Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4]1=[O:14])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>C(OCC)(=O)C>[CH2:1]([N+:3]1([O-:23])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4]1=[O:14])[CH3:2]
Reactant: CCN1CCN(c2ccncc2)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC[N+]1([O-])CCN(c2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 74.3 %

Procedure:
1-Ethyl-3-(4-pyridyl)-2-imidazolidinone (0.71 g, 3.7 mmol) and 3-chloroperbenzoic acid (77%, 1.67 g, 7.4 mmol) were dissolved in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 40 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (2:3, v/v) were collected and concentrated to give the titled compound (0.57 g, 73%) as white crystals.
Reaction SMILES: C(OC([NH:8][C:9]1[C:13]([C:14]2[N:19]=[C:18]([OH:20])[C:17]([OH:21])=[C:16]([C:22]([O:24][CH3:25])=[O:23])[N:15]=2)=[CH:12][S:11][CH:10]=1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:8][C:9]1[C:13]([C:14]2[N:19]=[C:18]([OH:20])[C:17]([OH:21])=[C:16]([C:22]([O:24][CH3:25])=[O:23])[N:15]=2)=[CH:12][S:11][CH:10]=1
Reactant: COC(=O)c1nc(-c2cscc2NC(=O)OC(C)(C)C)nc(O)c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cscc2N)nc(O)c1O
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Ester 40 (828 mg, 2.25 mmol), prepared as described above, was treated with a 6:4 mixture of methylene chloride:trifluoroacetic acid (8 ml). The solution was stirred for 20 min then concentrated in vacuo and the residue dried to give methyl 2-(3-amino-4-thienyl)-4,5-dihydroxy-pyrimidine-6-carboxylate trifluoroacetate (860 mg, 99%) as a solid. 1H NMR (DMSO-d6): δ 8.32 (1H, s), 6.75 (1H, s), 3.87 (3H, s). MS m/z (MH)+ 268.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:18])[CH:12]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:20][C:21]1[CH:22]=[N+:23]([O-])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:12]2[CH2:13][C:14]([CH3:16])([CH3:17])[CH2:15]2)[NH:18][C:22]2[C:21]([CH3:20])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1cc2ccccc2[n+]([O-])c1
Reactant: CCOC(=O)c1ccc(C(N)C2CC(C)(C)C2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 64.3 %

Procedure:
(+/−)-4-[amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester (Intermediate 24) (45 mg, 0.17 mmol) was combined with 3-methylquinoline-N-oxide (27.4 mg, 0.172 mmol, Alfa Aesar, Ward Hill, Mass., USA) and dichloromethane (2 mL). Diisopropylethylamine (0.112 mL, 0.645 mmol) was added followed by bromotripyrrolidinophosphonium hexafluorophosphate (109 mg, 0.224 mmol). The solution was stirred at room temperature for 28 h before partitioning between ethyl acetate and aq. sat. NaHCO3. The separated aqueous layer was extracted with additional ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester (44.0 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.4 Hz, 2 H) 7.56-7.62 (m, 2 H) 7.46-7.53 (m, 3 H) 7.38-7.46 (m, 1 H) 7.12-7.20 (m, 1 H) 5.33 (dd, J=9.5, 6.7 Hz, 1 H) 4.77 (d, J=6.6 Hz, 1 H) 4.34 (q, J=7.2 Hz, 2 H) 2.67 (sxt, J=8.8 Hz, 1 H) 2.30 (s, 3 H) 1.97 (ddd, J=11.1, 8.1, 3.2 Hz, 1 H) 1.74-1.85 (m, 1 H) 1.66-1.73 (m, 2 H) 1.36 (t, J=7.1 Hz, 3 H) 1.16 (s, 3 H) 1.10 (s, 3 H); MS (M+1): 403.3.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:17][C:18]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5])=[O:19])(=[O:15])[CH3:14]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1c(N)cccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-6-nitrobenzonitrile (6.5 g) in pyridine (100 ml) is cooled in an ice bath and thereto is added dropwise acetoxyacetyl chloride (4.4 ml). The mixture is stirred at room temperature for 1 hour, and thereafter, pyridine is distilled off under reduced pressure, and then water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is washed with 1N hydrochloric acid and dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol to give the title compound (5.8 g) having the following physical properties.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CN1CCCC1=O.Br[Mg][CH2:23][CH:24]([CH3:26])[CH3:25].Cl>C1COCC1.C(OCC)C.[Fe+3]>[CH2:23]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11])[CH:24]([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)C[Mg]Br
Agent: [Fe+3]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CC(C)Cc1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1 g) and iron(3+) tris[(2Z)-4-oxopent-2-ene-2-oleate] (86 mg), and 1-methylpyrrolidin-2-one (2.8 ml) in THF (30 ml) was added a solution of 2M bromo(isobutyl)magnesium in diethyl ether (2.9 ml) under ice-cooling. The solution was stirred at room temperature for 30 minutes, and diluted with diethyl ether (30 ml), and then 1M HCl was carefully added thereto to complete the reaction. The reaction solution was extracted with EtOAc (100 ml), and the organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=100:0 to 95:5) to obtain 4-isobutyl-3-(trifluoromethyl)benzonitrile (320 mg) as a pale yellow liquid.
Reaction SMILES: [CH2:1]([C:4]1([CH2:21][OH:22])[CH2:9][CH2:8][CH2:7][N:6]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:5]1)[CH:2]=[CH2:3].O1C2C=CC=CC=2OC[CH:24]1CN1CCCC(COC)(C)C1>>[CH2:1]([C:4]1([CH2:21][O:22][CH3:24])[CH2:9][CH2:8][CH2:7][N:6]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Product: C=CCC1(COC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared from [3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]methanol using the procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[C:34](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30](=[O:33])(=[O:32])[NH:31][CH3:34])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNS(=O)(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.6 %

Procedure:
A mixture of 6-bromo-2-(4-sulfamoylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (264 mg), potassium carbonate (152 mg), methyl iodide (34 μl) and dimethylformamide (DMF) (5 ml) was stirred at room temperature for 5 hrs. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (83 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+](=[C:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[O:19])=[N-]>FC1C(F)=C(F)C(F)=C(F)C=1F.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[O:18][C:17]2[CH2:16][CH2:15][CH2:14][C:13](=[O:19])[C:12]=2[N:5]=1
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Reactant: N#Cc1ccccc1F
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: Fc1c(F)c(F)c(F)c(F)c1F
Product: O=C1CCCc2oc(-c3ccccc3F)nc21
Temperature: 60 °C

Procedure:
A mixture of rhodium acetate (32 mg, 72 μmol) and 2-fluorobenzonitrile (2.31 ml; 22 mmol) in perfluorobenzene (5 ml) is treated at 60° C. dropwise by a solution of diazocyclohexanedione (obtained in Stage 66.1; 1 g; 7.24 mmol) in 5 ml of perfluorobenzene. The reaction medium is maintained at 60° C. until exhaustion of the release of nitrogen (1 hour; TLC on SiO2: 2% MeOH/CH2Cl2). After cooling down to ambient temperature and filtration, the solvent of the filtrate is evaporated. The residue is purified by chromatography (SiO2: AcOEt/heptane: 1/1) in order to produce a light yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCOCC5)c4)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and morpholine (29 μL, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. Additional morpholine (29 μL, 0.33 mmol) was added and the mixture subsequently stirred at 60° C. in a sealed tube for 24 h. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (25 mg, 50%). LCMS (Method 5): Rt 3.66 min, m/z 748.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.0 Hz), 1.27 (9H, s), 1.46-1.56 (2H, m), 1.61-1.73 (2H, m), 1.75-1.98 (4H, m), 1.99-2.19 (2H, m), 2.42 (4H, t, J=4.0 Hz), 2.67 (2H, t, J=8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.20 (1H, m, obscured by water), ˜3.30 (1H, m, obscured by water), 3.53 (4H, t, J=8.0 Hz), 4.12 (2H, t, J=8.0 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95-6.99 (1H, m), 7.07-7.13 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.25-7.43 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.13 (1H, s), 8.21 (0.5H, s).
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:9]Cl)[C:6](=[O:11])[CH2:5]1.C([O:21][CH2:22][C:23]1[S:27][C:26]2=[N:28][C:29]([C:31]([F:34])([F:33])[F:32])=[CH:30][N:25]2[N:24]=1)C1C=CC=CC=1>O1CCOCC1.FC(F)(F)C(O)=O.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]([F:13])([F:12])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:9][C:30]2[N:25]3[C:26]([S:27][C:23]([CH2:22][OH:21])=[N:24]3)=[N:28][C:29]=2[C:31]([F:33])([F:34])[F:32])[C:6](=[O:11])[CH2:5]1
Reactant: O=C1CC(CC(F)(F)Cl)CN1CCl
Reactant: FC(F)(F)c1cn2nc(COCc3ccccc3)sc2n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(CC(F)(F)Cl)CN1Cc1c(C(F)(F)F)nc2sc(CO)nn12
Temperature: 90 °C
Yield: 36 %

Procedure:
A solution of 4-(2-chloro-2,2-difluoroethyl)-1-(chloromethyl)pyrrolidin-2-one a18 in dioxane (5 ml) is added to a hot solution (90° C.) of dry ZnCl2 (0.272 g, 2 mmol, 0.5 eq) and 2-[(benzyloxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a29 (1.3 g, 4 mmol, 1 eq) in dioxane (5 ml). The reaction mixture is heated at 90° C. for 3 days and 1,4-dioxane is removed under reduced pressure. The crude reaction mixture is taken up in trifluoroacetic acid (20 ml) and heated at 60° C. for 2 hours. After cooling, the trifluoro-acetic acid is removed under reduced pressure. The residue is purified by chromatography on silicagel (MeOH/CH2Cl2) and pure 4-(2-chloro-2,2-difluoroethyl)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one 7 (573 mg) is obtained after re-crystallization from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]C)[N:6]=[C:5]2[Cl:20].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[Cl:20]
Reactant: COc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.7 %

Procedure:
A solution of 6-bromo-4-chloro-2-(2-methoxyphenyl)quinazoline (0.14 g, 0.4 mmol) in CH2Cl2 (mL) was cooled in a dry ice/acetone bath. A solution of 1.0 M BBr3 in CH2Cl2 (1.2 mL, 1.2 mmol) was slowly added. The cooling bath was removed, and the reaction was stirred at room temperature for 2 h. The reaction was diluted with CH2Cl2 and made basic with a saturated NaHCO3 solution. The organic layer was separated, washed with water, dried over Na2SO4, and evaporated to give 6-bromo-4-chloro-2-(2-hydroxyphenyl)quinazoline (0.15 g).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:29][CH2:28][C:27]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:25]([F:24])[CH:26]=2)([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCc2cc(F)cc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 3-fluoro-5-trifluoromethyl-benzylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H25F4NO5 [M−H]−: 470.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:22])[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>N1C=CC=CC=1.C(Cl)Cl.C(OC(=O)C)C>[NH2:22][C:10]1[N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH:12]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=2)[N:9]=1
Reactant: COc1ccccc1Cn1cc(-c2cccc(N)c2)nc1N
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1Cn1cc(-c2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2)nc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
55.1 A solution of 100 mg 4-(3-aminophenyl)-1-(2-methoxybenzyl)-1H-imidazole-2-ylamine (0.34 mmol, Example 51) in 3 mL pyridine was combined with 74 mg 4-isopropylbenzenesulfonic acid chloride at 0° C., then stirred for 18 hr at room temperature. The batch was then diluted with methylene chloride, extracted with 1 M NaOH and with water, and the organic phase was then dried (Na2SO4) and concentrated, and the residue thus obtained was stirred in acetic ethyl ester, suctioned off, and dried (130 mg target product).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][N:24]2[CH:29]3[CH2:30][CH2:31][CH:25]2[CH2:26][C:27](=O)[CH2:28]3)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH:27]2[CH2:28][CH:29]3[N:24]([CH2:23][CH2:22][C:16]4[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=4)[CH:25]([CH2:31][CH2:30]3)[CH2:26]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccc(CCN2C3CCC2CC(=O)C3)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCN2C3CCC2CC(Nc2ccc(OC)c(OC)c2)C3)cc1OC
Reaction time: 8 h

Procedure:
To a stirred solution of 4 g (26 mmol) 3,4-dimethoxyaniline and 5 ml 14N methanolic HCl in 200 ml methanol, were added 5.7 g (20 mmol) of 8-[2-(3,4-dimethoxyphenyl)ethyl]-8-azabicyclo[3.2.1]octane-3-one (D1), followed by addition of 1 g (16 mmol) sodium cyanoborohydride. The reaction mixture was stirred overnight, slightly acidified and concentrated to dryness. The crude residue was filtered over a short column of silica gel using 95:5 methylene chloride:methanol. The expected fraction was triturated with ethyl acetate affording 4 g (47%) of the desired compound. mp.: 220° C. 1H NMR shows a mixture of two conformations of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH2:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:18][C:2]([O:4][CH3:5])=[O:3])[CH3:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: COC(=O)Cl
Reactant: CC(N)Cc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)NC(C)Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5.33 ml of methyl chloroformate were added dropwise to a mixture consisting of 12.6 gm of 1-(3'-nitro-phenyl)-2-amino-propane, 9.8 gm of potassium carbonate and 100 ml of acetonitrile, whereby the temperature of the mixture rose to 45° C, and the resulting mixture was boiled for 2 hours. Thereafter, the reaction mixture was diluted with ice water, and the crystals precipitated thereby were collected by suction filtration, washed with water and dried, yielding 11 gm of 1-(3'-nitro-phenyl)-2-(methoxycarbonyl-amino)-propane, m.p. 104° -105° C. This compound was hydrogenated in methanol in the presence of Raney nickel at atmospheric pressure and room temperature. Thereafter, the catalyst was removed by suction filtration, the methanol was distilled out of the filtrate, and the residue, 1-(3'-amino-phenyl)-2-(methoxycarbonyl-amino)-propane, was dissolved in acetonitrile. The resulting solution was admixed with the calculated amount of maleic acid, and the precipitate formed thereby was recrystallized twice from acetonitrile, yielding 5.5 gm of the maleate of the formula ##STR29## which had a melting point of 125° -127° C.
Reaction SMILES: C([N:8]([CH2:16][C:17]1[O:21][C:20]([C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][CH:33]2[C:42]3[N:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH2:36][CH2:35][CH2:34]2)[C:26]([OH:28])=[O:27])=[O:23])=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.[ClH:43].O1CCOCC1>CO>[ClH:43].[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][C:17]1[O:21][C:20]([C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][CH:33]2[C:42]3[N:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH2:36][CH2:35][CH2:34]2)[C:26]([OH:28])=[O:27])=[O:23])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC2CCCc3cccnc32)C(=O)O)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@@H](CCCNC1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in Example 11-5 (30.6 mg) was dissolved in methanol (0.7 ml), and 4 mol/l hydrochloric acid/dioxane solution (0.7 ml) was added. The mixture was stirred for 3 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol/water=7/3/0.5). The obtained product was added with an aqueous solution of hydrochloric acid, concentrated and then azeotropically distilled with water. The resulting solid was washed with ether to obtain a hydrochloride of the title compound (22.7 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH:26](=O)[CH3:27].[Na].C([BH3-])#N.[Na+].[OH-].[Na+]>O.C(O)(=O)C.CO>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:26][CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)nc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)OC)cn2)CC1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
6-[1-(3-amino-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid methyl ester (5 g) was added to methanol (100 ml) and with the addition of acetic acid (4 ml) and acetaldehyde (1.2 ml) at 5° C.˜10° C., the mixture was stirred for 30 minutes. With the addition of sodium cyanoborohyride (1 g), the mixture was stirred at 15° C. for 2 hours. Sodium cyanoborohydride (1 g) was added again, and the mixture was further stirred for 1 hour. Water (50 ml) and 3N-sodium hydroxide solution were added to the mixture for neutralization (pH 7.5) and then, methanol was concentrated under reduced pressure. After the mixture was extracted with chloroform, the separated organic layer was concentrated under reduced pressure. The residue was treated with ether for crystallization and recrystallized with ethyl acetate and hexane. The product was filtered and dried to give a desired compound of 4.1 g (yield: 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[O:10]>C(O)C>[CH3:17][O:16][C:14]([C:13]1[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:15]
Reactant: COC(=O)c1ccccc1NC(=O)CCl
Reactant: C1CNCCN1
Solvent: CCO
Product: COC(=O)c1ccccc1NC(=O)CN1CCNCC1

Procedure:
4.3 Grams of piperazine was added to 50 ml of ethanol, to this solution was added 2.3 g of methyl o-(α-chloroacetylamino)benzoate at a temperature of 40°-50° C. with stirring. The reaction mixture was stirred at the same temperature for 3 hours, then the reaction mixture was concentrated, to the obtained residue was added 20 ml of water, then saturated with sodium chloride, and extracted with chloroform. The chloroform layer was washed with a 10%-sodium hydroxide solution, then washed with a small amount of water and dried. After removal of the solvent by distillation, the residue obtained was purified by a silica gel column chromatography, and recrystallized from ether to obtain 2 g of o-methoxycarbonyl-α-(1-piperazinyl)-acetanilide in the form of colorless needle-like crystals. Melting point: 94°-96° C.