Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:8]([F:11])([F:10])[F:9])[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:8]([F:11])([F:10])[F:9])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(OC)(c1ccccc1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C(=O)O)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
210 g of methyl α-methoxy-α-trifluoromethylphenylacetate (obtained according to Example 1) were mixed with 600 ml of methanol at 25° C., and 860 ml of 1N aqueous sodium hydroxide solution were slowly added dropwise. The mixture was stirred at room temperature for 5 hours. Dilute aqueous hydrochloric acid was then used to adjust the pH to 1, and extraction was carried out using 2×200 ml of methylene chloride, the organic phase was dried over sodium sulphate and, finally, the solvent was removed. This gave 96% yield of α-methoxy-α-trifluoromethylphenylacetic acid (=190 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[CH3:19]O>>[CH3:19][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-carboxyphenylboronic acid (2.0 g) and sulfuric acid (0.1 ml) in methanol (50 ml) was refluxed overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo to give 4-methoxycarbonylphenylboronic acid (1.7 g) as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:19]=3[CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:30]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH2:25][CH3:26])([CH2:27][CH3:28])[C:19]=3[CH:29]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-diethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=O.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:28][O:27][C:20](=[O:26])[CH2:21][C:22]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:23]=1[CH3:25]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccccc1F)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1F)CCCC3
Yield: 86.6 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-fluorophenyl)methanone (0.275 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.320 g (86%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10](Cl)=[O:11])#[N:2].[CH2:24]([N:26](CC)[CH2:27]C)C.Cl.CNC>O1CCCC1>[CH3:24][N:26]([CH3:27])[C:10](=[O:11])[CH:9]=[CH:8][C:7]1[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: CCN(CC)CC
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)C=Cc1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
To a stirred solution of 0.5 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride and 1.3 grams (0.012 mole) of triethylamine in 100 mL of tetrahydrofuran was added 1.0 gram (0.012 mole) of dimethylamine hydrochloride. Upon completion of the addition, the reaction was stirred at ambient temperature for about 18 hours. The reaction mixture was then warmed to 65° C. Where it was stirred for 15 minutes. The reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate, and the solution was washed with water. The organic layer was treated with decolorizing carbon and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was triturated with petroleum ether, and a solid was collected by filtration, yielding 0.2 gram of N,N-dimethyl-3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylamide; m.p. 116°-120° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25](O)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)=[O:26])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(C(=O)N2CCOCC2)cc2cc(OCc3ccccc3)cnc21
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester (intermediate G), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, morpholine and N,N-diisopropylethylamine in DMF to give the desired product as colorless foam (70%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>>[OH:29][CH2:26][C:27]#[C:28][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Reactant: C#CCO
Product: Cc1cc(C(=O)CC(c2cccc(C#CCO)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 85, step 1, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 2-propyn-1-ol was prepared the title compound as a white foam, MS (ESI+): m/z=370.18 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCCc2ccc3c(c2)OCO3)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN(C)C=O.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
A mixture of 1B (5.0 g) and dimethylformamide (50 ml) is treated with sodium hydride (1.06 g). Benzylbromide (3.15 ml) was slowly added to the resulting reaction mixture and stirred at room temperature for 20 hours. The reaction mixture was poured into water. The mixture was extracted with diethyl ether twice. The combined organic phases were washed with water, dried and concentrated in vacuo. The crude product was chromatographed (hexane/dichloromethane, 1/1) to give the product as a white solid (4.5 g, 64%) with a melting point of 52°-53.5° C.
Reaction SMILES: Cl.C([NH:9][C@@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.C(O)(=O)C>[Pd].CO>[NH2:9][C@@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C[C@@H](NCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](N)C(=O)O

Procedure:
A mixture of 0.5 g of benzyl D-leucine hydrochloride, 20 ml of acetic acid and 20 ml of methanol was stirred with palladium under a hydrogen atmosphere until absorption ceased and the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel to obtain D-leucine.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:11]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[OH:12])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Product: OC(c1ccccc1)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43b (300 mg, 1.73 mmol) and phenylmagnesium bromide (1.73 mL, 3.46 mmol, 2 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Yellow solid. Yield: 138 mg, 42%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.91 (s, 1H), 7.29-7.34 (m, 1H), 7.35-7.50 (m, 7H), 7.68 (dd, J=8.2, 0.6 Hz, 1H), 7.73-7.78 (m, 1H), 7.94-7.99 (m, 2H), 8.68 (dd, J=1.6, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=74.1, 120.3, 126.5, 126.9, 128.0, 128.7, 128.7, 128.9, 135.0, 137.6, 139.0, 143.0, 148.2, 156.7; (ESI): m/z=261.97 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[OH:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])=[O:15])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCc2ccccc2)c(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ccccc2)c(Br)c1

Procedure:
In analogy to example 1f, 6-benzyloxy-5-bromo-nicotinic acid was coupled with (1R,2R)-2-amino-cyclohexanol hydrochloride (CAS [5456-63-3]) using TBTU and N,N-diisopropyl ethyl amine in N,N-dimethylacetamide to give 6-benzyloxy-5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1)([O-])=O.C1CCCCC=1>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:6][CH:5]=1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCCC1
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1CCCc1ccc(N)cc1
Yield: 103 %

Procedure:
45 mg of 5-[3-(4-nitrophenyl)propyl]-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole was dissolved in 6 ml of methanol, followed by the addition of 2 ml of cyclohexene. Then, 45 mg of 10% palladium-carbon was added thereto, followed by heating under reflux for 2 hours. After the reaction mixture was filtered, the filtrated was concentrated to obtain 43 mg of the title compound quantitatively as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18]>C(#N)C>[CH3:14][P:15]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])(=[O:19])[O:16][CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOP(C)OCC
Solvent: CC#N
Product: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-chloro-1,2-dinitrobenzene (13.2 g, 65.0 mmol) dissolved in acetonitrile (150 ml) is added, dropwise, diethyl methylphosphonite (16.0 g, 117.6 mmol). The mixture is stirred at RT for 20 hours, after which it is concentrated. The crude product is purified by column chromatography (developing with 50% ethyl acetate/hexane) to yield ethyl P-methyl-2-nitro-5-chlorophenylphosphinate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:17])=[CH:11][C:12]([NH2:16])=[C:13]([Br:18])[C:14]=1[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)c(OCc2ccccc2)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(F)c(OCc2ccccc2)c(F)c1Br
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 4-benzyloxy-3,5-difluorophenylamine (3.0 g) in THF (30 mL) was added N-bromosuccinimide (2.32 g) under ice-cooling, and the mixture was stirred for 30 minutes. Conc. Hydrochloric acid (2 mL) was added to the reaction mixture to precipitate a solid. The solid was collected by filtration and dried. The dried solid was dissolved in water, and the solution was added with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated to give 4-benzyloxy-2-bromo-3,5-difluorophenylamine (3.33 g).
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:39])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:35]([O:37]C)=[O:36])[CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:26])[N:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.[OH-].[Na+]>>[NH2:7][C:8]1[N:9]=[C:10]([OH:39])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:35]([OH:37])=[O:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])[N:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1c[nH]c(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)n1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CCc1nc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c[nH]1)C2
Yield: 43.8 %

Procedure:
Dimethyl N-{2-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl)ethyl]imidazol-4-ylcarbonyl}-L-glutamate (109 mg g, 0.2 mmol) and 0.5N sodium hydroxide (1 mL) are allowed to react analogously to the method described in Example 19 to yield N-{2-[2-(amino-4-hydroxy-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-6-yl)ethyl]imidazol-4-ylcarbonyl}-L-glutamic acid (38 mg, 44%, mp >260° C.): 1H NMR (DMSOd6) d 12.35 (br s, 1H), 12.21 (br s, 1H), 9.77 (br s, 1H), 7.80 (br s, 1H), 7.50 (s, 1H), 6.27 (s, 1H), 5.92 (s, 2H), 4.37 (m, 1H), 3.17 (br d, 1H, J=10.6 Hz), 2.79-2.61 (m, 3H), 2.44 (m, 1H), 2.26 (m, 2H), 2.07-1.76 (m, 3 H), 1.68-1.59 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:15][C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[C:12](Cl)[C:7]=2[CH:6]=1)=[O:4].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:15][C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[C:12]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cc2c(Cl)nc(N)nc2s1
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(NCc3ccccc3)nc(N)nc2s1
Temperature: 25 °C

Procedure:
The 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg, 0.39 mmol), benzylamine (100 μL) in 4 mL of THF are submitted to MW irradiation at 110° C. for 35 mins. The reaction was cooled to room temperature and worked up (acidic) and purified using standard conditions for a neutral compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=2)[N:14]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:13]=1[CH3:36])=O.Cl.[NH2:38][OH:39].NO>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=2)[N:14]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:13]=1[CH3:36])=[N:38][OH:39]
Reactant: COc1ccc(C(=O)c2c(C)n(S(=O)(=O)c3ccc(C)cc3)c3cc(OC(F)(F)F)ccc23)c(O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2c(C)n(S(=O)(=O)c3ccc(C)cc3)c3cc(OC(F)(F)F)ccc23)c(O)c1
Temperature: 90 °C

Procedure:
A solution of 8 (16 mmol), hydroxylamine hydrochloride (10 eq, 11.2 g) and pyridine (270 mL) was heated to 80° C. for 24 hours. Additional hydroxylamine (3 g) was added and the temperature increased to 90° C. After LC analysis confirmed the consumption of starting material, the reaction was cooled and the pyridine removed by rotary evaporation. The residue was dissolved in DCM and washed with water and 1M HCl. The organic layer was dried over Na2SO4 and concentrated. The reaction mixture was purified by flash chromatography eluding with 20% EtOAc/hexanes, Rf=0.4. The product was isolated as a white foam.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2>C(OCC)(=O)C>[NH2:12][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:11]
Reactant: Cc1ccc2c(c1[N+](=O)[O-])CNC2=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1N)CNC2=O
Reaction time: 12 h
Yield: 80 %

Procedure:
5-Methyl-4-nitro-2,3-dihydro-isoindol-1-one (800.00 mg, 4.16 mmol) was taken up in ethyl acetate in a Paar vessel and flushed with argon. Palladium on carbon (100 mg) was added and the argon atmosphere was replaced with hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen was then replaced with argon and the catalyst was removed by filtration through celite. The solvent was removed under reduced pressure to yield 539.8 mg of the desired amine. C9H10N2O MS m/e=163.2 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].N1C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH:41]=[C:40]([C@H:45]([CH3:49])[C:46](Cl)=[O:47])[CH:39]=[CH:38]2.O>CN(C)C=O.C1(C)C=CC=CC=1>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:46](=[O:47])[C@H:45]([C:40]2[CH:39]=[CH:38][C:37]3[C:42](=[CH:43][CH:44]=[C:35]([O:34][CH3:33])[CH:36]=3)[CH:41]=2)[CH3:49])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@@H](C)c2ccc3cc(OC)ccc3c2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Yield: 100.5 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (70 g) was suspended in dimethylformamide (350 ml) and pyridine (23.7 ml) and a solution of (S)-2-(6-methoxy-2-naphthyl)propionyl chloride (59.7 g) in toluene (250 ml) was added dropwise to the suspension over 10 minutes with stirring under ice-cooling. The mixture was stirred at room temperature for 4 hours, poured into water (1400 ml), and the precipitated oily substance was extracted with toluene and washed successively with 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 113 g of methyl (±)-4-[5-(1-imidazolyl)-α-{(S)-2-(6-methoxy-2-naphthyl)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate as pale-yellow oil. This was crystallized from isopropyl alcohol (560 ml), and the obtained crystals were recrystallized from isopropyl alcohol (300 ml) to give 42 g of methyl (S)-4-[5-(1-imidazolyl)-α-{(S)-2-(6-methoxy-2-naphthyl)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate as white crystals, melting point 156-158° C., optical rotation [α]D24 +87.3° (c=1, chloroform).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[C:8]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])#[N:9].C(O)(=O)C.N1CCCCC1>>[CH2:14]([O:13][C:11](=[O:12])[C:10]([C:8]#[N:9])=[CH:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCC(C=O)CC
Reactant: N#CCC(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCC(C=C(C#N)C(=O)OCc1ccccc1)CC
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a mixture of 2-ethylbutyraldehyde (2.0 mL, 16.2 mmol) and benzyl cyanoacetate (2.85 g, 16.2 mmol) at 0° C. was added acetic acid (0.1 mL, 1.62 mmol), then piperidine (0.16 mL, 1.62 mmol) dropwise. The ice bath was removed, and stirring continued for 10 minutes. Additional acetic acid (0.1 mL) and piperidine (0.16 mL) were added, followed by the additional of oven-dried 4A molecular sieves such that stirring was not impeded. The mixture was stirred 1.5 h, then partitioned between EtOAc and sat. NaHCO3 (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide 3.96 g (95%) of 2-cyano-4-ethyl-hex-2-enoic acid benzyl ester as a colorless oil. 1H NMR (CDCl3) δ 7.39 (m, 6H), 5.28 (s, 2H), 2.60 (m, 1H), 1.62 (m, 2H), 1.40 (m, 2H), 0.88 (t, J=7.6 Hz, 6H). 13C NMR δ 168.69, 161.40, 135.01, 128.90, 128.82, 128.50, 114.11, 109.94, 68.07, 46.35, 27.30, 11.95. IR (neat) 2233, 1729 cm−1. LRMS: m/z 256.1 (M−1). Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.75; H, 7.52; N, 5.50.