Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[F:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[F:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: Cc1ccc(F)c(C2CC(=O)C=C(N)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(F)c(C2CC(=O)c3c(C)ccnc3C2)c1
Reaction time: 2 h
Yield: 162.8 %

Procedure:
In ethanol (35 ml) and toluene (60 ml) was dissolved 1-amino-5-(2-fluoro-5-methylphenyl)cyclohexen-3-one (1.3 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (2.0 g) and powdery potassium hydroxide (0.32 g). The mixture was refluxed, and to the mixture was added powdery potassium hydroxide (0.07 g), 30 minutes later; were added powdery potassium hydroxide (0.07 g) and 3-oxobutylaldehydedimethylacetal (0.16 g), 1 hour later; and was added powdery potassium hydroxide (0.07 g), 1.5 hours later. The mixture was stirred at the same temperature for 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column (ethyl acetate-hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give 7-(2-fluoro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.3 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]2[N:11]([CH2:17][C:18]([N:20]3[C@H:25]([C:26](=[O:37])[NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])[CH2:24][C@@H:23]4[C@H:21]3[CH2:22]4)=[O:19])[CH:12]=[C:13]([C:14](=[O:16])[CH3:15])[C:8]2=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:14]([C:13]1[C:8]2[C:9](=[N:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[N:11]([CH2:17][C:18]([N:20]2[C@H:25]([C:26](=[O:37])[NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=3[F:36])[CH2:24][C@@H:23]3[C@H:21]2[CH2:22]3)=[O:19])[CH:12]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc2c(C(C)=O)cn(CC(=O)N3[C@@H]4C[C@@H]4C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2nc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-acetyl-1-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester (Example 689, 70 mg, 0.133 mmol) in THF (3 mL) and water (0.3 mL) was added a 2N aqueous LiOH solution (0.664 mL, 1.33 mmol). The reaction mixture was stirred at 25° C. for 16 h, then a 1N HCl aqueous solution was added to acidify the reaction mixture to pH=2 to 3. The resulting aqueous suspension was filtered, the solid was washed with water and then dried in vacuo. The crude solid was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20% to 100% CH3CN in H2O in 20 min, 100% CH3CN 2 min, CH3CN and H2O containing 0.1% TFA). The pure fractions were combined, CH3CN was evaporated under reduced pressure and the resulting aqueous solution was lyophilized to give the title compound as a white solid. MS: 513 [M+H]+, 535 [M+Na]+; tR (HPLC conditions k): 3.14 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:16]=[CH:17][N:18]([CH2:20][CH3:21])[CH3:19])[C:5]([CH3:15])=[N:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([N:16]=[CH:17][N:18]([CH2:20][CH3:21])[CH3:19])[C:5]([CH3:15])=[N:6][C:7]=2[O:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:25][CH:24]=1
Reactant: CCN(C)C=Nc1cc(Br)c(OCCCC(C)C)nc1C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(C)C=Nc1cc(-c2ccc(Cl)cc2)c(OCCCC(C)C)nc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 126.3 %

Procedure:
In a 10 ml single-necked round-bottomed flask equipped with a condensor (equipment flame-dried), 160 mg of crude N′-[5-bromo-2-methyl-6-(4-methyl-pentyloxy)-pyridin-3-yl]-N-ethyl-N-methyl-formamidine and 77.2 mg p-chlorophenyl boronic acid are dissolved in 1.20 ml of dioxane. To this solution, 162 mg of K3PO4 in 0.60 ml of water is added at ambient temperature under Argon atmosphere. The resulting biphasic mixture is degassed under Argon atmosphere for 20 minutes, whereupon 3.0 mg of tricyclohexylphosphine and 2.6 mg of bis(benzylideneacetone)palladium are added. The resulting suspension is vigorously stirred at a temperature of 100° C. for 5 hours. After letting the reaction mixture reach ambient temperature, 5.0 ml of a saturated aqueous NH4Cl solution is added. The water phase is extracted with AcOEt. The organic phase is dried over sodium sulfate, filtered and the solvent removed in vacuo to get 220 mg of a yellow oil. Purification by flash chromatography over a silica gel cartridge (20 g; 60 ml) of a solid deposition with heptane/ethyl acetate 9:1, then 4:1, then 3:2 (v:v) gave 80 mg of the compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.Cl.Cl.[NH2:12][C:13]1([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:12][C:13]1([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:17][CH2:16][N:15]([C:7]2[C:2]([Br:1])=[C:3]([NH2:9])[N:4]=[CH:5][N:6]=2)[CH2:14]1
Reactant: NC1(CNC(=O)c2ccc(F)cc2F)CCNC1
Reactant: Nc1ncnc(Cl)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncnc(N2CCC(N)(CNC(=O)c3ccc(F)cc3F)C2)c1Br
Temperature: 60 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 5-bromo-6-chloropyrimidin-4-amine (272.7 mg; 1.24 mmol; 1.02 eq.), N-[(3-aminopyrrolidin-3-yl)-methyl]-2,4-difluorobenzamide dihydrochloride (400.0 mg; 1.22 mmol; 1.0 eq.), potassium carbonate (336.8 mg; 2.44 mmol; 2.0 eq.) in DMSO (5.00 ml) was stirred at 60° C. overnight. The reaction mixture was workup and the crude was purified by reverse phase pre-HPLC (Waters, basic condition) to afford the title compound in 76% yield. LC-MS: (M+1=427, obsd.=427).
Reaction SMILES: [Cl:1][P:2]1([Cl:12])[N:7]=[P:6](Cl)([Cl:8])[N:5]=[P:4]([Cl:11])([Cl:10])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([O-:18])=[CH:16][CH:15]=1.[Na+]>O1CCCC1>[F:13][C:14]1[CH:20]=[CH:19][C:17]([O:18][P:6]2([Cl:8])[N:7]=[P:2]([Cl:12])([Cl:1])[N:3]=[P:4]([Cl:11])([Cl:10])[N:5]=2)=[CH:16][CH:15]=1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Reactant: [O-]c1ccc(F)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(OP2(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N2)cc1
Temperature: -78 °C

Procedure:
60 parts of hexachlorocyclotriphosphazene were charged into a reactor together with 500 parts of tetrahydrofuran, and the mixture cooled at -78° C. The previously prepared sodium p-fluorophenoxide solution was added dropwise and reacted as in Example 1. The resultant product was worked up as in Example 1 to yield p-fluorophenoxypentachlorocyclotriphosphazene (b.p. 107° C at 0.02 Torr).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][CH2:8][NH:9]C(OCC1C=CC=CC=1)=O)([CH3:6])=[O:5])[CH3:2].CCO>[Pd].CCOC(C)=O>[CH2:1]([O:3][P:4]([CH2:7][CH2:8][NH2:9])([CH3:6])=[O:5])[CH3:2]
Reactant: CCOP(C)(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(C)(=O)CCN
Yield: 89.2 %

Procedure:
(2-Benzyloxycarbonylamino-ethyl)-methyl-phosphinic acid ethyl ester (1.3 g, 4.56 mmol) and 10% Pd/C (485 mg) were combined in a flask and EtOH (46 mL) was added. The reaction flask atmosphere was exchanged for H2 and the reaction was run at room temperature until complete, as determined by TLC (eluent: 100% EtOAc). The reaction was then filtered through Supercell NF and the filtrate was concentrated to yield (2-amino-ethyl)-methyl-phosphinic acid ethyl ester (615 mg, 90%) as a yellow oil in which white crystals began to form under high vacuum.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.[C:13]1(C)C=CC=CC=1>>[CH:5]([C:6]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH2:13])=[O:4]
Reactant: CC(=O)OCC=CCOC(C)=O
Reactant: Cc1ccccc1
Product: C=C(C=O)CCOC(C)=O
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A solution of 1,4-diacetoxy-2-butene (0.5 g) and HRh(CO)(PPh3)3 tethered on zeolite-β (0.05 g) in toluene (25 ml) was heated in an autoclave at 80° C., under 1000 psig of synthesis gas (50% by volume H2 and 50% by volume CO gas). The reaction was monitored for gas absorption. After the theoretical amount of gas absorption (44 psig) took place and consequently there was no further gas uptake, the reaction was stopped and then the autoclave was cooled to room temperature. The solid catalyst was recovered by decantation of the reaction mixture. The reaction mixture was analyzed by HP 6890 gas chromatograph to give pure 2-Formyl-4-acetoxybutene (99.9% yield and 100% selectivity to 2-Formyl-4-acetoxybutene). Later toluene was removed from the reaction mixture by distillation to get the pure fraction of 2-Formyl-4-acetoxybutene (b.p. 78-79° C./5 mm Hg). The recovered catalyst was recycled five times. It was found that there was no losses in activity upon each recycle. ICP analysis also showed no leaching of the rhodium catalyst.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:14]([CH2:18][C:19]#[CH:20])[C:15](=O)[CH3:16])(C)(=O)=O>CO>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([CH2:18][C:19]#[CH:20])=[C:15]([CH3:16])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Reactant: Nc1cccnc1N
Solvent: CO
Product: C#CCc1c(C)nc2c(N)cccn12
Yield: 17.3 %

Procedure:
A mixture of 2,3-diaminopyridine (62.8 g) and 3-mesyloxy-5-hexyn-2-one (109.5 g) in methanol (126 ml) was refluxed for 20 hours. After methanol was evaporated in vacuo, sodium bicarbonate aqueous solution was added to the residue and then the mixture was extracted with ethyl acetate, washed with water and sodium chloride aqueous solution, and evaporated in vacuo. The resultant residue was subjected to column chromatography on silica gel (310 g) and eluted with a mixture of methylene chloride and acetonitrile. The eluates containing the object compound were combined and evaporated in vacuo. The residue was suspended in diethyl ether and the resultant precipitates were collected by filtration to give 8-amino-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (18.42 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@@H:34]([CH2:36][OH:37])[CH3:35]>CN1C(=O)CCC1>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11]([NH:33][C@H:34]([CH3:35])[CH2:36][OH:37])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(=O)(=O)N1CCCC1
Reactant: C[C@@H](N)CO
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCCC2)nc(SCc2ccccc2)n1

Procedure:
The subtitle compound was prepared as a yellow oil by the method of Example 43 step ii) by reacting the subtitle product of step ii) (8.26 g) with (R)-alaninol (3.61 g) in NMP (60 ml). Yield: 7.6 g.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCc1nc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
To a stirred solution of ethyl 3-(1H-benzo[d]imidazol-2-yl)propanoate 6a (2.85 g, 13.1 mmol, 1.0 eq.) in tetrahydrofuran (100 mL) at 0° C., was added 60% sodium hydride in mineral oil (784 mg, 19.6 mmol, 1.5 eq.), and the reaction was stirred at 0° C. for 20 minutes. Benzyl bromide (4.47 g, 26.1 mmol, 2.0 eq.) was added at 0° C., and the reaction was stirred, with warming to room temperature, for 16 hours. The mixture was concentrated in vacuo and water (100 mL) was carefully added. The aqueous layer was extracted with dichloromethane (3×75 mL), and the combined organic extracts were washed with 1M hydrochloric acid (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (5% MeOH:95% EtOAc) gave 6b as an orange oil (3.32 g, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH2:19][CH3:20])[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:15][CH:16]([CH2:19][CH3:20])[CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1
Yield: 19.1 %

Procedure:
A solution of 0.20 mole (37.2 g) of 4,4'-dihydroxybiphenyl, 0.10 mole (15.1 g) of the above 2-methyl-1-bromobutane, and 0.60 mole (33.7 g) of potassium carbonate in 300 ml of ethanol was refluxed for 16 hours. After the reaction, the reaction solution was filtered and concentrated, then purified by column chromatography to obtain 4.9 g of 4'-(2-methylbutoxy)-4-hydroxybiphenyl. (yield: 58%)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:27])=[C:4]([C:7]([O:10]C)=[CH:8][CH:9]=1)[C:5]#[N:6].B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:27])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 3-fluoro-2-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-6-methoxy-benzonitrile (560 mg, 1.5 mmol, 1 eq) in CH2Cl2 (30 mL) was added BBr3 (1.14 g, 4.5 mmol, 3 eq) and the reaction was stirred overnight. The mixture was then poured into water, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 10:1 to 5:1) to give the title compound as a yellow oil (360 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4](=[O:7])[O:5][CH:6]=1.[C:8](O)([CH3:11])([CH3:10])[CH3:9].S(=O)(=O)(O)O>O>[C:8]([CH:3]1[C:2]([OH:1])=[CH:6][O:5][C:4]1=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)O
Reactant: O=C1CC(O)=CO1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)C1C(=O)OC=C1O
Temperature: 40 °C
Yield: 7.4 %

Procedure:
To 4-hydroxy-2-furanone (50 g, 0.5 mol) in tert-butanol (50 ml, 0.53 mol) was added concentrated sulfuric acid (25 ml). The mixture was heated at 40° C. for 20 h then allowed to cool. Water (250 ml) was added and the mixture was extracted with diethyl ether (3×250 ml), the diethyl ether layers were combined, washed with brine (250 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a brown solid. The solid was purified by silica gel chromatography with 0%→100% ethyl acetate/isohexane as eluent followed by two recrystallisations from ethyl acetate/isohexane (1:1) to afford the required product (5.75 g). Data for the title compound: 1H NMR (400 MHz, DMSO) δ 1.21 (9H, s), 4.48 (2H, s), 11.40 (1H, s); MS (ES+) m/e 156 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[NH:9][CH:8]=[C:7]([C:18]#[N:19])[C:6]2=O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:18]#[N:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Product: COCCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Yield: 87.5 %

Procedure:
A mixture of 6-methoxy-7-(2-methoxyethoxy)-4-oxo-1,4,-dihydro-3-quinolinecarbonitrile (180 mg , 0.66 mmol) and 2.02 g of phosphorous oxychloride is heated at reflux for 40 minutes then concentrated in vacuo. The residue is added to water and the pH is adjusted to 8 by the addition of aqueous sodium bicarbonate. The solids are collected by filtration, washing with water and hexane, to provide 169 mg of 4-chloro-6-methoxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 178-180° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[O:12])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)Nc2ccccc2)cc1)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 28 h
Yield: 34.8 %

Procedure:
To a solution of 4-({[(5-chloro-2-thienyl)sulfonyl]amino}carbonylamino)benzoic acid (69 mg) in DMF (0.7 mL) was added aniline (21 uL, 0.23 mmol), DIEA (3 eq.) then PyBOP (85 mg, 0.16 mmol). The reaction mixture was stirred at room temp for 28 hr, acidified and HPLC purified to give {[(5-chloro(2-thienyl))sulfonyl]amino}-N-[4-(N-phenylcarbamoyl)phenyl]carboxamide (29 mg, 45%). ES-MS (M+H)+=436, 438 (Cl).
Reaction SMILES: Cl.[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].O.[CH3:15]COCC>C(N(CC)CC)C>[NH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([O:6][CH3:15])=[O:5]
Reactant: CCOCC
Reactant: CC(N)(C(=O)O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(N)c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4.3 g of methyl DL aminophenylpropanoate hydrochloride, 43 ml of demineralized water, 86 ml of ether and 3 ml of triethylamine was stirred at 20° C. for 10 minutes and the aqueous phase was extracted with ether. The combined ether phases were dried and evaporated to dryness under reduced pressure to obtain 8.3 g of methyl aminophenylpropanoate.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:14][C:15]([F:32])([F:31])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH:11][C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:19]4[CH:20]=[CH:21][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=4)=[CH:27][CH:26]=3)=[O:29])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: Cc1cnc2ccc([N+](=O)[O-])cn12
Product: Cc1cnc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 3-methyl-6-nitroimidazo[1,2-a]pyridine and 4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>ClC(Cl)C>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: CCCCC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCCCC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 33 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.10 g, 0.42 mmol), valeryl chloride (0.049 mL, 0.42 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-ylpentanamide (45 mg). MS (ESI) m/z 325; HPLC purity 100% at 210-370 nm, 10.8 min.; 98.4% at 250 nm, 10.8 min.; (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H28N2O+H+, 325.22744; found (ESI, [M+H]+), 325.2265.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[CH2:5][NH:6]CCO.[C:15]([O:22][CH2:23][CH3:24])(=[O:21])[C:16]([O:18]CC)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[F:13])[CH2:5][N:6]1[CH2:24][CH2:23][O:22][C:15](=[O:21])[C:16]1=[O:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: OCCNCc1cc(F)c(F)c(F)c1
Product: O=C1OCCN(Cc2cc(F)c(F)c(F)c2)C1=O
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[(3,4,5-trifluorobenzyl)amino]ethanol (6.91 g) and diethyl oxalate (20 mL) was stirred at 170° C. for one hour. The reaction solution was concentrated under reduced pressure, and then a diethyl ether was added to the residue. The precipitated crystals were collected by filtration and then air-dried to obtain 7.38 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:30])[C:20]3[C:25]([C:26](=[O:29])[C:27]=2[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>C1COCC1>[C:38]([O:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:18]1[C:19](=[O:30])[C:20]2[C:25]([C:26](=[O:29])[C:27]=1[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:41])[CH2:39][CH3:40]
Reactant: COc1ccc(C(CCCCC(=O)NO)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)ONC(=O)CCCCC(C1=C(C)C(=O)c2ccccc2C1=O)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 6-(4-methoxyphenyl)-6-(3-methyl-1,4-naphthoquinon-2-yl)hexanohydroxamic acid (2.8 g) in THF (40 ml) was added triethylamine (1.4 ml) followed by addition of propionyl chloride (669 mg) at 0° C. The reaction mixture was stirred for 1 hour and partitioned between water and ethyl acetate. The organic layer was dried and concentrated. The residue was purified with silica gel chromathography using hexane-ethyl acetate as an eluent to give the titled compound (2.1 g).