Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:13][CH2:12]2)[O:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[CH2:18]([O:17][C:15]([NH:14][C:11]1([C:8]2[O:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:13][CH2:12]1)=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1coc(C2(NC(=O)OCc3ccccc3)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC1(c2nc(C(=O)O)co2)CC1)OCc1ccccc1
Temperature: 70 °C
Yield: 56.2 %

Procedure:
2-(1-Benzyloxycarbonylamino-cyclopropyl)-oxazole-4-carboxylic acid ethyl ester (0.44 g, 1.3 mmol) was dissolved in THF (10 mL) and to this solution was added 2N NaOH (2.0 mL, 4.0 mmol). The mixture was heated at 70° C. for 17 h. The mixture was neutralized with 2N HCl and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give 2-(1-benzyloxycarbonylamino-cyclopropyl)-oxazole-4-carboxylic acid (0.22 g, 0.73 mmol) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc2[nH]nc(NC(=O)c3ccccc3)c2c1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12)c1ccccc1
Yield: 82 %

Procedure:
N-[5-(3-Fluorobenzenesulfonylamino)-1H-indazol-3-yl]benzamide can be obtained as described in Example 2 from 0.45 g of N-(5-amino-1H-indazol-3-yl)benzamide, 10 ml of pyridine and 0.35 g of 3-fluorobenzenesulfonyl chloride. 0.6 g of N-[5-(3-fluorobenzenesulfonylamino)-1H-indazol-3-yl]-benzamide is thus obtained in the form of a white solid melting at 225° C. (analysis C20H15FN4O3S, % calculated C, 58.53; H, 3.68; F, 4.63; N, 13.65; O, 11.69; S, 7.81. % found C, 58.38; H, 3.42; N, 13.56; S, 7.44).
Reaction SMILES: [CH3:1][O:2][NH3+:3].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:1][O:2][N:3]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Br:5])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(=O)c1ccccc1Br
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: CO
Product: CON=C(C(=O)OC)c1ccccc1Br

Procedure:
5.2 g (62 mmol) of 0-methylhydroxylamine hydrochloride is added to a solution of 10 g (41 mmol) of methyl 2-bromophenylglyoxylate in 30 ml of methanol, and the mixture is refluxed for 2 hours. The mixture is evaporated down, and the residue is taken up in ethyl acetate and washed with water. After drying and evaporating down, there remains 6.9 g (62%) of compound E.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].[ClH:42]>O.C(O)C>[ClH:42].[ClH:42].[CH:1]1([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(OCCCOC4CCCCC4)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(N2CCN(c3ccc(OCCCOC4CCCCC4)cc3)CC2)cc1

Procedure:
A mixture of ethyl 4-[4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazin-1-yl]benzoate (290 mg) in the mixed solvent of tetrahydrofuran (15 ml) and ethanol (3 ml) was treated with 10% sodium hydroxide aqueous solution (0.50 ml), and the mixture was refluxed for 8 hours. After cooling, water was added to the reaction mixture, and the acidity of the mixture was adjusted to pH 1 with 1N-hydrochloric acid. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give 4-[4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazin-1-yl]benzoic acid dihydrochloride (96 mg) as a pale brown solid.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][C:22]2[C:23]([N+:28]([O-:30])=[O:29])=N[CH:25]=[CH:26][CH:27]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC1C=CC=[C:35]([C:39]([F:42])([F:41])[F:40])C=1[N+]([O-])=O.BrCC1C([N+]([O-])=O)=NC=CC=1>>[C:8]1([C:7](=[N:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:35]([C:39]([F:42])([F:41])[F:40])[C:23]=2[N+:28]([O-:30])=[O:29])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccnc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1c(CBr)cccc1C(F)(F)F
Agent: O=[N+]([O-])c1ncccc1CBr
Product: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1

Procedure:
Ethyl 2-(diphenylmethyleneamino)-3-[2-nitro-3-(trifluoromethyl)phenyl]propanoate (18) Ethyl 2-(diphenylmethyleneamino)-3-[2-nitro-3-(trifluoromethyl)phenyl]propanoate (18) was prepared according to the general procedure for the synthesis of ethyl 2-(diphenylmethyleneamino)-3-(2-nitropyridin-3-yl)propanoate (5) in Example 1, except that 1-(bromomethyl)-2-nitro-3-(trifluoromethyl)benzene (17) from the previous step was used in place of 3-(bromomethyl)-2-nitropyridine (3) (Yield: 3.2 g, 28% over 2 steps).
Reaction SMILES: [CH2:1]1[CH2:15][O:14][C:3]2([CH2:8][CH2:7][C:6]([CH3:13])([C:9](OC)=[O:10])[CH2:5][CH2:4]2)[O:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.O>CCOCC>[CH2:15]1[CH2:1][O:2][C:3]2([CH2:4][CH2:5][C:6]([CH3:13])([CH2:9][OH:10])[CH2:7][CH2:8]2)[O:14]1
Reactant: COC(=O)C1(C)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(CO)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89.8 %

Procedure:
The thus-obtained methyl 4,4-ethylenedioxy-1-methylcyclohexanecarboxylate (37.8 g) was dissolved in ether (100 ml), and the solution was added dropwise to a refluxing suspension of LiAlH4 (6.7 g) in ether (400 ml). After the addition, the mixture was stirred at room temperature for an hour and then cooled with ice. Ethyl acetate (20 ml) and then water (35 ml) were added dropwise cautiously thereto. The solid precipitate was filtered off, and the filtrate was distilled under reduced pressure to give 4,4-ethylenedioxy-1-methylcyclohexanemethanol (29.5 g, 89.9% yield, b.p. 120°-125° C./0.5 mmHg, m.p. 42°-43° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=O)[CH2:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[C:4]([Cl:29])[CH:3]=1.Cl.[NH2:31]O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:16]([F:18])([F:19])[F:17])[O:20][N:31]=3)[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[C:4]([Cl:29])[CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: FC(F)(F)c1cc(-c2cn(-c3ccc(Br)cc3Cl)c(-c3ccccc3Cl)n2)no1
Yield: 87.4 %

Procedure:
To a 50 mL flask attached with condenser was added 1-(1-(4-bromo-2-chlorophenyl)-2-(2-chlorophenyl)-1H-imidazol-4-yl)-4,4,4-trifluorobutane-1,3-dione (138 mg, 273 μmol) and MeOH (12 mL). To the solution was added hydroxylamine-HCl (190 mg, 2.73 mmol). The reaction solution was allowed to stir at reflux for 1.5 h. The solution was concentrated in vacuo and the residue was taken into EtOAc and washed with aq. NaHCO3 (50 mL×2). The EtOAc phase was partitioned, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed through a 12 g SiO2 column using a 100% hexane to 60% EtOAc gradient to yield 120 mg (86% yield) of title compound. MS (ESI) 508.3, 510.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=C(N=C=S)C=CC=1>>[CH3:48][O:52][C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: COc1cccc(N=C=S)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(OC)c4)cc3)ccc2C1=O

Procedure:
The compound of example 278 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-methoxyphenyl isothiocyanate. The compound of example 278 was used directly without isolation, for the preparation of compound of example 279.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS[C:17]1[N:22]=[C:21]([OH:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[O:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSc1ncc([N+](=O)[O-])c(O)n1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2ncc([N+](=O)[O-])c(=O)[nH]2)o1
Yield: 78.9 %

Procedure:
A mixture containing 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (4.72 g; 22.0 mmoles) and 2-methylthio-5-nitro-4-hydroxypyrimidine (4.0 g; 21.37 mmoles) in 20 ml of ethanol was heated at reflux temperature for 18 hours. The reaction mixture was evaporated under reduced pressure, and the residue was recrystallized from 2-methoxyethanol to give 5.96 g of the title compound, mp 201°-204° C.
Reaction SMILES: C(Cl)Cl.C(O)(=O)C.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([CH3:32])=[CH:19][C:20]([O:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28]C)=[O:27])=[N:21][CH:22]=2)=[CH:13][C:12]=1[F:33])(=[NH:10])[NH2:9].Br[CH2:35][C:36]([C:38]1([C:41]([F:44])([F:43])[F:42])[CH2:40][CH2:39]1)=O.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].O>[F:33][C:12]1[CH:13]=[C:14]([C:17]2[C:18]([CH3:32])=[CH:19][C:20]([O:23][CH2:24][C:25]([CH3:30])([CH3:31])[C:26]([OH:28])=[O:27])=[N:21][CH:22]=2)[CH:15]=[CH:16][C:11]=1[C:8]1[NH:10][C:36]([C:38]2([C:41]([F:44])([F:43])[F:42])[CH2:40][CH2:39]2)=[CH:35][N:9]=1
Reactant: O=C(CBr)C1(C(F)(F)F)CC1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(C(=N)N)c(F)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2ncc(C3(C(F)(F)F)CC3)[nH]2)c(F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture in which methylene chloride (8 mL) and a saturated brine (8 mL) were added to methyl 3-{[5-(4-carbamimidoyl-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate acetic acid salt (400 mg), 2-bromo-1-[1-(trifluoromethyl)-cyclopropyl]ethanone (289 mg) and potassium carbonate (404 mg) was stirred at 50° C. for 8 hours. The organic layer was separated, and concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (2.0 mL) and methanol (2.0 mL), and after adding 2N aqueous sodium hydroxide solution (3.0 mL) to the solution, the resulting mixture was stirred at 50° C. for 3 hours. The mixture was diluted by ethyl acetate, and then, neutralized by adding 1N hydrochloric acid. The organic layer was separated, ether was added to the residue obtained by concentrating the mixture under reduced pressure and the resulting mixture was stirred. The precipitated solid was collected by filtration and dried to obtain 3-{[5-(3-fluoro-4-{5-[1-(trifluoromethyl)cyclopropyl]-1H-imidazol-2-yl]phenyl)-4-methylpyridin-2-yl}oxy}-2,2-dimethylpropanoic acid (339 mg).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([CH3:18])=[C:16]([N+:19]([O-])=O)[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]>CCOC(C)=O.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)[C:17]=1[CH3:18]
Reactant: CCS(=O)(=O)c1ccc(-c2c(OCC(=O)OC)ccc([N+](=O)[O-])c2C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(-c2c(OCC(=O)OC)ccc(N)c2C)cc1
Reaction time: 2 h

Procedure:
10% Pd/C (0.15 g) was added to a solution of the product from example 165 step (ii) in EtOAc (20 ml) was hydrogenated at RT and 3 bar for 2 h. The mixture was filtered through celite and the filtrate evaporated to give the sub-title compound. Yield 1.4 g.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[NH:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(CCCC2=NCCN2)cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CCCC2=NCCN2)cc1)OCc1ccccc1
Yield: 76 %

Procedure:
To a solution of compound 55 (318 mg, 1.56 mmol) in DMF (1 mL) was added dropwise CbzCl (0.29 mL, 2.03 mmol) at 0° C. with stirring. The reaction mixture was stirred at room temperature for 3 h. The DMF was removed by vacuum. The residue was purified with silica gel column chromatography (EtOAc:CH3OH:TEA=3:1:0.2) to give compound 56 (400 mg, 76%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ7.70 (s, 1H), 7.30-7.40 (m, 5H), 7.25 (d, 2H, J=8.3 Hz), 6.98 (d, 2H, J=8.3 Hz), 5.15 (s, 2H), 3.65 (s, 4H), 2.50 (t, 2H, J=7.4 Hz), 2.43 (d, 2H, J=7.4 Hz), 1.85-1.97 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:33]([O-])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>ClCCl>[P:33]([O:11][C@H:10]1[O:12][C@@H:13]([CH3:32])[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:34]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1O[C@H](OP(=O)(OCc2ccccc2)OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Yield: 95 %

Procedure:
A solution of 2,3,4-tri-O-benzyl-L-fucopyranose (0.50 g, 0.86 mmol) in 20 ml of dry dichloromethane and freshly recrystallized dibenzyl phosphate (0.24 g, 0.86 mmol) is stirred under a nitrogen atmosphere at room temperature for about 1 h. The solution is then concentrated and purified by chromatography (toluene/acetone 7:1). Dibenzyl 2,3,4-tri-O-benzyl-β-L-fucopyranosyl phosphate (5) is obtained in a yield of 95% as a colorless oil (0.57 g). TLC (toluene/acetone 7:1 gives an Rf of 0.45, [α]578 =-9.7 (c=1, chloroform).
Reaction SMILES: [CH2:1]([CH2:5][CH:6]([NH2:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][NH2:4].C(O)(=O)C(C)=O.N[C@H](C(O)=O)CS>O>[NH2:10][C@H:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:1][CH2:2][CH2:3][NH2:4]
Reactant: NCCCCC(N)C(=O)O
Agent: CC(=O)C(=O)O
Agent: N[C@@H](CS)C(=O)O
Solvent: O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
10 mmol of MTDC and 20 mmol of L-lysine base are dissolved in 20 ml of water at room temperature. The transparent solution is then lyophilized. In the solution no pyruvic acid or free cysteine could be detected.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([O:33][CH2:34][CH3:35])[CH:23]=2)[C:10]=1[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])C.[OH-].[Na+]>>[C:38]([CH2:37][CH2:36][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([O:33][CH2:34][CH3:35])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])([OH:40])=[O:39]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Yield: 98.1 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-ethoxy-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy]-butyric acid ethyl ester (150 mg, 0.25 mmol) and 1.0 N aqueous sodium hydroxide (2.5 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(3-ethoxy-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy]-butyric acid (136 mg, 99%) as a light brown waxy solid: ES(+)-HRMS m/e calcd for C31H38O7S (M+H)+ 555.2411, found 555.2410.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([Cl:12])=[O:9]
Reactant: O=C(O)c1occc1Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1occc1Br

Procedure:
Compounds of this invention with Formulae I-IX may be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of 3-bromo-furan-2-carboxylic acid with thionyl chloride produces intermediate, 3-bromo-furan-2-carbonyl chloride, followed by refluxing with 4-trifluoromethyl-benzamidoxime in pyridine produces the product 5-(3-bromo-furan)-3-(4-trifluoromethyl-phenyl)-[1,2,4]-oxadiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22](=O)[CH2:23][O:24][CH2:25][CH3:26])=[CH:16][CH:15]=3.O.[NH2:35][NH2:36]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:35][N:36]=[C:22]([CH2:23][O:24][CH2:25][CH3:26])[CH:21]=1)=[CH:16][CH:15]=3
Reactant: CCOCC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)[nH]n1

Procedure:
The process is carried out as in Example 43 above, with compound A 1-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-ethoxybutane-1,3-dione and hydrazine hydrate
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:12]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][N:26]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[CH2:14][C@H:13]([NH:15][C:16]3[N:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12]2)[CH2:27][CH2:28]1
Reactant: Clc1ncnc2c1ncn2[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Reactant: C1COCCN1
Product: c1ccc2nc(N[C@H]3C[C@H](n4cnc5c(N6CCOCC6)ncnc54)C3)ncc2c1
Temperature: 100 °C

Procedure:
N-(Trans-3-(6-chloro-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (example 21, 0.0681 g, 0.194 mmol) was dissolved in morpholine (2.0 ml, 22.97 mmol) and heated in the microwave to 100° C. for 20 minutes. The solution was evaporated to dryness under reduced pressure and further dried under high vac. Purification using silica chromatography (0-10% methanol in dichloromethane gradient) gave the desired N-(trans-3-(6-morpholino-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (0.038 g, 0.094 mmol, 48.8% yield) as an off white solid. M+1: 403.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.80 (ddd, J=13.30, 8.31, 4.79 Hz, 2 H) 3.02-3.20 (m, 2 H) 3.85 (t, J=4.69 Hz, 4 H) 4.33 (br. s., 4 H) 4.78-4.94 (m, 1 H) 5.30 (quin, J=7.60 Hz, 1 H) 5.93 (br. s., 1 H) 7.23-7.34 (m, 1 H) 7.62 (d, J=8.22 Hz, 1 H) 7.66-7.75 (m, 2 H) 7.96 (s, 1 H) 8.37 (s, 1 H) 9.02 (s, 1 H).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][CH:3]=[CH:2]1.[H-].[Na+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH:2]=[CH:3]1
Reactant: O=C1NC=COc2ccccc21
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OC=CN1CCCCBr
Reaction time: 0.5 h

Procedure:
1.0 g of 4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in 50 ml of dimethylformamide, then 298 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 4.7 g (3 equivalents) of 1,4-dibromobutane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[Br:22]Br.S([O-])([O-])=O.[Na+].[Na+]>[Cl-].C([N+](CC)(CC)CC)C.[Br-].[K+]>[CH2:1]([C:8]1[C:13]([Br:22])=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCOCCOc1cccc(Cc2ccccc2)n1
Agent: CC[N+](CC)(CC)CC
Agent: O=S([O-])[O-]
Agent: [Br-]
Product: CCOCCOc1ccc(Br)c(Cc2ccccc2)n1

Procedure:
A mixture of 1 g of 2-benzyl-6-(2-ethoxyethyl)oxypyridine, 125 mg of tetraethylammonium chloride and 279 mg of potassium hydroxide was suspended in 5 ml of an aqueous potassium bromide solution (2.5 g of potassium bromide was dissolved in 10 ml of water). Into the suspension was added dropwise a mixture of 0.23 ml of bromine and 5 ml of the aforementioned aqueous potassium bromide solution by using a dropping funnel with stirring under ice-cooling over 10 minutes. The mixture was returned to room temperature and stirred overnight. Then, an aqueous sodium sulfite solution was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 5% ethyl acetate/hexane as an eluent for separation and purification, to give 1.2 g of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:13])[NH:8]2.ClCCl.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[CH:17]1([C:20]([N:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:13])=[O:21])[CH2:19][CH2:18]1
Reactant: COc1cccc2c1CC[C@H](C)N2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2c1CC[C@H](C)N2C(=O)C1CC1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A 1000-mL 3-necked round-bottom flask was charged with (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (47.41 g, 267.5 mmol), dichloromethane (500 mL), and pyridine (38 mL). Cyclopropanecarbonyl chloride (28.4 g, 271.7 mmol) was added dropwise with stirring at 0° C., and the resulting solution stirred for 3 h at 0° C. The reaction mixture was poured into 400 mL of water/ice, and then washed with 2 N hydrochloric acid (1×100 mL) and brine (3×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 0-15% ethyl acetate/petroleum ether) to afford (2S)-1-cyclopropanecarbonyl-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (64.6 g, 98%) as a yellow solid. MS (ES, m/z): 246 [M+H]+