Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([CH:17]([F:19])[F:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([F:27])=[C:4]([Si](CC)(CC)CC)[CH:3]=1.BrC1N=C([C@](N[S@@](C(C)(C)C)=O)(C(F)F)CC(OC(C)(C)C)=O)C(F)=C([Si](CC)(CC)CC)C=1.[F-].[K+].C(O)(=O)C.C([O-])(O)=O.[Na+].BrC1N=C([C@@](N[S@@](C(C)(C)C)=O)(C(F)F)CC(OC(C)(C)C)=O)C(F)=CC=1>O.CN(C=O)C.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([CH:17]([F:18])[F:19])[CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:5]([F:27])=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@@](CC(=O)OC(C)(C)C)(N[S@](=O)C(C)(C)C)C(F)F)c1F
Agent: CC(C)(C)OC(=O)C[C@@](N[S@](=O)C(C)(C)C)(c1nc(Br)ccc1F)C(F)F
Agent: CC[Si](CC)(CC)c1cc(Br)nc([C@](CC(=O)OC(C)(C)C)(N[S@](=O)C(C)(C)C)C(F)F)c1F
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@](N[S@](=O)C(C)(C)C)(c1nc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a polypropylene flask and cap was added a mixture of (R)-tert-butyl 3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate and (5)-tert-butyl 3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (0.411 g, 0.699 mmol), THF (3 mL) and DMF (3.0 mL). To the solution was added potassium fluoride (0.112 g, 1.923 mmol) and acetic acid (0.110 mL, 1.923 mmol). The reaction mixture was stirred at rt for 18 h. The solution was poured into sat NaHCO3 (25 mL) and diluted with water (25 mL). The solution was extracted with EtOAc (2×50 mL). The combined extracts were washed with water and brine and then dried (Na2SO4) and concentrated to give a 3:1 mixture of (R)-tert-butyl 3-(6-bromo-3-fluoropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate and (S)-tert-butyl 3-(6-bromo-3-fluoropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (0.324 g, 0.684 mmol, 98% yield) as a colorless oil. This material was used directly in the following step. MS m/z=473, 475 M+, Calculated for C17H24BrF3N2O3S: 473.35.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:32]=[CH:31][C:10]([CH2:11][C@@H:12]2[CH2:17][O:16][CH2:15][CH2:14][N:13]2[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[O:19])=[CH:9][C:8]=1[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>C(Cl)Cl>[OH:6][C:7]1[CH:32]=[CH:31][C:10]([CH2:11][C@@H:12]2[CH2:17][O:16][CH2:15][CH2:14][N:13]2[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[O:19])=[CH:9][C:8]=1[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: COc1ccc(C[C@@H]2COCCN2C(=O)c2ccccc2-n2nccn2)cc1-c1ncccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccccc1-n1nccn1)N1CCOC[C@H]1Cc1ccc(O)c(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Boron tribromide 1M soln. in DCM (0.8 mL, 0.8 mmol) was added to a −78° C. solution of [(R)-3-(4-methoxy-3-pyrimidin-2-yl-benzyl)-morpholin-4-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone Example 5 (72 mg, 0.16 mmol) in DCM (5 mL) and after complete addition the the reaction mixture was warmed to RT and stirred for 6 h. The reaction was quenched with sat. aq. NaHCO3 and the layers were separated. The aqueous layer was extracted with DCM (2×) and the combined organic extracts were dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method F) to give the title compound as a white solid. LC-MS D: tR=0.80 min; [M+H]+=443.03.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:11][CH2:12][C:13]#[C:14][CH2:15]Cl>CN(C)C=O>[Cl:11][CH2:12][C:13]#[C:14][CH2:15][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: ClCC#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(CC#CCCl)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 29.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 1.30 g, 11.50 mmol) was dissolved in N,N-dimethylformamide (20 mL) and chilled to 0° C. A 60% dispersion of sodium hydride in mineral oil (552 mg, 13.80 mmol) was added portion wise, the ice bath was removed and the reaction continued to stir for 20 min. The 1,4-dichloro-but-2-yne (2.83 g, 23.00 mmol) was dissolved in N,N-dimethylformamide (5 mL) and chilled to 0° C. The 3-nitro-1H-pyrazole solution was added dropwise to the 1,4-dichloro-but-2-yne solution while stirring at 0° C. The ice bath was removed and the reaction continued to stir for 20 min. The solution was diluted with ethyl acetate (400 mL), washed with water (2×200 mL), saturated aqueous brine solution (2×100 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) afforded 1-(4-chloro-but-2-ynyl)-3-nitro-1H-pyrazole (682 mg, 30%) as a yellow oil which eventually solidified: H1-NMR (400 MHz, CDCl3) δ 4.18 (2H, t, J=2.0 Hz), 5.08 (2H, t, J=2.0 Hz), 6.92 (1H, d, J=2.4 Hz), 7.70 (2H, d, J=2.4 Hz).
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+].[CH:15]([O:28][C:29]([C:31]1[N:32]2[CH:35]([S:36][CH2:37][C:38]=1[CH2:39][OH:40])[CH:34]([NH:41][C:42](=[O:71])[C:43]([C:65]1[N:69]=[C:68]([NH2:70])[S:67][N:66]=1)=[N:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:33]2=[O:72])=[O:30])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[K+].[Br-].C([O-])(O)=O.[Na+]>ClCCl.O>[CH:15]([O:28][C:29]([C:31]1[N:32]2[CH:35]([S:36][CH2:37][C:38]=1[CH:39]=[O:40])[CH:34]([NH:41][C:42](=[O:71])[C:43]([C:65]1[N:69]=[C:68]([NH2:70])[S:67][N:66]=1)=[N:44][O:45][C:46]([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:33]2=[O:72])=[O:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CO)CSC23)ns1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=O)CSC23)ns1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
2.1 (via TEMPO, NaOCl): A suspension of 22.47 g 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester in 110 ml of dichloromethane was treated with a solution of 369 mg of KBr and 958 mg of NaHCO3 in 70 ml of water, the mixture was cooled to 0° C. and treated with a solution of 391 mg of TEMPO (available from Fluka or as described in Synthesis, 1971, p. 190) in 2 ml of dichloromethane. The mixture was treated under vigorous stirring with 29 ml of NaOCl in water (9.93%) over 2 h and stirring was continued for 2 h after which time HPLC indicated completion of the reaction. The reaction mixture was filtered over Celite, the organic layer was washed with brine, treated with MgSO4 and charcoal and filtered. The filtrate was stirred with 25 g of silica for 10 min, filtered and the filtrate was evaporated to dryness to give 16.61 g of the NMR-pure 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester as a foam. IR (neat): 3432 w (NH2, NH), 1800 m, 1783 m, 1670 m (C═O). 1H-NMR (d6-DMSO): 9.98 (d, J=9.2, 1H, NH); 9.51 (s, 1H, CHO); 8.14 (s, br., 2H, NH2); 7.55-7.25 (m, 25H, H—ar.); 7.10 (s, 1H, CH(Ph)2); 6.30 (dd, J=9.2 and 5.6, 1H, H—C(7)); 5.41 (D, J=5.6, 1H, H—C(6)); 3.93 and 3.49 (each d, J=each 18, 2H, H2C(4)). MS (CI): 807/100, M+H+).
Reaction SMILES: C(OC(N1CCC(C(NN[C:18]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:21]=2)=[O:19])=O)CC1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:87][N:88]([NH2:99])[C:89]([O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)=[O:90]>CN(C=O)C.C(OCC)(=O)C>[CH3:87][N:88]([NH:99][C:18](=[O:19])[C:20]1[CH:34]=[CH:33][C:23]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:22]([O:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:21]=1)[C:89]([O:91][CH2:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)=[O:90]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(=O)OC(C)(C)C
Reactant: CN(N)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(NC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(OCC(=O)OC(C)(C)C)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of the product of Example 2, starting material step (c) (470 mg), HBTU (460 mg) and HOBT (190 mg) in DMF (3 ml) under argon was added diisopropylethylamine (0.63 ml). After 2-3 minutes the resultant pale yellow reaction mixture was added to benzyl 2-methylcarbazate (Dutta, A. S. et al (1975), J. Chem. Soc. Perkin Trans. I, 1712-20) (200 mg). The reaction mixture was stirred at ambient temperature under argon for 3.5 hours then diluted with ethyl acetate (50 ml) and washed with water, dilute KHSO4 (aq.) and dilute NaOH (aq.) and water, dried (MgSO4) and evaporated to give benzyl 2-methyl-3-(3,4-di-t-butoxycarbonylmethoxybenzoyl)carbazate (0.61 g) as a glass; NMR Spectrum (DMSO-d6) 1.43 (18H, s), 3.13 (3H, br s), 4.70 (2H, s), 4.75 (2H, s), 5.02-5.20 (2H, br), 6.99 (1H, m), 7.20-7.50 (7H, m), 10.68 (1H, br); Mass Spectrum m/Z 544 (M+). In the ambient temperature NMR spectrum, ancillary signals attributable to rotamers were observed.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12]O)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.C[Si]([Br:22])(C)C.[Li+].[Br-]>CC#N>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][Br:22])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CC(C)n1nc(Br)c2ccc(CO)cc2c1=O
Reactant: C[Si](C)(C)Br
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CC(C)n1nc(Br)c2ccc(CBr)cc2c1=O
Temperature: 80 °C
Yield: 44.4 %

Procedure:
A solution of 4-bromo-7-hydroxymethyl-2-isopropyl-2H-phthalazin-1-one (0.74 g, 2.5 mmol) in MeCN (5 ml) was added dropwise to a stirred suspension of trimethylsilyl bromide (TMSBr) (0.9 g, 6.3 mmol) and LiBr (0.41 g, 5 mmol) in MeCN (15 ml). The reaction mixture was heated to 80° C. for 24 hours, after which time the reaction mixture was cooled to RT and the solvent removed under vacuum. The resulting residue was purified by flash column chromatography (elution: 85% heptane, 15% EtOAc) to give the title compound (0.4 g, 44% yield) as a white solid. 1H-NMR: (250 MHz, D6- DMSO), 8.37 (1H, s), 8.03 (1H, d), 7.94 (1 H, d), 5.26-5.09 (1H, m), 4.93 (2H, s), 1.35 (6H, d).
Reaction SMILES: O[CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[C:7](=[O:9])[CH:8]=1.C(N(S(F)(F)[F:37])CC)C>ClCCl>[F:28][C:27]([F:30])([F:29])[C:23]1[CH:22]=[C:21]2[C:26]([C:17]([S:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]3[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][F:37])[O:4][CH:5]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: O=c1cc(CO)occ1OCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=c1cc(CF)occ1OCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
2-Hydroxymethyl-5-[5-(7-trifluoromethyl-quinolin-4-ylsulfanyl)-pentyloxy]-pyran-4-one EHT 5909 (100 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL). The mixture was stirred at 0° C. for 15 min. Diethylaminosulfur trifluoride (DAST, 33 μL, 0.25 mmol) was added via syringe. The mixture was stirred at room temperature for 10 min. The solution was evaporated. The crude product was purified by flash chromatography on silica using as eluent CH2Cl2:MeOH=99:01. 5-(5-(7-(Trifluoromethyl)quinolin-4-ylthio)pentyloxy)-2-(fluoromethyl)-4H-pyran-4-one EHT 8817 was obtained (48 mg, 35% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1)#[N:18].[OH-].[Na+].O>C1(C)C(C)=CC=CC=1>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]3=[N:26]2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: N#Cc1ccc(NN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: N#Cc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 25 °C

Procedure:
38.5 ml of a 0.17 M solution of ethyl 4-chloroquinoline-3-carboxylate in xylene, and 0.96 g of p-cyanophenylhydrazine in 30 ml of xylene are mixed and heated at 115° to 120° for 3 hours. The mixture is then cooled to room temperature, and stirred with 20 ml of 1 N aqueous sodium hydroxide and sufficient water to dissolve all solids. The aqueous layer is separated, washed twice with diethyl ether, then treated with an aqueous solution of 1.07 g ammonium chloride, and the resulting precipitate is collected, washed with water and dried to yield the 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing peaks in the IR-spectrum at 885, 830, 780, 755 and 730 cm-1.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:9]=[C:8]([NH:10]C(=O)C(C)(C)C)[CH:7]=[CH:6][CH:5]=1)C.Cl>O1CCOCC1>[NH2:10][C:8]1[N:9]=[C:4]([CH2:2][OH:1])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(CO)n1
Temperature: 90 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a solution of dioxane (15 mL) was added N-[6-(1-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide (1.5 g, 7.2 mmol) and aqueous hydrochloric acid (6N, 15 mL) and the mixture was stirred at 90° C. for 14 h. The solution was cooled 0° C., triturated with diethyl ether (2×30 mL) and the aqueous layer was neutralized using sodium hydroxide to approximately pH 8. The mixture was diluted with chloroform/IPA (10:1, 50 mL). The mixture was washed with saturated brine solution (2×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the above-titled intermediate as a white solid (0.86 g, 96%). HPLC: Rt 0.628 min. (99.5% area). 1H NMR (400 MHz, CDCl3), δ: 7.48 (t, J=7.4 Hz, 1H), 6.66 (d, J=7.3 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 4.58 (s, 2H), 4.23 (bs, 2H). LCMS (ESI): m/z: 125.2.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([CH2:9][N:10]1[C:15]2[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[C:18]([F:20])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:24])=[O:8])C>O1CCOCC1>[C:7]([CH2:9][N:10]1[C:15]2[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[C:18]([F:20])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:24])([OH:8])=[O:6]
Reactant: CCOC(=O)CN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
Sodium hydroxide (0.9 g) and water (20 ml) were added to a mixture of 4-ethoxycarbonylmethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (5.96 g) and 1,4-dioxane (50 ml). The mixture was stirred at room temperature for one day. Afterthe solvent was distilled off, the residue was mixed with water (100 ml), then filtered. The filtrate was acidified with hydrochloric acid, and extracted with methyl isobutyl ketone (150 ml). After the extract was washed with water, it was dried with anhydrous sodium sulfate, and then the solvent was distilled off to give the desired 4-carboxymethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (4.8 g). mp. 177°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][C:19](=O)[CH:18]([CH3:22])[O:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CSC.B>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH3:22])[O:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:29][CH:30]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)C(=O)N3)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)CN3)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-methyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (1.45 g, 3.14 mmol) in THF (25 ml.) was added borane dimethyl sulfide (1M in THF) (0.343 g, 4.71 mmol, Aldrich) at 0° C. and reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was quenched with MeOH (15 mL) and the solvent was removed under vacuum. The residue obtained was diluted with MeOH and stirred at 25° C. for 1 h, then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in hexanes as the eluent to afford 1.3 g of N-(4-methoxybenzyl)-2-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE AE) as off white solid in 92% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH:11]=[CH:10]1>C(CN)O>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:14][CH2:15][CH2:16][OH:22])[C:12]=2[CH:11]=[CH:10]1
Reactant: Cc1cc(F)ccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: NCCO
Product: Cc1cc(F)ccc1-n1ccc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 180 °C
Yield: 162.9 %

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(700 mg, 1.7 mmol), prepared by the procedures of Step 1 and Step 2 in the Example 46, was dissolved in ethanolamine(10 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 3 hours. After removing the excess ethanolamine by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 600 mg of desired compound as solid in 81% of yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[O:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[C:40](B(O)O)[C:35]=2[O:34][CH2:33][CH2:32]1>>[O:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)[NH:20][C:19]4=[O:29])[C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: OB(O)c1cccc2c1OCCO2
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc5c4OCCO5)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 1,4-benzodioxan-5-boronic acid in step C. MS (ESI): mass calcd. for C20H14N4O5, 390.1; m/z found, 391.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.00 (s, 1H), 12.87 (s, 1H), 8.97 (s, 1H), 8.25 (s, 2H), 8.10 (d, J=7.8 Hz, 1H), 7.73 (s, 1H), 7.28-7.24 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 4.30 (s, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH2:34]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([CH2:21][NH:34][CH3:33])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(Cc3ccccc3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 91 %

Procedure:
Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (5.0 g, 0.0102 mmol) were dissolved in 2.0 M solution of MeNH2 in THF (35 mL) in an autoclave and heated to 80° C. over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, dichloro methane/methanol 0->20%) to yield the title compound (3.25 g, 91%) as a light yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([CH2:23][N:24]3[CH2:28][CH:27]([NH:29][C:30]([C:32]4[CH:33]=[CH:34][C:35]5[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=5[CH:42]=4)=[O:31])[CH2:26][CH:25]3[C:43](O)=[O:44])[CH2:13][C:12]2=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([CH2:23][N:24]3[CH:25]([C:43]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:44])[CH2:26][CH:27]([NH:29][C:30]([C:32]4[CH:33]=[CH:34][C:35]5[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=5[CH:42]=4)=[O:31])[CH2:28]3)[CH2:13][C:12]2=1
Reactant: C1COCCN1
Reactant: COc1ccc2ncc3c(c2c1)CC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1C(=O)O)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2c1)CC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1C(=O)N1CCOCC1)CO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Morpholine (2 μL, 0.024 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-pyrrolidine-2-carboxylic acid (14 mg, 0.024 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by 1-hydroxybenzotriazole (4 mg, 0.027 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5 mg, 0.028 mmol, 1.15 eq) and N,N-diisopropylethylamine (13 μL, 0.073 mmol, 3.0 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-5-(morpholine-4-carbonyl)-pyrrolidin-3-yl]-amide as a white lyophilized powder (12 mg, 76% yield).