Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:13])(C1C=CC=CC=1)[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C(C)(C)C.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[O:45]1CC[NH:47][C:46]1=O>O1CCCC1.C(N(CC)CC)C>[CH:2]([C@H:3]1[CH2:4][O:5][C:46](=[O:45])[NH:47]1)([CH3:13])[CH3:1]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: O=C1NCCO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CC(C)[C@H]1COC(=O)N1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,3-dimethyl-3-phenyl propionic acid (2.1 g, 12 mmol, from Reference Example 22) in anhydrous tetrahydrofuran (24 mL) is added under inert atmosphere triethylamine (2.0 mL) and the mixture is cooled to −78° C. in a dry-ice acetone bath. Pivaloyl chloride (1.5 mL, 13 mmol) is added dropwise, causing the immediate formation of a white precipitate. The reaction mixture is allowed to sit for 15 minutes at −78° C. and is then stirred at 0° C. in an ice-water bath. In a separate flask, a solution of (S)-4-isopropyl-2-oxazolidinone (1.5 g, 12 mmol) in anhydrous tetrahydrofuran (27 mL) is prepared under inert atmosphere and cooled to −35° C. in a dry-ice/acetone bath. A small amount of triphenylmethane (<5 mg) is added as an indicator of deprotonation. n-Butyllithium (1.6 M solution in hexanes, 7.7 mL, 12 mmol) is added dropwise via syringe. After 30 minutes of stirring at 0° C., the flask containing the mixed anhydride is re-cooled to −78° C. in a dry-ice/acetone bath. The solution of the lithium anion of the oxazolidinone is added to the mixed anhydride solution via cannula. The source flask is washed twice with tetrahydrofuran (4 mL×2) and these washings are also transferred via cannula to the mixed anhydride solution. The reaction mixture is stirred at −78° C. for 1 hour, 0° C. for 1 hour, and allowed to warm to room temperature overnight. The following morning, water (˜15 mL) is added and stirring is continued for 20 minutes. The aqueous phase is extracted thrice with diethyl ether. The combined extracts are washed with saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and concentrated under reduced pressure to afford (3.6 g, >100% crude) of a pale yellow oil. The crude material is purified by flash chromatography (ethyl acetate/hexanes) to afford 1.5 g (44%) of a clear, colorless oil. MS (ES+): (M+H)=290.0
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[C:14]([CH3:20])[C:13]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([OH:19])[CH3:18])=[C:14]([CH3:20])[C:13]=2[CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(C)O)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]ethanone (0.53 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (10 mL) and methanol (1 mL), and sodium borohydride (90%, 0.16 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (0.53 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C@@H:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]([CH3:25])=[CH2:24])[CH:20]=2)[C:15](=[O:26])[O:14]1>ClCCCl>[CH3:12][C@@H:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]3([CH3:25])[CH2:24][O:9]3)[CH:20]=2)[C:15](=[O:26])[O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)c1ccc2c(c1)C[C@@H](C)OC2=O
Solvent: ClCCCl
Product: C[C@@H]1Cc2cc(C3(C)CO3)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
mCPBA (774 mg, 4.49 mmol) was added to a solution of (3R)-3-methyl-6-(prop-1-en-2-yl)-3,4-dihydro-1H-isochromen-1-one (605 mg, 2.99 mmol) in DCE (15 mL). The reaction was stirred at room temp for 3 h before it was complete by TLC. The reaction was then partitioned between saturated sodium bicarbonate solution and DCM. The aq. layer was further extracted with DCM (2×75 mL) the combined organic layers were dried over magnesium sulfate, filtered, and purified via MPLC (10-50% EtOAc/Hex) to give the title compound: LC-MS: (M+H)+219;
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:13]1=[O:30].[C:31](ON1C(=O)CCC1=O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[C:31]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1.[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[C:13]1=[O:30]
Reactant: O=C(ON1C(=O)CCC1=O)c1cccnc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (200 mg) and 2,5-dioxopyrrolidinyl nicotinate (120 mg) were dissolved in DCM (20 mL). The mixture was stirred on a magnetic stirrer at room temperature. Triethylamine (1 mL) was added in one portion and the mixture was allowed to react overnight. The reaction mixture was then poured into DCM (30 mL), washed with saturated sodium bicarbonate solution three times (30 mL/wash) and brine (30 mL), dried with anhydrous magnesium sulfate, and filtered. The solvent was removed by rotary evaporation in vacuo. The crude product was purified by silica gel column chromatography (eluted with chloroform:acetone=5:2) to yield pure title compound (239 mg). 1HNMR (CDCl3, ppm) δ 9.04 (d, 1H, J=11.2 Hz), 8.72 (s, 1H), 8.13 (d, 1H, J=8.0 Hz), 7.87-7.90 (m, 2H), 7.76-7.78 (m, 2H), 7.41 (dd, 1H, J=8.0, 11.2 Hz), 6.73 (d, 1H, J=9.6 Hz), 5.86-5.98 (m, 2H), 5.05-5.08 (m, 1H), 3.00-3.15 (m, 1H), 2.80-2.95 (m, 2H), 2.12-2.28 (m, 1H), 2.10-2.20 (m, 2H), 0.97-1.05 (m, 3H), 0.85-0.88 (m, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[C:9]([CH2:15][CH3:16])[CH:8]=1>CN(C=O)C.O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[C:9]([CH2:15][CH3:16])[CH:8]=1
Reactant: CCc1cc(Br)ccc1CBr
Reactant: c1cn[nH]c1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(Br)ccc1Cn1cccn1
Temperature: 80 °C
Reaction time: 13 h
Yield: 79.6 %

Procedure:
A solution of pyrazole (616 mg, 9.1 mmol) in anhydrous DMF (30 mL) was treated with naH (60%, 362 mg). 4-Bromo-1-bromomethyl-2-ethyl-benzene (2.5 g, 9.1 mmol) was added and the resulting solution was stirred at 80° C. for 13 hours before it was cooled down to room temperature. The mixture was diluted with H2O, extracted with Et2O. The combined organic extracts were washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the desired product (1.92 g, 80% yield). 1H NMR (300 MHz, CDCl3): δ 1.15 (t, J=7.5 Hz, 3 H), 2.59–2.66 (m, 2 H), 5.30 (s, 2 H), 6.26–6.28 (m, 1 H), 6.86–6.88 (m, 1 H), 7.29–7.32 (m, 2 H), 7.37–7.38 (m, 1 H), 7.54–7.55 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.NC1(C(O)=O)CCN(C(OC(C)(C)C)=O)CC1.[Cl:35][C:36]1[C:37]([F:57])=[C:38]([NH:42][C:43]2[C:52]3[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([CH:53]=O)[CH:51]=3)[N:46]=[CH:45][N:44]=2)[CH:39]=[CH:40][CH:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[Cl:35][C:36]1[C:37]([F:57])=[C:38]([NH:42][C:43]2[C:52]3[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([CH2:53][NH:1][C:2]4([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]4)[CH:51]=3)[N:46]=[CH:45][N:44]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(N)(C(=O)O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Pharmacore, or may be prepared using analogous methodology described for the preparation of 4-Amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in J. Org. Chem. 1996, 61, 7650-7651, 0.221 g, 0.906 mmol) and molecular sieves 4 Å (ca. 200 mg) were added to a rapidly stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde (0.20 g, 0.604 mmol) in a mixture of 5% v/v acetic acid in dichloromethane (2 ml). Sodium triacetoxyborohydride (0.192 g, 0.906 mmol) was added over a period of 3 hours. The reaction mixture was concentrated, dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (1 ml). The reaction mixture was stirred for 1 hour at room temperature, concentrated and purified by preparative LCMS (acidic hydrophilic system) to afford the intermediate 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid as a white foam; Mass Spectrum: (M+H)+ 560. The foam was dissolved in aqueous formaldehyde (1 ml) and acetic acid (0.1 ml) was added followed by sodium cyanoborohydride (100 mg) at 0° C. The reaction mixture was purified directly by preparative LCMS (acidic system) to give 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-3-carboxylic acid (0.03 g, 10.2%) as a white foam; Mass Spectrum: (M+H)+ 488.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 23.9 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (23 mg, 24% over 2 steps) as a orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.35 (s, 1H), 8.33 (s, 1H), 8.30 (dd, J=8.8, 1.9 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.04 (dd, J=9.6, 2.5 Hz, 1H), 7.49 (s, 2H), 7.26 (d, J=9.5 Hz, 1H), 4.22 (p, J=6.3 Hz, 1H), 4.12 (dd, J=12.0, 6.5 Hz, 1H), 3.96 (dt, J=10.9, 7.5 Hz, 1H), 3.86 (m, 2H), 2.78 (p, J=7.2 Hz, 1H), 2.65 (td, J=15.3, 14.8, 6.8 Hz, 1H), 2.40 (td, J=13.3, 5.3 Hz, 1H), 1.20 (m, 4H); ESI MS m/z 534 [C28H25Cl2N5O2+H]+; HPLC 99.6% (AUC), tR=10.29 min.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH2:28])[CH:22]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]1([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH3:28])[CH:22]=3)[C:9]=2[OH:8])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=C(c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1)c1ccccc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1C(C)c1cccc(-c2cccc(-c3ccccc3)c2O)c1
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A solution of 34 (1.1 g, 2.35 mmol) in methanol (15 mL) and ethyl acetate (30 mL) was treated with 20% palladium on activated carbon (50% wet, 0.05 g) and was hydrogenated at 40 psi in a Parr shaker for 3 hr. The catalyst was filtered out and washed with ethyl acetate. The filtrate was stripped and the crude product was purified by chromatography on silica (50 g) 2% ethyl acetate in hexane (3 L) to afford pure E1 (0.85 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=1.C1C(=O)N([Cl:40])C(=O)C1>>[Cl:40][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 37.9 %

Procedure:
Following General Procedure 1H, tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (200 mg, 0.43 mmol) was reacted with NCS (68 mg, 0.52 mmol) to afford the desired product (79 mg, 38%) as a brown solid. ESI MS m/z 485 [C25H25ClN2O4S+H]+.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C(=O)(O)[O-].[Na+].O.[Cl:31][CH2:32][CH2:33][OH:34]>S(=O)(=O)(O)O>[Cl:31][CH2:32][CH2:33][O:34][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OCCCl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (1 g.) was dissolved in 2-chloroethanol (50 ml.) and concentrated sulphuric acid (6 drops) added to the solution. The mixture was stirred at room temperature for 1 hour, neutralised with sodium bicarbonate solution and poured into water (500 ml.). The precipitate formed was extracted into ether (2 × 100 ml.) and the combined extracts washed with water (2 × 100 ml.). The organic layer was dried over anhydrous sodium sulphate and evaporated to a yellow oil (1.5 g.) which was purified by preparative tlc using ethyl acetatepetroleum ether, 1/1 run 3 times. The main band (RF ~0.2 - 0.3) gave the title compound (640 mg.) as an off-white foam identical with a previously prepared sample.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:8][C:9]=2[S:11][CH3:12])[S:4][C:3]=1[C:21](=[O:23])[NH2:22].S([O-])(O[O-])(=O)=[O:25].[K+].[K+]>CO.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][S:14]([C:17]([F:19])([F:18])[F:20])(=[O:16])=[O:15])=[CH:8][C:9]=2[S:11]([CH3:12])=[O:25])[S:4][C:3]=1[C:21](=[O:23])[NH2:22]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSc1cc(OS(=O)(=O)C(F)(F)F)nc2sc(C(N)=O)c(N)c12
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2sc(C(N)=O)c(N)c12
Temperature: 0 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
Trifluoromethanesulfonic acid 3-amino-2-carbamoyl-4-methylsulfanyl-thieno[2,3-b]pyridin-6-yl ester (500 mg, 1.29 mmol) was dissolved in MeOH (10 mL), chilled to 0° C., and potassium peroxymonosulfate (950 mg, 1.55 mmol) dissolved in water (15 mL) was added. The mixture was stirred for 18 h after which it was filtered to give the desired trifluoromethanesulfonic acid 3-amino-2-carbamoyl-4-methanesulfinyl-thieno[2,3-b]pyridin-6-yl ester in 86% yield.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].F[P-](F)(F)(F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH2:28])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1
Yield: 88 %

Procedure:
A solution of 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl-]oxazolidine-2-one (3.2 g, 11.4 mmol; prepared as described in Example 3), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (6.5 g, 17.1 mmole) and N,N′-diisopropylethylamine (5.9 g, 7.9 ml, 45.6 mmol) in DMF (12 ml) was stirred at room temperature for 20 min. Ammonium chloride (1.2 g, 22.8 mmol) was added, and the reaction mixture was stirred at r. t. overnight. Most of the solvent was removed under vacuum, and the residue taken up in ethyl acetate and washed twice with 3% aq. citric acid and brine. Organic layer was dried (Na2SO4) and concentrated under vacuum. Crude material was purified by silica gel chromatography eluting with 15% methanol in ethyl acetate to afford a white crystalline product (2.8 g, 91%). HPLC Rt=4.7, MS (m/z): [M+H]+=280.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.C(O)(=O)C.[ClH:42].O>O1CCOCC1>[ClH:42].[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C

Procedure:
The title compound was prepared using the previously described procedure and the following reagants: t-butyl oxycarbonyl-methionyl-valyl-tryptophan (4.61 grams), 32 milliliters of glacial acetic acid and 17.5 ml (106.2 mmoles) 6.07 N hydrochloric acid in dioxane. Yield is 3.2 grams. Analysis calculated for C21H30N4O4S.HCL.H2O: C, 51.57; H, 6.80; N, 11.46. Found: C, 51.29; H, 6.59; N,-11.72.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.C(N(CC)CC)C.[O:31]([CH2:38][CH2:39][CH2:40]Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C.CN(C)C=O>[O:31]([CH2:38][CH2:39][CH2:40][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(CCCOc2ccccc2)CC1)c1c2n(c3ccccc13)CCCO2

Procedure:
A stirred solution of N-(4-piperidinylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (E21) (250 mg, 0.80 mmole) and triethylamine (0.25 ml, 1.8 mmole) in a mixture of acetonitrile (15 ml) and N,N-dimethylformamide (10 ml) was treated with 3-phenoxypropyl bromide (0.13 ml, 0.88 mmole) and the solution heated under reflux for 48 h. The mixture was allowed to cool, then concentrated in vacuo and the residue dissolved in ethyl acetate (25 ml) and washed with water (20 ml). The organic solution was dried (MgSO4), concentrated in vacuo and the residue purified by flash chromatography on silica gel eluting with 0-20% methanol/ethyl acetate to afford the title compound as a pale pink solid after trituation with ether (44mg) mp 120-126° C.
Reaction SMILES: [OH-:1].[Na+].O=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[C:13]=1[O:22][CH3:23])[CH2:5][CH2:6][CH2:7]CC(O)=O.[OH2:24]>CO>[CH3:23][O:22][C:13]1[C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:4][CH2:5][CH2:6][C:7]([OH:24])=[O:1]
Reactant: COc1ccc(C(=O)CCCCC(=O)O)c(OC)c1OC
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCCC(=O)O)c(OC)c1OC
Temperature: 25 °C
Yield: 78 %

Procedure:
17 g of sodium hydroxide was dissolved in 200 mL of methanol in a 1000 mL round bottom flask. The reaction mixture was cooled to room temperature and 66 (6.78 g, 22.90 mmol) was added followed by 60 mL of water and 300 mL of anhydrous methanol, and the reaction mixture was refluxed for 30 min. The solvent was evaporated under reduced pressure and the reaction mixture was neutralized with dilute hydrochloric acid and the reaction mixture was extracted with ether (200×3) and the combined organic phases were washed with water and dried over sodium sulfate and solvent evaporated under reduced pressure. The crude product was purified by column chromatography (30:70 EA:Hex) to yield 12.86 g of 57 as pale yellow colored oil (78%). Rf: 0.15 (40:60 EtOAc:Hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[ClH:17].Cl.[NH2:19][C:20]1[C:29]([NH2:30])=[C:28]2[C:23]([CH:24]=[C:25]([C:32]([OH:34])=[O:33])[CH:26]=[C:27]2[OH:31])=[CH:22][CH:21]=1.S(=O)(O)[O-].[Na+]>CCO.O>[ClH:17].[C:11]1([C:10]2[C:3]([O:2][CH3:1])=[C:4]([C:5]3[NH:19][C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[C:27]([OH:31])[CH:26]=[C:25]([C:32]([OH:34])=[O:33])[CH:24]=5)[C:29]=4[N:30]=3)[CH:7]=[CH:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Reactant: COc1c(C=O)cccc1-c1ccccc1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1c(-c2ccccc2)cccc1-c1nc2c(ccc3cc(C(=O)O)cc(O)c32)[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
To an agitated solution of 2-methoxy-3-phenylbenzaldehyde (0.020 g, 0.08 mmol) in EtOH (0.80 mL) was added 7,8-Diamino-1-hydroxy-3-naphthoic acid dihydrochloride (0.02 g, 0.07 mmol) and sodium bisulfite (0.02 g) in water (0.20 mL). The solution was heated to 60° C. and agitated over 18 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The tan residue was subjected to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.008 g, 20%) MS(ES) m/z 411 [M+H].