Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[CH:42]2[CH2:43][NH:44][CH2:45][CH2:46][N:41]2[CH2:40][CH2:39][O:38]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[CH2:45][CH2:46][N:41]4[CH:42]([CH2:37][O:38][CH2:39][CH2:40]4)[CH2:43]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CN2CCOCC2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCOCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 57.1 %

Procedure:
A 8 ml sealed vial was charged with 124 mg (0.233 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl) -3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577); 83 mg (0.584 mmol) of octahydropyrazino[2,1-c][1,4]oxazine (EP 472826), 90 mg (0.701 mmol) of potassium carbonate; the reagents were dissolved in 0.5 ml of DMSO. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc 90/10-30/70) affording the title compound as a white solid 85 mg (0.133 mmol).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=[O:2].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccccc1C(=O)O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g of 2-carboxymethyl-benzoic acid were dissolved in 16 ml of fuming nitric acid. 16 ml of ice water was added into the resulting solution after stirred at room temperature for 2 hr, then filtrated to obtain a precipitation, dried in vacuum to obtain 1.99 g of 5-nitro-2-carboxymethyl-benzoic acid.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([C:6]2[C:7]([NH2:18])=[N:8][CH:9]=[N:10][C:11]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:5][CH2:4]1.C(OC([NH:26][CH2:27][CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=O)(C)(C)C>>[ClH:39].[ClH:1].[NH2:26][CH2:27][CH2:28][CH:29]([C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:30]([N:15]1[CH2:16][CH2:17][N:12]([C:11]2[C:6]([CH:3]3[CH2:5][CH2:4]3)=[C:7]([NH2:18])[N:8]=[CH:9][N:10]=2)[CH2:13][CH2:14]1)=[O:31]
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)cc1
Reactant: Nc1ncnc(N2CCNCC2)c1C1CC1
Agent: Cl
Product: NCCC(C(=O)N1CCN(c2ncnc(N)c2C2CC2)CC1)c1ccc(Cl)cc1

Procedure:
4-Amino-1-[4-(6-amino-5-cyclopropyl-pyrimidin-4-yl)-piperazin-1-yl]-2-(4-chlorophenyl)-butan-1-one dihydrochloride was prepared by substituting 5-piperazin-1-yl-1H-indazole with 5-Cyclopropyl-6-piperazin-1-yl-pyrimidin-4-ylamine dihydrochloride and substituting (D)-Boc-4-chlorophenylalanine with 4-tert-Butoxycarbonylarnino-2-(4-chlorophenyl)-butyric acid in Example 34, Step 2, then removing the Boc protecting group as described in Example 34, Step 3. 1H NMR (CD3OD, 400 MHz) δ 8.04 (s, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.19 (m, 1H), 3.95 (m, 1H), 3.85 (m, 2H), 3.61 (m, 3H), 3.22 (m, 2H), 2.95 (m, 1H), 2.82 (m, 1H), 2.31 (m, 1H), 2.01 (m, 1H), 1.56 (m, 1H), 1.08 (m, 2H), 0.47 (m, 2H). LCMS (APCI+) m/z 415, 417 [M+H]+; Rt=1.87 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h
Yield: 89.6 %

Procedure:
1st stage: A solution of 21 g of indole-4-carboxylic-acid-methylester in 100 ml of methylene-chloride, 24.9 ml of triethylamine and 7.34 g of 4-dimethyl-aminopyridine is proportionately mixed at 0° C. with 34.2 g of p-toluene-sulfonic-acid-chloride. After 16 h at 0° C., the mixture is diluted with methylene chloride, washed neutral with saturated sodium bicarbonate solution and NaCl solution, and the solvent is distilled off in vacuum. 35.37 g of 1-tosylindole-4-carboxylic-acid-methylester with a m.p. of 145°-147° C. (diisopropylether) is obtained.
Reaction SMILES: [NH2:1][NH2:2].C(O)C.[OH:6][C:7]([CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](OCC)=[O:9].Cl.NN>CO.C(O)CO.N1C=CC=CC=1.O1CCCC1.O1CCOCC1.C(O)(C)C>[OH:6][C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:2][NH:1][C:8]1=[O:9]
Reactant: NN
Reactant: CCOC(=O)C(O)(CC(=O)c1ccncc1)C(=O)OCC
Agent: Cl
Solvent: OCCO
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)C1(O)CC(c2ccncc2)=NNC1=O

Procedure:
The preparation of lower-alkyy 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylates by reacting di-(lower-alkyl)hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH2.nHxAn (III), where PY and R are defined as in formula I above and n, x and An are defined as in formula III above, is carried out by heating the reactants at about 60° C. to 100° C., preferably about 75° C. to 85° C., and preferably in the presence of a suitable solvent, e.g., a lower-alkanol such as methanol, ethanol or isopropyl alcohol. Other suitable solvents would be dioxane, tetrahydrofuran, pyridine, ethylene glycol, and the like. Preferred R-hydrazine salts are the dihydrochlorides or sulfates. This preparation is illustrated below in Examples C-2 through C-17. Also note Example B-1 where diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate was refluxed with hydrazine monohydrochloride in methanol for a relatively short period (less than 2 hours) to produce ethyl 2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate which, as shown in Example C-1, was readily dehydrated by treating a solution of it in a suitable solvent, e.g., acetonitrile, ethanol, tetrahydrofuran or dioxane with hydrogen chloride to produce ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=O>>[CH3:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[Cl:1]
Reactant: Cc1cccc(C)c1OC(=O)Cl
Reactant: [Cl-]
Agent: [Al+3]
Product: Cc1cccc(C)c1Cl
Temperature: 200 °C

Procedure:
0.3 g of anhydrous aluminium chloride was of 2,6-dimethylphenyl chloroformate and the mixture was heated to 200° C. at normal pressure. A further 150 g of 2,6-dimethylphenyl chloroformate and a further one gram of anhydrous aluminium chloride were then metered in over a period of 2 hours and the 2,6-dimethylchlorobenzene formed was simultaneously distilled off. The reaction did not proceed to completion and a mixture of 2,6-dimethylphenyl chloroformate and 2,6-dimethylchlorobenzene was obtained. Separation by distillation gave a 74% yield of 2,6-dimethylchlorobenzene (based on the conversion).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)(Cl)Cl>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCCCl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2Co3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was portioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%). mp 143°-144° C.; 1H NMR (CD3OD, 400 MHz) β 1.65 (dq, J1 =3.16 Hz, J2 =11.9 Hz, 2H), 1.90-2.00 (m, 4H), 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H), 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: Nc1ncccc1C(=O)c1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)cc1C(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a suspension of (2-aminopyridin-3-yl)(6-bromopyridin-2-yl)methanone (5.76 g, 20.7 mmol) in acetonitrile (120 ml) was added N-bromosuccinimide (4.05 g, 22.77 mmol). The resulting mixture was stirred at room temperature for 1 hour before mixture was concentrated in vacuo to approximately 20 ml. The solid was then collected by filtration and washed with minimal acetonitrile and dried to leave title compound as a brown solid (4.23 g, 57%). 1H NMR (DMSO-d6) 7.93-7.89 (4H, m), 8.03-7.99 (1H, m), 8.22 (1H, d), 8.36 (1H, d). ES+ 357.99.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([N:13]([CH2:15][CH:16]=C)[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClCCl.[O:21]=[O+][O-]>CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:16]([OH:21])[CH2:15][N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[O+][O-]
Reactant: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Solvent: ClCCl
Solvent: CO
Product: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.96 g. portion of 1-(5-t-butylisoxazol-3-yl)-3-allyl-3-methylurea was dissolved in 25 ml. of 1:1 by volume dichloromethane:methanol, and the solution was cooled to -78°. Ozone diluted in dry air was bubbled into the solution with good stirring for 30 minutes, after which tlc analysis indicated that the starting material was gone. Nitrogen was bubbled through the mixture for 10 minutes to remove residual dissolved ozone, and then 1 ml. of dimethyl sulfide was added and the mixture was allowed to warm to ambient temperature with continual stirring. The reaction mixture was then diluted with water, the layers were separated, and the product was isolated from the organic layer substantially as shown in Example 2 above to obtain 2.6 g. of the desired product, m.p. 168°-174°. The nuclear magnetic resonance analysis of the product indicated that it was substantially identical to that of Example 1 above.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[NH2:10])[CH:2]=1.N1C=CC=CC=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:9]=2[NH:10][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cccnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1Oc1cccnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A yellow solution of 2-(pyridin-3-yloxy)-5-(trifluoromethyl)aniline (263 mg, 1.035 mmol) and pyridine (108 μL, 1.341 mmol) in dry THF (8 mL) was treated dropwise with phenyl chloroformate (156 μL, 1.242 mmol) during 5 min at 0° C. The resulting suspension yellow suspension was stirred at 0° C. for an additional 5 min and then allowed to warm up to room temperature and stirred for 3 h. The yellow suspension was filtered over cotton, washed with Et2O and diluted with EtOAc. The yellow solution was washed with sat. aqueous NaHCO3 (30 mL) and H2O (30 mL), dried and concentrated to dryness to give a yellow oil. Purification by column gave a tan solid. Yield: 300 mg (77%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:49])([CH3:48])[CH3:50])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cn1cc(Br)cc(Nc2cnccn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 160a (140 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (410 mg, 1.0 mmol), Pd(dppf)Cl2 (25 mg, 0.025 mmol), K3PO4 (220 mg, 1.0 mmol), sodium acetate trihydrate (136 mg, 1.0 mmol), acetonitrile (15 mL), and water (0.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (100:1 to 25:1) to afford 160b (150 mg, 52%) as a yellow solid. MS-ESI: [M+H]+ 570.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=[O:12])=[CH:4][C:3]=1[O:32][CH3:33].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])O.[Na+]>CS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])=[CH:15][CH:14]=3)=[CH:10][C:9]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:4][C:3]=1[O:32][CH3:33]
Reactant: COc1cc(C(=O)C(CC(=O)c2ccc(OCCN(C)C)cc2)c2ccncc2)ccc1Cl
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cc(-c2oc(-c3ccc(OCCN(C)C)cc3)cc2-c2ccncc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
The product of Example 1 Step 2 (450 mg, 0.96 mmol) was added to a stirred suspension of phosphorus pentoxide (400 mg) in dry methane sulphonic acid (4ml). After stirring at room temperature for 1 hour, the reaction mixture was cautiously poured into a stirred solution of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the organic phase washed with water and brine, dried and concentrated in vacuo to give the title compound (400 mg, 93%); MS(ES+) m/e 449,451 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NC2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with cyclohexylamine (Aldrich) to give the title product. LC-MS (ES+) 746 [(M+H)+].
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][C@@H:8]([CH2:14][NH2:15])[C@@H:9]([CH3:13])[CH:10]([CH3:12])[CH3:11])(C)(C)C>Cl>[NH2:15][CH2:14][C@@H:8]([C@@H:9]([CH3:13])[CH:10]([CH3:12])[CH3:11])[CH2:7][C:6]([OH:16])=[O:5]
Reactant: CC(C)[C@H](C)[C@H](CN)CC(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)[C@H](C)[C@H](CN)CC(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of the amine 23 and lactam 24 (500 mg) in 3 M hydrochloric acid were heated to reflux for 9 hours, then stirred at room temperature for 15 hours. The solution was concentrated and the resultant solid subjected to a sequential purification which involved ion exchange chromatography (Dowex 50WX8, strongly acidic), oxalate salt formation then further purification by ion exchange chromatography (Dowex 50WX8, strongly acidic) to give the Example 2 (343 mg) as a white solid. 1H NMR (D2O) δ2.87 (m, 2H), 2.22 (dd, 1H, J=15.4 and 3.4 Hz), 2.12 (m, 1H), 1.93 (dd, 1H, J=15.4 and 9.5 Hz), 1.38 (m, 1H), 1.12 (m, 1H), 0.77 (d, 1H, J=6.6 Hz), 0.74 (d, 1H, J=6.6 Hz), 0.70 (d, 1H, J=6.8 Hz). MS, m/z (relative intensity): 174 [M+H, 100%].
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])=[O:19])[C:15]([OH:35])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[OH-].[Na+:38]>CC(C)=O>[O:36]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])=[O:19])[C:15]([O-:35])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[Na+:38]
Reactant: CC(C)NC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)NC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1[O-]
Temperature: 25 °C

Procedure:
5-(1,1-Dioxido-1,2-thiazinan-2-yl)-N-{4-fluoro-2-[(isopropylamino)carbonyl]benzyl}-8-hydroxy-1,6-naphthyridine-7-carboxamide (203 mg, 0.39 mmol) was suspended in acetone (2 mL) and sodium hydroxide (0.39 mL, 0.39 mmol, 1N aqueous solution) was added. The flask was gently warmed to make the solution homogeneous and the solution was then filtered through a glass fiber filter to remove any dust. The solution was stirred at room temperature until solids crashed out of solution. The solids were collected by vacuum filtration to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([CH2:16][C:17]([OH:19])=O)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>>[CH2:1]([CH2:16][C:17]([Cl:40])=[O:19])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)Cl

Procedure:
A three-necked flask equipped with a stirrer, a reflux condenser and a thermometer was charged with 132 g of farnesylacetic acid, 140 g of triphenylphosphine and 500 ml of carbon tetrachloride, and the contents were heated under reflux of carbon tetrachloride for 4 hours. The reaction mixture was filtered to remove a formed solid matter, the carbon tetrachloride distilled off, 500 ml of n-hexane added, the mixture ice-cooled and the crystalline precipitate filtered off. The n-hexane was then distilled off, leaving 146 g of crude farnesylacetyl chloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([OH:28])=O)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].Cl.[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:22]([O:21][C:19](=[O:20])[NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=2[C:26]([NH:38][CH2:37][C:36]2[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:40][CH:39]=2)=[O:28])=[CH:17][CH:16]=1)([CH3:24])([CH3:23])[CH3:25]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)NCc2ccc([N+](=O)[O-])cc2)s1
Temperature: 25 °C
Reaction time: 73 h
Yield: 93 %

Procedure:
A mixture of 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylic acid (100 mg), (4-nitrobenzyl)amine hydrochloride (46.5 mg), 1-hydroxybenzotriazole (36.7 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40.2 mg) in DMF (2 ml) was stirred at ambient temperature for 73 hours. The reaction mixture was poured into saturated NaHCO3, and extracted with CHCl3. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo to give tert-butyl{4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl)amino]carbonyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate (123.7 mg) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:12][O:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:12][O:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:15]1
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Reactant: CO[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CO[C@H]1CCN(Cc2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a stirred solution of 31 (0.4 g, 2.6 mmol) and (S)-3-methoxy-pyrrolidine (0.4 g, 3.2 mmol) in dichloromethane (10 mL) was added acetic acid (0.01 mL, 0.25 mmol). After 30 minutes, sodium triacetoxyborohydride (1.1 g, 5.3 mmol) was added to the above mixture and stirred at rt for 15 minutes. The reaction mixture was diluted with water (10 mL), treated with saturated NaHCO3 solution to get pH˜8 and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel flash chromatography, eluting with 2% MeOH/DCM to afford 32 (0.25 g, 40%) as a liquid. Rf: 0.3 (5% MeOH/DCM); (m/z): 238 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 9.28 (1H, d, J=2.8 Hz), 8.59-8.56 (1H, m), 7.71 (1H, d, J=8.8 Hz), 3.93-3.80 (3H, m), 3.16 (3H, s), 2.73-2.62 (2H, m), 2.56-2.53 (1H, m), 2.50-2.47 (1H, m), 2.06-2.02 (1H, m), 1.72-1.65 (1H, m).