Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[C:21]([O:25][C:26]([NH:28][CH:29]1[C:33]2([CH2:35][CH2:34]2)[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(#N)C>[C:21]([O:25][C:26]([NH:28][CH:29]1[C:33]2([CH2:34][CH2:35]2)[CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CNCC12CC2
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CC2
Yield: 74.6 %

Procedure:
200 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 150 mg of compound 11 and 70 mg of triethylamine were added to 5 ml of acetonitrile and the mixture was refluxed for 24 hours. After cooling, the solvent was removed under reduced pressure and to the residue was added water. The precipitate was collected by filtration and washed successively with water, acetonitrile, ethanol and ether and dried. The procedure gave 245 mg of 7-(7-tert-butoxycarbonylamino-5-azaspiro[2,4]heptan-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid melting at 205°-207° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([Cl:18])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid (109 mg, 0.54 mmol) in dichloromethane (2.7 ml) was added oxalyl chloride (545 ul, 1.09 mmol) followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvents were then removed to obtain 119 mg (99%) of (1R*,2S*,4R*)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride.
Reaction SMILES: [CH2:1]([S:3][C:4]1[O:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[CH2:1]([S:3]([C:4]1[O:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)=[O:26])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: ClCCl
Product: CCS(=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (ice/water) solution of 4.2 g. of 2-ethylthio-4,5-diphenyl-oxazole pre-dissolved in 30 ml. of methylene chloride is added in portions over 5 minutes, 30 g. of m-chloro-peroxybenzoic acid. Examination by TLC after 2 hours indicates the presence of essentially all of the sulfinyl compound (reaction complete). The precipitated m-chloro-benzoic acid is filtered off and the methylene chloride solution is washed successively with a 10 % solution of sodium sulfite and with saturated sodium bicarbonate solution, dried, evaporated in vacuo to dryness, and the residue further dried overnight in vacuo to yield 2-ethylsulfinyl-4,5-diphenyl-oxazole, m.p. 133°-134° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10]C)=[O:8])(=[O:3])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17].Cl>C(O)C.N1CCCCC1.O>[C:7]([C:6]1[CH:5]=[C:4]2[C:14](=[CH:13][CH:12]=1)[O:15][CH:21]([C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[N+:16]([O-:18])=[O:17])[CH2:2][C:1]2=[O:3])([O:9][CH3:10])=[O:8]
Reactant: CCOC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1[N+](=O)[O-])O2

Procedure:
A mixture consisting of ethyl 3-acetyl-4-hydroxy-benzoate (6 g) and 2-nitro-benzaldehyde (5 g) dissolved in ethanol (100 ml and piperidine (100 ml) was kept at reflux temperature for 24 hours. The mixture was then cooled, diluted in water (800 ml), acidified with hydrochloric acid, extracted with ethylacetate, washed with water and evaporated to dryness to obtain as raw product, 6-carbomethoxy-2'-nitro-flavanone. This product (6.8 g) was dissolved in chloroform (40 ml) and treated with a solution of benzoyl peroxide (0.15 g) and N-bromosuccinimide (3.8 g) dissolved in chloroform (60 ml). The mixture was kept at reflux temperature for 4 hours, then evaporated to dryness under vacuum at low temperature; then the residue, dissolved in ethanol 95% (150 ml), was treated with sodium hydrate 4 N (25 ml) at room temperature for a night. After acidification with hydrochloric acid and filtration, 6-carboxy-2'-nitro-flavone (3.7 g) was obtained, which was subsequently treated with stannous chloride (20 g) in concentrated hydrochloric acid (15 ml) and glacial acetic acid (15 ml) at reflux temperature for 4 hours. After cooling, dilution with water, neutralisation with ammonium hydrate 28 Be, the precipitate was filtered to give, after crystallisation from dimethylformamide, 6-carboxy-2'-amino-flavone (1.8 g; m.p. > 300° C).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:11]C(=O)C)([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:11])([CH3:9])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(C)c1cccc(Br)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(N)c1cccc(Br)n1
Yield: 81.4 %

Procedure:
Combine N-[1-(6-bromo-pyridin-2-yl)-1-methyl-ethyl]-acetamide (3.3 g, 12.8 mmol) with 5N HCl (200 mL) and reflux overnight. Cool, add ice and neutralize with 1:1 ice: 50% NaOH until the mixture turns cloudy. Extract with dichloromethane, dry (Na2SO4), and evaporate to give 1-(6-bromo-pyridin-2-yl)-1-methyl-ethylamine (2.24 g, 81%). MS (m/z) 215 and 217 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[CH3:12][NH2:13]>CO>[OH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([NH:13][CH3:12])=[O:2]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cccc(O)c1
Yield: 60.6 %

Procedure:
A solution of 3-hydroxybenzoic acid methyl ester (2.00 g, 0.0131 mol), methylamine (0.06 mol) and methanol (30 mL) was heated to 155° C. for 12 hours in a sealed tube. The solvent was removed in vacuo and the product was purified by column chromatography over silica gel using a gradient elution from 5 to 8% methanol in dichloromethane to give 1.20 g (60.4%) of 3-hydroxy-N-methylbenzamide as a yellow solid. MS [M+H] 152.2, 1H NMR (CDCl3) δ (ppm) 7.55 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.01 (m, 1H), 6.65 (b, 1H), 6.20 (b, 1H), 3.03 (d, J=4.8 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:13]([I:14])=[CH:12][C:11]([C:15](=[O:27])[C:16]([C:18]2[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=2)=[O:17])=[CH:10][C:9]=1[I:28].Br[CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].Cl>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][O:7][C:8]1[C:9]([I:28])=[CH:10][C:11]([C:15](=[O:27])[C:16]([C:18]2[CH:19]=[C:20]([I:26])[C:21]([OH:25])=[C:22]([I:24])[CH:23]=2)=[O:17])=[CH:12][C:13]=1[I:14])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(C(=O)c1cc(I)c(O)c(I)c1)c1cc(I)c(O)c(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(COc1c(I)cc(C(=O)C(=O)c2cc(I)c(O)c(I)c2)cc1I)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.4 %

Procedure:
Cesium carbonate (1.30 g, 4.0 mmol) was suspended in a solution of 1,2-bis-(4-hydroxy-3,5-diiodophenyl)-ethane-1,2-dione (as prepared in Example 15, 1.49 g, 2.0 mmol) and benzyl 2-bromoacetate (0.46 g, 2.0 mmol) in 8 mL DMF. The mixture was stirred at RT for 16 hours and was poured into 1 M HCl. The resulting precipitate was isolated by filtration, then was dissolved in hot chloroform and filtered through Celite. The solvent was removed by rotary evaporation, and the crude material was purified by silica gel column chromatography (5% MeOH in CH2Cl2), yielding the title compound as a yellow powder (258 mg, 14%). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 8.23 (s, 2H), 7.45-7.34 (m, 5H), 5.27 (s, 2H), 4.73 (s, 2H). HPLC (50-90), 15.74 min. LRMS (EI−) calc'd for [C23H14I4O6—H] 893.0, found 892.6.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.CN(C)CC.C[Si](Cl)(C)C.Br[CH2:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][C:22]=1[Cl:35].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].P(=O)(O)(O)O>C1COCC1.O.C(OCC)(=O)C>[Cl:27][C:26]1[CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:23]=[C:22]([Cl:35])[C:21]=1[CH2:20][C@@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:7][C:6]1=[O:8]
Reactant: O=C1CC[C@@H](CO)O1
Reactant: Fc1ccc(-c2cc(Cl)c(CBr)c(Cl)c2)cc1
Agent: CCN(C)C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1O[C@H](CO)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Dissolve commercially available (S)-5-hydroxymethyl-dihydro-furan-2-one (33.0 g, 284 mmoles) in 450 mL of THF, and then add 31.2 g (427 mmoles) of dimethylethylamine along with 50 mL of THF (rinse). Place the mixture under nitrogen and cool in an ice/water bath. Add trimethylsilyl chloride 39.8 mL (313 mmoles) while maintaining the temperature below 13° C. Filter the mixture and rinse the cake with THF (2×100 mL). Cool the solution of TMS (trimethylsilyl) protected lactone to −78° C. and add 4-bromomethyl-3,5-dichloro-4′-fluoro-biphenyl (71.2 g, 213 mmoles). Add a 1 M solution of lithium hexamethyldisilazide in THF (264 mL, 264 mmoles) over 1 h at −65 to −78° C. After stirring for 1 h, add a 600 mL solution of 120 mL of conc. phosphoric acid in water. After stirring for 10 min at room temperature, add 1 L of ethyl acetate and stir the mixture for 10 min. The layers separate. Wash the organic layer with water (2×500 mL). Evaporate the solvent down to a solution of approximately 250 mL and add an additional 250 mL of EtOAc. Evaporate the solvent until a solution of approximately 300-350 mL remains. Heat the mixture to reflux and add 494 mL of heptane. Allow the slurry to cool to room temperature, collect the solids by filtration, and rinse with heptane (2×100 mL). Dry the solid under vacuum to afford 62.1 g (59%) of the titled compound. MS (m/z): 369 (M+1, 35Cl), 371 (M+1, 37Cl).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][CH2:15][OH:16].C([O-])(O)=O.[Na+]>CO>[CH2:1]([N:5]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(O)c1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCN(CCO)c1cccc(O)c1
Yield: 54 %

Procedure:
0.1 mol of 3-(n-butylamino)phenol in 100 ml of methanol is heated under reflux for 10 h with 0.11 mol of 2-bromoethanol and 0.1 mol of NaHCO3. After cooling, the reaction mixture is filtered, the solvent removed under reduced pressure and the residue fractionated to give 3-[N-(n-butyl)-N-(2-hydroxyethyl)amino]phenol.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[C:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[C:10]([C:34]3[CH:35]=[CH:36][C:31]([S:30][CH3:29])=[CH:32][CH:33]=3)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=c1c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)cnn1-c1ccccc1
Product: CSc1ccc(-c2cnn(-c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Yield: 92 %

Procedure:
The 2-phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-pyridazinone was coupled with 4-(methylthio)phenylboronic acid as in Example 9 to provide 2-phenyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 915 mg, 92%) which was immediately oxidized with peracetic acid as in Example 9 to provide the title compound after column chromatography (silica gel, 1:1 hexanes-ethyl acetate) and crystallization from diethyl ether-hexanes (yield: 288 mg, 69%). mp 219–220° C. 1H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H), 7.15 (t, J=9 Hz, 2H), 7.30 (m, 2H), 7.46 (m, 1H), 7.56 (m, 4H), 7.64 (m, 2H), 7.90 (d, J=9 Hz, 2H), 8.24 (s, 1H). MS (DCI/NH3) m/z 421 (M+H)+, 438 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:10]=[C:9]1[CH2:24][O:25][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:10]=[C:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2C(=O)OC(C)(C)C)C1
Agent: F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2c(cc(CO)n2C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,5-bis(t-butoxycarbonyl)-2-(t-butyldiphenylsiloxy)methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (2.10 g) in pyridine (20 ml), a mixture of hydrogen fluoride and pyridine was added at 0° C., followed by stirring at room temperature for 1 hour. After the reaction mixture was poured into ethyl acetate (50 ml) and ice water (300 ml) which had been stirred in advance, the resulting mixture was separated. The water layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (150 g of silica gel, hexane:ethyl acetate=3:1), whereby the title compound (882 mg) was obtained as a colorless, transparent caramel-like substance.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[C:32]([NH2:33])=[CH:31][CH:30]=[N:29]2)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:28]2[C:32]([NH:33][CH:1]=[C:15]3[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]3=[O:19])=[CH:31][CH:30]=[N:29]2)=[CH:34][CH:35]=1.[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCOC(OCC)OCC
Product: COc1ccc(Cn2nccc2NC=C2C(=O)OC(C)(C)OC2=O)cc1
Temperature: 80 °C

Procedure:
A stirred mixture of triethoxymethane (339 mL, 2037 mmol), and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (35.2 g, 244 mmol) was heated to 80° C. for 1 hour. A suspension of 1-(4-methoxybenzyl)-1H-pyrazol-5-amine [41.4 g, 204 mmol; prepared according to the procedure described by Misra, R. N., et al. Bioorg. Med. Chem. Lett. 2003, 13, 1133-1136, except desalting was performed as follows: 1-(4-methoxybenzyl)-1H-pyrazol-5-amine hydrochloride (44 g) was partitioned between MTBE (300 mL) and 1N aqueous NaOH (300 mL), after separating the phases, the aqueous suspension was re-extracted with MTBE (8×100 mL), followed by drying (Na2SO4) the combined organic phases, and concentration in vacuo to obtain the free-based 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (30 g)] in triethoxymethane (339 mL, 2037 mmol) was added at once and heating at 80° C. was continued for 18 hours under N2. After cooling to room temperature, toluene azeotrope (2×200 mL) was utilized to remove EtOH. The resulting suspension was diluted with diethyl ether (500 mL) and filtered to obtain a yellow solid (33.5 g, 46%). 1H NMR (400 MHz, CDCl3) δ 11.13 (d, J=13 Hz, 1H), 8.26 (d, J=13 Hz, 1H), 7.50 (d, J=2 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 6.21 (d, J=2 Hz, 1H), 5.28 (s, 2H), 3.78 (s, 3H), 1.74 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>[Pt].C(#N)C>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CS(=O)(=O)NCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Product: CS(=O)(=O)NCCNc1c(N)cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 8 L stainless steel Parr vessel was charged with N-[2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]methanesulfonamide (61 g), 5% Pt/C catalyst (6.0 g) and acetonitrile (3 L). The vessel was evacuated, filled with hydrogen (45 psi, 3.1×105 Pa), and shaken at ambient temperature overnight. The reaction mixture was filtered through CELITE filter agent and concentrated under reduced pressure to provide N-[2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]methanesulfonamide.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[CH3:28][NH2:29]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:29][CH3:28])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CC#N
Product: CNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.51 g, 1.32 mmol) (Jochims, J. C. et al, Tetrahedron, 1965, 21(9), 2611-16) in CH3CN, was added neat methylamine hydrochloride (0.18 g, 2.64 mmol). The reaction was stirred at room temperature until complete by TLC (1.5 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography on silica gel (EtOAc:hexanes, 1:1), providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-methylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.35 g, 62% yield).1H NMR (500 MHz, CDCl3) δ 2.06 (s, 3H), 2.08 (s, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 2.98 (s, 3H), 3.82-3.88 (m, 1H), 4.10-4.16 (m, 2H), 4.28 (dd, 1H, J=4.6, 12.5 Hz), 5.17-5.22 (m, 2H), 5.74 (d, 1H, J=8.1 Hz), 5.92 (s, 1H), 6.21 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:18]([O-])([OH:20])=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([NH:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)ccc1NC(=O)C(F)(F)F
Product: O=C(O)c1cc(F)cc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Temperature: 0 °C
Yield: 80 %

Procedure:
5-Fluoro-2-(2,2,2-trifluoroacetamido) benzoic acid (140; 1.29 g, 5.1 mmol) was added, in small portions, to fuming nitric acid (7 mL) at 0° C. The resulting reaction mixture was stirred at 0° C. for 1 hand then poured into ice-water (10 mL). The resulting precipitate was collected by filtration, washed with water and dried to afford 5-fluoro-3-nitro-2-(2,2,2-trifluoroacetamido)benzoic acid 141 (1.2 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:51])[CH2:24][NH:25][C:26](=[O:50])[CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:49])[C@@H:37]3[CH2:41][CH2:40][CH2:39][N:38]3C(OC(C)(C)C)=O)=[CH:31][CH:30]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:52])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.C(OCC)(=O)C.[ClH:59]>>[ClH:1].[ClH:59].[Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:51])[CH2:24][NH:25][C:26](=[O:50])[CH:27]=[CH:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:49])[C@@H:37]3[CH2:41][CH2:40][CH2:39][NH:38]3)=[CH:33][CH:34]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:52])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)[C@@H]5CCCN5C(=O)OC(C)(C)C)cc4)c3Cl)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)[C@@H]5CCCN5)cc4)c3Cl)c2n1

Procedure:
8-[2,6-Dichloro-3-[N-[4-[(N-tert-butoxycarbonyl-L-prolyl)amino]cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (170 mg) was treated with 4M hydrogen chloride-ethyl acetate (2 ml) at ambient temperature for 30 minutes. The reaction mixture was concentrated to give 8-[2,6-dichloro-3-[N-[4-(L-prolylamino)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline dihydrochloride (152 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([CH3:12])=[N:7]2.[F-:14].[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([F:14])[C:6]([CH3:12])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc2cccc(Br)c2nc1F
Temperature: 90 °C
Yield: 105 %

Procedure:
A 1-L, three-necked round-bottomed flask equipped with a mechanical stirrer, a nitrogen gas inlet, and a temperature probe was charged 5-bromo-3-chloro-2-methylquinoxaline (21.5 g, 83 mmol), DMSO (215 mL) and KF (4.85 mL, 209 mmol), and the resulting mixture was heated at 90° C. for 2.5 h. The mixture was cooled to RT and ice/water (430 mL) was added. The precipitated solid was collected by vacuum filtration and then washed with water (100 mL) and dried in vacuo to afford 5-bromo-3-fluoro-2-methylquinoxaline (126f; 21 g) as a brown solid, which was used without further purification in the subsequent step: 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (1H, d, J=2.2 Hz), 8.01 (1H, d, J=1.2 Hz), 7.59 (1H, t, J=7.9 Hz), 2.79 (3H, d, J=1.4 Hz). 19F NMR (377 MHz, CDCl3) δ ppm −70.61 (1F, br. s.). m/z (ESI, +ve) 240.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:15])=[O:5])[CH3:2].[BH4-].[Na+].CO>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1O
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
The compound of step 1 (0.439 g, 0.900 mmol) was dissolved in THF (4 ml). The mixture was cooled to −30° C. and sodium borohydride (35 mg, 0.90 mmol) was added followed by dropwise addition of methanol. After 30 min, the mixture was partitioned between diethyl ether and 2 N hydrochloric acid, the aqueous phase was extracted with diethyl ether, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound as a mixture of stereoisomers.