Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[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.C(N)CCCCCC.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)[NH:49][CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55](OC3C=CC=CC=3)=[CH:54][CH:53]=2)C)=CC=1)C(O)=O)C>>[CH3:21][O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: CCCCCCCN
Product: CCCCCCCCNC(=O)C(C)(C)Oc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and heptylamine 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 C21H33NO5 [M+H]+: 380.
Reaction SMILES: [C:1]1([NH:7][S:8]([CH:11]=[CH2:12])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:42])[CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:28][C:26]=2[N:27]=1>CCO>[OH:42][C@@H:34]([CH2:33][O:32][C:29]1[CH:30]=[CH:31][C:25]2[S:24][C:23]([CH3:22])=[N:27][C:26]=2[CH:28]=1)[CH2:35][N:36]1[CH2:37][CH2:38][N:39]([CH2:12][CH2:11][S:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH2:40][CH2:41]1
Reactant: C=CS(=O)(=O)Nc1ccccc1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCS(=O)(=O)Nc4ccccc4)CC3)ccc2s1
Temperature: 85 °C

Procedure:
To a solution of phenyl(vinylsulfonyl)amine (141 mg, 0.77 mmol) and DIEA (0.47 mL, 4.9 mmol) in EtOH (7.5 mL) was added (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (470 mg, 1.5 mmol, crude). The solution was heated for 2 hours at 85° C. on a J-Kem™ block. Upon cooling, the reaction mixture was concentrated to an oil and purified via flash column chromatography (4:1 EtOAc/MeOH) to afford [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]phenylamine.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2].O=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=2)[N:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CCCCCC=O
Reactant: CCC1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCCCCN1CCC(CC)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C

Procedure:
To a solution of rac-8-ethyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate HC)(13 mg, 0.041 mmol) in DCE (2 ml) was added ethyl 7-oxoheptanoate (24.84 mg, 0.144 mmol) followed by sodium triacetoxyborohydride (69.9 mg, 0.330 mmol). The reaction mixture was left to stir at room temperature under an atmosphere of nitrogen. Water (10 ml) was added and the resulting mixture was extracted with EtOAc (3×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (10 ml) to afford the title product;
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[N:34]=[C:6]2[CH2:7][N:8]([C@H:11]3[CH2:16][O:15][C@H:14]([C:17]4[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=4[F:25])[C@@H:13]([NH:26]C(=O)OC(C)(C)C)[CH2:12]3)[CH2:9][CH2:10][N:5]2[N:4]=1.[ClH:37]>>[ClH:37].[ClH:37].[F:36][C:2]([F:1])([F:35])[C:3]1[N:34]=[C:6]2[CH2:7][N:8]([C@H:11]3[CH2:16][O:15][C@H:14]([C:17]4[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=4[F:25])[C@@H:13]([NH2:26])[CH2:12]3)[CH2:9][CH2:10][N:5]2[N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2CCn3nc(C(F)(F)F)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Agent: Cl
Product: N[C@H]1C[C@@H](N2CCn3nc(C(F)(F)F)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F

Procedure:
tert-Butyl [(2R,3S,5R)-5-[2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl]-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate from Step A was dissolved in a solution of hydrogen chloride (1 mL, 3N in ethyl acetate) and evaporated after two h to yield (2R,3S,5R)-5-[2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl]-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine, dihydrochloride salt. LC-MS 422.13 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:27])=[CH:22][CH:23]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(CCc1ccc(O)cc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 55 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3-(4-hydroxyphenyl) propionic acid in 55% yield following procedure 1. The product was chromatographed on silica and crystallized from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=357, 1H NMR (MeOH-d4): 2.61 t, 7.4 Hz (1H), 2.89 t, 7.4 Hz (1H), 6.37 s (1H), 6.72 d, 8 Hz (2H), 7.00–7.06 m (3H), 7.11 t, 7 Hz (1H), 7.27–7.35 m (2H), 7.38 d, 8 Hz (1H), 7.54 d, 7 Hz (1H), 7.58 dd, 7.1 Hz (1H), 7.67 d, 8 Hz (1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[N:28]1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]([CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[N:28]3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3ccccc23)CC1
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccccc43)nc12
Temperature: 125 °C
Yield: 88.2 %

Procedure:
To a stirred solution of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 338 μmol), tert-butyl 4-(1H-indazol-3-yl)piperidine-1-carboxylate (102 mg, 338 μmol) in dioxane (2.5 mL) was added sodium tert-butoxide (71.5 mg, 744 μmol) and bis(tri-tert-butylphosphine)palladium(0) (17.3 mg, 33.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, and the filter cake washed with ethyl acetate. The combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 4-(1-(7-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-3-yl)piperidine-1-carboxylate (198 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][C:18]([CH3:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32]1[C:33](=O)[C:34](=[O:38])[C:35]=1[O:36]C)([CH3:30])([CH3:29])[CH3:28]>CO>[C:27]([O:31][C:32]1[C:35](=[O:36])[C:34](=[O:38])[C:33]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][C:18]([CH3:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH:11]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1c(OC(C)(C)C)c(=O)c1=O
Reactant: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(N)c2)cc1
Solvent: CO
Product: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(Nc3c(OC(C)(C)C)c(=O)c3=O)c2)cc1
Yield: 82.9 %

Procedure:
Following a similar procedure to that described in Example (94c), 1.19 g of 3-[(4-methoxyphenyl)-(1-methyl-1-phenylethylamino)methyl]phenylamine [prepared as described in step (b) above], 886 mg of 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione and 40 ml of methanol were reacted, to obtain 1.42 g of the title compound as a white foamy solid.
Reaction SMILES: [N:1]([CH:4]([C:7]1[N:8]=[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:10]2[C:11](=[O:14])[C:12]=1[I:13])[CH2:5][CH3:6])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:7]1[N:8]=[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:10]2[C:11](=[O:14])[C:12]=1[I:13])[CH2:5][CH3:6]
Reactant: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1I
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(N)c1nc2cccc(C)n2c(=O)c1I
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(1-azidopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.10 g, 8.40 mmol) in tetrahydrofuran (20 mL) and water (6.06 mL) was added a 1.0 M solution of trimethylphosphine in tetrahydrofuran (0.1 mmol) at room temperature and stirred for 1 hour. To the mixture was added EtOAc and the mixture was extracted twice with 1N HCl. The combined extracts were neutralized with solid sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step (2.58 g, 89.5%). LCMS calculated for C12H15IN3O (M+H)+: m/z=344.0. Found: 344.2.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][CH:7]([Cl:30])[C:8]([NH:10][C:11]1[N:15]([C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[C:18]([F:28])[C:17]=2[F:29])[N:14]=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl>[Cl:4][C:12]1[CH:13]=[N:14][N:15]([C:16]2[C:17]([F:29])=[C:18]([F:28])[C:19]([C:24]([F:27])([F:26])[F:25])=[C:20]([F:23])[C:21]=2[F:22])[C:11]=1[NH:10][C:8](=[O:9])[CH:7]([Cl:6])[Cl:30]
Reactant: O=C(Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F)C(Cl)Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F)C(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
0.9 ml (0.011 mol) of sulphuryl chloride in 5 ml of methylene chloride are added dropwise to a solution of 4.1 g (0.01 mol) of 5-dichloroacetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 20 ml of methylene chloride at 0° C.-5° C. The mixture is stirred at room temperature for 16 hours and diluted with 30 ml of methylene chloride, the solution is washed with saturated sodium bicarbonate solution and sodium chloride solution in succession and dried over magnesium sulphate and the solvent is removed in vacuo. 3.9 g (87.2% of theory) of 4-chloro-5-dichloroacetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 115° C.-116° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1)[CH3:25]>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:31][C:29]4[CH:28]=[N:27][N:26]([CH2:24][CH3:25])[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Product: CCn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (110 mg, 0.33 mmol) and 1-ethyl-4-amino-1H-pyrazole (44 mg, 0.39 mmol) in 1-butanol (3 mL) was heated at 120° C. overnight, LC-MS showed the desired product and some de-Boc product. After the mixture was cooled to rt, it was diluted with methylene chloride (3 ml), then N,N-diisopropylethylamine (0.11 mL, 0.66 mmol) and di-tert-butyldicarbonate (72 mg, 0.33 mmol) were added, the resulting mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc (30 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized with EtOAc to give the title compound as an off-white solid. LC-MS (ES, Pos.): 410 [MH+]. 1H NMR (CDCl3, 400 MHz): δ=1.51 (s, 9H), 1.56 (t, J=7.3 Hz, 3H), 2.50 (m, 2H), 3.66 (m, 2H), 4.16 (m, 2H), 4.22 (q, J=7.3 Hz, 2H), 6.04 (s, 1H), 6.17 (s, 1H), 6.57 (s, 1H), 7.56 (s, 1H), 7.95 (s, 1H), 8.38 (s, 1H), 10.96 (br s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH2:21][O:13][C:12]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH:1]=[O:2])[CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC2)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of methyl 3-formyl-4-hydroxybenzoate (2 g, 11.10 mmol) in DMF (20 ml), K2CO3 (3.07 mg, 22.2 mmol) and (bromomethyl)cyclopropane (2.156 ml, 22.2 mmol) were added. The mixture was stirred at RT for 2 hours. The reaction was quenched with water, and the product was extracted with EtOAc. The organic layer was washed with water (2×) and NaCl sat. sol., dried over Na2SO4 and evaporated under vacuum to give 2.6 g of the desired compound (quantitative yield).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28].[CH3:29][O:30][C:31]1[CH:32]=[C:33](/[CH:43]=[CH:44]/[C:45](O)=[O:46])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[CH3:29][O:30][C:31]1[CH:32]=[C:33](/[CH:43]=[CH:44]/[C:45]([NH:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]2=[O:28])=[O:46])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN1CCCCC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(/C=C/C(=O)NN2CCCCC2=O)ccc1-n1cnc(C)c1

Procedure:
IPEA (0.26 ml), HOBT (121 mg) and EDC (172 mg) were sequentially added to a suspension of 1-aminopiperidin-2-one hydrochloride (92 mg) and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (CAS No. 870839-41-1, 150 mg) in DMF (4 ml), and the reaction solution was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine. The combined aqueous layers were reextracted with ethyl acetate (twice). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate to obtain 97 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@@H](C(O)=O)[C@H](C)O.O=C([C@H](CC1C=C(O)C(O)=CC=1)N)O.C1NC=NC=1C[C@@H](N)C(O)=O.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.C1C=CC2NC=C(C[C@@H](N)C(O)=O)C=2C=1.C1(C2N[C@H](C(O)=O)CC2)C=CC=CC=1>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: C[C@H](O)[C@@H](N)C(=O)O
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
replace with: D-Phe, Tyr, D-Thr, L-Dopa, His, D-His, Trp, D-Trp, Trans-3, 4 or 5-phenylproline, cis-3, 4, or 5-phenylproline;
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[F:24][C:25]([F:33])([F:32])[C:26]1[O:30][C:29]([NH2:31])=[N:28][N:27]=1>>[F:24][C:25]([F:33])([F:32])[C:26]1[O:30][C:29]([NH:31][C:8]([CH:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:9])=[N:28][N:27]=1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Reactant: Nc1nnc(C(F)(F)F)o1
Product: O=C(Nc1nnc(C(F)(F)F)o1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 220-223° C.(decomp.), and MS: m/e=362.2 (M+H+) was prepared in accordance with the general method of example 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamine [U.S. Pat. No. 2,883,391].
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH2:15]=[C:16]([CH3:18])[CH3:17].C(=O)([O-])O.[Na+]>ClCCl>[O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CCC(C(=O)O)O1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(=O)O1
Reaction time: 8 h

Procedure:
In 100 ml of dichloromethane was dissolved 5.0 g of 5-oxo-2-tetrahydrofurancarboxylic acid. To the solution was added 0.3 ml of concentrated sulfuric acid at -60° C., to which was added an excess volume of isobutene (about 50 ml). The reaction mixture was allowed to stand at room temperature overnight in a sealed vessel, which was then poured into a cooled aqueous solution of sodium hydrogen carbonate. The dichloromethane layer was taken, washed with water and dried (Na2SO4), followed by concentration to give t-butyl 5-oxo-2-tetrahydrofurancarboxylate as colorless oil.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[CH2:16]1[O:33][C:19]2([CH2:24][CH2:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[CH:21][CH2:20]2)[O:18][CH2:17]1.Cl>C(Cl)Cl>[CH2:17]1[O:18][C:19]2([CH2:24][CH2:23][C:22]3([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=4)[CH:21]([CH2:1]3)[CH2:20]2)[O:33][CH2:16]1
Reactant: CC[Zn]CC
Reactant: N#Cc1cccc(C2=CCC3(CC2)OCCO3)c1
Agent: Cl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C23CCC4(CC2C3)OCCO4)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
Diethylzinc(1 M in hexane, 19 ml, 19 mmole) was mixed with 50 ml methylene chloride and the mixture was cooled to 0° C. Trifluoroacetic acid (2.1 g, 19 mmole) in 20 mL methylene chloride was added. The mixture was stirred at 0° C. for 20 minutes. Diiodomethane (5 g, 19 mmole) in 10 ml methylene chloride was then added, followed by 4-(3-cyanophenyl)-3-cyclohexene-1-one ethylene ketal (1.5 g, 6.2 mmole) in 20 mL methylene chloride. The mixture was stirred at room temperature overnight. 50 ml 1N hydrogen chloride solution was added to quench the reaction. The organic layer was separated, washed with water (2×50 mL) and dried over sodium sulfate. The product was purified by column using ethyl acetate/hexane (10/90) as the eluent to afford 6-(3-cyanophenyl)bicyclo[4.1.0]heptane-3-one ethylene ketal (0.8 g, 50%).
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:34][CH:33]=1)=[O:31])C.[OH-].[Li+]>C1COCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:34]=[CH:33][C:32]([C:30]([OH:31])=[O:29])=[CH:37][CH:36]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester (4.75 g, 12.10 mmol, 1 eq.) in 30% aqueous THF was treated with lithium hydroxide (0.87 g, 36.30 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14]C(OC(C)(C)C)=O)([CH3:13])[CH3:12])[CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH2:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CC(C)(C)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(CC(C)(C)N)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 3-(2-tert-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester (Preparation 33) (1.6 g, 5.2 mmol) in dichloromethane (160 ml) at 0° C. was treated with trifluoroacetic acid (13.6 ml) and left to warm to room temperature over 2 hours. The solvent was removed in vacuo and the product purified by cation exchange chromatography (methanol followed by 2M ammonia in methanol) to yield the title compound as an amber oil (1.06 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[CH:3]1.Cl.Cl[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]Cl>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])([CH3:8])[CH2:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:3]1
Reactant: CC1(C)C=C(c2ccccc2N)CC1(C)C
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2ccccc2N2CCNCC2)CC1(C)C
Temperature: 200 °C
Reaction time: 9 h
Yield: 50.9 %

Procedure:
A mixture of 2-(3,3,4,4-tetramethylcyclopent-1-enyl)phenylamine (331 mg, 1.54 mmol) produced in Example (54c), 1,2-dichlorobenzene (4.7 mL) and bis(2-chloroethyl)amine hydrochloride (330 mg, 1.85 mmol) was stirred for 9 hours at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was blown into the reactor several times to remove the hydrogen chloride gas in the reactor. The reaction mixture was air-cooled to room temperature, and then aqueous solution of potassium carbonate, ethyl acetate and methanol were added and extraction was performed three times with ethyl acetate. The obtained organic layers were dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 223 mg of the title compound as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](=[O:17])[NH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:15]2[C:14](=[O:17])[C:13]([C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)[CH2:26][CH2:25]1
Reactant: ClCC1CC1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(OC)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(OC)c2)nn(CC2CC2)c1=O
Yield: 78.7 %

Procedure:
Using 6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 78.7%.