Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:22]([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][C:11]([O:13][CH3:22])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 15 mL of DMF charged with (3S)-3-[tert-butoxycarbonylamino]-3-phenylpropionic acid (8 mmol, 2.0 g), methyl iodide (15 mmol, 1.9 mL) and K2CO3 (15 mmol, 2.1 g), was stirred at RT for 16 h. The reaction mixture was poured into 50 mL of saturated NaHCO3, and the resulting solution was extracted with ether (3×50 mL). The combined organic phase was washed with 50 mL of H2O, dried with MgSO4, and the solvent removed under reduced pressure to yield the title compound as a slightly yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.26–7.38 (m, 5 H), 5.49 (br s, 1H), 5.13 (br s, 1H), 3.65 (s, 3H), 2.80–2.96 (m, 2H), 1.45 (s, 9H). MS (ESI): m/z 302 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH3:20])[C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][C:12]=1[CH3:20]
Reactant: NC(=O)c1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1nc(-c2ccc(F)cc2)oc1C
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of 667 mg (4.80 mmol) of 4-fluorobenzamide and 1.0 g (4.80 mmol) of methyl 4-bromo-3-oxo-pentanoate in 6 mL of dry toluene was heated at 120° C. for 16 h. The resulting dark slurry was cooled to rt, diluted with 10 mL of EtOAc, and washed with NaHCO3 (1×10 mL). The organic layer was separated, dried (MgSO4), and the solvents removed under reduced pressure. Purification of the material by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent to afford 308 mg of the title compound as a clear oil: 1H NMR (CDCl3, 400 MHz) δ7.97 (m, 2H), 7.11 (m, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36(s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:40])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:39])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]4C(=O)C5C(=CC=CC=5)C4=O)[N:22]=3)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.NN.[ClH:44]>C(O)C.CCOCC>[ClH:44].[NH2:28][CH2:27][C:23]1[N:22]=[C:21]([C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:11]([NH:10][C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=3)=[O:40])=[CH:18][CH:17]=2)=[O:39])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cccc(CN4C(=O)c5ccccc5C4=O)n3)cc2)no1
Agent: Cl
Agent: NN
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cccc(CN)n3)cc2)no1
Temperature: 70 °C

Procedure:
A suspension of N-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-6-((1,3-dioxoisoindolin-2-yl)methyl)picolinamide (60 mg, 0.11 mmol) from Step 1 of this example in ethanol was heated at 70° C. until a clear solution was observed. Hydrazine hydrate (0.1 mL) was then added, the resulting mixture was heated at 70° C. for 1 h. The reaction mixture was cooled to 0° C. and filtered through celite. The filtrate was concentrated under reduced pressure, and the crude residue was purified by preparative TLC, eluting with MeOH in DCM (10:1, v:v). The compound obtained was treated with 2N HCl in Et2O to form the corresponding hydrochloric acid salt. The salt was washed with cold water and dried in a vacuum oven to afford 6-(aminomethyl)-N-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)picolinamide hydrochloride (8 mg, 16%). LC-MS (ESI) m/z 409 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16]>C(O)CCC>[O:12]=[C:7]1[CH2:8][O:9][CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH:15][NH2:16])=[O:3]
Reactant: NN
Reactant: CCOC(=O)CN1CCOCC1=O
Solvent: O
Solvent: CCCCO
Product: NNC(=O)CN1CCOCC1=O
Yield: 56 %

Procedure:
As described for example 112a, (3-oxo-morpholin-4-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate at 100° C. for 6 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 56%). MS: m/e=174.4 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3].CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=1>O1CCCC1.O>[N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:25]2[CH:30]=[N:29][C:28]([CH:31]3[CH2:33][CH2:32]3)=[CH:27][N:26]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3]
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CN=[N+]=[N-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
To a solution of Example 220B (98 mg, 0.404 mmol) in tetrahydrofuran (1 mL) was added potassium t-butoxide (63.5 mg, 0.566 mmol) followed by addition of 2-bromo-5-cyclopropylpyrazine (Combi-Phos Inc) (89 mg, 0.445 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate (2×20 mL). Volatiles were removed with a stream of nitrogen. The residue was chromatographed on a 12 g SiO2 column eluted with 5% ethyl acetate/hexanes for 3 minutes and then with a gradient to 100% ethyl acetate over 20 minutes. The title compound (87 mg, 0.241 mmol, 59.7% yield) was isolated as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.09 (d, J=1.3 Hz, 1H), 8.06 (d, J=1.3 Hz, 1H), 5.44-5.39 (m, 1H), 4.12-4.04 (m, 1H), 3.71 (dd, J=12.4, 5.3 Hz, 1H), 3.64 (d, J=12.3 Hz, 1H), 3.57 (dd, J=12.4, 4.6 Hz, 1H), 3.39 (dd, J=12.4, 3.2 Hz, 1H), 2.30-2.06 (m, 3H), 1.41 (s, 9H), 0.97-0.90 (m, 2H), 0.87-0.81 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[C:5]2[CH3:13].[NH4+].[OH-].CCCCCC.C(Cl)[Cl:23]>O=P(Cl)(Cl)Cl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:23])[CH:6]=[C:5]2[CH3:13]
Reactant: Cc1cc(=O)[nH]c2ccc(Br)cc12
Reactant: ClCCl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc2ccc(Br)cc12
Temperature: 0 °C

Procedure:
A 0.46 g, (0.0019 mole) sample of 6-bromo-4-methyl-2-(1H)-quinolinone was dissolved in 3.0 ml POCl3 under N2 with stirring and heated to reflux for 2 hours. The solution solidified into a purple gum; 2.0 ml of extra POCl3 was added to dissolve the solid. The solution was then slowly poured onto a vigorously stirred slurry of 8 ml concentrated NH4OH and approximately 75 g of ice. An immediate pink crystalline solid formed. The slurry was transferred to a separatory funnel and extracted with five 30 ml portions of CH2Cl2. The extracts were washed with two 40 ml portions of water and dried over MgSO4. The solvent was removed under vacuum, leaving a rusty red crystalline solid, 0.48 g (97%). The product was taken up in hot absolute ethanol, Norite A decolourising carbon added, and filtered through Celite to yield a yellow liquid. Slow cooling of the ethanolic solution gave very fine, pink crystals, m.p. 139.1°-139.80° C. TLC showed Rf 0.25 on silica with 1:1 hexane:CH2Cl2 eluent. Anal. Calcd. for C10H7BrClN: C, 46.82; H, 2.75; N, 5.46; Br, 31.15; Cl, 13.82. Found: C, 46.97; H, 2.79; N, 5.42; Br, 31.08; Cl, 13.79.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:15][CH:12]2[CH2:14][CH2:13]2)[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: NC1CC1
Reactant: CC(=O)c1cnc(Cl)c(Br)c1
Product: CC(NC1CC1)c1cnc(Cl)c(Br)c1

Procedure:
1-(5-Bromo-6-chloropyridin-3-yl)ethanone and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give N-[1-(5-bromo-6-chloropyridin-3-yl)ethyl]cyclopropylamine [REx(113-2)] as a pale yellow oil.
Reaction SMILES: [OH-].[K+].I[CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([SH:22])=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1>O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([S:22][CH3:4])=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1
Reactant: CI
Reactant: Fc1ccc(Cn2c(S)nc3cncnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CSc1nc2cncnc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a stirred mixture of 4.6 parts of Potassium hydroxide and 200 parts of water were added portionwise 1.7 parts of iodomethane, followed by the dropwise addition of 3.8 parts of 9-[(4-fluorophenyl)methyl]-9H-purine-8-thiol. Upon complete addition, the whole was stirred for 2 hours at room temperature. The precipitated product was filtered off and dried, yielding 3.45 parts (73.9%) of 9-[(4-fluorophenyl)methyl]-8-(methylthio)-9H-purine; mp. 167.1° C. (interm. 25).
Reaction SMILES: S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH:14]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1.[C:33]1([CH3:39])[CH:38]=CC=[CH:35][CH:34]=1>O>[CH:14]1([N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:30](=[O:29])/[CH:31]=[CH:32]/[C:28]2[CH:35]=[CH:34][C:33]([CH3:39])=[CH:38][CH:27]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc(NC2CCCCC2)nc1
Reactant: CC1CCCO1
Reactant: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1ccc(/C=C/C(=O)N(c2ccccn2)C2CCCCC2)cc1
Temperature: 50 °C
Yield: 62 %

Procedure:
5.50 g (0.034 mol) of 4-methylcinammic acid, 61 ml of toluene and 0.27 g (3.7 mmol) g of N,N-dimethylormamide are provided and mixed with 4.8 g (0.041 mol) of thionyl chloride. Stirring takes place for 1 hour followed by heating to 50° C. The toluene and excess thionyl chloride are drawn off under vacuum. Then 18 ml of toluene and 4.8 g (0.037 mol) of ethyldiisopropylamine are added at 60° C. A solution of 6.8 g (0.037 mol) of cyclohexyl-2-pyridylamine in toluene is added and stirred for 1 hour at 60° C. Hydrolysis with water is performed and 2-methyltetrahydrofuran is added. The organic phase is separated and washed with water, 1 N NaOH and again with water. The organic phase is rotated and the residue crystallised from MTBE. The crystallised solid is drawn off, washed with MTBE and dried, wherein the desired compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][N:19]=1.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:20][N:19]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (5.00 g, 23.0 mmol) in dichloromethane (100 mL) was added 6-chloronicotinic acid (4.71 g, 29.9 mmol) and 2-chloro-1,3-dimethylimidazolium chloride (8.56 g, 50.6 mmol). After the suspension was stirred for 15 min at ambient temperature, it was cooled to 0° C. and N,N-diisopropyl ethyl amine (19.7 mL, 115 mmol) was added slowly. The reaction mixture was stirred for 18 h while warming to ambient temperature. It was washed with aqueous sodium carbonate (saturated) and the aqueous layers were extracted with dichloromethane. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 50:50) afforded the title compound (4.78 g, 61%) as a light yellow solid. MS: m/e=339.2 [M+H]+.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]1.[ClH:12].[NH2:13][OH:14]>N1C=CC=CC=1>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][C:5](=[N:13][OH:14])[C:6]=2[CH:11]=1
Reactant: Cl
Reactant: C1=COc2ccccc2C=C1
Reactant: NO
Solvent: c1ccncc1
Product: ON=C1CCCOc2ccc(Cl)cc21

Procedure:
A solution of 50 g of the benzoxepine previously obtained and 26 g of hydroxylamine hydrochloride in 200 ml of pyridine is kept at the reflux temperature of pyridine for 51/2 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][C:8]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[CH:22][CH:23]=2)[CH:31]=[CH:35][CH:34]=[CH:33]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)C(NC(=O)CCc1ccc(N)cc1)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(NC(=O)CCc1ccc(-n2cccc2)cc1)C(=O)OCC
Temperature: 65 °C

Procedure:
4,6 g of diethyl 4-aminobenzylacetamidomalonate in 104 ml of acetic acid are placed in a three-necked flask which is maintained under nitrogen. 7.02 g of sodium acetate are added, followed by 1.87 ml of 2,5-dimethoxytetrahydrofuran. The mixture is heated at 65° C. for 1 h 15 min, then cooled down and extracted with 100 ml of dichloromethane and 100 ml of distilled water. The aqueous phase is separated off after settling and then washed with 3 times 100 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water and then with 100 ml of a saturated solution of NaCl, separated off after settling and then dried over magnesium sulphate; the phases are filtered and then evaporated to dryness under reduced pressure (50 kPa) in order to yield 6.2 g of a solid which is purified by flash chromatography (eluent CH2Cl2/acetone 75/25 by volume). This results in 3.57 g of diethyl 4-(1-pyrrolyl)benzylacetamidomalonate in the form of a beige solid which melts at 110° C.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)#[N:2].Cl.[OH:15][NH2:16].C(N([CH2:22][CH3:23])CC)C>CO>[CH3:23][C:22]1[O:15][N:16]=[C:1]([CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[N:2]=1
Reactant: CCN(CC)CC
Reactant: NO
Reactant: N#CCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Product: Cc1nc(COc2ccc([N+](=O)[O-])cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-Cyanomethyl-4-nitrophenol (8 g) was dissolved in methanol (50 mL) and to the solution was added hydroxyamine HCl (3.4 g) and triethylamine (9.4 mL). The reaction mixture was refluxed for 4 d and the solvent was removed under reduced pressure. The residue was redissolved in THF (50 mL). To the solution was added AcCl (23 mL) and triethylamine (50 mL). The reaction mixture was stirred at rt overnight, then added water (30 mL) and NaOH (18 g). The reaction solution was refluxed overnight, then diluted with water (200 mL). The aq. solution was extracted with EtOAc (2×150 mL). After separation, the combined EtOAc layers were dried, evaporated. The residue was purified by flash column chromatography (EtOAc/hexanes=1/2, 1/1, EtOAc) and recrystallized from EtOAc and hexanes to give O-(5-methyl-1,2,4-oxadiazol-3-yl)methyl-4-nitrophenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:25][O:24][C:20](=[O:23])[CH2:21][O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 5 h
Yield: 58.2 %

Procedure:
To a solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (prepared as in Example 1, 150 mg, 0.535 mmol) in THF (2 mL) was added methyl glycolate (82.5 μL, 1.07 mmol) followed by DBU (160 μL, 1.07 mmol). The reaction was stirred for 5 h, diluted with 3/6/1 ethyl acetate/hexane/dichloromethane, and passed through a plug of SiO2 using 4/5/1 ethyl acetate/hexane/dichloromethane. The filtrate was concentrated, and the resulting solids triturated with dichloromethane/hexane to afford 95.1 mg (58% yield) of the titled ester as a white solid. ESI-MS m/z 306 (MH+), 304 (M−H)−.
Reaction SMILES: [N+:1]([O-:12])([O:3][CH2:4][CH:5]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][OH:7])=[O:2].ClC(Cl)(O[C:17](=[O:23])[O:18][C:19](Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[Si:31]([O:38][CH2:39]/[C:40](/[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[C:41](/[C:44]1[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1)\CO)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>ClCCl>[C:17](=[O:23])([O:18][CH2:19]/[C:41](/[C:44]1[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1)=[C:40](/[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)\[CH2:39][O:38][Si:31]([C:34]([CH3:37])([CH3:35])[CH3:36])([CH3:33])[CH3:32])[O:7][CH2:6][CH:5]([O:8][N+:9]([O-:11])=[O:10])[CH2:4][O:3][N+:1]([O-:12])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])OCC(CO)O[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\CO)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 127.4 %

Procedure:
To a −78° C. solution of 2.5 g (13.7 mmol) of 3-hydroxypropane-1,2-diyl dinitrate in 20 mL dichloromethane was added 1.36 g (4.57 mmol) of triphosgene followed by 1.22 mL (15.10 mmol) of pyridine. The resulting mixture was stirred for 5 min at −78° C. then warmed to rt for 15 min upon which the solution turned from cloudy to clear. The above solution was then transferred slowly to a −78° C. solution of 5.64 g (13.04 mmol) (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-ol and 1.11 mL (13.73 mmol) pyridine in 20 mL of dichloromethane. After complete addition, the reaction mixture was warmed to 0° C. and stirred for an additional 25 min. The reaction was then quenched with NH4Cl (aq) and the organic layer separated, dried (Na2SO4), filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography over silica gel (10-80% EtOAc/hexane) afforded 3.73 g of the title compound as an oil. 1H NMR (500 MHz, acetone-d6): δ 7.72 (d, 2H), 7.38 (d, 2H), 7.18-7.08 (m, 5H), 5.79-5.75 (m, 1H), 5.35 (s, 2H), 5.05 (dd, 1H), 4.87 (dd, 1H), 4.80 (s, 2H), 4.66 (dd, 1H), 4.49 (dd, 1H), 3.05 (s, 3H), 0.84 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH3:27][C:28]1[O:32][C:31]([CH:33]([NH2:35])[CH3:34])=[CH:30][CH:29]=1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:35][CH:33]([C:31]2[O:32][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:34])=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1ccc(C(C)N)o1
Product: Cc1ccc(C(C)Nc2ccc3c(NS(=O)(=O)c4cc(F)cc(F)c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=444.4 (M+H+), was prepared in accordance with the general method of example 61 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 1-(5-methyl-2-furyl) ethanamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[CH2:18]([S:20]([C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])=[CH:28][CH:27]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reactant: CCS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(F)cc23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A sealed tube containing (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (49 mg, 0.21 mmol), 1-ethanesulfonyl-4-fluoro-benzene (87 mg, 0.427 mmol), and potassium carbonate (73 mg, 0.53 mmol) was evacuated and filled with nitrogen. Anhydrous N,N-dimethylformamide (2 mL) was added. After being stirred at 100° C. overnight, the mixture was cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (10 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to give [4-(4-ethanesulfonyl-phenoxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (67.6 mg, 80%) as a white solid.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:26](=[O:27])[CH2:25][CH2:24][O:23][CH3:22])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: COCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COCCC(=O)Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,5-diamine (150 mg, 0.55 mmol) was dissolved in 3 mL pyridine and 3-methoxypropionyl chloride (70 mg, 0.0.57 mmol) and 4-dimethylamino pyridine (3 mg, 0.02 mmol) were added. The reaction mixture was stirred at 80° C. overnight and quenched by addition of 50 mL water and acetic acid until pH 5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0→0:100 gradient). The title compound was obtained as a brown solid (59 mg, 30%), MS: m/e=362.4 (M+H−).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1cc(F)cc(F)c1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cc(F)c(F)c(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,5-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.55-7.68 (m, 2H), 7.83-7.90 (m, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=5.1, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.