Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]([O:25]CC)=O)[N:12]([CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[NH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([NH:28][C:23]([C:11]2[N:12]([CH3:22])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2Cl)n1C
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of ethyl 4,5-di-(2,4-dichlorophenyl)-1-methylimidazole-2-carboxylate (20 mg, 0.045 mmol) from Step D in neat 1-aminopiperidine (1 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (1 mm, silica) (25% ethyl acetate in hexanes to afford the title compound. HPLC/MS: 497 (M+1), 499 (100%, M+3), 501 (M+5); Rt=3.95 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][CH:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:21][CH:17]([CH3:16])[C:18]#[C:19][CH3:20])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CC#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(C)Oc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 135 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 60 mg of 3-pentyn-2-ol, to which 29 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 130 mg of 4-(2,3-difluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (167)).
Reaction SMILES: [N+](=[CH2:3])=[N-].C(=O)(O)[O-].[Na+].[CH3:9][N:10]1[C:14]([OH:15])=[C:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[Cl:26])[C:12]([CH3:28])=[N:11]1>C(OCC)C.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:9][N:10]1[C:14]([O:15][CH3:3])=[C:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[Cl:26])[C:12]([CH3:28])=[N:11]1
Reactant: C=[N+]=[N-]
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1c(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c(C)nn1C
Temperature: 0 °C

Procedure:
In a four necked flask, 1.4 g of 1,3-dimethyl-4-(2-chloro-4-nitrobenzoyl)-5-hydroxypyrazole was dissolved in 10 ml of ethyl ether. The solution was cooled with ice-water and an ether solution of diazomethane was added and the reaction was carried out until ceasing nitrogen gas. Diazomethane and ether were distilled off from the reaction mixture to obtain the precipitate of the reaction product. The precipitate was dissolved in methylene chloride. The solution was mixed with a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and methylene chloride was distilled off to obtain a solid product. The solid product was dissolved in toluene and adsorbed on a silica gel column and eluted with methylene chloride to obtain 0.8 g of 1,3-dimethyl-4-(2-chloro-4-nitrobenzoyl)-5-methoxy pyrazole having a melting point of 97° to 98° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([C:17]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C2CC2)C1
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a mixture of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500 mg, 2.68 mmol) in CH2Cl2 (10 mL) was added cyclopropanecarboxylic acid (276 μL, 3.48 mmol), followed by the addition of HATU (1.3 g, 3.48 mmol) and triethylamine (725 μL, 5.2 mmol). The reaction was complete after stirring for 1 h. After quenching with water, the aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was purified via silica gel chromatography 0-20% EtOAc/CH2Cl2 to afford (R)-tert-butyl 3-(cyclopropanecarboxamido)pyrrolidine-1-carboxylate (500 mg, 73%). LC/MS: m/z 255.3 (M+H)+ at 2.33 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:15])[CH2:9][C:10](OCC)=O)[C:3](OCC)=[O:4].C(O[CH:19]([O:23]CC)[O:20][CH2:21][CH3:22])C.[NH3:26]>O(C(=O)CC)OOC(=O)CC>[OH:15][C:8]1[C:9]([C:19]([O:20][CH2:21][CH3:22])=[O:23])=[CH:10][NH:26][C:3](=[O:4])[C:2]=1[CH3:1]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(C)C(=O)OCC
Reactant: N
Agent: CCC(=O)OOOC(=O)CC
Product: CCOC(=O)c1c[nH]c(=O)c(C)c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of diethyl 2-methyl-3-oxopentanedioate (10 g, 46.25 mmol) in 1,1′-trioxidanediyldipropan-1-one (400 mL) was added triethoxymethane (38 mL, 231.25 mmol), and the mixture was heated at 120° C. for 4 h, followed by the addition of 30% ammonia (600 mL) at 0° C. The reaction mixture was stirred at RT for another 2 h. LCMS monitored the reaction was completed. The precipitate was collected via filtration and dissolved in dichloromethane (400 mL). The solid was filtered off, and the filtrate was concentrated to get the title compound (5.5 g, crude) as a yellow solid. MS (ES+) C9H11NO4 requires: 197. found: 198 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:11]1[CH2:32][CH:12]1[CH2:13][CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:17]([CH3:20])(=[O:19])=[O:18].O>CN(C)C=O.C1C=CC=CC=1>[OH:11][CH:12]([CH2:32][O:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH2:13][CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)CCCCCCN(CCCC1CO1)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCN(CCCC(O)COc1ccc(F)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (57%) (278 mg., 0.0065 mole) in a solvent mixture of benzene (25 ml.) and dimethylformamide (25 ml.) is added, over 30 minutes, a solution of p-fluorophenol (730 mg., 0.065 mole) in dimethylformamide (10 ml.). This mixture is stirred 30 minutes at room temperature, then treated with a solution of ethyl 7-[N-(4,5-epoxypentyl)methanesulfonamido]heptanoate (2.2 g., 0.0065 mole) in benzene (10 ml.). The reaction is heated at 90° C. for eighteen hours, then cooled and poured into water (100 ml.). The organic phase is collected, washed with brine and dried over sodium sulfate. Evaporation in vacuo affords a heavy oil that is purified by chromatography over silica gel, using chloroform to elute. Evaporation of the appropriate fractions affords the subject compound. The yield is 1.4 g. (47%) of heavy oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][C@@H:10]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC.[F:56][C:57]1[CH:58]=[C:59]([Mg]Br)[CH:60]=[CH:61][CH:62]=1.P([O-])([O-])([O-])=O.Cl>C(Cl)Cl.CCOC(C)=O>[CH:27]1[C:22]2[CH:21]([CH2:20][O:19][C:17]([NH:16][C@H:10]3[CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:12]([C:13](=[O:15])[C:61]4[CH:60]=[CH:59][CH:58]=[C:57]([F:56])[CH:62]=4)[CH2:11]3)=[O:18])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)c1cccc(F)c1
Temperature: -78 °C

Procedure:
N-Boc-trans-4-N-Fmoc-amino-L-proline (0.24 g, 0.19 mL, 0.001 mol) in CH2Cl2 (10 mL) was treated with diphenylphosphinic chloride (0.001 mol) at 0° C. in the presence of Et3N (0.10 g, 0.14 mL, 0.001 mol) for 2 h. EtOAc (10 mL) was then added to the mixture, which was then washed successively with H2O (5 mL), saturated NaHCO3 aqueous solution (5 mL), and brine (5 mL), and dried over Na2SO4. The organic layer was concentrated in vacuo, and the resulting residue was dissolved in THF (10 mL). The solution was then cooled to −78° C. 3-Fluorophenylmagnesium bromide solution (1.0 M in THF, 1 mL, 0.001 mol) was added, and the mixture was gradually warmed to room temperature before being poured into a mixture of 0.1 M phosphate buffer (pH=7.2, 5 mL) and 1 M HCl aqueous solution (5 mL) at 0° C. The aqueous layer was extracted with CH2Cl2 (10 mL×3). The combined organic layers were washed successively with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The solvent was evaporated in vacuo, and the residue was purified by column chromatography (silica gel, hexanes:EtOAc=7:3) to afford a white solid (XIII-5, 0.27 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1cc(Cl)ccc1O
Product: O=C(Nc1cc(Cl)ccc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-chlorophenol (705 mg, 4.9 mmol) and 2-fluoro-5-nitrobenzoyl chloride (1.00 g, 5.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])=[C:7]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:29][CH:28]=1.Cl[C:39](OCC)=[O:40].O>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[C:14](=[O:15])[N:16]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[C:39](=[O:40])[N:26]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[CH:31][CH:32]=4)[C:7]=3[C:6]=2[N:5]=1
Reactant: COc1ccc(CNC(=O)c2cnc3ccc(Cl)nc3c2Nc2ccc(C(C)(C)C#N)cc2)cc1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cnc4ccc(Cl)nc4c3n(-c3ccc(C(C)(C)C#N)cc3)c2=O)cc1
Temperature: 60 °C
Yield: 46.9 %

Procedure:
Sodium hydride (1.0 g, 25 mmol) was suspended in 25 mL DMF. To the resulting mixture was slowly added dropwise a solution of 6-chloro-4-((4-(2-cyanoprop-2-yl)phenyl)amino)-N-(4-methoxybenzyl)-1,5-naphthyridine-3-carboxamide (2.43 g, 5 mmol) in DMF (25 mL) at room temperature. After the completion of the dropwise addition, the resulting mixture was warmed up to 60° C. and reacted for 1 hr. To the reaction mixture was slowly added dropwise ethyl chloroformate (1.36 g, 12.5 mmol) under an ice bath. After the completion of the dropwise addition, the resulting mixture was warmed up to 60° C. and reacted for 16 hrs. The reaction was cooled to room temperature, then slowly poured into water, and extracted with ethyl acetate (3×150 mL). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was separated by silicagel column chromatography (EtOAc/PE=0-1/5) to produce a pale yellow solid (1.2 g).
Reaction SMILES: [Na].[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14])=[CH:4][C:5]#[N:6].[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:17]([O:16][C:15](=[O:19])[NH:2]/[C:3](/[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14])=[CH:4]\[C:5]#[N:6])[CH3:18]
Reactant: N#CC=C(N)c1ccc(F)cc1Cl
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1Cl

Procedure:
At 40° C., 982 mg (42.7 mmol) of sodium were dissolved in ethanol (53 ml). 5.6 g (28.5 mmol) of 3-amino-3-(2-chlor-4-fluorophenyl)prop-2-enonitrile and 7.4 g (62.7 mmol) of diethyl carbonate were added, and the reaction solution was stirred under reflux for 4 h. 200 ml of ethyl acetate and 150 ml of water were added to the reaction mixture, and the pH was adjusted to pH=5 with hydrochloric acid. The organic phase was separated off, dried over magnesium sulfate and concentrated on a rotary evaporator. Removal of the solvent gave 6.77 g (88% of theory) of the product as a mixture of E and Z isomers.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][N:10]([CH3:13])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1.[C:16](OCC)(=[O:18])C>[Pd]>[CH3:16][O:18][CH:8]1[C:7]2[CH:15]=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]1=[O:14]
Reactant: COc1ccc2c(c1)CC(=O)N(C)C=C2
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COC1C(=O)N(C)CCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
Weigh out 5% Pd on carbon (100 g) to a suitable container and wet the catalyst with ethyl acetate (2 L) while maintaining a nitrogen blanket. Charge the catalyst slurry to a 10-gallon autoclave and rinse the container with ethyl acetate (1 L) while maintaining a nitrogen purge. Add 8-methoxy-3-methyl-1,3-dihydrobenzo[d]azepin-2-one (920 g, 4.5 mol) to the autoclave and rinse with ethyl acetate (4 L). Purge the autoclave with nitrogen, seal the autoclave and pressurize with hydrogen to 50 psi while stirring at 800 rpm and maintaining the reaction temperature between 20-30° C. The reaction is determined to be complete by 1H NMR after 5 hours. Filter the autoclave contents over hyflo and rinse with ethyl acetate, then concentrate the filtrate to obtain the product methoxy-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one as an off-white solid (868 g, 93% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][S:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:27].C([O-])(O)=O.[Na+]>C(#N)C.O>[CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([OH:27])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S1Cc2ccccc2-c2ccccc21
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Solvent: O
Product: OC1Sc2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 60 %

Procedure:
To a stirred solution of 6H-dibenzo[b,d]thiopyran-5-oxide (2 g; 0.0093 mol), 2,6-lutidine (4 ml; 0.034 mol) and acetonitrile (40 ml) was added a solution of trifluoro acetic anhydride (3.2 ml; 0.022 mol) in acetonitrile (10 ml) at 0° C. After 2 hours a solution of NaHCO3 (1 g) in water (25 ml) was quickly added at 0° C. and then the mixture was allowed to warm to room temperature. After 2 hours the mixture was poured into water (200 ml) and extracted with diethyl ether. The extracts were dried, concentrated and separated on silica gel chromatography column (ethyl acetate:cyclohexane 1:4 as eluant) to give 6H-dibenzo[b,d]thiopyran-6-ol; (1.2 g; yield 60%); m.p. 83°-86° C. By proceeding analogously the following compounds were obtained:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:16]1([CH2:15][N:11]2[C:12]3[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=3)[CH:8]=[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.093 mmol), β-alanine (660 mg, 7.4 mmol) and NaOMe solution (11 mL, 5.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 20 mg of the title compound as a yellow solid. MS: (+) m/z 436.38 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:5][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+].[C:30]([O:39]N1C(=O)CCC1=O)([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=O>C1COCC1.O>[OH:12][C:6]1([CH2:5][CH:4]([NH:13][S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:3][N:2]([CH3:1])[C:30](=[O:39])[O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CNCC(CC1(O)CCCCC1)NS(=O)(=O)c1ccc(C)cc1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(CN(C)C(=O)OCC[Si](C)(C)C)CC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of 1-(3-(methylamino)-2-(tosylamino)propyl)cyclohexanol in 3:1 THF/H2O v/v (4 mL) was added K2CO3 (240 mg, 1.74 mmol), followed by Teoc-OSu (248 mg, 0.96 mmol). The resulting solution was stirred at rt for 30 min and the organic solvent was removed under reduced pressure. The residue was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried, filtered and concentrated under vacuum. The residue was chromatographied on silica gel to give 2-(trimethylsilyl)ethyl 3-(1-hydroxycyclohexyl)-2-(tosylamino)propylmethylcarbamate (300 mg, 74% for two steps). MS m/z 469 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[C:17]([C:22]([O:24][CH3:25])=[O:23])=[N:18][CH:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1nccnc1Cl
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
To a 350 mL sealable tubed was added 4-(pyridin-2-ylamino)phenol (5.16 g, 27.7 mmol), methyl 3-chloropyrazine-2-carboxylate (4.78 g, 27.7 mmol), and cesium carbonate (9.93 g, 30.5 mmol) with DMSO. The tube was sealed and heated to 100° C. for three days. After cooling to temperature, the reaction was diluted with water and extracted with ethyl acetate. The combined, dark brown organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The brown residue was adsorbed onto silica under high vacuum and flash purified on (0.5 to 10% MeOH/DCM), affording the product as a pale tan solid (7.44 g, 23.1 mmol, 83%). MS (ESI, pos. ion) m/z: 323.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Na].C1(O)C=CC=CC=1.[O:18]1[CH2:33][CH:19]1[CH2:20][N:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH:23]1[O:25][CH2:24]1>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:24][CH:23]2[CH2:22][N:21]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:20][CH:19]([CH2:33][OH:18])[O:25]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Solvent: Oc1ccccc1
Product: COc1ccc(OCC2CN(Cc3ccccc3)CC(CO)O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
6.21 G of p-methoxyphenol (0.05 mole Aldrich) is dissolved in 150 ml of dry dioxane and 0.4 g of finely cut sodium is added to the mixture. Stirring is continued for 1 hour after which all of the sodium is reacted with the phenol. Then 10.96 g (0.05 mole) N,N-bis(2,3-epoxypropyl)benzylamine is added and the mixture stirred for 1/2 hour under nitrogen. A flask is fitted with a reflux condenser and the mixture added and heated at reflux for 18 hours. After cooling to room temperature, the entire mixture is poured into 300 ml of water and stirred for 1/2 hour. The aqueous mixture is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined, washed with 200 ml of water and 200 ml of saturated NaCl solution. The CHCl3 layer is then dried over anhydrous NaSO4 and evaporated in vacuo to yield 15.4 g (90%) of crude product as a pale yellow oil. The oil is chromatographed on 300 g of neutral Alumina III to give 11.8 g of the title A compound (69%). The 11.8 g of product is dried in vacuo to give the title A as a clear colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C@H:26]([N:33]([C:41](=[O:43])[CH3:42])[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:25][C@@H:24]3[CH3:44])=[O:22])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1)=[O:5])C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:41]([N:33]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C@H:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][CH2:11][N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[C:4]([OH:5])=[O:3])=[CH:16][CH:17]=2)=[O:22])[C@@H:24]([CH3:44])[CH2:25]1)(=[O:43])[CH3:42]
Reactant: CCOC(=O)c1nccn1CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCn3ccnc3C(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,4R)-1-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-1H-imidazole-2-carboxylic acid was prepared from (2S,4R)-1-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-1H-imidazole-2-carboxylic acid ethyl ester. The ester (0.100 g, 0.16 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 4 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-1-[3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-1H-imidazole-2-carboxylic acid in 65% yield.