Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:19]2[C:27]3[C:26](Cl)=[N:25][CH:24]=[N:23][C:22]=3[N:21]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:20]=2)=[O:18])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:35]C1C2C(C(C3C=CC=C([N+]([O-])=O)C=3)=O)=CN(C3CCCC3)C=2N=CN=1>>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:19]2[C:27]3[C:26]([NH2:35])=[N:25][CH:24]=[N:23][C:22]=3[N:21]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:20]=2)=[O:18])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ncnc2c1c(C(=O)c1cccc([N+](=O)[O-])c1)cn2C1CCCC1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(Cl)c23)c1
Product: CC(C)(C)OC(=O)NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1

Procedure:
The title compound was prepared from {3-[3-(4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester (452 mg, 0.94 mmol) by a procedure analogous to that described for (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitro-phenyl)methanone. MS: 460.3/360.3 (MH+); HPLC Rf: 6.45 min. (HPLC method 4).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]N(C)C=O.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C>CO.C(Cl)(Cl)Cl>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Chloro-6-methylnicotinic acid (25.0 g) was suspended in a mixed solvent of dimethylformamide (100 mL) and chloroform (100 mL), and to this suspension were added dimethylaminopyridine (21.3 g) and methanol (4.67 g). Finally, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (33.5 g) was added to the mixture, followed by stirring at room temperature for 6 hours. After the reaction mixture was concentrated, ethyl acetate (300 mL) was added thereto. The mixture was washed successively with water, 10% ammonium chloride, water, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4, v/v) to give the title compound (24.6 g) as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:3])[CH3:2].Cl.[Br:21][C:22]1[CH:27]=[CH:26][C:25](ON)=[C:24]([Cl:30])[CH:23]=1>>[C:1]([O:4][CH2:5][CH:6]1[N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH:9]2[C:26]3[CH:27]=[C:22]([Br:21])[CH:23]=[C:24]([Cl:30])[C:25]=3[O:12][CH:10]2[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: NOc1ccc(Br)cc1Cl
Agent: Cl
Product: CC(=O)OCC1CC2Oc3c(Cl)cc(Br)cc3C2CN1C(=O)OC(C)(C)C
Yield: 8 %

Procedure:
The product obtained from step I (1.33 g, 4.9 mmol) was reacted with O-(4-bromo-2-chlorophenyl)hydroxylamine hydrochloride following the procedure of Example 29 step B. Purification by column chromatography (SiO2, 49:1 to 19:1 hexanes/ethyl acetate) afforded tert-butyl 3-(acetoxymethyl)-8-bromo-6-chloro-1,4,4a,9b-tetrahydrobenzofuro[3,2-c]pyridine-2(3H)-carboxylate (203 mg, 8%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.43 (s, 1H), 7.38 (d, J=1.8 Hz, 1H), 5.14 (br s, 2H), 4.10-4.07 (m, 3H), 3.16-3.14 (m, 1H), 2.80 (d, J=17.4 Hz, 1H), 2.04 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:15])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][Br:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2cc(C)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc2cc(CBr)ccc2n1
Yield: 62.6 %

Procedure:
Compound 45 (0.300 g, 1.50 mmol) was diluted in anhydrous benzene (10 mL). N-Bromosuccinimide (0.280 g, 1.57 mmol) and a catalytic amount (˜0.020 g) of benzoyl peroxide were added, and the mixture was heated to reflux under nitrogen until an orange tint was no longer visible in the solution refluxing in the condenser (around 2 h 40 min). The mixture was cooled, concentrated, and purified by flash column chromatography (SiO2), eluting with a gradient of 10% to 12% EtOAc in CH2Cl2 to yield the product (0.262 g, 63%) as a flocculent yellow solid. The 1H NMR chemical shifts for this compound are identical to those previously reported in the literature. 1H-NMR (500 MHz; CDCl3): δ 8.44 (br d, J=8.6 Hz, 1 H), 8.30 (br s, 1 H), 8.17 (d, J=9.0 Hz, 1 H), 7.82 (m, J=9.1 Hz, 2 H), 7.72 (dd, J=8.6, 2.1 Hz, 1 H), 4.67 (s, 2 H), 2.29 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[CH:4][CH:3]=1.[I:16]N1C(=O)CCC1=O>C(O)(=O)C.ClCCl.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[C:4]([I:16])[CH:3]=1
Reactant: Oc1ccc(Cl)c(-c2ccc(F)cc2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1cc(-c2ccc(F)cc2)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of 6-chloro-4′-fluorobiphenyl-3-ol (Preparation 104, 280 mg, 1.26 mmol) in acetic acid (2.5 mL), dichloromethane (2.5 mL) and concentrated sulfuric acid (25 μL) was added N-iodosuccinimide (272 mg, 1.21 mmol) at room temperature. The reaction mixture was stirred for 18 hours at room temperature. Dichloromethane (60 mL) was added and the organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography eluting 33% dichloromethane in heptane to afford the title compound (306 mg, 70%) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.O1CCCC1.[CH3:17][NH2:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:18][CH3:17])=[N:6][CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-bromo-2-chloro-3-nitropyridine (456 mg, 1920 μmol) was dissolved in MeOH (6.0 ml) and methylamine, 2.0 M solution in tetrahydrofuran (2.5 ml, 5.0 mmol) was added. The reaction was stirred at room temperature for 6 hours, allowed to stand at room temperature overnight, and then concentrated. material was taken directly to the next step.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[C:1]([O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)[CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(CN2CCC(OC(=O)c3ccccc3)CC2)c1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
0.207 g (0.0006 mol) of 1-(3-nitro-benzyl)-piperidin-4-yl benzoate was dissolved in 12 ml of ethanol and treated with 0.12 g of Raney-nickel. The mixture was hydrogenated at room temperature and under normal pressure for 8 hrs. The catalyst was filtered off and, after concentration, the residue was chromatographed on silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.097 g (52%) of 1-(3-amino-benzyl)-piperidin-4-yl benzoate was obtained as yellowish crystals; m.p. 95°-97°.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[CH:25][CH:26]=2)[C@@H:9]([OH:10])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(I)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 g of 5-iodo-2′-deoxyuridine (5.65 mmole) was dissolved in 30 ml of pyridine, 5 ml of TEA and 2.16 g of MMTr-Cl (6.99 mmole) were sequentially added thereto, and stirred at room temperature for 4 hours. Then, pyridine was removed under a reduced pressure with a rotary evaporator, the residue was treated with a mixture of water and CH2Cl2, the CH2Cl2 layer was separated, dried under MgSO4, and then, CH2Cl2 was removed under a reduced pressure. The resulting residue was subjected to column chromatography (silica gel 60, 230˜400 meshes, Merck) to obtain the title compound as a pale yellow solid. The chromatography was conducted using a mixture of CH2Cl2 and methanol as an eluting solution whose mix ratio was gradually changed from 100:1 to 50:1 (v/v).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[CH2:49]([O:48][CH:47]([O:51][CH2:52][CH3:53])[C@@H:46]([N:34]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[C:32](=[O:33])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH3:54])[CH3:50]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 94 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-4-oxobutanoate IV-16) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)[CH:13]=1)=[O:6]
Reactant: COC(=O)c1ccc(-c2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)O)cc1
Yield: 73.3 %

Procedure:
Methyl 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate (1.63 g, 4.28 mmol) and lithium hydroxide monohydrate (376 mg, 9.0 mmol) were mixed in water (5 ml) and THF (10 ml) and stirred at room temperature for 90 h. The pH was adjusted to pH3 by addition of hydrochloric acid (2N) and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (75 ml), brine (75 ml), dried (magnesium sulphate) and concentrated under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/ethanol/ammonia (30:8:1 then 20:8:1). The solvents were evaporated under vacuum to give 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylic acid (1.15 g, 73%).
Reaction SMILES: [CH3:1][C:2]([N:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:27])[CH:22]([NH2:26])[CH2:23][CH2:24][CH3:25])[N:17]=[CH:16]1)([CH3:14])[CH2:3][CH2:4][NH:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[C:37]([F:39])[CH:38]=1)[CH2:35][C:34](=O)[CH2:33][CH2:32]2>>[CH3:14][C:2]([N:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:27])[C@@H:22]([NH:26][CH:34]2[CH2:33][CH2:32][C:31]3[C:36](=[C:37]([F:39])[CH:38]=[C:29]([F:28])[CH:30]=3)[CH2:35]2)[CH2:23][CH2:24][CH3:25])[N:17]=[CH:16]1)([CH3:1])[CH2:3][CH2:4][NH:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7]
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CCNC(C)c2ccccc2)cn1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CCN[C@H](C)c2ccccc2)cn1

Procedure:
2-Amino-pentanoic acid {1-[1,1-dimethyl-3-(1-phenyl-ethylamino)-propyl]-1H-imidazol-4-yl}-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to afford the title: 538.6 m/z (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH:15]([CH:18]([C:24](OCC)=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]([CH:18]([CH:15]([CH3:16])[CH3:17])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Solvent: c1ccncc1
Product: CCOC(=O)C(C(=O)Nc1cccc(F)c1)C(C)C

Procedure:
Prepared according to procedure A using 3-fluoroaniline (8.70 mL, 90 mmol), pyridine (10.92 mL, 135 mmol) and diethyl isopropylmalonate (20.02 mL, 99 mmol). The crude was purified by column chromatography (Hexanes:EtOAc, 1:0 to 4:1) to give ethyl 2-(3-fluorophenylcarbamoyl)-3-methylbutanoate.
Reaction SMILES: [N:1]([CH:4]([O:16][CH2:17][CH2:18][OH:19])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[N+:2]=[N-:3].[H-].[Na+].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23]>C1COCC1>[N:1]([CH:4]([O:16][CH2:17][CH2:18][O:19][CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:28])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CBr
Reactant: [N-]=[N+]=NC(COc1cccc(C(=O)O)c1)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCOC(COc1cccc(C(=O)O)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
To a solution of 3-[2-azido-2-(2-hydroxy-ethoxy)-ethoxy]-benzoic acid (0.535 g, 2 mmol) in dry THF (6 ml) was added NaH (60% dispersion, 0.246 g, 6 mmol) at 0° C. After 10 minutes, ethyl-2-bromoacetate (0.488 ml, 4.4 mmol) was added. The reaction was then warmed up to room temperature and stirred for 4 hours. The reaction was quenched by pouring it into ice-cold water (50 ml). The mixture was extracted with DCM (2×50 ml) and the DCM extracts were discarded. The aqueous layer was then acidified to pH 2 with 1 N HCl, and extracted with DCM (2×50 ml). These DCM *extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography (1×20 cm). The title compound, eluted with 2% methanol in DCM, was obtained as an oil (0.223 g, 31.6%). ES-MS, m/z 351.95 (M−1).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7](=[P:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:8]1[C@H:11]([CH2:12][C:13]([OH:15])=[O:14])[C@@H:10]([C@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[C:9]1=[O:26])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:53](Cl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([C:7](=[P:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[N:8]1[C@H:11]([CH2:12][C:13]([O:15][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])=[O:14])[C@@H:10]([C@H:16]([O:18][Si:19]([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:21])[CH3:20])[CH3:17])[C:9]1=[O:26])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)OC(=O)C(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.65 g of (3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(carboxymethyl)azetidine-2-one in 4 ml of toluene were added under ice-cooling 0.14 ml of triethylamine and 0.12 ml of pivaloyl chloride, and the mixture was stirred at room temperature. The resulting precipitate was collected by filtration, and the filtrate was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 0.60 g of (3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(pivaloyloxycarbonyl)methyl]azetidine-2-one.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)=[O:9].[NH2:28][C:29]1[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:40])[CH:30]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.C(N(C(C)C)CC)(C)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]([NH:28][C:29]2[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:40])[CH:30]=2)=[O:20])[CH2:15][CH2:16]1)=[O:9]
Reactant: COC(=O)c1cc(C)c(N)cc1C
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)c(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a stirred solution of 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (670 mg, 1.82 mmol) and methyl 4-amino-2,5-dimethylbenzoate (390 mg, 2.18 mmol) in dichloromethane (3.6 mL) and diisopropylethylamine (0.413 mL) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (829 mg, 2.18 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane containing from 3% to 5% methanol to provide methyl 4-{3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}-2,5-dimethylbenzoate (568 mg, 59% yield). LCMS (10-70) Rt=4.55; [M+H+] found 530.4.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.[ClH:26].O1CCOCC1>C(OCC)(=O)C>[ClH:26].[C:7]1([N:6]2[CH:5]=[CH:4][N:3]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccn(-c3ccccc3)c2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1n(-c2ccccc2)ccn1C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
tert-Butyl 4-(2-oxo-3-phenyl-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (290 mg, 844 μmol) was dissolved in ethyl acetate (3.0 mL). 4M Hydrogen chloride in 1,4-dioxane (3.0 mL, 12 mmol) was added to the mixture. Reaction was allowed to stir at room temperature for 18 hours. Material was concentrated by roto-vap. Residue was triturated in diethyl ether. Solids were filtered and washed with diethyl ether. Air was pulled through the filter cake to dry. Title compound was obtained as tan solid in 91% yield. MS (M+H)+=244.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]2[S:13][C:14]([CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:15][C:11]=2[CH:10]=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:27]=[CH:26][C:12]2[S:13][C:14]([CH2:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:15][C:11]=2[CH:10]=1)[CH2:34][C:30]1[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCc1cc2cc(CNCc3ncc[nH]3)ccc2s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCc1cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (197.9 mg) obtained in Example 120-6 was dissolved in methanol (10 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (68.0 mg) and sodium cyanoborohydride (64.7 mg). After that, the solution was adjusted to pH 5 with acetic acid, followed by stirring overnight at room temperature. After the solvent had been distilled off, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (228.7 mg) of the subject compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:24])[CH3:23])=[CH:14][C:13]=2[CH3:27])=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH:22]([N:19]1[C:20]2[C:15](=[CH:14][C:13]([CH3:27])=[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=3)[CH:21]=2)[C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(cc1Nc1ccc(C(=O)O)cc1)N(C(C)C)CCC2(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
A solution of 4-(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-ylamino)-benzoic acid ethyl ester (Compound 46, 10.5 mg, 0.0275 mmol) in ethanol (1 mL) was treated with 2N KOH (0.5 mL) and stirred at 50° C. for 18 hours. The solvent was removed under reduced pressure and the residue was washed with ethyl acetate and acidified with 2N HCl. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexane, Rf=0.10) to give the title compound (9.3 mg, 96%) as a white solid: 1H NMR (300 MHz, CDCl3): δ1.17 (d, 6 H, J=6.6 Hz), 1.29 (s, 6 H), 1.72 (t, 2 H, J=6.0 Hz), 2.12 (s, 3 H), 3.15 (t, 2 H, J=6.0 Hz), 3.98 (sp, 1 H, J=6.6 Hz), 5.72 (br s, 1 H), 6.62 (s, 1 H), 6.79 (d, 2 H, J=8.7 Hz), 7.05 (s, 1 H), 7.96 (d, 2 H, J=8.7 Hz)