Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:36].F[P-](F)(F)(F)(F)F.Cl.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([N:35]([CH3:36])[CH3:34])=[O:25])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)N(C)C)ccc2-n2cccc23)cc1OC

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid (40 mg, 0.09 mmol), HATU (34 mg, 0.090 mmol), N,N-dimethylamine hydrochloride (7.3 mg, 0.090 mmol) and iPr2NEt (62 μL, 0.36 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O). Pure fractions were combined and evaporated to yield 1′-(4-ethyl-3-methoxybenzoyl)-N,N-dimethylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide. ESI-MS m/z calc. 473.6. found 474.5 (M+1)+; Retention time: 1.80 minutes (3 min run).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[CH2:13]([C:15]1[NH:16][CH:17]=[C:18]([CH3:20])[N:19]=1)[CH3:14]>>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]2[C:1]3[N:16]([C:15]([CH2:13][CH3:14])=[N:19][C:3]=3[CH3:2])[CH2:17][CH2:18][CH:20]=2)=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: CCc1nc(C)c[nH]1
Product: CCc1nc(C)c2n1CCC=C2c1ccc(Cl)cc1

Procedure:
Combine 25 g (0.14 mol) of 4-chlorophenyl cyclopropyl ketone with 50 g (0.45 mol) of 2-ethyl-4-methylimidazole, and heat to 175° C. under argon for 40 hr. Isolate the title compound by column chromatography on 500 g of silica gel using 1% methanol/methylene chloride as solvent.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH2:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:23][C@@H:11]1[CH2:12][C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 23 °C

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine (0.098 g, 0.00027 mol) in Methylene chloride (2.0 mL, 0.031 mol) at 0° C. was added triethylamine (0.076 mL, 0.00054 mol) and benzyl chloroformate (0.044 mL, 0.00031 mol). The reaction was warmed to 23° C. overnight. The reaction was quenched by addition of water3 and the mixture was extracted with methylene chloride (3×). The organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 8% EtOAc/hexanes) to obtain 73 mg (54%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Br:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=O>>[Br:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:19]=1/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1cc(Br)c(C=CC(=O)O)cc1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3Br)nc2n(CCC)c1=O
Yield: 56.3 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.0 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.80 g (9.75 mmol) of 2-bromo-4,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.38 g (yield 56%) of Compound 57 as pale yellow needles.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Cl[CH:20]([CH3:24])[C:21]([OH:23])=[O:22]>C1(C)C(C)=CC=CC=1>[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:11][CH:12]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reactant: CC(Cl)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
208 parts of 50% sodium hydroxide solution are added portionwise at about 90° C. and at a reduced pressure of 270 mbar to a solution of 255 parts of 4-(2',4'-dichlorophenoxy)-phenol and 132 parts of 2-chloropropionic acid in 1,200 parts of xylene. By distilling off the water present in the reaction mixture, the reaction temperature is maintained at 90° C. The addition being complete, stirring is continued for 15 minutes at this temperature, subsequently the batch is brought to normal pressure. 400 Parts of water are then added, and stirring is continued for 10 minutes at 85° C. The batch is subsequently acidified at this temperature with 120 parts of phosphoric acid, and stirring is continued for 10 minutes. After elimination of the water phase via a separating funnel, xylene is distilled off under a pressure of 80 mbar, and the solids are dried at 60° C. and 250 mbar. 327 Parts of 2-[4'-(2,4-dichlorophenoxy)-phenoxy]-propionic acid are obtained. The content of pure final product is 99.5%, corresponding to a yield of 99.5% of theory. The residual amount of 4-(2',4'-dichlorophenoxy)-phenol is 0.3%.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.[H-].[Na+]>>[CH:13]1([CH2:16][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: O=Cc1c(Cl)n(CC2CC2)c2ccccc12
Yield: 98.2 %

Procedure:
Prepared from (1) (18 g), cyclopropylmethyl bromide (16.2 g) and NaH (2.8 g) yielding (4) (23 g), m.p. 108°-109° C. In this reaction THF was used as solvent instead of DMF and the reaction mixture was partly evaporated before treatment with water.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[N:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:12])=[CH:4][CH:3]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 56 %

Procedure:
Using general procedure A, 4-amino-N-benzyl-N-methyl-benzenesulfonamide (Mikhura, I. V.; et al., Russ. J. Org. Chem., 36, 1, 2000, 64-68) (852 mg, 3.09 mmol) and 1-Boc-4-piperidone (677 mg, 3.40 mmol) afforded 4-[4-(benzyl-methyl-sulfamoyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (796 mg, 64%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>N1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2ccccc2)N(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and phenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-phenoxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>>[CH:18]([NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23])([CH3:20])[CH3:19]
Reactant: CC(C)N=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CC(C)NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 71.2 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.077 mL (0.78 mMol) isopropyl isocyanate, 0.146 gm (71%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Br)cn1
Yield: 70 %

Procedure:
In a solution of 2.87 g of 2-amino-5-bromopyrimidine in 40 mL of pyridine, 6.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 2 days. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of 1,4-dioxane, a solution of 3.09 g of potassium hydroxide in 30 mL of water was added and stirred at room temperature for 3 hours. After the completion of the reaction, 20 mL of hydrochloric acid was added in the reaction mixture under cooling with ice and with stirring, extracted with ethyl acetate (50 mL×1), the organic phase was washed with 50 mL of 3N hydrochloric acid, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with neutral alumina column chromatography that was eluated with chloroform to obtain 5.52 g of the aimed product as white crystal.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35](O)[N:34]=2)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]2[N:34]=[C:35]([O:11][CH2:12][CH2:13][N:14]([CH3:15])[C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:36]=[CH:37][CH:38]=2)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(O)n2)c1=O
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 22.1 %

Procedure:
A mixture of 112b (3.3 g, 10 mmol), 5-Bromo-3-(6-hydroxypyridin-2-ylamino)-1-methylpyridin-2(1H)-one 101a (7.4 g, 25 mmol) and Cs2CO3 (4.1 g, 12.5 mmol) in DMF (40 mL) was stirred at 100° C. for 4 h. The mixture partitioned between EA and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give tert-butyl 2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl(methyl)carbamate 112c (1.0 g, 22%) as a yellow solid. ESI-LCMS: m/z=454.9
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:10][C:11]1[O:12][C:13]2[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[C:16]([O:25][C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[C:14]=2[CH:15]=1.O>CN(C=O)C>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C:16]2[C:14]3[CH:15]=[C:11]([CH2:10][N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])[O:12][C:13]=3[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: O=C1CCCN1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CN3CCCC3=O)oc2c1
Yield: 24.8 %

Procedure:
To a solution of 2-ketopyrrolidine (75.1 mg, 0.882 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 44 mg, 1.1 mmol) at room temperature. After stirring the reaction for 30 min, ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285a) (200 mg, 0.441 mmol) was added. The mixture was stirred at room temperature for another 2 h. Water was added to the reaction, and the product was extracted with CHCl3. The combined organic layer was dried and concentrated. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 95/5) to give the title compound (50 mg, 25%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 1.98-2.14 (m, 2 H) 2.42 (t, J=8.10 Hz, 2 H) 3.06 (s, 3 H) 3.44 (t, J=7.06 Hz, 2 H) 4.38 (q, J=7.16 Hz, 2 H) 4.58 (s, 2 H) 6.49 (d, J=0.75 Hz, 1 H) 7.04-7.12 (m, 2 H) 7.61 (d, J=1.13 Hz, 1 H) 7.83-7.94 (m, 2H) 8.05 (t, J=1.13 Hz, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: NCCNCCO
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCNCCO
Temperature: 60 °C
Yield: 77.8 %

Procedure:
2 g of 4-fluoro-3-methyl nitrobenzene, 1.61 g of 2-(2-aminoethylamino)ethanol and 2.14 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.4 g of 2-[2-(4-nitro-2-methylphenylamino)ethylamino]ethanol (5) were obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=O)C.[CH3:27][NH:28][NH:29][CH3:30]>C1(C)C=CC=CC=1.O>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:29]([CH3:30])[N:28]([CH3:27])[C:4](=[O:3])[C:5]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CNNC
Reactant: CCOC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(OC)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)n(C)n(C)c2=O)cc1
Temperature: 120 °C
Yield: 53 %

Procedure:
3-(4-methanesulfonylphenyl)-2-(4-methoxyphenyl)-3-oxo-propionic acid ethyl ester was dissoved in 20 ml of toluene and then 0.24 g of dimethyl hydrazine was added to the solution. The apparatus containing the mixture was heated and refluxed at 120° C. for 24 hours in the Dean-Stark trap apparatus. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The obtained organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant was recrystalized with n-hexane to give 160 mg of the title compound as a yellow solid(yield 53%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4](NC1CC1)=[O:5].Cl.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][CH2:25][NH2:26]>>[NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:26][CH2:25][CH2:24][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1)=[O:5]
Reactant: NCCc1ccc2ccccc2c1
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: Cl
Product: CC[C@H](N)[C@H](O)C(=O)NCCc1ccc2ccccc2c1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using 2-(naphthalen-2-yl)ethanamine hydrochloride in the seventh step (step B7).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].C[O-].[Na+].Cl.Cl[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3]1=[O:11]
Reactant: ClCc1cccnc1
Reactant: Cn1c(=O)[nH]c2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)n(Cc2cccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A mixture of 25 parts of 1,3-dihydro-1-methyl-2H-benzimidazol-2-one, 64 parts of sodium methanolate solution 30% and 240 parts of methanol is stirred for one hour at room temperature. Then there are added 27.88 parts of 3-(chloromethyl)pyridine hydrochloride and stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and the formed precipitate (sodium chloride) is filtered off. The filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 16 parts (39.3%) of 1,3-dihydro-1-methyl-3-(3-pyridinylmethyl)-2H-benzimidazol-2-one; mp. 90° C.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1.[I:38]I>C1COCC1>[I:38][CH:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(I)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole (2.62 g, 38.5 mmol), triphenylphosphine (10.1 g, 38.5 mmol), and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (6.0 g, 32 mmol) were combined in 20 mL of THF and cooled in an ice bath. A freshly prepared solution of iodine (9.76 g, 38.5 mmol) in 20 mL of THF was then added at the rate of maintaining the internal temperature below 12° C. After the addition was complete, the reaction was allowed to warm to RT and stirred for 16 h. The reaction mixture was partitioned between MeOtBu and 10% NaHSO3. The aqueous layer was back extracted with MeOtBu (2×) and the combined orgnia layers were washed with brine, dried (Na2SO4) and concentrated. The crude material was chromatographed through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide tert-butyl 3-iodopyrrolidine-1-carboxylate as a colorless oil. MS (ESI, pos. ion) m/z: 241.6 (M−56).
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[CH:3]([CH2:4][C:5](=[O:13])[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=[O:14]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[NH:1]1[C:11]2[C:12]3[C:3](=[CH:4][C:5](=[O:13])[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[C:2]1=[O:14]
Reactant: O=C1CC2C(=O)Nc3cccc(c32)N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C1Nc2cccc3[nH]c(=O)cc1c23

Procedure:
A mixture of (±)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione from Step C (200 mg, 1.06 mmol), and activated manganese (IV) oxide (185 mg, 2.13 mmol) was heated in toluene (3 mL) at 110° C. for 1 h. The mixture was filtered through a pad of Celite, washing with CH2Cl2:MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=187 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH2:22][CH3:23])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(Cl)Cl.O.O.[NH2:31][NH2:32]>>[NH:31]([C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH2:22][CH3:23])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[NH2:32]
Reactant: CCOc1cc2cc(CO)cc(-c3ccnc(Cl)c3)c2cc1OCC
Reactant: NN
Solvent: O
Solvent: ClCCl
Product: CCOc1cc2cc(CO)cc(-c3ccnc(NN)c3)c2cc1OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1-(2-chloro-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (3.90 g) in hydrazine hydrate (17.8 ml) is refluxed for 9 hours. The mixture is stirred at room temperature for 10 minutes, and further stirred under ice-cooling for 10 minutes. To the mixture are added methylene chloride and water, and the methylene chloride layer is separated, washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is dissolved in hot ethanol (20 ml), and allowed to cool overnight to give 1-(2-hydrazino-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (3.19 g).