Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH:20]1[OH:26])=[O:18])[CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:4].O.[Li+].[OH-]>O1CCOCC1>[OH:26][CH:20]1[CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24][CH:19]1[C:17]([N:10]([CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:9]1[CH:8]=[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:18]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1O)C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCOCC2)C(O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
3-[(2-Hydroxy-4-methyl-cyclohexanecarbonyl)-(tetrahydro-pyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (31 mg, 0.062 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (0.6 ml) and then LiOH 1N (310 ul, 0.310 mmol) was added. After 4 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to obtain 14 mg (52%) of 3-[(2-Hydroxy-4-methyl-cyclohexanecarbonyl)-(tetrahydro-pyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 31).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([C:8](=[NH:12])[O:9][CH2:10][CH3:11])[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)Cl.CCCCCC.CCOC(C)=O>[CH2:23]([O:22][C:20]([N:12]=[C:8]([CH:5]1[CH2:6][CH2:7][O:2][CH2:3][CH2:4]1)[O:9][CH2:10][CH3:11])=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)C1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCOC(=O)N=C(OCC)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
Ethyl tetrahydro-2H-pyran-4-carbimidate hydrochloride (1.646 g, 8.50 mmol) was suspended in DCM (21.25 mL) and cooled to 0° C. Pyridine (3.09 mL, 38.2 mmol) was added and the solution was stirred for 15 min. Ethyl chloroformate (1.384 g, 12.75 mmol) was added dropwise. The reaction mixture was allowed to warm to RT and stir overnight. The reaction mixture was diluted with 50% hexane/EtOAc and the resulting suspension was filtered through a plug of diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue dried under high vacuum for several hours to yield ethyl N-ethoxycarbonyltetrahydro-2H-pyran-4-carbimidate (1.80 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 4.12 (m, 2H), 4.07 (m, 2H), 3.85-3.83 (m, 2H), 3.31-3.24 (m, 2H), 2.69-2.68 (m, 1H), 1.69-1.68 (m, 4H), 1.23 (m, 6H).
Reaction SMILES: [Cs].[Cl-].C([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])(OC(C)(C)C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[NH2:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: NCCCC[C@H](N)C(=O)O
Temperature: 55 °C
Reaction time: 48 h

Procedure:
Attachment of N--Boc--Lys(Cl--z) to chloromethyl resin was performed by the cesium salt method. A sample of chloromethyl resin (200 g.) containing 0.74 mmol chloride per gram is treated with the cesium salt of Boc--Lys--(Cl--z) resulting from the neutralization of Boc--Lysine with cesium carbonate. About 73.8 grams of Boc--Lysine is dissolved in 80% methanol and 20% water and adjusted to pH 7.0 with about 29 grams of cesium carbonate. The resulting solution is dried on a rotary evaporator, then dried three more times after three additions of 100 milliliters of xylene. To the cesium salt of Boc--Lys(Cl--z) was added 200 grams of chloromethyl resin as above and sufficient 1-Methyl-2-Pyrrolidinone to make about 1.90 liters total volume. The resulting mixture is stirred at 55° C. for 48 hours. The resin was then washed extensively with methanol, then water, then again with methanol. The resin was air dried, then dried under vacuum. After cleavage of lysine from the resin with HF, amino acid analysis gave one peak corresponding to 0.36 mmol/gm.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CS(C)=O.O>[S:19]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ccc2ncc(-c3cc4ncccc4s3)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5ncccc5s4)n3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (40 mg, 0.139 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (20 mg, 0.139 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.695 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 40 mg of the yellow solid, 79%.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:19])[C:11]2[C:16]([C:17]=1[O:18][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
Reaction time: 60 h

Procedure:
A mixture of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (6.48 g, 20 mmol; Example D-28 a), benzyl bromide (3.6 ml, 30 mmol), K2CO3 (12.44 g, 90 mmol) and acetone (300 ml) was refluxed with stirring for 2.5 d. The solvent was then evaporated in vacuo. To the residue was added water (100 ml) and the mixture was extracted with EtOAc (100 ml). The organic phase was dried over MgSO4 and evaporated in vacuo to give the title compound as a yellowish solid; MS-(+)-ion: M+1=414.1.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([O:28]CC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[Br:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
A suspension of ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (0.18 g, 0.002 mol) and 1N NaOH (0.6 mL in 1:1 v/v EtOH/Water) was stirred at room temperature for 1.5 h. The reaction mixture was acidified with 5% citric acid and filtered the precipitate. It was washed with water, followed by ethanol and dried in vacuo to afford the title compound (0.14 g, 77%) as a light brown powder: 1H NMR (CD3OD/400 MHz)=δ 9.03 (s. 1H), 8.60 (s, 1H), 7.61 (m. 1H), 7.00 (m, 2H), 6.52 (s, 1H), 5.51 (s, 2H), 5.30 (s. 2H), and 2.52 (s, 3H); 19F NMR (CD3OD/400 MHz)=δ−111.75 (m) and −116.06 (m); ES-HRMS m/z 466.0209 (M+H C19H15N4O3BrF2 requires 466.0209).
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]([CH3:20])[C:8]=2[N:9]=1)=O.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:26][C:4]2[N:5]=[CH:6][C:7]3[CH:12]=[C:11]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]([CH3:20])[C:8]=3[N:9]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: Cn1c(Cc2ccccc2)cc2cnc(S(C)=O)nc21
Product: Cn1c(Cc2ccccc2)cc2cnc(NC3CCCC3)nc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of the sulfoxide (50 mg) from Step 3 and cyclopentylamine (1 mL) was stirred at 100° C. overnight. Excess cyclopentylamine was removed and the residue was purified by preparative TLC (25% EtOAc/hexanes) to give the desired product (26 mg). MS: 307.3 (M+H).
Reaction SMILES: C([C:4]1[C:8](C)=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])(O)=O.[Li]I.O.O.C1(C(O)=O)CCCCC1>N1C(C)=CC(C)=CC=1C>[C:10]1([C:7]2[S:6][C:5]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[CH:4][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(-c2ccccc2)sc(NC(=O)C2CCCCC2)c1C(=O)O
Agent: [Li]I
Solvent: Cc1cc(C)nc(C)c1
Solvent: O=C(O)C1CCCCC1
Solvent: O
Product: O=C(Nc1ccc(-c2ccccc2)s1)C1CCCCC1

Procedure:
This compound (m.p. 174° C.) was prepared from N-(3-carboxy-methyl-5-phenyl-2-thienyl)-cyclohexane carboxamide (31.1 g, 0.1 mole) and LiI.2H2O (48.1 g, 0.32 mole) by refluxing in collidine (125 ml.) according to the procedure of Example 53 (a). This compound was also prepared according to the procedure of Example 53(b), using cyclohexane carboxylic acid as the acylating agent. The products of the two processes were spectrally identical and had a melting point of 175° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:28]=[CH:27][N:16]3[C:17](=[O:26])[C:18]([C:21]4[N:22]=[N:23][NH:24][N:25]=4)=[CH:19][N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)(C)([CH3:3])[CH3:2].COC1C=CC(CN2N=NC(C3C(=O)N4C=CC(C(O)=O)=C[C:44]4=[N:43][CH:42]=3)=N2)=CC=1.N1C=CC(C2N=C(N)SC=2)=CC=1>>[N:43]1[CH:44]=[CH:2][C:1]([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:28]=[CH:27][N:16]4[C:17](=[O:26])[C:18]([C:21]5[N:25]=[N:24][NH:23][N:22]=5)=[CH:19][N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)=[CH:3][CH:42]=1
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(-c4nn[nH]n4)cnc3c2)n1
Reactant: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)O)ccn4c3=O)n2)cc1
Agent: Nc1nc(-c2ccncc2)cs1
Product: O=C(Nc1nc(-c2ccncc2)cs1)c1ccn2c(=O)c(-c3nn[nH]n3)cnc2c1

Procedure:
Reactions were performed in the same manner as in Example 10, (F) by using 3-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxylic acid (120 mg, 0.32 mmol) and 4-(4-pyridyl)-1,3-thiazol-2-amine (62 mg, 0.35 mmol) to obtain 35.7 mg (27% for the two steps) of the title compound as orange crystals.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][C:33]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5C(OC(C)(C)C)=O)=[N:32][CH:31]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:11][CH:10]([CH3:12])[C@@H:9]([C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][C:33]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)=[N:32][CH:31]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)[NH2:8]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonylamino)-2-methylpropyl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.05 g, 3.27 mmol) in CH2Cl2 (20 mL) was added TFA (5 mL, 64.9 mmol) and the solution was allowed to stir for 2 h. The solvents were removed in vacuo, the residue was dissolved in CH2Cl2: MeOH (1:1) (ca. 10 mL) and absorbed onto an MCX cation exchange cartridge (Oasis). The resin was washed with MeOH and the desired material was released by elution with NH3 in MeOH (2M). The solvents were removed in vacuo to afford the title compound (0.622 g, 91%) as a yellow foam which was sufficiently pure for use in subsequent steps. 1HNMR (500 MHz, CD3OD) δ 7.85-7.88 (m, 4H), 7.75 (m, app d, J=8.2 Hz, 4H), 7.70 (app d, J=5.8 Hz, 2H), 4.96 (t, J=8.2 Hz, 1H), 4.30 (d, J=8.5 Hz, 1H), 3.54-3.57 (m, 1H), 3.47-3.52 (m, 1H), 2.55-2.62 (m, 1H), 2.38-2.46 (m, 1H), 2.28-2.36 (m, 1H), 2.15-2.24 (m, 1H), 1.17 (d, J=6.7 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H). LCMS: Anal. Calcd. for C26H30N6: 426; found: 427 (M+H)+.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6]C=C[C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.[S:29]1C=CC=C1CS>>[OH:26][CH2:25][C@H:24]([NH:23][C:21]1[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=[C:13]([S:10][CH2:9][C:3]2[S:29][CH:6]=[CH:7][CH:2]=2)[N:22]=1)[CH3:27]
Reactant: SCc1cccs1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Product: C[C@H](CO)Nc1nc(SCc2cccs2)nc2[nH]c(=O)cnc12
Yield: 56.6 %

Procedure:
The titled compound (0.076 g) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.20 g) and 2-thienylmethylmercaptan (0.050 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]1[CH:20]=[N:19][C:18]([CH3:21])=[N:17]1.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[N:33]=[C:34](Cl)[C:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]=2[N:37]=1>C(#N)C>[Cl:31][C:32]1[N:33]=[C:34]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[N:16]2[CH:20]=[N:19][C:18]([CH3:21])=[N:17]2)[C:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]=2[N:37]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: CNCCCOc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCN(C)c2nc(Cl)nc3c2CCC3c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a solution of N-methyl-3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propan-1-amine (Preparation L, 1.20 g, 4.15 mmol) in acetonitrile (50 mL) was added diisopropylethylamine (0.731 g, 5.66 mmol) followed by 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation R, 1 g, 3.77 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 50% ethyl acetate in pet-ether) to get 2-chloro-N-methyl-N-(3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (1.2 g, 61.2%) as a light yellow solid. LC-MS (M+H)+=518.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.95 (1H, s), 8.05-7.93 (3H, m), 7.30-7.11 (5H, m), 4.35-4.31 (2H, m), 4.18-4.14 (1H, m), 3.87-3.70 (2H, s), 3.28 (3H, s), 3.21-3.07 (2H, m), 2.54-2.50 (1H, m), 2.27-2.24 (2H, m), 2.01-1.98 (1H, m).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[C:18]([C:20]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=2[F:27])([OH:19])[CH2:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[C:18]([C:20]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=2[F:27])([OH:19])[CH2:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1CC2(CC2)CCC1(O)c1cc(O)ccc1F
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Add H2O (9 mg, 0.500 mmol) and TMSCl (18 mg, 0.167 mmol) to a solution of 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol (41 mg, 0.139 mmol) in 2-butanone (30 mL). Stir the mixture at 0° C. for 2 hours. Concentrate the mixture under vacuum to give 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol hydrochloride as white solid (46 mg, Yield: 100%). 1H NMR (400 MHz, D2O) δ 7.13-7.15 (d, J1=6.8, J2=3.2, 1H), 6.93-6.98 (d, J1=12.0, J2=8.8, 1H), 6.69-6.73 (m, 1H), 3.05-3.10 (m, 1H), 2.65-2.76 (m, 8H), 2.44-2.45 (m, 1H), 2.27-2.35 (m, 2H), 1.70-1.74 (m, 1H), 0.96-0.98 (m, 1H), 0.79-0.82 (m, 1H), 0.45 (m, 1H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1)(=O)=O.[CH2:23]([O:25][C:26](=[O:39])[C@@H:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:19]([O:18][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][O:5][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C@H:27]([O:36][CH2:37][CH3:38])[C:26]([O:25][CH2:23][CH3:24])=[O:39])=[CH:34][CH:33]=2)=[CH:10][CH:11]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Yield: 75.5 %

Procedure:
3-{4-[(tert-Butoxycarbonyl)amino]phenyl}propyl methanesulfonate (360 mg, 1.093 mmol) and (S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (260 mg, 1.093 mmol) were mixed in acetonitrile (30 ml). Potassium carbonate (anhydrous, 226.6 mg 1.639 mmol) was added. The mixture was heated to reflux overnight and thereafter it was evaporated to dry. Ethyl acetate (20 ml) and water (5 ml) were added into the residue. The two phases were separated and the water phase was extracted with ethyl acetate (10 ml×2). The organic phases were combined and washed with 0.1 M sodium hydroxide aqueous solution, water and brine and dried with magnesium sulfate. The solvent was evaporated in vacuum and an oil mixture was left. Column chromatography of the oil mixture on silica gel using ethyl acetate/heptane (20:80) as eluant gave the desired product (389 mg), yield 75.5%.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5].[OH-].[Na+].Cl>CO.C1COCC1>[CH3:29][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:8])([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1CCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc2ccccc2c1CCCCc1ccccc1)C(=O)O
Yield: 67.3 %

Procedure:
40 mg 2-methyl-2-{[1-(4-phenyl-butyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were reacted with 150 μl of 2 M sodium hydroxide in 1 ml methanol and 1 ml THF for 1 h at 60° C. The reaction mixture was then acidified with 2 M hydrochloric acid and the precipitated product was collected by filtration and dried in vacuo to yield 26 mg of 2-methyl-2-{[1-(4-phenyl-butyl)-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: [C:1]1([B:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[B:26]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[OH:27])[OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]O>C(O)C>[C:1]1([B:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[B:26]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[O:27][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[O:12][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(c1ccccc1Oc1ccccc1B(O)c1cccc2ccccc12)c1cccc2ccccc12
Reactant: CN(C)CCO
Solvent: CCO
Product: CN(C)CCOB(c1ccccc1Oc1ccccc1B(OCCN(C)C)c1cccc2ccccc12)c1cccc2ccccc12

Procedure:
The entitled compound (32 mg) was obtained by allowing 86 mg of bis(4,4′-(naphthyl-hydroxyboryl)phenyl) ether and 31 mg of dimethylethanolamine to act in 0.25 mL of ethanol.
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH2:20][CH3:21])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>CN(C=O)C>[F:79][C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([F:80])[CH:76]=1)[CH2:72][C@H:58]([NH:57][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[C:5]([C:3]([N:2]([CH3:1])[CH2:19][CH2:20][CH3:21])=[O:4])[CH:6]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-{[Methyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (350 mg, 1.2 mmol) in DMF (5 mL) is added diisopropylethylamine (835 μL, 4.8 mmol), HATU (554 mg, 1.5 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (488 mg, 1.2 mmol). The reaction is stirred for 16 h at room temperature. The reaction is partitioned between chloroform and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/chloroform) gives the title compound. ESI MS m/z 605.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:10][C:6]1[CH2:7][CH2:8][CH2:9][C:5]=1[CH2:4][CH2:3][O:2][CH3:1])(=[O:13])[CH3:12]
Reactant: COCCC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Product: COCCC1=C(OC(C)=O)CCC1

Procedure:
The subject compound is prepared from 2-(2-methoxyethyl)cyclopentan-1-one (Example 895) and acetic anhydride by the procedure of Example 10. The product is an oil, b.p. 60° C (0.2 mm.)
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(N)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.C(Cl)(=O)CCCCCCC/C=C\CCCCCCCC>>[CH2:13]([NH:27][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: NC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
N-Tetradecyl-N-(D-galactopyranosyl)-amine was prepared from 30 g of D-galactose and 53 g of tetradecylamine as described in Example 45. The galactosylamine was reacted with oleoyl chloride by the method described in Example 11.