Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[C:10]2([F:24])[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:34])[C:10]2([F:24])[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)C2(F)F)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)C2(F)F)CC1
Yield: 150.7 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3,3-difluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (3.621 g, 10.73 mmol) was dissolved in dry benzene (100 ml), and the solution was mixed with Lawesson's reagent (2.192 g, 5.420 mmol) and heated under reflux for 1 hour. After cooling, benzene was evaporated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=5:1, to thereby obtain 2.886 g (76.1%) of the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl-].[NH2:23][C:24]([NH2:26])=[NH2+:25].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:6])[C:3]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][C:2]=1[NH2:1]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-c2cccnc2)cc1N
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)c(N)cc1-c1cccnc1
Reaction time: 0.25 h

Procedure:
1.0 g of methyl 2-amino-4-(3-pyridyl)-5-methylsulfonylbenzoate [obtainable by reacting methyl 2-amino-4-bromo-5-methylsulfonylbenzoate with pyridine-3-boronic acid] is dissolved in 15 ml of 1-methylpyrrolidone and the solution is stirred for 15 min. Subsequently 0.9 g of guanidinium chloride and 2.6 ml of diisopropylethylamine are added and the mixture is stirred at room temperature for one hour. Customary workup gives N-diaminomethylene-2-amino-4-(3-pyridyl)-5-methylsulfonylbenzamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:22]=[CH:23][CH:24]=1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccc(Cl)c1
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Cl)c1

Procedure:
Coupling of N-tert-butoxycarbonyl-L-methionine (1a) and 3-chloroaniline (2c) according to General Procedure A, gave after purification on a SILICA GEL column hexane-acetone (3:1) an oily liquid of (3c) (C16H23N2O3S1Cl1, 94%), Rf=0.40 (hexane-acetone 3:1), [α]D23 =-36.8° (c 1.44, CHCl3), IR (KBr) ν: 440, 461, 519, 548, 606, 681, 739, 777, 864, 880, 903, 963, 999, 1026, 1049, 1076, 1099, 1165, 1252, 1267, 1300, 1368, 1393, 1427, 1456, 1483, 1506, 1522, 1539, 1595, 1670, 1684, 1697, 2336, 2361, 2868, 2918, 2978, 3061, 3086, 3131, 3198, 3291, 3522, 3545 cm-1, 1H NMR (CDCl3) δ: 8.472 (br s, 1H, Ar--NH), 7.616-7.629 (m, 1H, ArH), 7.240-7.283 (m, 1H, ArH), 7.153 (dd, 1H, J 7.8 Hz and 8.1 Hz, ArH), 7.023 (d, 1H, J 7.8 Hz, ArH), 5.377 (br s, 1H, NH), 4.407-4.427 (m, 1H, Hα), 2.566-2.618 (m, 2H, CH2γ), 2.116-2.184 (m, 1H, Hβ), 2.084 (s, 3H, CH3ε), 1.940-2.070 (m, 1H, Hβ), 1.425 (s, 9H, t-Bu); EIMS (70 eV) m/z (%): 358 (M+, 2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:40][C:41](OC2C=CC=CC=2)=[O:42])[C:27](=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH:22][C:41]([NH:40][C:26]2[CH:25]=[C:24]([Cl:23])[CH:39]=[CH:38][C:27]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:42])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)cc1NC(=O)OCc1ccccc1
Yield: 62 %

Procedure:
960 mg (3.00 mmol) of 3-benzyloxycarbonylamino-4-methylbenzenesulfonamide and 1.14 g (3.00 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 8 to obtain 1.14 g (yield 62% of benzyl 2-{[(3-benzyloxycarbonylamino-4-methylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 2.30 (3H, s), 5.17 (2H, s), 5.36 (2H, s), 7.20 (1H, dd), 7.33-7.48 (1H, m), 7.63 (1H, d), 7.97 (1H, d), 8.11 (1H, s), 8.25 (1H, s), 9.27 (1H, s), 10.30 (1H, s), 12.20 (1H, br).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[CH3:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:10][C:12](=[O:13])[C:11](=[O:17])[NH:9]2
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CCOC(=O)C(=O)OCC
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C

Procedure:
A mixture of 4,5-dimethyl-benzene-1,2-diamine (60 g) and diethyl oxalate (600 mL) was heated under reflux for 1 h and then cooled. The precipitate of 6,7-dimethyl-1,4-dihydro-quinoxaline-2,3-dione was filtered off and washed with 96% ethanol to give 38 g of the title compound. ESI-MS: m/z 191.1 [MH+], 403.3 [2MNa+]; required MW=190.2
Reaction SMILES: [CH3:1][SH:2].[CH3:3][C:4]1[C:5]([N+]([O-])=O)=[C:6]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:3][C:4]1[C:5]([S:2][CH3:1])=[C:6]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CS
Reactant: CCOC(=O)c1ccc(C)c(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)c(C)c1SC
Temperature: -10 °C
Reaction time: 72 h

Procedure:
A solution of methanethiol (22 ml) in dry dimethyl formamide was added to a mixture of ethyl 3,4-dimethyl-2-nitrobenzoate (21.54 g) and potassium carbonate (20.02 g) in dry dimethyl formamide while maintaining the temperature below -15° C. The mixture was stirred at -10° C. for 0.5 hours and at room temperature for 3 days. Water was added and the mixture was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane (8:1) to give ethyl 3,4-dimethyl-2-methylsulphenylbenzoate (21.25 g) as a clear oil, NMR (CDCl3) 1.4(t,3H), 2.3(s,3H), 2.35(s,3H), 2.55(s,3H), 4.4(q,2H), 7.1(d,1H), 7.2(d,1H).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8](O)=[C:7]([C:12]#[N:13])[C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:17])=O>CN(C=O)C>[Br:17][C:8]1[CH:9]=[CH:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:14])[C:7]=1[C:12]#[N:13]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCn1ccc(O)c(C#N)c1=O
Solvent: CN(C)C=O
Product: CCCCn1ccc(Br)c(C#N)c1=O
Temperature: 110 °C
Yield: 70.9 %

Procedure:
To a solution of intermediate 4 (39 g, 203 mmol) in DMF (600 ml) was added phosphoric tribromide (116 g, 406 mmol) and the mixture was heated at 110° C. for 1.5 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 6 (36.7 g, 72%).
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:20][OH:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH:20]=[O:21])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1cccs1)n1cc(CO)cc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a solution (20 mL) of [5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methanol (480 mg) in acetonitrile were added tetra-n-propylammonium perruthenate (80 mg), N-methylmorpholine N-oxide (407 mg) and molecular sieves 4A powder (500 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as colorless crystals (yield 272 mg, 57%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([Cl:16])=[N:15][C:7]=1[NH2:6]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 70 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Concentrated sulfuric acid (25 mL) and 2-amino-6-chloro-nicotinic acid (4.3 g, 25 mmol) described in Production Example 4-1-1A (or 4-1-1B) were added to methanol (50 mL) while cooling with ice followed by stirring for 5 hours at 70° C. After allowing to cool on standing, the reaction mixture was neutralized with sodium bicarbonate (90 g). The resulting solid was filtered to obtain the title compound (3.2 g, 17 mmol, 68%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>O1CCCC1>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:30][CH:31]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NC(C)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
(±)-Cis-N-[1-(4-acetylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. To a solution of (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. (100 mg, 0.24 mmol) in 2.5 ml tetrahydrofuran was added acetyl chloride (44 mL, 0.63 mmol) followed by triethylamine (88 μL, 0.63 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (3:1) to give the title compound (51 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].C[N:16]([CH:18]=O)C>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[C:4]([C:18]#[N:16])[C:3]=1[C:18]#[N:16]
Reactant: CN(C)C=O
Reactant: Cc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1Sc1ccc(Sc2ccccc2C)c(C#N)c1C#N
Yield: 42 %

Procedure:
2-Methylthiophenol (10.60 g, 85.5 mmol), potassium carbonate (11.82 g, 82.0 mmol) and ditosylated dicyanohydroquinone (20.00 g, 42.7 mmol) in DMF (75 mL) were reacted as described above. The mixture was isolated as described above to give a yellow oil. The material was purified by flash column chromatography (eluting 10% ethyl acetate:isohexane) to give the title compound as a yellow solid (8.85 g, 23.8 mmol, 42%). [Found: C, 70.7%; H, 4.6%; N, 7.5%; S, 17.2%; C22H16N2S2 requires C, 70.9%; H, 4.3%; N, 7.5%; S, 17.2%]; MS (EI+) 372 (M+, 100%), 357 (M-CH3, 8), 339 (20).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: Fc1ccc(I)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Yield: 111.3 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (525 mg, 2.0 mmol) and 1-fluoro-4-iodobenzene (0.35 mL, 3 mmol) according to the general procedure F. Obtained as a yellow solid (793 mg).
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>O>[C:15]1(=[O:25])[N:19]([CH:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[N:4]([CH3:14])[CH2:3]2)[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN1CC(Cl)C(=O)Nc2ccccc21
Agent: [K]
Solvent: O
Product: CN1CC(N2C(=O)c3ccccc3C2=O)C(=O)Nc2ccccc21
Reaction time: 1 h

Procedure:
A mixture of 1.05 g of 3-chloro-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one and 1.0 of potassium phthalimide is warmed to 90° overnight. The reaction mixture is poured into 20 ml of water and stirring is continued for 1 hr. Isolation and drying affords 3-phthalimido-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4](=[O:7])[CH2:5][Cl:6].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:9]([NH:2][C@@H:3]([CH3:8])[C:4](=[O:7])[CH2:5][Cl:6])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](N)C(=O)CCl
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously stirred suspension of (S)-3-amino-1-chloro-2-butanone, monohydrochloride (3.0 g., 19.0 mmole) in 150 ml. of tetrahydrofuran at 0°-5° is added, sequentially, benzoyl chloride (2.2 ml., 19.0 mmole), triethylamine (2.65 ml., 19.0 mmole), and sodium bicarbonate (1.6 g., 19.0 mmole). The reaction mixture is stirred for 15 minutes in the cold and then for 2 hours at room temperature. The solvent is evaporated and the residue is partitioned between ethyl acetate (400 ml.) and ice-water (40 ml.). The organic layer is washed with 5% potassium bisulfate (2×30 ml.) and water (3×30 ml.), then dried and evaporated. The resulting crystalline residue is recrystallized from benzene-petroleum ether giving three crops of comparable purity totaling 3.67 g.; m.p. 119.5°-121.5° (first crop), 118°-119.5° (third crop). A portion is recrystallized once more giving an analytically pure sample of (S)-3-(benzoylamino)-1-chloro-2-butanone; m.p. 119.5°-121°.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:34]([O:36][CH3:37])=[O:35])[C@@H:25]([CH3:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=1)C.[OH-].[Li+].Cl>C1COCC1>[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:38])=[O:3])[CH:11]=[CH:10][CH:9]=2)=[C:14]([CH2:23][N:24]([C:34]([O:36][CH3:37])=[O:35])[C@@H:25]([CH3:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:15]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(NC(C)=O)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(NC(C)=O)ccc1Oc1cccc(CC(=O)O)c1)[C@@H](C)Cc1ccccc1
Temperature: 25 °C

Procedure:
To [3-(4-acetylamino-2-{[methoxycarbonyl-((S)-1-methyl-2-phenyl-ethyl)-amino]-methyl}-phenoxy)-phenyl]-acetic acid ethyl ester (0.048 g, 0.09 mmol) in THF (2 mL) was added 1N aqueous lithium hydroxide (2 mL), and the reaction was stirred over the weekend at room temperature. Once no starting material was seen by analytical LCMS, the mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by preparative HPLC and converted to the free base with saturated aqueous NaHCO3 to give the title compound. M+H=491.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][O:8]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][C:3]1=[O:19].[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[O-])[CH3:21].[K+]>>[CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][O:8][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[CH2:20][CH3:21])[CH2:4][C:3]1=[O:19]
Reactant: CCc1ccccc1[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(C)C2)cc1
Agent: [K+]
Product: CCc1ccccc1OCC1CC(=O)N(C)C1

Procedure:
The compound is prepared from 1-methyl-4-tosyloxymethyl-pyrrolidin-2-one described in Example 17, and potassium 2-ethyl-phenoxide, as described in Example 17. B.p. (0.3 mm Hg)=186° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: COc1cccc([C@@H](C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4cccc(OC)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-methoxy-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.N([O-])=O.[Na+].O.[BrH:17]>CO>[Br:17][C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(N)sc1C
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(Br)sc1C

Procedure:
2.8 g of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate was dissolved in 30 ml methanol and 7 ml hydrobromic acid, followed by adding dropwise an aqueous solution of 1.2 g sodium nitrite thereinto under ice-cooling. After stirring the reaction solution under ice-cooling for 30 minutes, a solution, previously heated at 60° C., of 1.3 g cuprous bromide in 7 ml hydrobromic acid was added thereto, followed by stirring at 60° C. for 1 hour. The reaction solution was ice-cooled and water was-added, followed by extracting with diethyl ether. The organic layer was extracted with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.47 g of methyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:10]([CH2:14]C)[C:11]([OH:13])=[O:12])C(C)C.[CH:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)([CH3:18])[CH3:17].Cl>O1CCCC1.C(NC(C)C)(C)C>[CH:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:10]([CH3:14])([CH3:6])[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CCC(CC(C)C)C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)c1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
in tetrahydrofuran (40 ml) was dissolved in diisopropylamine (3.08 ml) and to the mixture was added n-butyl lithium (13.8 ml; 1.6 M hexane solution) at −78° C. and thereto was added isobutylbutyric acid (0.93 ml) dropwise and the mixture was stirred for 1 hour at 30° C. To the reaction mixture was added a solution of 4-isopropylbenzyl chloride (2.19 g) in tetrahydrofuran (10 ml) at −78° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to cool hydrochloric acid and was extracted with ethyl acetate. The extract was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (1.73 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.C([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O.CCN(CC)CC>CCO>[CH:9]1([C:4]2[CH:5]=[C:6]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1nc(Cl)cc(C2CCCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(C2CCCC2)cc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
A solution of crude 2-amino-4-chloro-6-cyclopentylpyrimidine (150 mg, 0.76 mmol), N—BOC piperazine (184 mg, 0.99 mmol) and Et3N (210 uL, 1.5 mmol) in EtOH (2 mL) was heated at 70° C. for 16 h. The reaction was cooled to rt and concentrated and the crude residue purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (34 mg, 11%). MS (ESI): mass calcd. for C18H29N5O2, 347.2; m/z found, 348.3 [M+H]+. 1H NMR (MeOD): 6.01 (s, 1H), 3.66-3.58 (m, 4H), 3.53-3.43 (m, 4H), 3.33 (td, J=3.3, 1.6, 1H), 2.90-2.75 (m, 1H), 2.05-1.90 (m, 2H), 1.87-1.77 (m, 2H), 1.77-1.62 (m, 4H), 1.53-1.46 (m, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:24][CH2:23][CH2:22][Br:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: BrCCCBr
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCBr

Procedure:
A mixture of 4.13 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 7.6 ml of 1,3-dibromopropane and 3.0 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone was stirred at reflux for 73 hours. An additional 1.0 g of potassium carbonate was added and reflux was continued for 19 hours at which time 1.0 g of potassium carbonate was added. After 16 hours reflux, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was chromatographed on 200 g of silica gel and eluted with 15% ethyl acetate-toluene to give 4.82 g of [4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid ethyl ester.