Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.CN(C)[CH:30]=[O:31]>O1CCCC1.O>[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: Fc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1ccncc1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Form a solution of lithium diisopropylamide by the addition of n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to diisopropylamine (8.40 mL, 0.06 mol) in tetrahydrofuran (200 mL) at 0 to −10° C. under a nitrogen atmosphere. Stir for 30 min. Cool to −70° C. and add 3-fluoropyridine (4.29 mL, 0.05 mol) dropwise via syringe. Stir for 1 hour at this temperature. Add N,N-dimethylformamide (7.75 mL, 0.10 mol) dropwise via syringe and stir for 2 hours near −70° C. Add water (200 mL) when the mixture warms to −20° C. and extract with ethyl acetate. Dry the combined extracts over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel, allowing for isolation of the desired aldehyde (4.28 g, 68%) as an oil. MSEI): M+ 125.0 m/z.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH:15]=[CH:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: O=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(C(=O)C=Cc2ccccc2F)c(Cl)c1Cl
Yield: 54.9 %

Procedure:
To 500 ml of ethanol was added [2,3-dichloro-4-(1-oxo-ethyl)phenoxy]acetic acid (19.73 g, 0.075 mole), 2-fluorobenzaldehyde (13.63 g, 0.11 mole), sodium hydroxide (10 g, 0.25 mole) in 20 ml of water and 50 ml of ethanol with stirring under nitrogen. The reaction mixture was refluxed for a total of 11/2 hours. The reaction mixture was cooled, filtered, the gelatineous solid dispersed in water acidified with hydrochloric acid, stirred, filtered and washed with water. The residue was extracted with methylene chloride and ethyl acetate, washed with water, and concentrated under reduced pressure to give 15.2 g of [2,3-dichloro-4-(3-(2-fluorophenyl)-1-oxo-2-propenyl)phenoxy]acetic acid which melted at 191°-194° C. after purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:28][NH:29][CH3:30]>C1COCC1.CN(C=O)C>[OH:26][C@H:25]([CH2:27][N:29]([CH3:30])[CH3:28])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN(C)C
Temperature: 75 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), and dimethylamine (1.24 ml of a 2M solution in THF, 2.48 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by trituration with methanol to give (2R)-7-(2-hydroxy-3-dimethylaminopropoxy)4-(indol-5-yloxy)-6-methoxyquinazoline (265 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]([C:12]#[N:13])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.O>[NH2:1][C:2]1[C:7]2=[CH:8][C:9]([C:12]#[N:13])=[C:10]([C:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: N#Cc1cc2c(N)ncnn2c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2c(C#N)cc3c(N)ncnn23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To the solution of 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (1.00 g, 4.20 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.95 g, 6.30 mmol) in DMF (50 mL) and DME (6.9 mL), was added sodium carbonate in water (2M, 6.3 mL). The mixture was degassed for 15 min. Dichloro[bis(diphenylphosphino)ferrocene]palladium(II) CH2Cl2 adduct (307 mg, 0.42 mmol) was added. The mixture was stirred at 80° C. under nitrogen overnight then cooled to rt. The mixture was filtered through Celite®, washing with EtOAc (100 mL) then 20% MeOH/DCM (100 mL). The filtrate was concentrated to dryness. ISCO® purification (20% EtOAc/hexane then EtOAc) afforded title compound (1.0 g, 69.4%). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 2H), 7.97 (s, 1H), 7.34 (s, 1H), 6.38 (t, 1H), 4.02 (d, 2H), 3.58 (t, 2H), 2.62 (t, 2H), 1.41 (s, 9H); LC-MS m/z [M+H]+ 341.2, RT 3.16 min.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[CH2:47][CH2:48][NH2:49]>C1COCC1>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH2:47][CH2:48][NH:49][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=4)[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:10][C:11]=3[CH:29]=2)=[O:31])[CH:50]=[CH:51][CH:52]=1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(CCN)c1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(CCNC(=O)c2ccc3c(c2)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 3-methoxyphenethylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 576.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[NH:8][C@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[H-].[Na+].[CH2:27](I)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Reactant: ICCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(C)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N(CCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 8-ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting peak from Example 74, Part B, (30 mg, 0.09 mmol) in 1 mL of DMF at ambient temperature was added sodium hydride (4 mg of 60% in mineral oil, 0.10 mmol) and phenethyliodide (33 mg, 0.14 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. Starting material remained so the reaction was heated at 60° C. for 4 h. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (elution with 3:1 hexane ethyl acetate) to afford 16 mg (41%) of the title compound as an oil. LRMS (ESI): 435.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Br)cc1
Yield: 81.1 %

Procedure:
1.79 g (0.00931 mol) of 1-benzyl-4-hydroxy-piperidine and 2.3 ml (0.0164 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 1.63 g (0.00745 mol) of 4-bromobenzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 2.26 g (81%) of 1-benzyl-piperidin-4-yl 4-bromo-benzoate were obtained as white crystals; m.p. 71°-72°.
Reaction SMILES: Cl.[CH:2]1([NH:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].O.[CH3:15][C:16]1[O:17][C:18]([CH3:24])=[CH:19][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[CH:2]1([N:7]([C:21]([C:20]2[CH:19]=[C:18]([CH3:24])[O:17][C:16]=2[CH3:15])=[O:22])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: ONC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(=O)N(O)C2CCCC2)c(C)o1
Temperature: 25 °C

Procedure:
27.5 Parts of N-cyclopentylhydroxylamine hydrochloride is dissolved in 200 parts of dichloromethane; a solution of 33.6 parts of sodium hydrogen carbonate in 300 parts of water is then added. At room temperature and while stirring thoroughly, 31.8 parts of 2,5-dimethylfuran-3-carboxylic chloride is dripped into this mixture. After stirring the mixture for 1 hour the organic phase is separated, dried over anhydrous sodium sulfate and evaporated. The oil which remains soon solidifies and the crystals obtained are stirred with petroleum ether, suction filtered and dried. There is obtained 14.3 parts of N-cyclopentyl-2,5-dimethylfuran-3-hydroxamic acid having a melting point of from 107° to 109° C. ##SPC9##
Reaction SMILES: [Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][NH:9][CH2:10][C:4]=2[CH:3]=1.CCN(CC)CC.[C:21](Cl)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:9]1[CH2:10][C:4]2[CH:3]=[C:2]([Br:1])[CH:13]=[N:12][C:5]=2[NH:6][C:7](=[O:11])[CH2:8]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CNCc2cc(Br)cnc2N1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)OCc2ccccc2)Cc2cc(Br)cnc2N1
Reaction time: 8 h
Yield: 31 %

Procedure:
A suspension of 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (1.08 g, 4.46 mmol) in CH2Cl2 (60 mL) was treated with Et3N (0.80 mL, 5.7 mmol) and then cooled in an ice bath. The chilled suspension was treated dropwise with CbzCl (4.5 mmol) to give a clear solution. The ice bath was removed and the solution was allowed to stir overnight. The mixture was diluted with CH2Cl2 (90 mL), washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99.5:0.5 to 99:1) gave the title compound (0.52 g, 31%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.31-8.36 (m, 2H), 7.49-7.71 (m, 1H), 7.34-7.40 (m, 4H), 7.19-7.21 (m, 1H), 5.08-5.12 (m, 2H), 4.43-4.65 (m, 4H); MS (ESI) m/e 376 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[N:6][CH:7]=1.C1C(=O)N([Br:18])C(=O)C1>CC#N>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[N:6][C:7]=1[Br:18]
Reactant: Nc1cnc(CCO)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(CCO)nc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-aminopyrazin-2-yl)ethanol (30 mg, 0.216 mmol) in CH3CN (719 μL) was added NBS (38.4 mg, 0.216 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched by sat. NaHCO3, then extracted by EtOAc, The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo yielding crude 2-(5-amino-6-bromopyrazin-2-yl)ethanol which was used in next step reaction without purification. LCMS (m/z): 218.0/220.0 (MH+), 0.33 min.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=1)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:14]N(C)C=O.C(OCC)(OCC)OCC>C(OCC)(=O)C>[O:5]=[C:4]1[C:3]([C:1]#[N:2])=[C:7]2[C:8]([C:9](=[O:13])[CH2:10][CH2:11][CH2:12]2)=[CH:14][NH:6]1
Reactant: CN(C)C=O
Reactant: N#CC(C(N)=O)C1=CC(=O)CCC1
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Product: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2

Procedure:
75 parts of α-cyano-3-oxo-1-cyclohexen-1-acetamide in 400 parts by volume of dimethylformamide and 75 parts of triethyl orthoformate are heated on a steam bath for 3 hours to 16 hours. Solvent was then removed in vacuum to give a syrup which is taken up in ethyl acetate. Cooling of this solution gives 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile which is identical to the product of Example 3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27](C)[C:28](=O)OC(C)(C)C)[CH2:23]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[CH:15][C:8]=3[C:6]=2[N:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH3:28][NH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:4]2[C:5]3[CH2:12][CH2:11][CH2:10][C:9]4[N:13]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:14]=[CH:15][C:8]=4[C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:23]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2nc(N)nc3c2CCCc2c-3cnn2-c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CCN(c2nc(N)nc3c2CCCc2c-3cnn2-c2ccccc2)C1

Procedure:
The product from Example 11E (5 mg) was dissolved in dichloromethane (0.5 ml) and treated with trifluoroacetic acid (0.5 mL) for 1 hour at ambient temperature. The reaction mixture was concentrated and triturated with ether to yield the title compound: 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1 H), 8.16 (s, 1 H), 7.59 (m, 5 H), 3.84 (m, 2 H), 2.91 (t, J=6.78 Hz, 2 H), 2.67 (m, 4H), 2.45 (s, 3H), 2.27 (m, 2 H), 2.14 (m, 3 H); MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13])[C:3]([NH2:5])=[O:4].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].CN1CCN(C)C1=O>>[Cl:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:6]=1[CH:2]([NH:1][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)C(N)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CN1CCN(C)C1=O
Product: NC(=O)C(Nc1ccccc1[N+](=O)[O-])c1c(Cl)cccc1Cl
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 0.092 parts of α-amino-2,6-dichlorobenzeneacetamide, 0.032 parts of 2-fluoronitrobenzene and 1 part of 1,3-dimetyl-2-imidazolidinone was stirred for 6 hours at 140° C. The product was extracted and the extract was dried, filtered and evaporated at 100° C. and 133-266 Pa. The residue was purified by column chromatography (HPCL; silica gel; CH2Cl2 /CH3OH 99:1→90:10), yielding 0.12 parts of (-)-2,6-dichloro-α-[(2-nitrophenyl)amino]benzeneacetamide (e.e.=90%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CO.FC(F)(F)C(O)=O.[CH2:16]([S:18]([C:21]1[CH:51]=[CH:50][C:24]([O:25][C:26]2[C:40]([CH2:41]NC(=O)/C=C\C(O)=O)=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17]>C(Cl)(Cl)Cl.[Cl-].[NH4+]>[CH2:16]([S:18]([C:21]1[CH:51]=[CH:50][C:24]([O:25][C:26]2[C:40]([CH2:41][CH2:1][OH:4])=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2CNC(=O)/C=C\C(=O)O)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.0 mg of the obtained alcohol compound was dissolved in 1 ml of trifluoroacetic acid, and stirred at room temperature for 1.5 hours. The solvent was evaporated away, and the residue was diluted with chloroform and neutralized with aqueous saturated sodium hydrogencarbonate solution. This was extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, to obtain 9.0 mg of a trifluoroacetate. Potassium carbonate was added to a methanol (1 ml) solution of 9.0 mg of the trifluoroacetate, and stirred at room temperature for 30 minutes. This was diluted with chloroform, and aqueous saturated ammonium chloride solution was added to it, extracted with chloroform, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain 6.6 mg of the entitled compound as a colorless amorphous substance.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl>[F:10][C:3]1[CH:4]=[CH:5][C:6]([CH:8]=[CH2:9])=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: C=Cc1ccc(F)c(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: C=Cc1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-1-fluoro-4-vinyl-benzene (8 g), morpholine (20 mL), Pd2(dba)2 (1.83 g), di-t-butyl-biphenylphosphine (1.2 g), K3PO4 (17 g) in DME (60 mL) was stirred at reflux for 4 h. The reaction mixture was cooled down to room temperature, diluted with methylene chloride, and filtered. The filtrate was concentrated in vacuo. The crude product was purified by Flash Chromatography of Biotage eluting with 7% ethyl acetate in hexanes to give the title compound as an oil (5 g).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:14])[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1F)C(=O)O
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 15.4 %

Procedure:
To a solution of the above crude Boc-Tyr(2-F)-OH (0.82 g), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.77 g, 2.11 mmol) and CMPI (0.81 g, 3.17 mmol) in THF (5 ml), TEA (1.18 ml, 8.44 mmol) was added under cooling with ice and stirred at room temperature for 23 hours. The reaction mixture was mixed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:concentrated aqueous ammonia=30:1:0.05), giving the titled compound (0.21 g, 15%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[NH:7][C:6]([S:8][CH3:23])=[N:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)NC(=S)NC1c1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(SC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-pyrimidinecarboxylic acid, ethyl ester (1.0 g., 3.1 mmole) in dry acetone (10 ml.) is treated with finely ground potassium carbonate (1.0 g.) and methyl iodide (220 μl., 3.5 mmole). The reaction flask is tightly stoppered and the suspension is allowed to stir at room temperature overnight. It is then diluted with ethyl acetate and the white solid is filtered off. The filtrate is washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to give a light yellow foam. Crystallization from etherhexane provides 820 mg. of off-white crystalline product. This material is combined with that from another run (200 mg.) and triturated with hexane to give an analytically pure sample of 1,4-dihydro-6-methyl-2-(methylthio)-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester; m.p. 91.5°-93°. TLC (silica gel; ethyl acetate: hexane, 40:60) Rf =0.36.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:35])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:35])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(Cl)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 39.4 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3,4-dichloro-phenyl)-acrylonitrile (2.6 g, 8 mmol) prepared in Example 68a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-3-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.7 g, 39%).