Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:9]([O:13][CH2:14][CH2:15][NH2:16])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][CH2:14][CH2:15][NH:16][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OCCN
Reactant: O=Cc1ccncc1
Product: CC(C)(C)OCCNCc1ccncc1

Procedure:
Using 4-pyridine carboxaldehyde and O-tert butyl ethanolamine, and the synthetic procedure described for Intermediate 16, a crude sample of the title compound was prepared, which was used directly in the next stage of the synthetic sequence.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[N:16]=[CH:15]1>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:19]2[CH2:20][CH2:21][C:22]3[NH:14][CH:15]=[N:16][C:17]=3[CH2:18]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1nc2c([nH]1)CCNC2
Reactant: O=C(O)CCCCC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCCC1CCCCC1)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-cyclohexylpentanoic acid (0.94 g, 5.10 mmol) in DCM (4 mL) carbonyldiimidazole (0.83 g, 5.12 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then added to a solution of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (5.10 mmol) in DCM (4 mL). After 2.5 h DCM (50 mL) was added and the mixture was washed with water (3×15 mL). The organic layer was then dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol 9:1) whereby 0.35 g (24%) of the title amide was obtained as an oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[N:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=[O:28])=CC=1.[Cl-]>O>[C:1]1([CH:7]2[NH:13][C:8](=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCCCC1c1ccccc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCCCC(c2ccccc2)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 250 ml round-bottomed flask equipped with N2 inlet were added 7.33 g (38.8 mmol) 2-phenylcyclohexanone oxime (Chem. Ber., 55, 3664 (1922)) and 25 ml pyridine. The solution was cooled to 0° C. and 9.61 g (50.4 mmol) p-toluenesulfonyl chloride was added. The reaction was allowed to stir overnight as the ice melted, and then poured into water. Excess chloride was skimmed off the surface, and the reaction mixture was stirred at pH 4 for 3 hours. The precipitate was filtered, washed with water, and dried to a solid, 4.65 g (55%), mp 135°-137° C. (J. Am. Chem. Soc., 82, 4671 (1960)gives mp 139°-141° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nc(Cl)ccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Cl)ccc1CBr
Temperature: 25 °C

Procedure:
Methyl 6-chloro-3-methylpyridine-2-carboxylate (3.46 g, 18.6 mmol), NBS (3.32 g, 18.6 mmol) and AIBN (61 mg, 0.37 mmol) were stirred in refluxing CCl4 (40 mL) for 6 hours. The mixture was then cooled to room temperature and purified directly by silica gel chromatography (2-20% EtOAc/hexanes) to give the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.C(O[CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)(=O)C>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][CH:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:3]1)=[O:9])[CH3:12]
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)N1CCCC(N)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
A mixture of 3-amino-1-carbethoxypiperidine and 9-acetoxyxanthene in dry toluene is refluxed by the procedure of Example 1 to give N-(N-ethoxycarbonyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[Cl-].[NH4+].[OH-].[NH4+].Cl.[C:10]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])C=O)([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+]>CO.O1CCCC1>[C:23]([C:20]1[CH:19]=[C:16]([CH:15]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:21]=1[OH:22])[CH2:1][NH2:2])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN)cc(C(C)(C)C)c1O
Reaction time: 4 h

Procedure:
The covalent bonding of an antioxidant to a polymer to yield (An)nR can also be carried out as follows: first, to 0.1 mole of sodium cyanoborohydride (II), J. Am. Chem. Soc. Vol. 93, pages 2897 to 2904, 1971 and 0.2 mole of ammonium chloride in 50 ml of methanol:50 ml tetrahydrofuran is added sufficient concentrated ammonium hydroxide and concentrated hydrochloric acid alternatively, to give a pH between 5 and 7 as ascertained by touching a drop of the solution to wet universal indicator paper. Next, 0.1 mole of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (I) is added and the reaction stirred for about 4 hours while maintaining the pH of the reaction vessel at about pH 5 to 7. Then, the mixture is treated with 20 ml of 1 molar sodium hydroxide and extracted with 200 ml of a 10:1 volume of ethyl ether: hexane mixture to give 3,5-di-tert-butyl-4-hydroxybenzylamine (III), which is purified by silica gel column chromatography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:24]=1)#[CH:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1CCCCC1>O.CC(C)=O.[Pd](Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:22]#[C:21][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc2ccccc2c1Br
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(C)=O
Product: CCCS(=O)(=O)c1cccc(C#Cc2c(OCC(=O)OC(C)(C)C)ccc3ccccc23)c1
Temperature: 60 °C

Procedure:
A mixture of (1-bromo-naphthalen-2-yloxy)-acetic acid tert-butyl ester (Intermediate 217; 500 mg; 1.48 mmol), 1-ethynyl-3-(propane-1-sulfonyl)-benzene (618 mg; 2.97 mmol) and PPh3 (39 mg; 0.15 mmol) in water (4.40 ml) and Acetone (5.6 ml) was treated with palladium(II) chloride (13 mg; 0.07 mmol) and piperidine (295 μl; 2.97 mmol) and heated at 60° C. for 2 days. The reaction mixture was extracted with EtOAc, the organic phase was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a yellow sticky solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][C:33]([CH3:36])([CH3:35])[NH2:34])[CH2:23][CH3:24])[CH3:21].C(#N)C>C(OCC)(=O)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][C:33]([NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])([CH3:35])[CH3:36])[CH2:23][CH3:24])[CH3:21]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1CC(C)(C)N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)CC1CCCCN1CC(C)(C)NC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 62 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-l-yl]-1,1-dimethyl-ethanamine in a yield of 62% of theory. Colourless crystals, m.p. 160°-162° C. (acetonitrile and ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCC(O)c1cc2c(cc1C)OCO2
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 90.2 %

Procedure:
2.27 g of 1-(6-methyl-1,3-benzodioxol-5-yl)-1propanol, 0.1 g of p-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolved in 80 ml of benzene to obtain a solution. This solution was heated under reflux for 12 hours, while removing generated water. The reaction mixture was poured into water. The aqueous layer was basified and washed with ether. The aqueous layer was acidified and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated in a vacuum to obtain a pale yellow solid. This solid was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.83 g of the title compound as a white crystal.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:14])[CH:11]([OH:13])[CH3:12])=[CH:6][CH:5]=1)[CH3:3]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH2:14])[C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=1)[CH3:1]
Reactant: C=C(c1ccc(C(C)C)cc1)C(C)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=C(C(C)=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.75 g of alcohol 45 is dissolved in 300 ml of methylene chloride, and 25.1 g of manganese dioxide is added under nitrogen. It is stirred overnight at room temperature, filtered on Celite, and the residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 937 mg of title compound 46 in addition to 635 mg of the starting material is obtained as colorless oils.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:5](=[O:7])[N:6]=1.[CH:12]1(N)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:1][C:2]2[O:3][CH:4]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:5](=[O:7])[N:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCCC1
Reactant: CC(C)CC1OC(N)=NC1=O
Product: CC(C)CC1OC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isobutyl-1,3-oxazol-4(5H)-one and cycloheptylamine according to Method G+H.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C:7]([N:9]([C:11]1[C:12]([Cl:31])=[C:13]([C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)[CH3:10])=[O:8])=[O:4].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1)([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:31][C:12]1[C:11]([N:9]([CH3:10])[C:7](=[O:8])[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:44]2[CH2:45][CH2:46][N:41]([C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=3)[CH2:42][CH2:43]2)=[CH:29][CH:28]=[C:27]([Cl:30])[C:13]=1[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CBr)c3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCN(c5ccc([N+](=O)[O-])cc5)CC4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
A mixture of 8-[3-[N-(bromoacetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (90 mg), 4-nitro-1-(1-piperazinyl)benzene (48 mg) and potassium carbonate (94 mg) in dimethylformamide (2 ml) was stirred at ambient temperature for 1 hour and water added thereto. The mixture was extracted with ethyl acetate twice, and the combined organic layer was washed with water, dried and concentrated. The residue was purified by preparative thin-layer chromatography (10% methanol in dichloromethane) to give 8-[2,6-dichloro-3-[N-methyl-N-[2-[4-(4-nitrophenyl)piperazin-1-yl]acetylglycyl]amino]benzyloxy]-2-methylquinoline (44 mg).
Reaction SMILES: [SH2:1].[CH:2]([NH:6][C:7]1[C:12]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[C:11]([Cl:21])[N:10]=[C:9]([C:22]#[N:23])[N:8]=1)([CH2:4][CH3:5])[CH3:3].O.C(O)(=O)C>C(N(CC)CC)C.CN1CCCC1=O>[CH:2]([NH:6][C:7]1[C:12]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[C:11]([Cl:21])[N:10]=[C:9]([C:22](=[S:1])[NH2:23])[N:8]=1)([CH2:4][CH3:5])[CH3:3]
Reactant: S
Reactant: CCC(C)Nc1nc(C#N)nc(Cl)c1-c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CCC(C)Nc1nc(C(N)=S)nc(Cl)c1-c1c(F)cccc1Cl

Procedure:
At room temperature, hydrogen sulfide was introduced for 5 minutes into a solution of 1.0 g (2.9 mmol) of 4-sec-butylamino-6-chloro-5-(2-chloro-6-fluorophenyl)pyrimidine-2-carbonitrile in 0.36 g of triethylamine and 12 ml of N-methylpyrrolidone. After the reaction had ended, 20 ml of water were added, the mixture was neutralized with acetic acid and extracted with methyl tert-butyl ether and the organic phase was washed with water, dried over magnesium sulfate and concentrated.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:33])[CH2:31][CH3:32])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:33])[CH2:31][CH3:32])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)CC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
20 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 368 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxypropyl)imidazole-5-carbonitrile [prepared as described in step (b) above] dissolved in 20 ml of ethanol, and the resulting mixture was heated under reflux for 6 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 316 mg of the title compound as an amorphous solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][CH2:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[N+:23]([O-:29])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N+:16]=1[O-:30].C(OCC)C>C(Cl)(Cl)Cl>[CH3:12][S:13]([CH2:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[N+:23]([O-:29])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N+:16]=1[O-:30])=[O:9]
Reactant: COC(=O)c1c(CSC)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(CS(C)=O)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 1 h

Procedure:
A solution of m-chloroperbenzoic acid (9.4 g., 0.0465 m of 85 percent material) in chloroform (75 ml.) was added dropwise to a solution of 2-methylthiomethyl-3-carbomethoxyquinoxaline 1,4-dioxide (13.0 g. 0.0465 m) in chloroform (100 ml.). The mixture was stirred for one hour and then added dropwise, with stirring, to diethyl ether (1.1 liters). The yellow solid which precipitated was filtered off, washed with diethyl ether (50 ml.) and then with hexane (100 ml.) and dried. Yield = 13.4 g., 97 percent of product: m.p. 141°-142°C.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[N:5][CH:4]=1.[CH3:22][NH:23][CH3:24]>C1COCC1>[CH:16]1([C:8]([C:6]2[O:7][C:3]([CH2:2][N:23]([CH3:24])[CH3:22])=[CH:4][N:5]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNC
Reactant: OC(c1ccccc1)(c1ncc(CBr)o1)C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)Cc1cnc(C(O)(c2ccccc2)C2CCCCC2)o1
Reaction time: 8 h

Procedure:
A solution of (5-bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol (Intermediate 4) (3.2 g, 9.2 mmol) in THF (40 mL) was treated with a 2 M solution of dimethylamine in THF (40 mL, 80 mmol). A suspension formed after stirring for a few minutes. The reaction mixture was left at RT overnight and then the solid was filtered off and discarded. The filtrate was concentrated under reduced pressure and the residue was partitioned between DCM and satd. sodium hydrogen carbonate solution (aq.). The organic layer was dried (Na2SO4) and evaporated to afford the title compound as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CCOC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 286.9 %

Procedure:
To a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (102.9 g, 448.9 mmol) in EtOAc (1 L) at 10.9° C. was added a NaOH solution (2.5 M, 269 mL), and the biphasic reaction mixture warmed to 15.9 and then stabilized. Phenyl chloroformate (98.4 g, 156.5 mmol) was added in one portion and the temperature rose to 25.5 and then stabilized. The ice bath was removed and the reaction was monitored by HPLC. After 1 hour an additional 25 mL of 2.5 M NaOH was added. The reaction mixture was stirred overnight, and then diluted with EtOAc (200 mL). The organic layer was washed with brine (1 L), dried over Na2SO4 (200 g) and concentrated to about 400 to 500 mL of EtOAc. The concentrated solution was warmed to 60° C. After the solids had dissolved, heptane (2 L) was slowly added, during which solids formed. After stirring for 30 minutes the solid was collected via filtration and the cake was washed with 400-500 mL of heptane. The cake was dried in a vacuum oven at ambient temperature to yield 156.9 g (95.0%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.39-7.31 (m, 6H), 7.26-7.225 (m, 2H), 7.13 (br s, 2H), 6.96 (br s, 1H), 6.47 (br s, 1H), 2.42 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34]([O:36]C)=[O:35])=[N:4]1)[CH3:2].O.[K]>CO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34]([OH:36])=[O:35])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(=O)OC)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [K]
Solvent: CO
Solvent: O
Product: CCn1nc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a suspension of methyl 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (3 g, 5.95 mmol) in a mixed solvent of water (25.00 mL) and methanol (75 mL) was added potassium hydtoxide (1.668 g, 29.7 mmol). The mixture was stirred at room temperature for 0.5 h and then heated to reflux for 1 h when the yellow suspension turned into a clear yellow solution. LCMS indicated completion of the reaction. The mixture was cooled to room temperature and concentrated. The residue was dissolved in water (100 mL), and was then acidified to ˜pH 1 using aq. 6N hydrochloric acid. The white precipitates were collected by filtration, and the filtrate was extracted with ethyl acetate (2×100 mL). The combined organic layers were concentrated to provide more white solids that were combined with previous white precipitates and dried under high vacuum to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (2.8 g, 5.71 mmol, 96% yield). LCMS: (M+H)+: 491.4.
Reaction SMILES: [CH3:1][C:2]([CH3:45])([CH3:44])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:32]([F:43])[CH:31]=1)[C@H:19]([O:24][CH2:25][CH3:26])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5]>C(O)C.[Pd]>[CH3:45][C:2]([CH3:1])([CH3:44])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:32]([F:43])[CH:31]=1)[C@H:19]([O:24][CH2:25][CH3:26])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:5]
Reactant: CCO[C@H](C(=O)OC)[C@@H](C/C=C/c1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCO[C@H](C(=O)OC)[C@@H](CCCc1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 104740.4 %

Procedure:
A solution of methyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoate (350 mg, 0.566 mmol) in ethanol (15 mL) was hydrogenated over 10% palladium on charcoal (60 mg) at 3 bar and 20° C. for 16 h. The mixture was filtered through Arbocel filter aid and concentrated under reduced pressure. The residue was dissolved in cyclohexane and evaporated (twice) to give methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hexanoate (368 gm, 105%), as a colourless foam, which was taken onto the next step without purification.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12][C@H:11]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10]1.NN>C1(C)C=CC=CC=1>[F:1][C:2]([F:38])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Agent: NN
Solvent: Cc1ccccc1
Product: N[C@H]1CC[C@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 80 °C
Yield: 94.6 %

Procedure:
To a solution of 2-((1S,3R)-3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentyl)isoindoline-1,3-dione (122 mg) in toluene (0.89 mL) was added anhydrous hydrazine (69 μL), and the reaction mixture was heated at 80° C. for 12 h. The precipitate was removed by filtration, and the filtrate was evaporated in vacuo to give the title compound (88 mg). 1H NMR (400 MHz, CDCl3) δ 1.45 (1H, m), 1.66 (2H, broad s), 1.68 (1H, dd, J=7.2, 13.2 Hz), 2.04 (2H, m), 2.20 (1H, m), 2.45 (1H, dd, J=7.6, 13.2 Hz), 3.43 (1H, quintet, J=7.2 Hz), 3.52 (1H, d, J=8.8 Hz), 3.61 (1H, d, J=8.8 Hz), 4.45 (1H, d, J=13.2 Hz), 4.50 (1H, d, J=13.2 Hz), 7.23 (5H, m), 7.58 (2H, s), and 7.73 (1H, s). HRMS m/z calcd for C21H22F6NO (M+H)+ 418.1607. found 546.1620.