc(Oc2ccccc2)cn1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(Oc2ccccc2)cn1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-phenoxypyridine-2-carboxylic acid (10 g, 46.5 mmol) in tetrahydrofuran (150 ml) was added N,N′-carbonyldiimidazole (8.29. g, 51.1 mmol), and the mixture was heated under reflux for 1 hr. After cooling the reaction solution to room temperature, monobenzyl malonate magnesium salt (10.5 g, 25.6 mmol) was added, and the mixture was heated under reflux for 2 hrs. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective substance (11.2 g, 76%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH2:19])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.P(OC)(OC)OC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1cncc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COP(OC)OC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C=Cc1cncc2ccccc12
Temperature: 120 °C

Procedure:
To a mixture of 3 g of 4-bromoisoquinoline, 6.2 mL of acrylic acid tert.-butyl ester and 2.66 mL of DIPEA in 30 mL of DMF under argon was added 0.169 mL of P(OMe)3 and 160 mg of Pd(OAc)2. The reaction mixture was heated for 2 h at 120° C. and the DMF was evaporated under vacuo. The resulting residue was diluted with DCM and filtered over a pad of silica gel. The filtrate was washed with 10%-citric acid, water and brine. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 94/6 to 50/50 as eluant to yield 2.7 g of 3-isoquinolin-4-yl-acrylic acid tert.-butyl ester as a yellow solid.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:30][C:29]([CH2:28][C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)=[N:31][C:11]=3[C:10]=2[CH:13]=1
Reactant: COc1ccc(CC(=N)N)cc1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2cc(F)ccc2NC(=O)C3)cc1

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:26])[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)=[O:17])[CH2:9][O:10][CH2:11][O:12][CH2:13][CH3:14])[CH:2]=[CH2:3].CN1CCN(C)C1=O.[CH3:35][O:36][CH2:37]Cl>O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>[CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([CH2:35][O:36][CH3:37])[CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)=[O:17])[CH2:9][O:10][CH2:11][O:12][CH2:13][CH3:14])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)CC[C@@H](COCOCC)NC(=O)c1ccc(C#N)cc1
Reactant: COCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: C=CCOC(=O)[C@@H](COC)C[C@@H](COCOCC)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound prepared in Example 4 (1.87 g) and 1,3-dimethyl-2-imidazolidinone (1.7 ml) in tetrahydrofuran (THF; 20 ml), 1M lithium bis(trimethylsilyl)amide (11.4 ml; in THF) was dropped at −78° C., and then the mixture was stirred for 30 minutes at same temperature. Methoxymethyl chloride (1.2 ml) was added to the reaction mixture, and the mixture was stirred for 3 hours. The reaction mixture was diluted with a saturated aqueous solution of ammonium chloride, and warmed to room temperature, and then the solution was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (toluene:ethyl acetate=2:1) to give the title compound (1.45 g) having the following physical data.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O.C(OC(=O)C)(=O)C.C(OCC)(=O)C.CCCCCC.S(=O)(=O)(O)[O-].[K+]>N1C=CC=CC=1.O.CCOCC.CO>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH:11]=[CH:10]1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 3 h

Procedure:
To a solution of PGE2, 1,15-lactone (350 mg) in 10 ml of dry pyridine was added 4 ml of acetic anhydride. The solution was allowed to stand at 25° for 3 hours. TLC analysis (25% ethyl acetate/hexane) showed no starting material, only a single, less polar spot. The reaction mixture was cooled in an ice bath and treated dropwise over 15 min. with 20 ml of methanol. The temperature was allowed to rise to 25° over about 2 hours. After an additional 18 hrs. at 25° , the reaction mixture of ice, ether, water, and 70 ml of 2N aqueous potassium bisulfate and extracted thoroughly with ether. The combined extracts were washed with water, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford PGA2, 1,15-lactone as a residue.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH2:14][S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(O)=O>C1COCC1.CO.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(OCCCl)c1CS(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(OCCCl)c1CS(=O)(=O)c1cccc2ccccc12
Reaction time: 20 h
Yield: 93.8 %

Procedure:
A mixture of 1-[2-(2-Chloro-ethoxy)-6-nitro-phenylmethanesulfonyl]-naphthalene (0.9 g, 2.24 mmoles) and 10% Pd/C in THF (10 mL), methanol (10 mL), and formic acid (2 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off-white solid (0.78 g, 2.1 mmoles).
Reaction SMILES: [N:1]1([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:23][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[CH2:2][CH2:3]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(Br)ccc32)CC1
Reaction time: 3.5 h
Yield: 99.2 %

Procedure:
A solution of compound 2 (2.0 g, 6.61 mmol) in dry DMF (10 mL) was treated with N-bromosuccinimide (1.17 g, 6.61 mmol) in DMF (10 mL) at 0° C. over a period of 30 min. The reaction was stirred at same temperature for 3.5 h. The reaction was diluted with water (200 mL) and product was extracted into ethyl acetate (3×25 mL). The combined ethyl acetate layer was washed with water (2×50 mL), brine (25 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (ethyl acetate:hexanes, 1:4) to obtain compound 3 (2.5 g, 99%) as a syrup. 1H NMR (CDCl3) δ 7.13-7.10 (m, 2H), 6.27 (d, 1H, J=9.0 Hz), 4.28-4.20 (m, 2H), 3.50-3.40 (m, 1H), 3.35 (t, 2H, J=8.4 Hz), 2.93 (t, 2H, J=8.4 Hz), 2.75 (t, 2H, J=12.9 Hz), 1.78-1.72 (m, 2H), 1.60-1.49 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %) 381, 383 (MH+, 3), 325, 327 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].C([O-])(=O)C.[NH4+]>C(O)(=O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:14]/[N+:11]([O-:13])=[O:12])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1cc(F)cc(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cc(F)cc(Cl)c1
Yield: 58.5 %

Procedure:
Dissolve 3-chloro-5-fluorobenzaldehyde (4.0 g, 25.2 mmol) in glacial acetic acid (15 mL). Add nitromethane (4.1 mL, 75.7 mmol) and ammonium acetate (1.94 g, 25.2 mmol) and heat to reflux for 4 hours. Cool and pour over ice. Dilute with 2 N sodium hydroxide and extract with ethyl acetate, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes) to give the desired compound as a beige solid (2.97 g, 58%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C@H:13]([CH2:17]O)[CH:14]([CH3:16])[CH3:15]>ClC1C=CC=CC=1>[CH:14]([C@H:13]1[CH2:17][O:11][C:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:12]1)([CH3:16])[CH3:15]
Reactant: O=C(O)CCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(CCc2ccccc2)=N1
Yield: 86 %

Procedure:
Under an argon atmosphere, a mixture of 3-phenylpropionic acid (3.0 mmol), (L)-valinol (3.6 mmol), Zn4(OCOCF3)6O (0.15 mmol) and chlorobenzene (5 mL) was heated under reflux for 12 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (V/V)) to give (S)-4-isopropyl-2-(2-phenylethyl)-1,3-oxazoline in 86% yield.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[C:5]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][C:3]=1[OH:25].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[Br:1][C:2]1[C:3]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:4][C:5]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])=[C:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12])[C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)c(Br)c(Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1Br
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a mixture of 0.042 g (0.090 mmol) of 17, 0.016 g (0.11 mmol) of t-butyldimethylsilyl chloride, and 0.003 g (0.010 mmol) of DMAP in 2 mL of dichloromethane under argon at 25° C. was added 0.05 mL (0.260 mmol) of triethylamine. The reaction mixture was stirred for 3 h, diluted with 30 mL of water, and extracted three times with diethyl ether (30 mL each). The combined ether extracts were with 30 mL of brine, dried (MgSO4), and concentrated to give 0.051 g (99% yield) of 4.
Reaction SMILES: C1([O:6][C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][C:15]=4[C:11]=3[C:10]([CH:21]=[O:22])=[CH:9][CH:8]=2)CCCC1.[OH-].[Na+]>Br.O>[OH:6][C:7]1[C:12]2[O:13][C:14]3[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][C:15]=3[C:11]=2[C:10]([CH:21]=[O:22])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OC2CCCC2)c2oc3cc[n+]([O-])cc3c12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc(O)c2oc3cc[n+]([O-])cc3c12
Temperature: 75 °C
Yield: 80 %

Procedure:
A well stirred suspension of 6-(cyclopentyloxy)[1]benzofuro[3,2-c]pyridine-9-carbaldehyde 2-oxide (200 mg, 0.671 mmol) in 48% aqueous hydrobromic acid (10 mL) was heated to 70-80° C. for 2-3 hours. The reaction mixture was cooled to room temperature and diluted with water (50 mL) and was made alkaline (pH=9-10) by means of a 10% aqueous solution of sodium hydroxide. It was then washed with ethyl acetate (2×25 mL). The aqueous layer was then acidified with acetic acid (pH=4-5) and stirred at 10-15° C. for 30-40 minutes. The solid obtained was filtered and dried to afford 6-hydroxy[1]benzofuro[3,2-c]pyridine-9-carbaldehyde-2-oxide (Yield=80-90%).
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15](=O)[CH2:16][C:17](=O)[CH2:18][CH3:19])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][NH2:24].O>CO>[CH:1]1([C:5]2[C:14]([C:15]3[CH:16]=[C:17]([CH2:18][CH3:19])[NH:24][N:23]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: CCC(=O)CC(=O)c1cc(C(=O)OC)c(C)cc1C1CCC1
Solvent: CO
Solvent: O
Product: CCc1cc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)n[nH]1
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a solution of methyl 4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate (compound 445.1, 300 mg, 0.990 mmol, 1.00 equiv) in methanol (15 mL) was added NH2NH2.H2O. The resulting solution was stiffed for 1.5 h at 80° C. in an oil bath, and then concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate, then washed with 3×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to yield 188 mg (64%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]3[C:25]=2[C:24](SC)=[N:23][CH:22]=[N:21]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][C:46]=1[F:47])[NH2:43]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]3[C:25]=2[C:24]([NH:43][C:42]2[CH:44]=[CH:45][C:46]([F:47])=[C:40]([Cl:39])[CH:41]=2)=[N:23][CH:22]=[N:21]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncnn2ccc(COCC3CN(C(=O)OC(C)(C)C)CCO3)c12
Reactant: Nc1ccc(F)c(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(COCc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A solution of 2-(4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, 0.15 mmol) in CH2Cl2 (3 mL) was cooled to 0 C and treated with a solution of mCPBA (56 mg, 0.32 mmol) in CH2Cl2 (2 mL). The reaction was stirred for 15 minutes at 0 C then warmed to room temperature. To this solution was added 3-chloro-4-fluoroaniline and stirred at room temperature for one hour. The resulting orange solution was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3, then saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. Preparative reverse-phase HPLC afforded the desired compound (30 mg, 41%). HPLC tR=4.383 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol, 4 min gradient, monitored at 220 nm). LC/MS (M+H)=492.