Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][OH:23]>CN(C)C=O>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:21][CH2:22][OH:23]
Reactant: OCCCl
Reactant: Oc1ccccc1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccccc1OCC(F)(F)F
Temperature: 102.5 °C
Reaction time: 10 h
Yield: 56.5 %

Procedure:
To a mixture of 2-(2,2,2-trifluoroethoxy)phenol (XI) (6 g, 0.03 mole), N,N-dimethylformamide (50 ml) and potassium carbonate (13.0 g, 0.09 mole) was added 2-chloroethanol (4.2 ml, 0.06 mole). Reaction mixture was heated to 100-105° C. and stirred for 10 hours. Reaction mass was filtered and the filtrate was concentrated under reduced pressure to distill out the N,N-Dimethyl formamide. To the residue was added water and product was extracted in ethyl acetate (50 ml). The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (5/95) as eluent to give 4.0 g of (XIV) as oil. Purity (By GC)=95%
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].[CH2:17](O)[CH2:18]C.[OH-].[K+].C(Br)CC>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:17][CH3:18])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CCCO
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCBr
Solvent: O
Product: CCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
of 1-acetamido-2-nitro-4-thiocyanatobenzene in 70 ml. of n-propyl alcohol containing 4.8 g. potassium hydroxide is treated with 2.6 g. n-propylbromide. The mixture is stirred overnight at 15°-20° C., then poured into water, and extracted with chloroform. The dried extracts are stripped under vacuum and the residual red oil is dissolved in 25 ml. of acetic anhydride. A few drops of sulfuric acid are added and the mixture left at 20°-25° C for 1 hour. Sodium acetate is added and the solvent removed under vacuum. The residue is treated with water and the crude product filtered off. Recrystallization from methanol gives 1-acetamido-2-nitro-4-n-propylthiobenzene. (This intermediate may also be obtained directly by alkylation of 1-acetamido-2-nitro-4-thiocyanatobenzene with n-propylbromide in dimethylformamide in the presence of sodium borohydride.)
Reaction SMILES: C1(C2NN=C(N[C:10]3[N:15]=[C:14]([NH:16][C@H:17](C4C=CC(F)=CC=4)C)[C:13]([CH2:26]O)=C[C:11]=3[F:28])C=2)CC1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>C(Cl)Cl>[N:41]([CH:13]([C:14]1[N:15]=[CH:10][C:11]([F:28])=[CH:17][N:16]=1)[CH3:26])=[N+:42]=[N-:43]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CO)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A round-bottom flask containing 1-(5-fluoropyrimidin-2-yl)ethanol (Method 74, 0.79 g, 5.55 mmol) was charged with triethylamine (0.67 g, 6.66 mmol) and anhydrous DCM (10 ml). The solution was cooled to 0° C., and methanesulfonyl chloride (0.70 g, 4.1 mmol) was added dropwise. The resulting mixture was allowed to stir at room temperature for 2 hours, at which point the volatile components were removed using a rotary evaporator. The residue was dissolved in DMF (15 ml) and treated with sodium azide (0.72 g, 11.1 mmol). The resulting mixture was stirred at room temperature for 60 hours. It was then partitioned between EtOAc and brine. The organic layer was obtained, dried (Na2SO4), and evaporated to dryness. The crude material was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a colourless oil (0.60 g, 65% yield over two steps). GC-MS, 167 (M), 138 (M-N2), 125 (M-N3); 1H NMR (CDCl3) δ 8.60 (s, 2H), 4.60 (m, 1H), 1.65 (d, 3H).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9]Cl)[CH2:4][CH2:3]1.[NH2:11][CH2:12][CH2:13][OH:14].[Cl-].[Na+]>O>[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:11][CH2:12][CH2:13][OH:14])[CH2:4][CH2:3]1
Reactant: ClCCN1CCOCC1
Reactant: NCCO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: OCCNCCN1CCOCC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 16.3 %

Procedure:
A mixture of 2-morpholinoethylchloride hydrochloride (23 g, 0.12 mol) and 2-aminoethanol (22 mL, 0.36 mol) was stirred at 140° C. for 5 hours. After the reaction mixture was cooled to room temperature, water (0.10 L) was added thereto. The resulting aqueous solution was saturated with sodium chloride and extracted with chloroform (100 mL×6). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was distilled to obtain 2-(2-morpholinoethylamino)ethanol (3.4 g, 16%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5]([Cl:22])[C:6]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:7][CH:8]=2)[N:3]=1.[CH:23]([C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)([CH3:25])[CH3:24].[H-].[Na+]>CN1C(=O)CCC1>[Cl:12][C:10]1[C:9]2[C:4](=[C:5]([Cl:22])[C:6]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:7][CH:8]=2)[N:3]=[C:2]([N:28]2[CH:29]=[CH:30][C:26]([CH:23]([CH3:25])[CH3:24])=[N:27]2)[CH:11]=1
Reactant: CC(C)c1cc[nH]n1
Reactant: Clc1cc(Cl)c2ccc(OCCN3CCOCC3)c(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)c1ccn(-c2cc(Cl)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)n1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To mixture of 2,4,8-trichloro-7-(2-morpholin-4-yl-ethoxy)-quinoline (0.34 g, 0.95 mmol) and 3-isopropyl-1H-pyrazole (0.63 g, 5.7 mmol) in NMP (3 ml) was added NaH (60% in mineral oil) (0.042 g, 1.05 mmol). The mixture was stirred at room temperature for over night and it monitored by LC-MS. The crude material was purified by pre-HPLC to afford 4,8-dichloro-2-(3-isopropyl-pyrazol-1-yl)-7-(2-morpholin-4-yl-ethoxy)-quinoline (0.204 g, 0.47 mmol).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1CCCN.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]([CH3:28])[CH2:24][C:25]([NH2:27])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]([CH3:28])[CH2:24][CH2:25][NH2:27]
Reactant: CC(CC(N)=O)c1cc2ccccc2[nH]1
Agent: NCCCc1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Product: CC(CCN)c1cc2ccccc2[nH]1
Yield: 75 %

Procedure:
This compound was prepared in in the manner described above for (19a) using 3-indolyl-butyramide and lithium aluminum hydride. A 75% yield was obtained as a yellow solid: mp 51-53° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[CH2:9]1.[Cl:15][C:16]1[C:22](Cl)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>CN(C=O)C.CCOC(C)=O>[NH2:20][C:19]1[C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]([Cl:15])=[C:22]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[CH2:9]2)[CH:21]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: N#CC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (2.93 g, 21.3 mmol) was added to a mixture of pyrrolidine-3-carbonitrile hydrochloride (1.41 g, 10.6 mmol) and 4,5-dichloro-2-nitroaniline (2.00 g, 9.7 mmol) in DMF (8 mL). The reaction mixture was stirred at 120° C. overnight, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, concentrated and the crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH2:23][OH:24])[CH:19]=2)=[CH:8][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:24][CH2:23][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH2:5][CH2:4][N:3]=3)=[CH:26][CH:25]=2)[O:22][N:21]=1)(=[O:29])[CH3:28]
Reactant: OCc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of 2.80 g of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-isoxazolemethanol (Example 11) and 0.82 g of acetic anhydride in pyridine was allowed to stand overnight at room temperature. The reaction mixture was poured into ice water and the solid material which formed was collected, dried and recrystallized from isopropyl alcohol to give 2.5 g of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-isoxazolemethanol acetate, colorless solid, m.p. 76°-77° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:41]=[CH:40][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=[C:24]3[C:37](=S)[NH2:38])=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.C([O-])(=O)C.[NH4+:48]>CC(C)=O.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:41]=[CH:40][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=[C:24]3[C:37](=[NH:48])[NH2:38])=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(C(=O)NCCc2ccc3c(c2)c(C(N)=S)cn3C(=O)OC(C)(C)C)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CI
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(C(=O)NCCc2ccc3c(c2)c(C(=N)N)cn3C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
t-Butyl 5-[2-[4-(3-t-butoxycarbonylaminoprop-1-ynyl)-benzoylamino]ethyl}-3-thiocarbamoyl-indole-1-carboxylate (73 mg, 0.13 mmol, reference example 78) is dissolved in acetone (75 mL) and methyl iodide (5 mL) added. This mixture is heated to reflux. After 15 minutes, the solvent is removed in vacuo giving a yellow residue. MS (ion spray) m/e 591 (M+H+). The residue (80 mg, 0.13 mmol) is dissolved in MeOH (15 mL) and ammonium acetate (0.5 g) added and this mixture heated at reflux for 20 minutes. The solvent is removed in vacuo and the residue partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 and the combined organic layers washed with water, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by reverse phase HPLC eluting with 30-70%/15 minutes, giving 22 mg. MS (ion spray) m/z 560 (M+H+).
Reaction SMILES: [OH:1][C:2]([CH2:24][CH:25]=[CH2:26])([CH2:21][CH:22]=[CH2:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].O[C:28](CC=C)(CC=C)CCCCCCCCCCCC(C)(C)C(O)=O.CC(C)(CCCCCCCCCCCC(CC=C)(O)CC=C)CO>>[CH3:18][O:17][CH:15]([O:16][CH3:28])[C:14]([CH3:19])([CH3:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH2:24][CH:25]=[CH2:26])([OH:1])[CH2:21][CH:22]=[CH2:23]
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)OC
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)O
Agent: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)CO
Product: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(OC)OC

Procedure:
##STR16## Methyl 14-hydroxy-2,2-dimethyl-14-(2-propenyl)-16-heptadecenoate ##STR17## 14-Hydroxy-2,2-dimethyl-14-(2-propenyl)-16-heptadecenal; ##STR18## 14-Hydroxy-2,2-dimethyl-14-(2-propenyl)-16-heptadecenoic acid ##STR19## and 2,2-Dimethyl-14-(2-propenyl)-16-heptadecene-1,14-diol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]([F:38])([F:37])[CH2:35]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:35][C:34]([F:38])([F:37])[F:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCC(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCC(F)(F)F)C1
Yield: 39 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2,2,2-trifluoroethylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (70 mg, 39%). LCMS (method B): RT=4.00 min, M+H+=528.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:8]2[NH:9][CH:10]=[CH:11][CH:12]=2)=O)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].C(O)COCCO>O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:8]2[NH:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc[nH]1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Clc1ccc(Cc2ccc[nH]2)cc1

Procedure:
Heat 20 g of 2-(4-chlorobenzoyl)pyrrole, 15 g of hydrazine hydrate, 28 g of potassium hydroxide and 100 ml of diethylene glycol to 150° for 2 hours. Allow the mixture to cool. Dilute it with water to twice its volume. Add hydrochloric acid to it until its pH is about 3 before extracting it with diethyl ether. Free the organic phase from solvent to obtain 2-(4-chlorobenzyl)pyrrole as oil remaining behind. Dissolve the oil in 25 ml of ethanol, and add this solution dropwise to a boiling mixture of 150 ml of 20% strength hydrochloric acid and zinc amalgum (prepared from 100 g of zinc, 10 g of mercury chloride and 150 ml of 0.5 N hydrochloric acid). Then add a further 200 ml of 20% strength hydrochloric acid and 50 g of amalgam and boil the resulting reaction mixture for a further 4 hours. Allow the mixture to cool, filter it, extract the filtrate with ethyl acetate (5×200 ml), concentrate the organic solution, add 6 N sodium hydroxide solution to the concentrate until zinc salts therein dissolve, and then extract with diethyl ether. Concentrate the ether solution. Dissolve the oil remaining behind in 200 ml of ethanol and hydrogenate on Pt/C contact. Filter the catalyst from the hydrogenated product. Concentrate the filtrate and then distil the concentrate under a vacuum to obtain the title compound [b.p. 76° to 79° at 0.005 mm of Hg]. The hydrochloric melts at 190° to 192°.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:13][C:14]1[CH:15]=[C:16]([N:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=3[N:11]=[CH:10]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=[N+]([O-])c1cccc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc2c1ncn2-c1cccc(Br)c1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
4-Nitrobenzimidazole (see Example 19. 0.75 g, 4.6 mmol), 1,3-dibromobenzene (1.11 ml, 9.2 mmol), potassium carbonate (0.64 g, 4.6 mmol) and a catalytic amount of Cu-bronze were mixed in dry 1-methyl-2-pyrrolidone (2 ml) and heated to 140° C. for 3 days. One equivalent of 1,3-dibromobenzene was added and heating was continued for 24 hours. The cooled reaction mixture was extracted with ethyl acetate. The extract was dried and concentrated and eluted through silica gel with ethyl acetate/methanol (9:1) to yield 7 g (33 mg, mp 180°-182° C.).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([C:15]1[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH:20]=1)[CH2:13][CH3:14].Cl>C(O)C.[Na]>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH:18]1[CH2:19][CH2:20][CH:15]([CH2:12][CH2:13][CH3:14])[C:16](=[O:21])[CH2:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCCC1=CCCCC1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
A solution of sodium metal (30 mg, 1.30 mmol) in absolute ethanol (4.0 mL) was stirred at −10° C. for 0.5 h. Diethyl malonate (3.5 mL, 23 mmol) was added at −10° C. followed by addition of a solution of 2-propylcyclohexenone (3.0 g, 21.7 mmol) in absolute ethanol (3.0 mL). The reaction mixture was stirred an additional 12 h at room temperature. The reaction mixture was acidified to pH 3 with 10% hydrochloric acid and then extracted several times with diethyl ether. The combined ether extracts were washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield a yellow oil. Purification by flash column chromatography (silica, 83:17 hexanes/ethyl acetate) gave 2-(3-oxo-4-propyl-cyclohexyl)-malonic acid diethyl ester (5.07 g): 1H NMR (300 MHz, CDCl3) δ 4.21 (q, J=7 Hz, 2H), 4.20 (q, J=7 Hz, 2H), 3.30 (s, 0.5H), 3.28 (s, 0.5H), 2.67–1.55 (m, 8H), 1.43–1.11 (m, 10H), 0.90 (t, J=7 Hz, 1.5H), 0.90 (t, J=7.0 Hz, 1.5H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=O.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]2[NH:5][CH:4]=[C:3]3[C:15](=[O:17])[N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=[C:2]3[C:11]=2[CH:10]=1)([O-:14])=[O:13]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCN(CC)CC
Product: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccccc1
Temperature: 135 °C
Yield: 85 %

Procedure:
In a vial were added 4a, phenyl hydrazine and triethylamine. The vial was sealed and heated to 135° C. for 12 hours. The product was collected by filtration and was washed with methanol in 85% yield. 1H-NMR (DMSO-d6) δ (ppm): 7.19 (1H, tt, J=7.32, 1.22 Hz), 7.42 (2H, t, J=7.56 Hz), 7.84 (1H, d, J=9.03 Hz), 8.16 (2H, dd, J=8.30, 1.22 Hz), 8.82 (1H, s), 8.89 (1H, d, J=2.44 Hz). m/z 307.3 (MH+).
Reaction SMILES: C[N:2](C)[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(CC)CC.NCCCCN>CC#N>[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)[C@@H](Cc1ccccc1)C(=O)O
Agent: NCCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-dimethylphenylalanine (15) (1.19 g, 6.2 mmol), Et3N (1.29 ml, 9.3 mmol), and 1,4-diamino butane (303 μl, 3.0 mmol) were dissolved in CH3CN (50 mL). O-benzotriole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) was added, and the reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The mixture was vacuum filtered (EtOAc), further concentrated under reduced pressure, and subjected to flash chromatography (EtOAc, then 10% Et3N in EtOAc) to afford 1.06 g (80%, non-optimized) of (16a) as white crystals. [α]25−105.7 (c=0.19, CHCl3); FTIR (neat) 1649, 1455, 1384, 748, 700 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.19-7.16 (m, 8H), 6.89 (t, J=5.7 Hz, 211), 6.40 (s, 1H), 5.90 (s, 1H), 3.13-3.04 (m, 6H), 3.12 (dd, J=12.7, 5.3 Hz, 2H), 2.79 (dd, J=13.4, 5.1 Hz, 2H), 2.23 (s, 12H), 1.24 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 171.68, 129.44, 128.88, 127.91, 125.69, 70.61, 41.91, 38.25, 32.84, 26.52; HRMS calculated for C26H39N4O2 (M+H)+ required 439.3073, found 439.3074.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[F:29])=[CH:14][CH:13]=2)[C:9]([CH3:30])=[N:8][C:7]=1[CH3:31])(=[O:5])[NH2:4].C(O)(=O)C>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[F:29])=[CH:16][CH:17]=2)[C:9]([CH3:30])=[N:8][C:7]=1[CH3:31])(=[O:5])[NH2:4]
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3F)cc2)nc1C(N)=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
Powdered potassium hydroxide (72.7 mg, 1.30 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetate (Intermediate 25-1; 170 mg, 0.43 mmol) in tert-butanol (2.0 mL) at 40° C. under nitrogen. The resulting suspension was stirred at 40° C. for 20 minutes. A thick precipitate formed so the reaction was quenched with acetic acid (0.124 mL, 2.16 mmol) in ethanol (20.0 mL) and the resulting solution stirred for a further 20 minutes before being evaporated to dryness. The resulting solid was partitioned between water (5 mL) and EtOAc (15 mL). The aqueous layer showed a pH=4˜5. The organic layer was separated and the aqueous re-extracted with EtOAc (2×5 mL). The combined organics were washed with brine (15 mL), dried over MgSO4 and evaporated in vacuo to give product. This was washed with Ether (5 mL) and dried under vacuum at room temperature to give an off white solid. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% formic acid) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetic acid (80 mg, 48.8%) as a colourless
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[N+](=[CH2:14])=[N-]>CCOC(C)=O.CO.CCOCC>[CH3:14][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=1)[NH2:11]
Reactant: C=[N+]=[N-]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)ccc1N

Procedure:
To a suspension of 5-chloroanthranilic acid (6.1 g) in AcOEt-MeOH (20 ml+10 ml), a solution of an excess amount of diazomethane in ether (50 ml) was added at 0° C. After termination of reaction, reaction solvent was evaporated to dryness to give the title compound (6.6 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:8])[CH3:2].Br[CH2:19][CH2:20][CH2:21][Cl:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]([CH3:16])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(C)C(=O)c1ccc(OCCCCl)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 58.6 %

Procedure:
A mixture of 4-(4-hydroxyphenyl)-3-methyl-4-oxo-butyric acid ethyl ester (12.5 g, 52.9 mmol), 1-bromo-3-chloropropane (11.3 mL, 114.6 mmol) and K2CO3 (21.9 g, 159 mmol) in acetone (200 mL) was stirred at 60° C. for 15 h. The reaction was cooled to RT and filtered over celite and the filtrate was evaporated at reduced pressure to give a crude residue. The crude residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted twice with methylene chloride. The combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude product. The crude product was purified by ISCO (330 g) chromatography using 15% EtOAc in hexane to produce 4-[4-(3-chloro-propoxy)-phenyl]-3-methyl-4-oxo-butyric acid ethyl ester (9.7 g, 56%), MS m/z 267 (M−45).