Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH:11]([CH3:52])[CH:12]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]2[C:44](=[O:45])[CH2:43][O:42][C:41]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[N:40]2)=[CH:34][CH:33]=1)[C:13]([NH:15][C:16]1[C:17]([CH3:31])=[C:18]([CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:19]=[CH:20][CH:21]=1)=[O:14]>ClCCl>[CH3:8][O:9][CH2:10][CH:11]([CH3:52])[CH:12]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]2[C:44](=[O:45])[CH2:43][O:42][C:41]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[N:40]2)=[CH:34][CH:33]=1)[C:13]([NH:15][C:16]1[C:17]([CH3:31])=[C:18]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1)=[O:14]
Reactant: COCC(C)C(C(=O)Nc1cccc(CCC(=O)OC(C)(C)C)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)C(C(=O)Nc1cccc(CCC(=O)O)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.27 ml (3.45 mmol) of trifluoroacetic acid was added dropwise to a solution of 106 mg (0.17 mmol) of tert-butyl 3-{3-[(4-methoxy-3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]-2-methylphenyl}propanoate (Example 170A) in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 3 h. The reaction solution was then concentrated to dryness under reduced pressure. The residue obtained was purified by preparative HPLC. This gave 66 mg (0.12 mmol, 68% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[N:13])C.C(O[CH:18](OCC)[CH2:19][NH2:20])C>CO>[ClH:1].[NH:20]1[CH:19]=[CH:18][N:14]=[C:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[N:13]
Reactant: CCOC(=N)c1ccccc1C#N
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: CO
Product: N#Cc1ccccc1-c1ncc[nH]1
Yield: 3.6 %

Procedure:
A solution of 2-cyano-benzimidic acid ethyl ester hydrochloride (43 g, 0.20 mol) and 2,2-diethoxy-ethylamine (30 ml, 0.21 mol) in methanol (430 ml) was aged at room temperature for 1 h. The reaction mixture was concentrated to remove methanol and conc. sulfuric acid (110 ml) was added. After heating on a steam bath for 1.5 h, the reaction mixture was diluted with water (700 ml) and extracted with chloroform. The aqueous phase was made strongly basic with sodium hydroxide and extracted with chloroform. Hydrochloric acid (12N) was added to give pH 3-4, tar was filtered and the filtrate was concentrated. The resultant brown solid was sublimed at 200-220° C. The purified solid was dissolved in hydrochloric acid solution (6N, 110 ml), byproducts filtered and the filtrate concentrated. The residue was diluted with ethanol (100-120 ml) containing hydrochloric acid (12N, 1 ml), boiled briefly and filtered. Further concentration and cooling of the filtrate gave 2-(1H-imidazol-2-yl)-benzonitrile hydrochloride (1.5 g). The filtrate was concentrated further and diluted with acetone. Filtration gave 2-(1H-imidazol-2-yl)-benzoic acid hydrochloride (7.3 g). Dilution of the filtrate with acetone and filtration of the resultant solid gave additional 2-(1H-imidazol-2-yl)-benzonitrile hydrochloride; mp 200-204° C.; IR 4.5μ.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH:8]([CH3:11])[C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][CH:7]1[CH:8]([CH3:11])[CH2:9][CH2:10][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCC(=O)C(C)CC1
Reactant: NCc1ccccc1
Product: CC(=O)N1CCC(C)C(NCc2ccccc2)CC1

Procedure:
Racemic 1-(4-benzylamino-5-methyl-azepan-1-yl)-ethanone was prepared in the same manner from racemic 1-acetyl-5-methyl-azepan-4-one. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C(O)=O.C(N(CC)CC)C.Cl>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccc(Cl)cc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OC(CCl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
2-Chloro-4′-chloroacetophenone (189.6 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (2.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, 1 M hydrochloric acid (1.2 ml) was added, and the reaction product was extracted with ethyl acetate (2 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a desired compound, (+)-2-chloro-1-(4′-chlorophenyl)ethanol (172.8 mg; yield: 90.2%; optical purity: 91.6% ee).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16](Cl)[N:15]=3)[C@H:10]([CH3:28])[CH2:9]2)=[N:6][CH:7]=1.Br.[CH3:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16]([N:33]4[CH2:34][CH2:35][CH2:36][C@H:32]4[CH3:31])[N:15]=3)[C@H:10]([CH3:28])[CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(Cl)n2)[C@H](C)C1
Reactant: C[C@@H]1CCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1

Procedure:
Heat a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-2-chloro-6-(4-fluoro-phenyl)-pyrimidine (7.7 g, 16.2 mmol), (R)-2-methylpyrrolidine hydrobromide [prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54(1):209] (3.5 g, 21.1 mmol) and K2CO3 (5.1 g, 37.3 mmol) in DMA at 110° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 10% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:5][C:6](=[CH:8][C:9]=1[CH3:10])[OH:7])[OH:4].[OH-].[Na+:14]>>[Na+:14].[C:1]([O-:12])(=[O:11])[C:2]1[C:3](=[CH:5][C:6](=[CH:8][C:9]=1[CH3:10])[OH:7])[OH:4]
Reactant: Cc1cc(O)cc(O)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(O)cc(O)c1C(=O)[O-]

Procedure:
Orsellinic acid (1.65 g, 8.86 mmol) is dissolved in 8.4 mL of 1 N aqueous NaOH with slight warming. The solution is then concentrated to dryness under vacuum to give orsellinic acid sodium salt as a dry powder.
Reaction SMILES: [CH3:1][P@:2]([C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:4][CH2:5][P@:6]([CH3:16])([C:8]([CH3:15])([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])=[O:3]>C(Cl)(Cl)Cl>[CH3:16][P:6]([C:8]([CH3:15])([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH2:5][CH2:4][P:2]([CH3:1])([C:17]([CH3:23])([CH3:24])[CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:3])=[O:7]
Reactant: CC(C)(C)CC(C)(C)[P@](C)(=O)CC[P@@](C)(=O)C(C)(C)CC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)P(C)(=O)CCP(C)(=O)C(C)(C)CC(C)(C)C

Procedure:
The resultant product was found to be (+)-(R, R)-1,2-bis-[methyl(1,1,3,3-tetramethylbutyl)phosphinoyl]ethane having an optical rotation of [α] 25D=+2.36 (C 1.04, CHCl3). The results of this compound analyzed by NMR and other means are shown below.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:39]1([C:46]([NH:48][C@@H:49]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:50](O)=[O:51])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:50](=[O:51])[C@@H:49]([NH:48][C:46]([N:39]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:47])[CH2:53][CH:54]([CH3:56])[CH3:55])[CH2:21][CH2:20]2)[CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)=CCN(c1ccc(NC(=O)OCc2ccccc2)cc1)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCN(c1ccc(NC(=O)OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
(4-Benzyloxycarbonylamino-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (0.35 g, 0.88 mmol) was dissolved in; DMF (8 mL), treated with Hunig's base (0.47 mL, 2.64 mmol), (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.21 g, 0.88 mmol), and HBTU (0.34 g, 0.88 mmol). The reaction was stirred 2 hours, then diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 5% MeOH/CH2Cl2 to give 0.49 g (93%) of the desired product.
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.NC1[S:60][N:59]=[C:58]([CH2:61][C:62](=[O:64])[CH3:63])N=1>ClCCl>[O:64]=[C:62]([CH3:63])[CH2:61][C:58]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:60][N:59]=1
Reactant: CC(=O)Cc1nsc(N)n1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)Cc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 90 mg, 0.28 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole (41 mg, 0.30 mmol). The resulting solution was stirred for 5 min before 1-(5-amino-1,2,4-thiadiazol-3-yl)-2-propanone (56 mg, 0.29 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(2-oxo-propyl)-[1,2,4]thiadiazol-5-yl]-amide (51 mg, 40%) as a light yellow solid: HR-ES-MS m/z calculated for C21H23ClN4O4S [M+H]+ 463.1202, observed 463.1202; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.47 (br. s., 1H), 1.59-1.76 (m, 1H), 1.79-1.95 (m, 1H), 2.18 (s, 3H), 4.00 (s, 2H), 4.29 (d, J=18.4 Hz, 1H), 1.59 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.01 (dd, J=10.9, 4.8 Hz, 1H), 7.37 (td, J=7.5, 1 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.54 (m, J=7.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 13.37 (s, 1H).
Reaction SMILES: NC1C=C(C=C([N+]([O-])=O)C=1C(=O)C1C=CC=CC=1)C(O)=[O:6].N[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([N+:41]([O-:43])=[O:42])[C:31]=1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:26]([OH:28])=[O:27]>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([C:31]2[C:30]([N+:41]([O-:43])=[O:42])=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=2[OH:6])=[O:40])=[CH:34][CH:35]=1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(Cl)cc1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: O=C(O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1

Procedure:
By replacing in Example 1, step A, 3-amino-4-benzoyl5-nitrobenzoic acid with 3-amino-4-(4'-chlorobenzoyl)-5-nitrobenzoic acid and following the procedure described, 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoic acid is obtained as a hemihydrate with a melting point of 266.5°-267.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]5[CH:40]=[C:39]([F:41])[C:38]([O:42][CH3:43])=[CH:37][C:36]=5[CH2:44][CH3:45])=[CH:32][CH:33]=4)[N:28](C4CCCCO4)[N:27]=3)[N:17](COCC[Si](C)(C)C)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:52]>CO>[ClH:52].[ClH:52].[ClH:52].[CH2:44]([C:36]1[CH:37]=[C:38]([O:42][CH3:43])[C:39]([F:41])=[CH:40][C:35]=1[C:31]1[CH:30]=[C:29]2[C:34]([C:26]([C:16]3[NH:17][C:11]4[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=4[N:15]=3)=[N:27][NH:28]2)=[CH:33][CH:32]=1)[CH3:45]
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c(n3COCC[Si](C)(C)C)CCN(C(=O)OC(C)(C)C)CC4)nn(C3CCCCO3)c2c1
Agent: Cl
Solvent: CO
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Temperature: 60 °C

Procedure:
To a solution of 2-[6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester (Preparation 30, 633 mg, 879 μmol) in methanol (20 mL) was added concentrated hydrochloric acid (12M, 8 mL) and the resulting solution was heated at 60° C. for 18 hours. A further amount of concentrated hydrochloric acid (12M, 4 mL) was added and the reaction mixture was heated at 60° C. for a further 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to furnish the title compound (410 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)(=[O:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:29]I>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C@H:11]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)(=[O:18])=[O:17])[CH2:12]1)[CH3:29])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Reaction time: 0.5 h

Procedure:
265 mg of sodium hydride was added with stirring under ice cooling to an N,N-dimethylformamide (10 mL) solution of 500 mg of (S)-6-{3-(tert-butoxycarbonylamino)pyrrolidin-1-ylsulfonyl}isoquinoline obtained in Step 1. After stirring in this state for 30 minutes, 0.8 mL of methyl iodide was added dropwise to the reaction solution, and the mixture was further stirred for 30 minutes for reaction. The reaction was terminated by the dropwise addition of water in small portions under ice cooling to the reaction solution. Then, 50 mL of water was added thereto, followed by three extractions with 50 mL of ether. The combined organic layer was washed with 100 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (acetone:hexane=1:1) to obtain 100 mg of the compound of interest as a colorless oil (19%).
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1C=CC=CC=1.[CH3:16][C:17]1[O:18][C:19]([CH3:25])=[CH:20][C:21]=1[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH:2]1([N:8]([C:22]([C:21]2[CH:20]=[C:19]([CH3:25])[O:18][C:17]=2[CH3:16])=[O:23])[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ONC1CCCCC1
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cc(C(=O)N(O)C2CCCCC2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.6 Parts of N-cyclohexylhydroxylamine hydrochloride is added to 300 parts of benzene; 20.2 parts of triethylamine is then introduced into the mixture. After stirring the mixture for 1 hour at room temperature, 15.9 parts of 2,5-dimethylfuran-3-carboxylic chloride is dripped in. The mixture is then stirred for a further hour and the precipitate is suction filtered, washed with water and then with petroleum ether, and dried. There is obtained 18.2 parts of N-cyclohexyl-2,5-dimethylfuran- 3-hydroxamic acid; m.p.: 135° - 137° C. ##SPC7##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=1)CCC>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([C:32]4[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Product: Cn1ccnc1-c1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure B from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and 2-(tri-n-butylstannyl)-N-methylimidazole (prepared according to the published method: J. Organometallic Chem., (1989), 61); δH [2H6]-DMSO 10.35 (1H,s), 9.17 (1H,s), 9.13 (1H,s), 8.65 (1H, s), 7.79 (2H,d), 7.32-7.55 (6H,m), 7.13 (1H,s), 7.09 (2H,d), 5.16 (2H,s), 4.10 (3H,s); m/z (M+1)+409.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][N:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]3)[C:8]=12.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[N:27]2)=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.CS(C)=O.C(#N)C.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH:30]=[CH:29][C:28]([C:31]([NH:18][C@H:15]3[CH2:16][CH2:17][N:13]([C:9]4[C:8]5[N:7]([CH:6]=[CH:5][C:4]=5[CH3:3])[CH:12]=[CH:11][N:10]=4)[CH2:14]3)=[O:32])=[N:27]2)=[CH:24][CH:25]=1.[ClH:1]
Reactant: Cc1ccn2ccnc(N3CC[C@H](N)C3)c12
Reactant: O=C(O)c1ccn(-c2ccc(Cl)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2ccnc(N3CC[C@H](NC(=O)c4ccn(-c5ccc(Cl)cc5)n4)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
40 mg (0.138 mmol) of (3S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine dihydrochloride and 31 mg (0.138 mmol) of 1-(4-chlorophenyl)pyrazole-3-carboxylic acid were dissolved in 0.5 mL of NMP. To this mixture were added 79 mg (0.207 mmol) of HATU and 0.120 mL (0.690 mmol) of N,N-diisopropylethylamine. The mixture was stirred at rt for 1 hour, then diluted with 3 mL of DMSO and injected directly onto a reverse-phase semi-preparative HPLC system (5-60% acetonitrile/water, 0.1% TFA). Pure fractions were concentrated in vacuo, dissolved in 1 mL of methanol and passed through a bicarbonate resin cartridge (PL-HCO3 MP SPE 500 mg/6 mL). To the resulting solution 15 μL of concentrated hydrochloric acid was added and the volatiles were removed in vacuo to give 49 mg of the desired product as an HCl salt (78% yield). 1H NMR (400 MHz, DMSO) δ 11.38 (s, 1 H), 8.78 (d, J=7.0 Hz, 1 H), 8.59 (d, J=3.0 Hz, 1 H), 7.95 (d, J=7.0, 2 H), 7.81 (m, 2 H), 7.61 (d, J=8.8 Hz, 2 H), 6.92 (s, 1 H), 6.85 (d, J=5.5 Hz, 1 H), 6.76 (d, J=2.2 Hz, 1 H), 4.70-4.65 (m, 1 H), 4.18-3.80 (m, 4 H), 2.48 (s, 3 H), 2.38-2.18 (m, 2 H); MS: (ES) m/z calculated for C22H21ClN6O [M+H]+ 421.2, found 421.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[CH:16][C:15]([S:19][C:20]([Cl:23])([Cl:22])[F:21])=[C:14]1[CH3:24].ClS([N:29]=[C:30]=O)(=O)=O.CN(C)C=O>C(#N)C.ClCCl>[C:30]([C:16]1[C:15]([S:19][C:20]([Cl:23])([Cl:22])[F:21])=[C:14]([CH3:24])[N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:7][C:2]=2[Cl:1])[C:17]=1[CH3:18])#[N:29]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc(SC(F)(Cl)Cl)c(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(C#N)c(SC(F)(Cl)Cl)c(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution containing 0.90 g (2.04 mmoles) of the 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-3-(dichlorofluoromethylthio)pyrrole prepared above in 8 mL of acetonitrile was added a solution of 0.18 mL (0.29 g, 2.07 mmoles) of chlorosulfonyl isocyanate in 1 mL of acetonitrile dropwise over a 5 minute period. After stirring at 0° C. for 2 hours, a solution of 0.18 mL of dimethylformamide in 1 mL of acetonitrile was added and the reaction mixture was maintained at 0° C. for an additional 1.5 hours. The reaction mixture was then diluted with dichloromethane, washed with water and the organic phase was dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure and column chromatography of the residue on silica gel with 4:1 v/v hexane-EtOAc provided 0.80 g (84%) of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-3-(dichlorofluoromethylthio)pyrrole (ASE 215) as a pale yellow solid of melting point 138.5° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH:12]([OH:18])[C:13](=[NH:17])[O:14]CC)[CH3:3].[O:19]1CCC[CH2:20]1>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH:12]1[O:18][C:20](=[O:19])[NH:14][C:13]1=[O:17])[CH3:3]
Reactant: CCOC(=N)C(O)c1c(F)cccc1OCC
Reactant: C1CCOC1
Agent: Cl
Product: CCOc1cccc(F)c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 66, using a reaction time of 3 hours at room temperature, ethyl 1-(2-ethoxy-6-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (0.56 g., 2 mmoles) in 55 ml. of tetrahydrofuran was converted to crude product. Recrystallization from toluene afforded purified 5-(2-ethoxy-6-fluorophenyl)oxazolidine-2,4-dione. (147 mg., m.p. 127°-128° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21](Cl)=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21]([C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(Cl)cn3)cc2s1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(-c4ccc(F)cc4)cn3)cc2s1
Yield: 24.9 %

Procedure:
Place 5-chloro-pyrazine-2-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (73 mg, 0.187 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), 4-fluorophenyl boronic acid (27 mg, 0.193 mmol), and potassium carbonate (134 mg, 0.97 mmol) in a solution of 1,4-dioxane (5 mL) and water (1 mL): Heat the reaction to reflux overnight. Chromatograph (silica gel, eluting with 7-17% MeOH:DCM) to yield 21 mg (25%) of the title compound. mass spectrum (ion-spray): (m/z)=503.0 (M+1). Retention time=4.51 min.