Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3CCCNC3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:30][CH2:29][N:28]([C:33]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[O:40])[CH2:31][CH2:32]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CCN(CC)CC
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Product: O=C(c1ccncc1)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 60 °C

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in tetrahydrofuron (2 mL) was added triethyl amine (20.2 mg, 0.19 mmol) (Aldrich), followed by the addition of isonicotinoyl chloride (28.5 mg, 0.16 mmol) (Aldrich). The mixture was heated at 60° C. for 14 hours and then cooled down to room temperature. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-{1-(pyridine-4-carbonyl)-piperidin-4-yl}-1,3-dihydro-indol-2-one as a white solid. (Yield 31 mg, 48.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:11](=[O:22])[NH:12][CH2:13][CH:14]=[C:15]([CH2:16][C:17]([N:19]=[N+]=[N-])=[O:18])[C:5]2=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]N>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:19][C:17](=[O:18])[CH:16]=[C:15]1[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]=2[C:11](=[O:22])[NH:12][CH2:13][CH2:14]1
Reactant: [N-]=[N+]=NC(=O)CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21
Reactant: CN(C)CCN
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)C=C1CCNC(=O)c2[nH]c3ccc(F)cc3c21
Temperature: 110 °C

Procedure:
A suspension of (7-Fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetyl azide, prepared as in reference 17, (10 mg, 0.33 mmol) and N,N-dimethylethylene-diamine (15 mg, 0.17 mmol) in dry toluene (1 mL) is heated at 110° C. for 1 hour. Toluene is removed in vacuum and the residue is purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.5% TFA) to afford N-(2-dimethylamino-ethyl)-2-(7-fluoro-1-oxo-1,3,4,10-tetrahydro-2H-azepino[3,4-b]indol-5-ylidene)-acetamide; 1H NMR (DMSO-d6) δ 2.85 (s, 6H), 3.19-3.22 (m, 2H), 3.25-3.30 (m, 2H), 3.44-3.48 (m, 2H), 3.49 (q, 2H, J=6.8 Hz), 6.34 (s, 1H), 7.18 (dt, 1H, J1=2.8 Hz, J2=8.8 Hz), 7.50 (dd, 1H, J1=4.4 Hz, J2=8.8 Hz), 7.74 (dd, 1H, J1=2.8 Hz, J2=10.4 Hz), 8.39-8.44 (m, 2H), 9.36 (bs, 1H), 12.12 (s, 1H); m/z [M++1] 345.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:12]NC(NC1C=CC(C([O-])=O)=CC=1)=O>>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(I)cc1
Reactant: CNC(=O)Nc1ccc(C(=O)[O-])cc1
Product: CC(=O)N(C)c1ccc(I)cc1

Procedure:
The desired compound is prepared according to the method of Example 3, step2, except substituting, 4-(N-acetylamino)iodobenzene, prepared as in step 1, for 4-(N-methylaminocarbonyl)aminobenzoate
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[O:27]=[C:28]1[NH:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:30]2[CH2:31][CH2:32][NH:33][C:28](=[O:27])[CH2:29]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C1CNCCN1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C1CN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CCN1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-oxopiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-oxopiperazine-1-carbonyl)benzamide. MS (Q1) 470 (M)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:12](N(CC)CC)C.O1CCCC1.[S:24]1[C:28]2[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[O:31][CH2:32][CH2:33][C:27]=2[CH:26]=[C:25]1[C:38](Cl)=[O:39].[H-].[Na+].CI>>[CH3:12][N:5]([C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])[C:38]([C:25]1[S:24][C:28]2[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[O:31][CH2:32][CH2:33][C:27]=2[CH:26]=1)=[O:39]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of 2-(trifluoromethyl)aniline (0.122 g, 0.755 mmol) and triethylamine (0.105 mL, 0.756 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added portion wise as a solid 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.100 g, 0.378 mmol). The reaction mixture was stirred at room temperature with LC/MS monitor for formation of the alkylated product and noted complete after 2 hours. After aqueous work up, the reaction mixture was concentrated in vacuo, taken into DMF and treated with sodium hydride (0.03 g, 1 mmol) at room temperature for several minutes. Methyl iodide (0.06 g, 0.4 mmol) was added and the reaction was stirred at room temperature for several hours, then concentrated in vacuo. The residue was taken into EtOAc and washed with water and saline, concentrated to a solid residue, taken into DMF at a concentration of 100 mg/ml and purified by preparative RP-HPLC to give 130. Yield=25% of theoretical. MS: (ESI+) 404.1
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([S:15][CH3:16])=[O:14].CN([CH:25](N(C)C)[O:26][C:27](C)(C)C)C.Cl.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O.CN(C)C=O>[CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[CH:25][O:26][CH3:27])[C:13]([S:15][CH3:16])=[O:14]
Reactant: CSC(=O)Cc1ccccc1COc1cc(C)ccc1C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC=C(C(=O)SC)c1ccccc1COc1cc(C)ccc1C
Temperature: 60 °C
Yield: 22 %

Procedure:
2 g (0.00665 mol) of S-methyl 2-(2,5-dimethylphenoxymethyl)-phenylthioacetate and 2 g (0.0115 mol) of bis-(dimethylamino)-tert-butoxymethane are heated to 60° C. for 1 hour. The mixture is then admixed with 6 ml of dimethylformamide and 3 ml of concentrated aqueous hydrochloric acid and heated to 60° C. for a further hour. The reaction mixture is admixed with water and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The resulting crude intermediate, S-methyl 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-hydroxymethylidene-thio acetate, is dissolved in 10 ml of dimethylformamide, admixed first with 1.6 g (0.0116 mol) of potassium carbonate and then with 0.8 g (0.00634 mol) of dimethyl sulphate and stirred at 20° C. for 24 hours. The mixture is poured into water and extracted with dichloromethane, the organic phase is dried over sodium sulphate, the solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel using diethyl ether/petroleum ether (1:1). 0.5 g (22.9% of theory) of S-methyl 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-methoxymethylidene-thioacetate is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-])=O)=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([Cl:23])[CH:3]=1>C(O)C.CC(O)=O.[Fe]>[NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([Cl:23])[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1N
Temperature: 25 °C

Procedure:
A solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (2 mmol; see Example 154) in ethanol (5 mL) and AcOH (1 mL) was added with iron powder (10 mmol). The reaction mixture was then heated to reflux for 6 h. The contents were cooled to RT, filtered through Celite pad, and the pad was washed with ethanol. The filtrates were combined and concentrated in vacuo. The residue obtained was purified on a silica gel column chromatography using MeOH/DCM as eluent to afford 4,5-diamino-2-chloro-N-(1H-indazol-6-yl)benzamide.
Reaction SMILES: [O:1]=[C:2]([N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:3][CH3:4].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C(OCC)(=O)C>[O:1]=[C:2]([N:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]1[CH2:7][CH2:8][N:9]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:11]1)[CH2:3][CH3:4]
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)N(c1ccccc1)C1CCN(CC(=O)OC)CC1
Yield: 53 %

Procedure:
A mixture of 4-[(1-oxopropyl)phenylamino]-piperidine (500 mg, 2.15 mmol), prepared according to the procedure of P. A. J. Janssen et al, U.S. Pat. No. 3,164,600, methyl bromoacetate (0.25 ml, 2.58 mmol), and potassium carbonate (594 mg, 4.3 mmol), in acetonitrile (2.5 ml) is stirred at room temperature for five hours. The reaction mixture is diluted with 1:1 water and ethyl acetate (20 ml total). The phases are separated and the aqueous phase extracted with ethyl acetate (2×) and the combined organics washed with brine, dried over sodium sulfate and then concentrated. The residue is chromatographed on silica gel (95/5 CHCl3 /MeOH) to give 4-[(1-oxopropyl)phenylamino]-1-piperidineacetic acid, methyl ester, as an oil: 348 mg, 53% yield. An equimolar amount of maleic acid in ether is added to a solution of the free base in ethyl acetate to give the maleate salt as a white solid; maleate salt: m.p. 130°-133° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31]#[N:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:31]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([C:15]1[CH:14]=[C:13]([NH:12][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=1)[CH2:28][C:27]2([CH3:30])[CH3:29])#[N:32]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a round bottom flask, 2-fluoro-benzenesulfonyl chloride (116 mg, 0.59 mmol) was added dropwise a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (65 mg, 0.81 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide as off-white solid (100 mg, yield: 42.4%). MS (ESI+APCI) M+1=436.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([N:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][O:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([N:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1.[C:30]1([CH3:33])[CH:29]=[CH:28][C:27]([S:24]([OH:26])(=[O:23])=[O:25])=[CH:32][CH:31]=1
Reactant: Nc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: Oc1ccccc1NCC1CN(Cc2ccccc2)CCO1
Temperature: 200 °C

Procedure:
A mixture of o-aminophenol (15 g.) and 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine (30 g.) was heated at 200° C. for 1 hour in an atmosphere of nitrogen. The reaction product was crystallised from ethanol to give 4-benzyl-2-(2-hydroxyanilinomethyl)morpholine as the toluene-p-sulphonic acid salt, m.p. 188°-190° C., which was hydrogenated in ethanol at atmospheric pressure using a 10% palladium-on-carbon catalyst.
Reaction SMILES: [OH:1][C@H](CCC1C=CC(F)=CC=1)CC(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=O.[OH:63][C@H:64]([CH2:116][CH2:117][O:118][C:119]1[CH:124]=[CH:123][CH:122]=[CH:121][CH:120]=1)[CH2:65][C:66](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=[O:67]>>[OH:63][CH:64]([CH2:116][CH2:117][O:118][C:119]1[CH:124]=[CH:123][CH:122]=[CH:121][CH:120]=1)[CH2:65][C:66]([OH:67])=[O:1]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCc1ccc(F)cc1
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCOc1ccccc1
Product: O=C(O)CC(O)CCOc1ccccc1
Reaction time: 0.42 h

Procedure:
Then, (R)-3-hydroxy-5-(4-fluorophenyl) valeryl CoA prepared in Reference Example 3 was added at a final concentration of 5 mM, and was incubated at 37° C. for 25 minutes, followed by adding to this pigment dispersion (R)-3-hydroxy-5-phenoxyvaleryl CoA (prepared by the method described in Eur. J. Biochem., 250, 432-439 (1997) after obtaining 3-hydroxy-5-phenoxyvaleric acid by hydrolyzing 3-hydroxy-5-phenoxyvalerate obtained by Reformatsky reaction with zinc, using as raw materials 3-phenoxypropanal synthesized by the method described in J. Org. Chem., 55, 1490-1492 (1990) and ethyl bromoacetate) so that the final concentration was 1 mM, then incubating the same at 37° C. for 5 minutes. After the reaction, electrophoretic particles were collected and suspended with kerosene as a dispersion medium in a same manner as Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([OH:16])=O)=[CH:10][N:9]1[CH3:17].[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=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>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([C:14]([NH:18][C:19]2[CH:40]=[CH:39][C:22]([O:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]5[CH2:38][CH2:37]5)=[O:35])[N:32]=4)[CH:29]=3)=[C:21]([F:41])[CH:20]=2)=[O:16])=[CH:10][N:9]1[CH3:17]
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1Cl
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1Cl
Yield: 60.2 %

Procedure:
In the same manner as in Example 46 and using 2-(2-chlorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (330 mg, 1.3 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol), HATU (490 mg, 1.3 mmol), N,N-diisopropylethylamine (340 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (260 mg, 60%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([CH:14]=O)=O)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:14][NH:19][CH2:16][CH2:17][NH:18]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: NCCN
Reactant: COc1cc(C(=O)C=O)ccc1[N+](=O)[O-]
Product: COc1cc(C2CNCCN2)ccc1[N+](=O)[O-]

Procedure:
(RS)-2-(3-Methoxy-4-nitrophenyl)piperazine was prepared according to the method described in Patent Application FR 2,351,108, but starting with 3-methoxy-4-nitrophenylglyoxal (36 g) and ethylenediamine (12.1 g). The crude product is purified by chromatography on 230-400 mesh silica (800 g) suspended in a mixture of dichloromethane (70%), ethanol (26%) and triethylamine (4%) and elution with the same mixture (2 liters). After concentration of the eluate under reduced pressure (20 kPa) at approximately 50° C., the expected product (18 g) is obtained in the form of a red oil, which was used without further purification for the subsequent steps.
Reaction SMILES: O=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12].C>O1CCOCC1>[N-:9]=[C:4]=[O:3].[CH3:2][O:16][C:15](=[O:17])[C@H:10]([C@H:11]([CH2:13][CH3:14])[CH3:12])[NH2:9]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](N)C(=O)OC
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of isoleucine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give isoleucine methyl ester isocyanate.
Reaction SMILES: Cl.[NH2:2]N.C[N:5](C)/[CH:6]=[C:7](\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)=O>C(O)C>[CH3:17][S:16][C:12]1[N:11]=[C:10]([C:8]2[NH:2][N:5]=[CH:6][C:7]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:14][N:13]=1
Reactant: NN
Reactant: CSc1nccc(C(=O)/C(=C/N(C)C)c2ccccc2)n1
Agent: Cl
Solvent: CCO
Product: CSc1nccc(-c2[nH]ncc2-c2ccccc2)n1

Procedure:
Hydrazine hydrochloride (78 mg, 1.13 mmol, 1.5 equiv) was added to a solution of (2E)-3-(dimethylamino)-1-[2-(methylthio)pyrimidin-4-yl]-2-phenylprop-2-en-1-one(3-2, 226 mg, 0.76 mmol, 1 equiv) in ethanol (10 mL). The solution was refluxed for 3 hours and concentrated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated to give 2-(methylthio)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine (3-3) as a tan colored gum.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[S:10][C:9]([C:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([N:21]3[C:26](=[O:27])[NH:25][C:24](=[O:28])[CH:23]=[N:22]3)=[CH:16][C:15]=2[Cl:29])([CH3:13])[CH3:12])=[N:8][C:7]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C.[OH-].[Na+].Cl.CCOC(C)=O>CO.C1COCC1>[Cl:20][C:19]1[CH:18]=[C:17]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[CH:23]=[N:22]2)[CH:16]=[C:15]([Cl:29])[C:14]=1[C:11]([C:9]1[S:10][C:6]([CH2:5][C:4]([OH:36])=[O:3])=[C:7]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:8]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)Cc1sc(C(C)(C)c2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(c1nc(-c2ccccc2)c(CC(=O)O)s1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of intermediate (9) (0.00183 mole) and NaOH 1N (0.0055 mole) in CH3OH (25 ml) and THF (25 ml) was stirred overnight at RT. The reaction mixture was acidified with 1N HCl (8 ml) and the resulting product was taken up into EtOAc. The organic layer was washed with brine, dried, filtered and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off, washed with DIPE, and dried, yielding 0.8 g (79%) of 2-[1-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)yl)phenyl]-1-methylethyl]-4-phenyl-5-thiazoleacetic acid (intermediate 10).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:50][C@@H:51]([CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:52][N:53]2[C:61](=[O:62])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]2=[O:63])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.21 g, 0.87 mmol), PyBrOP (610 mg, 1.3 mmol) and diisopropylethyl amine (0.76 mL, 4.35 mmol) in DCM (20 mL) at 25° C. was added 2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione HCl (380 mg, 0.96 mmol)[prepared according to Preparation 5]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (200 mg, 46%) as a white solid: LC-MS (ES) m/z=505 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35]>CS(C)=O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36][CH3:37])=[O:35])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cccc32)c1
Temperature: 170 °C
Yield: 24.9 %

Procedure:
A mixture of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 35 mg, 0.12 mmol) and methyl 3-(4-amino-1H-indazol-1-yl)benzoate (Intermediate 9) (32.7 mg, 0.12 mmol) was heated by microwave (250 W) at 170° C. for 45 minutes. The crude product was cooled, dissolved in DMSO/MeOH and purified by mass-directed autopreparation. The appropriate fractions were evaporated, dissolved in DCM, washed with aqueous sodium bicarbonate, passed through a hydrophobic frit and evaporated to give the title compound (16.7 mg).