Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][C@H:5]([C:13]([OH:15])=[O:14])[NH:6][CH2:7]2.S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][C@H:5]([C:13]([O:15][CH3:21])=[O:14])[NH:6][CH2:7]2
Reactant: CO
Reactant: O=C(O)[C@H]1Cc2c(Br)ccc(O)c2CN1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1Cc2c(Br)ccc(O)c2CN1
Temperature: 85 °C
Yield: 98 %

Procedure:
Slurry the 5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-3(R)-carboxylic acid (1.538 g, 0.005652 mol) in methanol (60 mL). Add sulfuric acid (305 uL, 0.00572 mol). Heat at 85° C. for 2.5 days. Cool the solution to room temperature and concentrate under reduced pressure to a volume of ˜5 mL. Add ethyl acetate (100 mL) and neutralize with 10% aqueous potassium carbonate. Separate the layers and extract the aqueous layer with ethyl acetate (1×100 mL). Combine the organic layers and dry over magnesium sulfate. Concentrate the filtrate to give the desired product (1.65 g, 98%) as a light pink solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[CH:13][N:14]=2)=[CH:5][CH:4]=1.Cl.[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1.CCN(CC)CC>C(Cl)Cl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10]3[S:11][C:12]([C:15](=[O:16])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])=[CH:13][N:14]=3)=[CH:7][CH:8]=2)(=[O:34])=[O:33])[CH:31]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Cc1ccccc1C(=O)c1cnc(Nc2ccc(CN)cc2)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1cnc(Nc2ccc(CNS(=O)(=O)c3cc(F)ccc3C)cc2)s1

Procedure:
A mixture of 35.8 mg (0.1 mmol)[2-(4-aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride, 25 mg (0.12 mmol) 5-fluoro-2-methyl-benzenesulfonyl chloride (commercially available) and 69 ul (0.5 mmol) NEt3 in 3 ml DCM was stirred at 60° C. for 16 h. After evaporation of the volatiles the residue was taken up in 1.5 ml MeOH/formic acid 2/1 and subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 10 mg (21%) of the title compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:20][N:19]=[C:18]([CH2:21][NH2:22])[CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:20][N:19]=[C:18]([CH2:21][NH:22][C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NCc1cc(-c2ccco2)on1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cc1ccccc1)NCc1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
To a solution of 7 mg of phenylacetic acid and 5 mg of C-(5-furan-2-yl-isoxazol-3-yl)-methylamine in DMF were added 8 mg of HOBt, 9 mg of EDC and 0.02 mL of TEA. After stirring at room temperature for 18 hrs, the reaction mixture was concentrated in vacuo. The concentrate was purified by preparative HPLC to produce 4 mg of the isoxazole derivative (Yield: 35%).
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([N:19]1[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:23]=2[C:22](=O)[O:21]C1=O)[CH:17]=[CH2:18].Cl>CN(C=O)C>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:19]([CH2:16][CH:17]=[CH2:18])[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:23]=2[C:22]=1[OH:21])=[O:8])[CH3:11]
Reactant: C=CCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(C(=O)OCC)c(O)c2cnc(-c3ccccc3)nc21

Procedure:
To a 50 ml. solution of NaOEt (0.3 g. Na-0.013 mole) was added 2.08 g. (0.013 mole) of diethyl malonate and this was stirred 10 minutes, then stripped to dryness. DMF was added to form a solution and then 1.85 g. (0.0065 mole) of 1-(2-propenyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and heated at reflux for 1.5 hours. When cool, the reaction was poured into dilute HCl and the resulting precipitate collected on a filter and rinsed with water. Recrystallization from ethyl acetate gave 1.0 g. of product--m.p. 177°-180° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][O:8][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC(C)(C)C)cc1
Reaction time: 17 h
Yield: 76.8 %

Procedure:
Dissolve ethylene glycol mono-tert-butyl ether (2.62 g, 22.17 mmol) and triethylamine (3.36 g, 11.02 mmol) in 40 mL methylene chloride at 0° C. Dissolve para-toluenesulfonyl chloride (4.2277 g, 22.17 mmol) in 10 mL methylene chloride and add it dropwise to the reaction. After 30 minutes raise the reaction to room temperature and allow it to stir for 17 hours. Dilute the reaction with methylene chloride and wash it with water (1×), 1N HCl (1×), saturated aqueous sodium hydrogen carbonate (1×) and brine (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 4.6387 g of crude toluene-4-sulfonic acid 2-tert-butoxyethyl ester. Dissolve this crude material (1.2423 g, 4.56 mmol) and di-benzyl iminodicarboxylate (1.4385 g, 5.04 mmol) (see Synthesis, 1988, 992-994) in 20 mL acetonitrile. Add potassium tert-butoxide (575.9 mg, 5.13 mmol) to the reaction mixture and heat it to reflux for 24 hours. Cool the reaction to room temperature and remove the solvent in vacuo. Dissolve the residue in methylene chloride and wash it with water (1×) and brine (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 1.9215 g of crude material. Purify via Biotage chromatography (EtOAc/Hexanes) to afford 387.8 mg of (2-tert-butoxyethyl)dicarbamic acid benzyl ester (22%). MS (ES): m/z 386.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH:11]([C:16]1[CH:20]=[C:19]([CH:21]=O)[O:18][N:17]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:31]C(O)=O>O>[CH2:37]([O:36][C:30](=[O:35])[CH:31]=[CH:21][C:19]1[O:18][N:17]=[C:16]([CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])[CH2:12][CH:13]([CH3:14])[CH3:15])[CH:20]=1)[CH3:38]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)c1cc(C=O)on1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C=Cc1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Temperature: 550 °C
Yield: 95.5 %

Procedure:
A stirred mixture of [1-(5-formyl-isoxazol-3-yl)-3-methyl-butyl]-carbamic acid benzyl ester (407 mg, 1.3 mmol), pyridine (10 ml) and ethyl hydrogen malonate (255 mg, 1.9 mmol) was warmed to 550° C. After 2 days the mixture was cooled to room temperature, poured into water and extracted into EtOAc (3×). The combined organics were washed with 1N HCl, water, and brine; dried over NaSO4, filtered and concentrated under reduced pressure to give 480 mg of a yellow oil. Purification by Flash 40(small) chromatography eluting with 1:3 EtOAc/hexane gave 220 mg of the title compound as a light yellow oil. MS [M+1]+387.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cncc(Br)c2)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
3,5-Dibromopyridine (500 mg, 2.11 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 1.9 mmol), 1,1′bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (172 mg, 0.211 mmol), and potassium phosphate tribasic (1.34 g, 6.33 mmol) were combined in a 20 mL microwave vial and dissolved in dioxane (9 mL) and water (1 mL). The vial was sealed and flushed with argon. The reaction mixture was stirred at 90° C. for 2 hours. The vial was then cooled to ambient temperature and diluted with ethyl acetate. The organic layer was washed with water, brine, and then dried over anhydrous magnesium sulfate. The solution was then filtered and concentrated in vacuo. The crude material was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 8.44 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 3.91 (s, 3H). LRMS (ESI) calc'd for C9H8BrN3 [M+H]+: 238. Found: 238.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37].C[O-].[Na+:41].CO>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O-:38])=[O:37].[Na+:41]
Reactant: O=C(Nc1ccc(F)c(-c2ccc(Cl)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(F)c(-c2ccc(Cl)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
6-Chloro-7-(4-(6-(4-chlorophenyl)-5-fluoropyridin-2-ylcarbamoyl)phenoxy)-chroman-4-carboxylic acid (16.1 mg, 0.0291 mmol) was dissolved in MeOH-THF (0.5 mL-0.5 mL) and 0.5 M sodium methoxide solution in methanol (58.19 μl, 0.0291 mmol) was added. The mixture was stirred at ambient temperature for 1 hour and concentrated. The residue was chased with dichloromethane multiple times and dried under high vacuum to provide 17.0 mg of the title compound as white solid (101.6%). MS (apci) m/z=553.0 (M+2H—Na).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)[C:5](=[O:18])[N:4]=[CH:3]1.[CH2:19](N)C>CO>[CH2:1]([N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:11]=[CH:12][CH:13]=2)[C:5](=[O:18])[N:4]=[CH:3]1)[CH3:19]
Reactant: CCN
Reactant: Cn1cnc(=O)c(-c2cccc(C(F)(F)F)c2)c1
Solvent: CO
Product: CCn1cnc(=O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
Two g. of the intermediate atropamide of Example 2 was reacted with 1 cc. of 20 percent aqueous ethylamine in 20 ml. of methanol. The reaction mixture was stirred at reflux temperature for 6 hours and evaporated to dryness, and the residue was recrystallized from ethyl acetatehexane. The product was 1.3 g. of 1-ethyl-5-(α,α,α-trifluoro-m-tolyl)-4(1H)-pyrimidinone, m.p. 172°-173° C.
Reaction SMILES: [C:1]([C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].N>C(O)C.[Rh]>[NH2:2][CH2:1][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CCCC1
Agent: [Rh]
Agent: N
Solvent: CCO
Product: CCOC(=O)C1(CN)CCCC1

Procedure:
20 g of ethyl 1-cyanocyclopentanecarboxylate are placed in 200 ml of a 10% solution of ammonia in ethanol and hydrogenated at 60° C. under a pressure of 100 bar in the presence of rhodium-on-alumina for 72 hours. After filtration on cellite®--and evaporation, the residue is chromatographed on silica using a DCM/methanol/20% aqueous ammonia mixture (98/2/0.5; v/v/v) as the eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[Cl:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[CH2:27][C:28]([NH:30][CH3:31])=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([O:26][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]4)=[O:12])[S:10][C:3]=23)[CH:23]=[CH:22][C:21]=1[CH2:27][C:28]([NH:30][CH3:31])=[O:29]
Reactant: CNC(=O)Cc1ccc(O)cc1Cl
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC(O)C1
Product: CNC(=O)Cc1ccc(Oc2ccnc3cc(C(=O)N4CC[C@@H](O)C4)sc23)cc1Cl

Procedure:
was prepared from coupling of (7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-hydroxy-pyrrolidin-1-yl)-methanone (2b) with intermediate 63a following Method C. 1H NMR (300 MHz, CD3OD) δ 8.45 (d, 1H, J=5.47 Hz), 7.84 (d, 1H, J=17.33 Hz), 7.40 (d, 1H, J=8.48 Hz), 7.29 (d, 1H, J=2.26 Hz), 7.13–7.08 (m, 1H), 6.74 (d, 1H, J=5.46 Hz), 4.42 (bs, 1H), 4.03–3.90 (m, 2H), 3.74–3.58(m, 5H), 2.66 (s, 3H), 2.10–1.97(m, 2H). LCMS (ESI+) [M+H]/z Calc'd 446, found 446. Anal. (C21H20N3O4SCl.0.7CH2Cl2), C, H, N.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([OH:25])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:42][CH3:43].O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([O:25][CH2:42][CH3:43])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1cc(F)c(-c2cccc(F)c2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
6-(Benzylthio)-1-(2,3′-difluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (510 mg, 1.082 mmol) was dissolved in DMF (2163 μl). Then potassium carbonate (149 mg, 1.082 mmol) was added followed by iodoethane (96 μl, 1.190 mmol). After stirring at rt for 1 d, water was added. A gummy solid was collected with an aid of water, and dried. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in heptane, to provide 6-(benzylthio)-1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)quinolin-2(1 H)-one (534 mg, 99% yield) as white solid. Ink (ESI) [M+H]+=500.0. NMR (400 MHz, DMSO-d6) δ ppm 1.00 (t, J=6.94 Hz, 3 H) 4.01-4.13 (m, 2 H) 4.24 (s, 2 H) 6.60 (d, J=8.80 Hz, 1 H) 6.70 (d, J=9.59 Hz, 1 H) 7.18-7.35 (m, 6 H) 7.38-7.48 (m, 3 H) 7.49-7.63 (m, 3 H) 7.79 (d, J=2.15 Hz, 1 H) 7.96 (d, J=9.59 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH2:25][O:26][CH3:27])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:28]([O:30]C)=[O:29])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:32]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH2:25][O:26][CH3:27])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:28]([OH:30])=[O:29])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:32]=1
Reactant: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1cc2cc(F)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of methyl 2-(5-fluoro-1-benzofuran-2-yl)-3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinoxaline-6-carboxylate (135 mg, 0.31 mmol) in methanol (35.0 mL) and water (1.0 mL) was added sodium hydroxide (55 mg, 1.38 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30.0 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(5-fluoro-1-benzofuran-2-yl)-3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinoxaline-6-carboxylic acid (100 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][C:14]=1[F:23].[OH-].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:14]=1[F:23]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(S(C)(=O)=O)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Methyl 6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylate (78.0 mg, 0.226 mmol) was dissolved in THF (0.2 mL) and MeOH (0.2 mL), and 1.0 M aq. NaOH (0.90 mL, 0.90 mmol) was then added. The reaction mixture was stirred at room temperature for 40 min. The solution was then neutralized with HCl (12 M) to pH=7 and concentrated under reduced pressure to remove all the solvents. The residue was dissolved in THF and MeOH, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a white powder. LCMS calc. for C13H9F3NO4S (M+H)+: m/z=332.0. Found: 332.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].C(O)(=O)C.[N+:19]([O-])([O-:21])=[O:20].[K+].OS(O)(=O)=O>O>[OH:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[CH2:6][C:5]2=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: CC1(C)CC(=O)c2cc(O)ccc2O1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2c(ccc(O)c2[N+](=O)[O-])O1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 250 mL round bottom flask equipped with a magnetic stir bar was added 3 (810 mg, 4.2 mmol) and 15 mL of glacial acetic acid. The mixture was stirred at room temperature until all of the solid dissolved. To a 25 mL vial was added KNO3 (469 mg, 4.6 mmol) and just enough distilled water to dissolve all the KNO3. The aqueous KNO3 solution was transferred to the reaction flask with a pipet. The reaction flask was lowered into an ice water bath (˜10° C.). Concentrated H2SO4 (1 mL) was added drop-wise. The mixture was stirred until all starting material was consumed, as monitored by TLC analysis. Ethyl acetate (20 mL) was added, and the biphasic mixture was transferred into a 500 mL separatory funnel. Saturated aqueous Na2CO3 was added cautiously until the aqueous layer was pH˜7. The aqueous phase was extracted in ethyl acetate (3×20 mL), the combined organic phases were washed with brine (1×50 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum. The dry crude product was passed through a silica gel column using 25:1 CH2Cl/EtOAc as eluent (Rf=0.3). The product gives off a red color on an analytical silica gel plate illuminated with a shortwave UV lamp. The fractions containing the pure product were transferred to a pre-weighed flask, the solvent was evaporated and the concentrate was dried under high vacuum. The reaction furnished 715 mg (72%) of 4 as a yellow solid. 1H NMR (300 MHZ, CDCl3): δ 7.70 (bs, 1H), 7.21 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 2.76 (s, 2H), 1.46 (s, 6H). 13C NMR (75.5 MHZ, CDCl3): δ 188.9, 154.4, 145.0, 126.4, 124.7(2), 113.1, 80.6, 49.0, 26.4; HRMS (EI+): calculated for C11H11NO5[M+] m/z 237.0637, found 237.0633.
Reaction SMILES: Cl.[N:2]1[CH:3]=[C:4]([C:11](Cl)=[O:12])[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[NH2:14][C:15]1[CH:16]=[C:17]([CH:35]=[CH:36][C:37]=1[Br:38])[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:19]>N1C=CC=CC=1>[Br:38][C:37]1[CH:36]=[CH:35][C:17]([C:18](=[O:19])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[CH:16][C:15]=1[NH:14][C:11]([C:4]1[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=[N:2][CH:3]=1)=[O:12]
Reactant: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(N)c2)CC1
Reactant: O=C(Cl)c1cnc2ccccn12
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(NC(=O)c3cnc4ccccn34)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Imidazo[1,2-a]pyridine-3-carbonyl chloride hydrochloride (0.97 mg, 4.46 mmol) was slowly added in portions to a stirred solution of 3-amino-4-bromo-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (step 1) (900 mg, 2.23 mmol) in dry pyridine (15 ml). The reaction was stirred at RT for 18 hrs and quenched with water. The solvent removed in vacuo. The residue was treated with a small amount of MeOH to dissolve insoluble material then partitioned between aq. NaHCO3 and DCM. The organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product mixture was crystallised from MeOH to give a white solid;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:8]([N:15]([CH2:17][CH2:18]Cl)[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:8]([N:15]([CH2:17][CH2:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCNCC1
Reactant: CN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCN1CCCCC1)Cc1ccccc1
Yield: 58.5 %

Procedure:
A solution of piperdine (1.16 g, 13.6 mmol), the title compound of Step 10 (3.0 g, 13.6 mmol) and NaHCO3 (3.94 g, 46.9 mmol) in EtOH (24 mL) was refluxed overnight in a modification of the procedure of Bach, et al. [J. Am. Chem. Soc. 79, 2221-2225 (1957)]. After filtration, the filtrate was concentrated to a yellow murky oil. The oil was dissolved into a 1.0M KOH solution (10 mL) and was extracted with EtOAc (3×5 mL). The organic layer was washed with a 5% NaHCO3, solution (5 mL), H2O (5 mL), and brine (5 mL) and then was dried over MgSO4. The filtrate was concentrated and purified by medium pressure column chromatography on silica gel [eluting NH4OH-EtOH-CHCl3 (1:5:94)] to give 1.85 g (58% yield) of the title compound as an oil. The proton spectral data were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:5]([CH3:17])[C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14]O)[CH2:2][CH2:3][CH3:4].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][CH2:14][C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:17])=[O:16]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)CCCCCC#CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)CCCCCC#CCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of 1.65 g of the product of Step B in 16.5 ml of methylene chloride cooled to −5° C. there were added 2.85 g of carbon tetrabromide and 2.25 g of triphenylphosphine. The reaction solution was stirred for 30 minutes at 0° C. and chromatographed on silica (eluant: methylene chloride—ethyl acetate 90-10) to obtain 1.82 g of the desired product.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Solvent: O
Product: O=C1CCCC(=NNc2ccc(Br)cc2)C1

Procedure:
A solution of 4-bromophenylhydrazine hydrochloride (2.24 g) and 1,3-cyclohexanedione (1.23 g) in water (60 ml) was stirred at room temperature for 1 h, giving a precipitate. The solid title compound was filtered off and dried (1.63 g). t.l.c (D), Rf 0.35 On cooling a second crop was obtained (0.395 g)