Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH3:14][NH2:15]>>[CH3:14][NH:15][C:3](=[O:2])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CN
Product: CNC(=O)[C@@H](N)Cc1ccccc1
Yield: 82 %

Procedure:
To a solution of ethanolic MeNH2 (8.0 M, 50 ml) was added (S)-phenylalanine methyl ester (23.0 g, 130 mmol). The resulting solution was stirred at room temperature until the amino ester was judged to be consumed by TLC analysis. The resulting solution was then concentrated to provide (S)-phenylalanine N-methyl amide (18 g, 82% yield) as a white solid. To a flask containing (S)-phenylalanine N-methyl amide (8.9 g, 50 mmol) was added THF (100 ml), trimethylacetaldehyde (5.4 g, 50 mmol), FeCl3 (1.7 g, 10 mmol) and 4 Å MS (5.0 g). The resulting mixture was stirred at room temperature for 36 h, then washed with H2O (3×100 mL). The combined organics were concentrated and the resulting residue was treated with HCl (27 mL, 1N in ether). The resulting heterogeneous mixture was filtered to removed the undesired trans isomer•HCl salt and the resulting solution was concentrated. The residue was recrystallized (9:1 pentane/CH2Cl2) to provide the product (1) as a crystalline solid (2.88 g, 23% yield, >99% ee). IR (film) 3343, 2958, 1605, 1028 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.31-7.17 (m, 5H, ArH), 4.04 (s, 1H, NCHN), 3.72-3.65 (m, 1H, CHCH2), 3.13 (dd, J=4.1, 13.7 Hz, 1H, CH2), 2.92 (dd, J=7.7, 13.7 Hz, 1H, CH2), 2.90 (s, 3H, NCH3), 0.82 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 175.3, 138.0, 129.8, 128.7, 126.8, 82.7, 77.8, 77.4, 76.9, 59.7, 38.6, 35.4, 31.0, 25.7; [α]D=−39.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC using a Chiralpak OD-H and OD guard column (3.0% i-PrOH/hexanes, 1 mL/min); (5S) isomer tr=16.7 min, (5R) isomer tr=20.1 min.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([F:7])=[CH:9][CH:10]=2)=[O:13])=[CH:5][CH:6]=1
Reactant: Cc1cccs1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(F)cc2)s1
Reaction time: 4 h

Procedure:
To a stirred mixture of 29.5 parts of 2-methylthiophene, 39.65 parts of p-fluorobenzoyl chloride and 280 parts of methylene chloride are added portionwise 40 parts of aluminium chloride while keeping the temperature at 20° C (water-bath). Upon completion, stirring is continued for 4 hours at room temperature. The reaction mixture is poured onto crushed ice and 50 parts of hydrochloric acid, while stirring vigorously. The layers are separated and the aqueous phase is washed with chloroform. The organic layers are dried and evaporated. The residue is taken up in benzene and the latter is evaporated again. The residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from ethanol at -20° C, yielding p-fluorophenyl 5-methyl-2-thienyl ketone; mp. 68° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28]>O1CCCC1>[CH3:25][N:26]([CH3:31])[S:27]([NH:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:29])=[O:28]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(=O)C1=Cc2cccc(N)c2OCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cccc(NS(=O)(=O)N(C)C)c2OCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (1.0 g) and triethylamine (4.18 ml) in tetrahydrofuran (10 ml) was added dimethylsulfamoyl chloride (2.30 ml) at 5° C. The reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 2,3-dihydro-9-dimethylsulfamoylamino-1-benzoxepin-4-carboxylate (0.89 g).
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:20]/[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[O:35][N:34]=[C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:32]=3)=[CH:25][CH:24]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.C(O)C>[C:4]1(/[C:10](=[N:20]/[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[O:35][N:34]=[C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:32]=3)=[CH:25][CH:24]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)no2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)no2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Lithium hydroxide monohydrate (194 mg) was added to a solution of ethyl E-6-phenyl-6-[4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)benzyloxyimino]hexanoate (790 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (4.7 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-phenyl-6-[4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)benzyloxyimino]hexanoic acid (637 mg, yield 85%) as colorless crystals. m.p. 91-92° C.
Reaction SMILES: C[C@@H](N)CC.BrC1C=C(C#N)C(N[C@H](C)CC)=CC=1C(OCC)=[O:10].[C:25]([C:27]1[C:37]([NH:38][C@H:39]([CH3:42])[CH2:40][CH3:41])=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([CH2:43][CH3:44])[CH:28]=1)#[N:26].C([Mg]Cl)C>>[NH2:26][C:25]([C:27]1[C:37]([NH:38][C@H:39]([CH3:42])[CH2:40][CH3:41])=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([CH2:43][CH3:44])[CH:28]=1)=[O:10]
Reactant: CCOC(=O)c1cc(N[C@H](C)CC)c(C#N)cc1CC
Reactant: CCOC(=O)c1cc(N[C@H](C)CC)c(C#N)cc1Br
Agent: CC[C@@H](C)N
Agent: CC[Mg]Cl
Product: CCc1cc(C(N)=O)c(N[C@H](C)CC)cc1C(=O)O

Procedure:
Synthesized according to the method of reagent preparation 50 by using (1R)-1-methylpropylamine in step 1 then following step 2 with the conversion of ethyl 2-bromo-4-cyano-5-{[(1R)-1-methylpropyl]amino}benzoate to ethyl 4-cyano-2-ethyl-5-{[(1R)-1-methylpropyl]amino}benzoate by treatment with ethylmagnesium chloride according to the method described in Synlett 1996, 5, 473-474 then proceeding through steps 3 and 4. 1H NMR (400 MHz, DMSO-d6): 7.94 (s, 1H), 7.81 (d, 1H), 7.49 (s, 1H), 7.27 (s, 1H), 6.98 (s, 1H), 2.67-2.75 (m, 2H), 1.44-1.53 (m, 2H), 1.06-1.15 (m, 6H), 0.89 (t, 3H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:11][C@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[C@H:8]([OH:9])[C@@H:6]1[OH:7])=[N+]=[N-]>CO.[Pd].C(OCC)(=O)C>[NH2:1][CH2:4][C@H:5]1[O:11][C@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[C@H:8]([OH:9])[C@@H:6]1[OH:7]
Reactant: [N-]=[N+]=NC[C@H]1O[C@H]([C@H](O)CO)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC[C@H]1O[C@H]([C@H](O)CO)[C@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 78.1 %

Procedure:
The azide (16) (0.12 g, 0.63 mmol) was stirred in methanol (5 ml) at room temperature under hydrogen in the presence of 10% palladium on carbon (10 mg). After 24 h, t.l.c. (5% methanol in ethyl acetate) indicated conversion of the starting material (Rf 0.3) to a single product (Rf 0.0). The reaction mixture was filtered through celite, the solvent removed in vacuo, and the resulting solid purified by ion exchange chromatography with Dowex 50W-X8 using 0.5M ammonia as eluant. After freeze drying, 1-amino-2,5-anhydro-1-deoxy-D-glycero-D-talo-heptitol (5) (95 mg, 8%) was obtained as a yellowish solid. The solid was taken up in water, and the solution neutralised with dilute aqueous hydrochloric acid. Freeze drying, followed by recrystallisation from methanol/chloroform, gave 1-amino-2,5-anhydro-1-deoxy-D-glycero-D-talo-heptitol hydrochloride (5) as a colourless crystalline solid, m.p. 189° C. (dec.). (Found: C, 36.61; H, 7.27; N, 5.42. C7H16O5NCl requires C, 36.61; H, 7.02; N, 6.10%); [α]D20 +38.6° (c 1.0 in CHCl3); δH (D2O) 3.00 (1H, dd, H-1, J1,1' 13.4 Hz, J1,2 8.8 Hz), 3.18 (1H, dd, H-1', J1',2 2.29 Hz), 3.52 (1H, dd, H-7, J6,7 5.0 Hz, J7,7' 12.1 Hz), 3.66 (1H, dd, H-7', J6,7' 2.7 Hz), 3.80 (1H, ddd, H-6, J5,6 9.0 Hz), 3.87 (1H, dd, H-3, J3,4 4.1 Hz), 4.17 (1H, dd, H-4); δC (D2O) 41.8, 63.1 (2 × t, C-1 , C-7), 69.0, 71.6, 74.3, 77.2, 79.6 (5 × d, C-2, C-3, C-4, C-5, C-6); m/z (NH3, DCI) 194 (M+H+, 100%).
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][CH:13]=1)([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3].N.CO>C(OCC)(=O)C>[NH2:17][CH2:16][CH2:15][CH2:14][C:10]1[CH:9]=[C:8]([C:2]([OH:1])([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC(C)(O)c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC(C)(O)c1cccc(CCCN)c1

Procedure:
Deprotection of 2-(3-(3-(2-hydroxyhexan-2-yl)phenyl)propyl)isoindoline-1,3-dione followed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate gradient), gave Example 120 a colorless oil. Yield (0.157 g, 90%): 1H NMR (400 MHz, CDCl3) δ 7.20-7.27 (m, 3H), 7.03-7.07 (m, 1H), 2.73 (t, J=7.2 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 1.70-1.84 (m, 4H), 1.53 (s, 3H), 1.42 (brs, 3H), 1.18-1.30 (m, 3H), 1.06-1.16 (m, 1H), 0.84 (t, J=7.2 Hz, 3H). ESI MS m/z 236.2 [m+H]+, 218.2 [m+H−H2O].
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10]C(C(O)=O)=[CH:5][CH:4]=1.[C:12](Cl)(=O)[C:13]([Cl:15])=[O:14].[Cl:18]CCl>>[Cl:18][CH2:2][C:3]1[CH:11]=[CH:10][C:12]([C:13]([Cl:15])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: ClCCl
Product: O=C(Cl)c1ccc(CCl)cc1
Temperature: 25 °C

Procedure:
A stirred suspension of 3.0 g (14 mmol) of 4-(bromomethyl)benzoic acid and 3.5 ml (41 mmol) of oxalyl chloride in 35 ml of dichloromethane was refluxed for 10 hours and cooled to room temperature. Evaporation afforded 4-(chloromethyl)benzoyl chloride as an oil which was used without purification. To a cooled (0° C.) solution of 2.6 g (14 mmol) of 4-(chloromethyl)benzoyl chloride and 2.0 g (18 mmol) of benzyl alcohol in 30 ml of dichloromethane was added 1.8 g (18 mmol) of triethylamine. The reaction was stirred at 0° C. for 0.2 hours, then at room temperature for an additional 1 hour and poured into 150 ml of EtOAc. The EtOAc layer was with three portions of water, dried over Na2SO4, filtered and evaporated. The crude product was flash chromatographed (5% EtOAc/hexanes) to give 0.7 g of product; m.p. 52°-54° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[S:13](=[O:21])(=[O:20])[NH:12][N:11]=2)=[CH:2]1.[CH3:22]I.Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27]>>[CH3:22][N:12]1[N:11]=[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:1]([CH2:25][C:26]([OH:28])=[O:27])[CH:2]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13]1(=[O:21])=[O:20]
Reactant: CI
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=S1(=O)NN=C(c2c[nH]c3ccccc23)c2ccccc21
Product: CN1N=C(c2cn(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The product of Example 17, step c) was alkylated with methyl iodide and t-butyl bromoacetate following the procedure described in example 17, step d). 1H NMR (DMSO-d6) δ 8.11-7.90 (m, 5H), 7.85 (s, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.22 (dt, J=0.9, 7.5 Hz, 1H), 7.15 (dt, J=1.2, 7.5 Hz, 1H), 4.72 (s, 2H), 3.51 (s, 3H); MS: ESI (negative): 368 (M−H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14](Cl)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:24]([N:26]([CH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25].[H-].[Na+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:40][CH:37]4[CH2:38][CH2:39][CH:34]([N:26]([CH2:24][CH3:25])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:35][CH2:36]4)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
For the preparation of the starting material compound 25.1, please refer to the experimental procedure for the synthesis of compound Example 25. To a solution of tert-butyl N-ethyl-N-(4-hydroxycyclohexyl)carbamate (intermediate 101.5, 322.68 mg, 1.33 mmol, 1.22 equiv) in distilled tetrahydrofuran (10 mL) was added sodium hydride (151.76 mg) slowly at 0° C. and the reaction mixture was stirred at room temperature for 30 min. Then (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (400 mg, 1.08 mmol, 1.00 equiv) in THF (5 mL) was added to the mixture via syringe and the resulting solution was stirred for 3 hr at ambient temperature. The reaction was then quenched by the addition of 40 mL of saturated aqueous NH4Cl and extracted with 3×80 mL of ethyl acetate. The combined organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to afford tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-ethylcarbamate (570 mg, 91%) as a colorless oil. MS (ES): m/z 576 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[CH3:26]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:30]2[CH:31]=[CH:32][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=2)[N:3]=1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.2 %

Procedure:
To a solution of 2,6-dichloro-3-trifluoromethyl pyridine (1 g, 4.54 mmol) in a mixture of toluene (11 mL), 1,4-dioxane (5.88 mL), and water (5.88 mL) were added sodium carbonate (0.96 g, 9.07 mmol), 4-ethylphenyl boronic acid (0.61 g, 4.08 mmol), and PdCl2(dppf)CH2Cl2 (0.75 g, 0.92 mmol). The mixture was stirred at 80° C. for 4 h, and then concentrated under reduced pressure. The product (0.69 g, 53%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 8.15 (d, 1H), 8.01 (d, 2H), 7.95 (d, 1H), 7.33 (d, 2H), 2.71 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:88]=[CH:87][C:72]([CH2:73][N:74]2[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76][CH2:75]2)=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:70]=[CH:71][C:72]([CH2:73][N:74]4[CH2:75][CH2:76][N:77]([C:80]([O:82][C:83]([CH3:84])([CH3:86])[CH3:85])=[O:81])[CH2:78][CH2:79]4)=[CH:87][CH:88]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 26.1 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.13 mmol), DMF (0.3 mL), ethanol (1.2 mL), 1M Na2S2O4 (3 eq, 0.38 mmol, 0.38 mL) and tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate (1.1 eq, 0.14 mmol, 45 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (22 mg, 27%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.32 (s, br, 4H, piperazine N(CH2)2), 3.55 (s, 2H, CH2), 3.62 (s, 2H, CH2), 3.67 (t, J=4.8 Hz, 4H, piperazine N(CH2)2), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.46 (d, J=8.1 Hz, 2H, phenyl H-3 & H-5), 7.78 (d, br, J=8.0 Hz, 1H, pyridine H-4), 8.14 (d, J=8.1 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.8, 1.6 Hz, 1H, pyridine H-6), 8.56 (d, J=1.7 Hz, 1H, pyridine H-2), 13.46 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32](Br)[CH:33]=[CH2:34].O>CN(C=O)C>[CH2:34]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24])[CH:33]=[CH2:32]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C(C)C
Temperature: 50 °C
Yield: 90.5 %

Procedure:
A suspension of (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.010 g, 0.028 mmol) and K2CO3 (0.019 g, 0.140 mmol) in DMF (1.0 mL) was treated with allyl bromide (0.024 mL, 0.280 mmol) and heated at 50° C. for 16 h. The reaction mixture was poured into 25 mL water and extracted with EtOAc (2×25 mL). The extracts were washed with 25 mL each water and brine, dried over MgSO4, filtered and concentrated to a yellow oil. Column chromatography (5–10% EtOAc in hexane gradient) gave 0.010 g (91%) of (3R)-4-allyl-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. This material (0.006 g, 0.015 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (1.0 mL) heated at 70° C. for 1 h to afford 0.004 g (80%) of Compound 126, a yellow solid. Rf 0.6 (9:1 CH2Cl2;MeOH); 1H NMR (400 MHz, CDCl3) δ 11.82 (broad s, 1H), 7.12 (d, 1H, J=8.9), 7.11 (s, 1H), 6.93 (d, 1H, J=8.9), 5.92–5.81 (m, 1H), 5.27–5.17 (m, 2H), 4.48 (d, 1H, J=10.9), 3.99 (dd, ABX, 1H, J=16.4, 5.8), 3.84 (dd, ABX, 1H, J=16.4, 5.8), 3.77 (dd, ABX, 1H, J=10.9, 2.8), 2.96–2.93 (m, 1H), 1.94–1.84 (m, 1H), 0.98 (d, 3H, J=6.7), 0.96 (d, 3H, J=6.7).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([NH:8][C:9](=[O:30])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=1)[CH:5]([CH3:7])[CH3:6].[OH-].[Na+].CO>C1COCC1.O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C@H:10]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:31])=[O:2])=[O:30])=[CH:13][CH:14]=1)[CH:20]=[CH2:21]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 42 (4.90 g, 11.3 mmol) was dissolved in THF (35 mL) and sodium hydroxide (17 mmol) pre-dissolved in water (10 mL) was added. A further 15 mL of THF and 20 mL of methanol were added to obtain a homogenous solution. The reaction mixture was stirred at rt for 18 h before being concentrated in vacuo. The residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white foam, 4.60 g, 97%.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:18]=[CH:17]C(C#N)=[CH:13][CH:12]=2)[C:8]2[CH:19]=[C:20]3[C:25](=[CH:26][C:7]=2[N:6]=1)[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH2:2][CH2:3][CH3:4].Cl.C[OH:29].[CH2:30]([OH:32])[CH3:31]>[OH-].[Na+]>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:18]=[CH:17][C:31]([C:30]([OH:29])=[O:32])=[CH:13][CH:12]=2)[C:8]2[CH:19]=[C:20]3[C:25](=[CH:26][C:7]=2[N:6]=1)[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc3ccccc3cc2n1Cc1ccc(C#N)cc1
Reactant: CO
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2cc3ccccc3cc2n1Cc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
A suspension of 420 mg of the product of Example 9 in 4 ml of ethanol and 7.5 ml of 2N of sodium hydroxide was refluxed for 21 hours and after cooling the suspension, 5 ml of ice were added. The mixture was neutralized to pH 7 with 7.5 ml of 2N hydrochloric acid and 30 ml of methanol were added, followed by heating to reflux and concentrating to 20 ml. After separating, 420 mg of the expected product were obtained. The 420 mg of above product were crystallized successively from isopropanol, then from ethyl acetate to obtain 260 mg of pure product melting at 220° C.
Reaction SMILES: CO.[NH3:3].[C:4]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:16](Cl)(=[O:18])=[O:17])(=[O:6])[CH3:5]>CO.O1CCCC1>[F:15][C:13]1[CH:12]=[CH:11][C:10]([S:16](=[O:18])(=[O:17])[NH2:3])=[C:9]([CH:14]=1)[CH2:8][NH:7][C:4](=[O:6])[CH3:5]
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NCc1cc(F)ccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Step 2) To a solution of 8N ammonia methanol solution (2 ml) in methanol (15 ml) was added dropwise a suspension of 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride obtained in Step 1 (1.34 g) in tetrahydrofuran (5 ml) under ice-cooling, and the mixture was allowed to warm to room temperature, and stirred for 1 hr. The reaction mixture was quenched with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-(5-fluoro-2-sulfamoylbenzyl)acetamide (1.34 g) as a white solid.