Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([C:9]([NH2:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:14]2[C:15]3[C:10](=[C:9]([NH2:16])[C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:11]([C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)=[C:12]([C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)[C:13]=2[C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: Nc1c2ccccc2c(N)c2ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c2ccccc2c(N)c2c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)c12
Reaction time: 96 h
Yield: 86 %

Procedure:
In dimethylformamide, 0.05 mol of 9,10-diaminoanthracene, 0.35 mol of p-nitroiodobenzene, 0.14 mol of anhydrous potassium carbonate, and copper powder were added and refluxed with stirring for 4 days. After the reaction was completed, the reaction mixture was filtered, and the filtered product was thoroughly washed with dimethylformamide, water and acetone, followed by drying. Thus, 0.043 mol of brown tetrakis(p-nitrophenyl)-9,10-diaminoanthracene was obtained.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16](=[O:17])[C:15]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:14]([OH:29])[CH2:13][C:9]32[CH2:12][O:11][CH2:10]3)=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:16](=[O:17])[C:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:14]([OH:29])[CH2:13][C:9]32[CH2:10][O:11][CH2:12]3)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)CC2(COC2)N(Cc2ccc(-c3ccccc3)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(O)CNC(=O)C1=C(O)CC2(COC2)N(Cc2ccc(-c3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution in chloroform (20.0 mL) of the compound (2.60 g) obtained in step (1) above, trifluoroacetic acid (8.00 mL) was added and the mixture was stirred at room temperature for 12 hours. After concentrating under reduced pressure, ethyl acetate was added to the residue. With continued stirring, n-hexane was added and the precipitate was recovered by filtration to give the titled compound as a pale brown solid (2.18 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[C:6]([CH3:27])[C:7]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)C.[CH:28](=O)[CH3:29]>>[CH2:28]([N:15]([C:7]1[C:6]([CH3:27])=[CH:5][C:4]2[C:3]([CH3:1])=[CH:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:8]=1)[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[CH3:29]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(CC)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Yield: 66.2 %

Procedure:
Following General Procedure D, ethyl 4-(5-ethyl-3,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 55, 0.37 g, 1.0 mmol) was reacted with acetaldehyde (0.56 mL, 10.0 mmol) to give 0.25 g (63%) of the title compound as a clear oil.
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:11]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:23]([O:22][C:20]([CH2:19][N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C@@H:10]([C:9]([OH:31])=[O:8])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)C[C@H](C(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](C(=O)O)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 99.7 %

Procedure:
N-(t-butyloxycarbonyl)methyl-N-t-butyloxycarbonyl-D-leucine benzyl ester (2.1 g) was dissolved in methanol (25 ml), and 10% palladium-carbon (210 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless oil (1.66 g, 96%), which was directly used for the next reaction.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].[CH:18]1([C@H:21]([NH:29][C:30]([C:32]2[C:41]3[C:36](=[C:37]([Cl:42])[CH:38]=[CH:39][CH:40]=3)[C:35](=[O:43])[N:34]([CH2:44][CH2:45][CH3:46])[C:33]=2[CH2:47]Br)=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:20][CH2:19]1.[OH-].[Na+]>C1COCC1>[CH:18]1([C@H:21]([NH:29][C:30]([C:32]2[C:41]3[C:36](=[C:37]([Cl:42])[CH:38]=[CH:39][CH:40]=3)[C:35](=[O:43])[N:34]([CH2:44][CH2:45][CH3:46])[C:33]=2[CH2:47][N:15]2[CH2:16][CH2:17][N:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:13][CH2:14]2)=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:20][CH2:19]1
Reactant: CCCn1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(Cl)c2c1=O
Reactant: CC(C)(C)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCn1c(CN2CCN(C(C)(C)C)CC2)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
Triethyl amine (280 μL, 2 mmol) and 1-tert-butyl-piperazine (96 mg, 0.67 mmol) were added to 3-bromomethyl-8-chloro-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (0.56 mmol) in 10 mL THF. The reaction mixture was stirred at room temperature for 30 minutes and poured into 50 mL 0.5 N NaOH (aq). The mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was flash chromatographed on silica gel (gradient heptane-ethyl acetate/methanol) to give 190 mg of the title compound, yield 60%. LC-MS (m/z) 567.8 (MH+); tR=1.07.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[F:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13].[CH2:16]([N:19]1[CH2:23][C:22](=[O:24])[N:21]([CH2:25]O)[C:20]1=[O:27])[C:17]#[CH:18]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[F:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14][CH2:25][N:21]1[C:22](=[O:24])[CH2:23][N:19]([CH2:16][C:17]#[CH:18])[C:20]1=[O:27])=[O:13]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: COC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C(/F)C(=O)OC)C2(C)C)C1=O

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,E) 2,2-dimethyl-3-(2-fluoro-3-oxo-3-methoxy-1-propenyl)-cyclopropane carboxylic acid and [3-(2-propyn-1-yl)-2,5-dioxo-1-imidazolidinyl]-methanol were reacted to obtain [3-(2-propyn-1-yl)-2,5-dioxo-1-imidazolidinyl]-methyl (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-methoxy-1-propenyl]-cyclopropanecarboxylate with a specific rotation of [α]D20 =+3.5°±2° (c=0.5% in chloroform).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([S:30][CH3:31])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:30][CH3:31])=[N:18][N:19]3[C:24]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:23][C:22]([C:26]([CH3:27])([CH3:29])[CH3:28])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: CSc1nn2c(Cl)cc(C(C)(C)C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCNCC3)cc(C(C)(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
0.67 g (7.7 mmol) of piperazine in 10 ml of DMF was added to a solution of 1.23 g (3.1 mmol) of 3-benzenesulphonyl-5-tert-butyl-7-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.25 g (18%) of 3-benzenesulphonyl-5-tert-butyl-2-methylsulphanyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 236-237°.
Reaction SMILES: COC1C(OCOC)=C(OC)C(OC)=C(OCOC)C=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[C:31]([O:32]COC)=[C:30]([O:36][CH3:37])[C:29]([CH2:38][CH2:39][O:40]COC)=[C:28]([O:44]COC)[C:27]=1[O:48][CH3:49].O1CCCC1.C(O)(C)C.Cl>O1CCCC1.C(O)(C)C>[CH3:49][O:48][C:27]1[C:28](=[O:44])[C:29]([CH2:38][CH2:39][OH:40])=[C:30]([O:36][CH3:37])[C:31](=[O:32])[C:26]=1[CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: COCOCCc1c(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(OC)c(OCOC)c2OC)c(OC)c1OCOC
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCCCC1=C(OC)C(=O)C(CCO)=C(OC)C1=O
Reaction time: 12 h

Procedure:
503 Milligrams of 1-[2,4,5-trimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[ 2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(2-methoxymethyloxyethyl)phenyl]pentane was dissolved in a mixed solvent of 5 ml of tetrahydrofuran with 5 ml of isopropanol, to this solution was added 1 millilter of tetrahydrofuran-isopropanol (1:1) solution of 20%-hydrogen chloride, and the whole mixture was stirred for 12 hours. After concentrated the reaction mixture, the residue was treated by an azeotropic distillation with benzene, then dissolved in 8 ml of methanol, further a small amount of sodium hydrogen carbonate was added thereto, and oxygen gas was blown into the solution. 2 Hours later, the solution was concentrated, and 50 ml of dichloromethane was added, then washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After concentrated, the residue was recrystallized from diethyl ether to obtain 123 mg of 2-(2,5,6-trimethoxy)-1,4-benzoquinon-3-yl)-5-[2,5-dimethoxy-6(2-hydroxyethyl)-1,4-benzoquinon-3-yl]pentane. Yellow crystals.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][CH:34]=1>O1CCOCC1>[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([C:2]2[N:27]=[CH:26][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)=[CH:35][CH:34]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Fc1ccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)cc1
Solvent: C1COCCO1
Product: Fc1ccc(COc2ccc(Nc3ncnc4cnc(-c5ccc(C6OCCO6)o5)cc34)cc2)cc1

Procedure:
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine (1.82 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.75 g) in dioxan (40 ml) were reacted together as in Procedure B. The mixture was evaporated and the residue suspended in dichloromethane. This was then filtered through celite and the solvent evaporated. The gummy residue was then triturated with hexane giving a beige solid (1.21 g); m/z 485 (M+1)+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[NH3:15]>C(O)(C)C>[NH2:15][CH2:3][CH:2]([OH:1])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: N
Reactant: N#Cc1ccc(OCCC2CO2)cc1
Solvent: CC(C)O
Product: N#Cc1ccc(OCCC(O)CN)cc1
Reaction time: 24 h
Yield: 93 %

Procedure:
4-[2-(2-Oxiranyl)ethoxy]benzonitrile (38.5 g, 204 mmol; from step (d) above) was mixed with NH3 (1200 mL, conc.) and isopropanol (450 mL). The mixture was stirred at r.t for 24 h. The solid (by-product) was filtered off and the solvents were evaporated, to give 39.1 g (93%) of sub-title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1.[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([O:26][C:11]2[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][CH:10]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Fc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 70 °C
Yield: 46.4 %

Procedure:
Add dropwise potassium tert-butoxide in THF (34.6 mL, 34.6 mmol) to a solution of p-bromofluorobenzene (6.1 g, 34.6 mmol) in THF (144 mL) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (5.0 g, 28.9 mmol) at RT. Heat the mixture at 70° C. overnight. Cool the mixture to RT, quench with water, dilute with Et2O, and wash once with saturated NH4Cl. Back extract the aqueous with Et2O, dry the combined organics over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, eluting with 25% EtOAc/hexane to give 4.4 g (46%) of the title compound. LC-MS/ES m/z (81Br) 274 [M−tertBu+H]+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)C2C=CC=CC=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C:39]#[CH:40]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([NH:37][CH2:38][C:39]#[CH:40])=[O:33])[C:15]2[CH:24]=[CH:23][CH:22]=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C#CCN
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: C#CCNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 183 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 49 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 536 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:8][CH:9]=1)[OH:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:8][CH:9]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=[N:26][CH:27]=3)[N:6]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC(O)c1coc(-c2ccc(F)cc2)n1
Product: O=C(NCC(O)c1coc(-c2ccc(F)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 45 %

Procedure:
This compound was synthesized from 2-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (120 mg, yield 45%). 1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J=1.8 Hz, 1H), 9.27 (d, J=1.8 Hz, 1H), 9.13-9.10 (t, J=5.6 Hz, 1H), 8.84-8.83 (t, J=1.8 Hz, 1H), 8.11 (s, 1H), 8.03-8.00 (dd, J=8.5 Hz, 5.5 Hz, 2H), 7.39-7.35 (t, J=8.9 Hz, 2H), 5.74-5.73 (d, J=5.2 Hz, 1H), 4.85-4.81 (m, 1H), 3.77-3.71 (m, 1H), 3.56-3.49 (m, 1H). MS (ESI) m/z: Calculated for C20H13F4N5O4: 463.09. found: 464.0 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C@H:15]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:16]([NH:18][N:19]1[CH2:23][CH2:22][C@H:21]([N:24]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:20]1)=[O:17])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C@H:15]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:16]([NH:18][N:19]1[CH2:23][CH2:22][C@H:21]([N:24]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:20]1)=[O:17]
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC[C@H]2CCCN2C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC[C@H]2CCCN2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.6 %

Procedure:
To a solution of (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide(50 mg, 0.0831 mmol), prepared in Step A, in DCM (2 mL) was added TFA (2 mL). After being stirred at rt for 1 h, the reaction solution was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (58.8 mg, 97.1%).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:49]([O:50]CC2C=CC=CC=2)[C@H:48]([O:58][C@@H:59]2[O:88][C@H:87]([CH3:89])[C@@H:78]([O:79]CC3C=CC=CC=3)[C@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]2[O:61]CC2C=CC=CC=2)[C@@H:47]([CH2:90][O:91]CC2C=CC=CC=2)[O:46][C@@H:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16](C(OCC3C=CC=CC=3)=O)[O:17][CH2:18]2)[C@H:14]([O:30]CC2C=CC=CC=2)[C@@H:13]1[O:38]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[C@@H:59]1([O:58][C@@H:48]2[C@@H:47]([CH2:90][OH:91])[O:46][C@H:10]([O:11][C@@H:12]3[C@@H:19]([CH2:18][OH:17])[C@@H:15]([NH2:16])[C@H:14]([OH:30])[C@H:13]3[OH:38])[C@H:9]([OH:8])[C@H:49]2[OH:50])[O:88][C@H:87]([CH3:89])[C@@H:78]([OH:79])[C@H:69]([OH:70])[C@H:60]1[OH:61]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3[C@H]4CON(C(=O)OCc5ccccc5)[C@H]4[C@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](N)[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
The compound (115 mg, 86.8 μmol) synthesized in Example 15 (15a) was dissolved in methanol (20 mL) and ethyl acetate (1 mL) and hydrochloric acid (10 μL) and 20% palladium hydroxide-carbon (115 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 4 hours. After celite filtration, the solvent was distilled off under reduced pressure and the residue was purified by ion exchange resin (Dowex 50w×8) column (water—5% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound (30 mg, 73%) as a colorless amorphous.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=2[CH:8]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:17]=[CH:16][C:10]4[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=4[CH:8]=3)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1ccoc2cc(OCCCCCl)ccc12
Solvent: O
Product: O=c1ccoc2cc(OCCCCN3CCN(c4ccccc4)CC3)ccc12

Procedure:
The title compound was prepared by the method described above in Examples 1-3. Thus, 7-(4-chlorobutoxy)-4H-1-benzopyran-4-one, as prepared above in Preparation 2, (3.79 g, 15 mmol) was treated with 1-phenylpiperazine (2.59 g; 16 mmol) in the usual way, yielding 3.76 g of 7-[4-(4-phenyl-1-piperazinyl)butoxy-]4H-1-benzopan-4-one.1.5 HCL (H2O), mp 204°-206° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([C:14](O)=[O:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].II.CO>C1COCC1>[OH:15][CH2:14][CH:12]1[CH2:13][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 25 °C
Yield: 27 %

Procedure:
To a stirred suspension of sodium borohydride (1.92 g, 50.6 mmol) in dry THF (20 mL) is added a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid in dry THF (20 mL) at 0° C. A solution of iodine (4.71 g, 18.6 mmol) in THF (20 mL) is added dropwise (caution: gas evolution) under N2 atmosphere. The reaction mixture is allowed to warm to room temperature then heated under reflux for 18 h. The resulting white suspension is cooled to room temperature. MeOH is added until the suspension dissolved. The mixture is concentrated under reduced pressure, then quenched with 1M aqueous KOH (100 mL) and extracted with DCM (3×150 mL). The organic phases are combined, washed with water followed by brine and concentrated under reduced pressure to give 2.13 g (27%) of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH2:5].COCCOC.Cl.[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]1[O:31][CH2:3][CH2:4][N:5]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Cl
Reactant: NCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccccc1C1=NCCO1

Procedure:
To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of 1,2-dimethoxyethane are added simultaneously solutions of 31 g. of 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 60 ml. of 1,2-dimethoxyethane and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4-dimethylaminopyridine the mixture is stirred at room temperature overnight. The solution is refluxed for one hour and filtered. The solid is oven dried and partitioned between methylene chloride and water. The layers are separated and the organic phase dried over magnesium sulfate. The organic layer is concentrated and the residue collected and crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:13]([Zn]CC)[CH3:14]>O1CCOCC1>[CH2:13]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1CC
Temperature: 70 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of ethyl 2-chloropyridine-3-carboxylate (15 g, 81 mmol) in anhydrous 1,4-dioxane (150 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (1.3 g, 1.6 mmol) followed by a diethylzinc solution (75 mL, 83 mmol, 1.1 M solution in toluene). The mixture was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction was quenched with MeOH. Ethyl acetate (200 mL) was added. The mixture was extracted with 0.2 N HCl (200 mL). The organic layer was recovered. The pH of the aqueous phase was brought around 6 with 2 N NaOH. The mixture was extracted with EtOAc (1×100 mL). The combined organic extracts were dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% ethyl acetate/hexane), affording ethyl 2-ethylpyridine-3-carboxylate (8.8 g, 61% yield)