Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:23].CO.[NH2:26][C@H:27]([C:35]([NH:37][C@H:38]([C:45]([NH:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:45]([NH:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH2:39][O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:23]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
5.3 g of Z-Arg-OH (17.3 mmols) are suspended in 15 ml of dimethylformamide and after cooling with an ice-sodium chloride mixture, 5.9 ml of hydrobromic acid in methanol (3.06 N, 18 mmols) are added. After brief stirring a clear colourless solution is produced. A solution of 5.6 g of H-Phe-Ser(tBu)-Gly-OCH3 (14.4 mmols) in 15 ml of dimethylformamide is added dropwise thereto at -18°C and a further 7 ml of dimethylformamide are added. A solution of 3.85 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride is then added, the cooling mixture is replaced by ice water after 1 hour, and after a further 3 hours the reaction mixture is stirred overnight at room temperature. The precipitate of dicyclohexylurea which has separated out is then filtered off and the filtrate is concentrated in vacuo to half its volume, cooled to 0°C and stirred into 600 ml of ether. The solution is decanted from the resulting precipitate, and the precipitate is washed with ether, dissolved in about 50 ml of methanol and again precipitated with 600 ml of ether. After again dissolving in methanol, the material is evaporated and dried in a high vacuum. In a thin layer chromatogram on silica gel layers the product shows: Rf52 = 0.48; Rf100 = 0.54; on Selekta cellulose Rf45 = 0.81.
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH2:20]([NH:24][CH:25]1[CH2:29][CH2:28][S:27][C:26]1=[O:30])[CH:21]([CH3:23])[CH3:22].O>ClCCl>[CH2:20]([N:24]([CH:25]1[CH2:29][CH2:28][S:27][C:26]1=[O:30])[S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH:21]([CH3:23])[CH3:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNC1CCSC1=O
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(C)C)C2CCSC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 mmol of N-methylmorpholine and 2.5 mmol of 4-methoxyphenylsulphonyl chloride are added at 0° C. to a solution of 2.5 mmol of the compound obtained in Step A in 15 ml of dichloromethane. After stirring for 12 hours at ambient temperature, the reaction mixture is poured into water and then extracted with dichloromethane. The combined organic phases are washed with a 2N hydrochloric acid solution, then with a 5% solution of NaHCO3, and then with water. After drying over sodium sulphate, filtration and evaporation, chromatography on silica gel (dichloromethane/methanol: 20/1) allows the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[Cl-].[NH4+].C([NH:21]C(C)C)(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:21])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Br)c(F)c1
Temperature: 70 °C
Reaction time: 75 h
Yield: 62.8 %

Procedure:
To a suspension of 4-bromo-3-fluorobenzoic acid (1.50 g, 6.85 mmol) in toluene (10 mL) at ambient temperature was added thionyl chloride (1.0 mL, 14 mmol). The reaction mixture was heated at 70° C. for 17 hours, at reflux for 1.5 hours, stirred at ambient temperature for 75 hours, heated at reflux for 18.5 hours, and stirred at ambient temperature for 1 hour. Thionyl chloride (0.25 mL, 3.4 mmol) was added and the reaction mixture was heated at reflux for 3 hours. The reaction was cooled and condensed to an oily solid mixture. Toluene (10 mL), ammonium chloride (0.73 g, 14 mmol) and diisopropylamine (3.6 mL, 21 mmol) were added, and the mixture was stirred at ambient temperature for 17 hours, heated at 50° C. for 5 hours, then cooled to ambient temperature. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL), separated, and the aqueous layer further extracted with EtOAc (15 mL). The combined organic extracts were washed with 1N HCl (20 mL), 1N NaOH (20 mL), brine (20 mL), dried (MgSO4), filtered, and concentrated to afford 4-bromo-3-fluorobenzamide (0.938 g, 63%) as a light-yellow solid which was carried on without further purification.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1cccc(C)c1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3c(C)cccc3OC)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxy-6-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].S(Cl)([Cl:23])(=O)=O.O.CCOC(C)=O>C(Cl)Cl>[Cl:23][CH:11]([C:6]1[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1)[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)n1nc(CC(=O)c2ccccc2)ccc1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(C(Cl)C(=O)c2ccccc2)ccc1=O
Reaction time: 5 h

Procedure:
A mixture of 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone (100 g) and sulfurylchloride (32.9 ml) in CH2Cl2 (200 ml) was refluxed with stirring for 5 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 6-(1-chloro-2-oxo-2-phenylethyl)-2-isopropyl-3(2H)-pyridazinone (100 g) as white powder.
Reaction SMILES: C(N(CCCC)CCCC)CCC.O[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2N=N1.CN([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29]N=1)C.NC(NN)=S.[CH3:38][N:39](C)[CH:40]=[O:41]>>[C:40]([NH:15][CH:19]1[CH2:18][CH2:23][CH2:22][CH2:21][CH2:20]1)([NH:39][CH:38]1[CH2:27][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:41]
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Reactant: CN(C)c1ccccn1
Agent: NNC(N)=S
Solvent: CCCCN(CCCC)CCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
[3S-[3α(Z),4α]]-3-[[(2-Amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (0.66 g), 0.3 g of tributylamine, 0.26 g of N-hydroxybenzotriazole and 0.01 g of dimethylaminopyridine were dissolved in 10 ml of dimethylformamide and a solution of 0.33 g of N,N-dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 20 minutes at room temperature, a solution of 0.28 g of (aminothioxomethyl)hydrazine in 10 ml of dimethylformamide was also added. Stirring was continued for 24 hours, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. The residue was dissolved in 20 ml tetrahydrofuran/methanol (1:1), filtered and a solution of 0.51 g of potassium perfluorobutanesulfonate in 5 ml of methanol was added followed by 20 ml of ether. The resultant precipitate of crude product was purified by column chromatography on HP-20 using water as an eluent and yielding 0.8 g of the title compound, melting point 218° C., (dec).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O[C@@H:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:24][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:10]3[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C@H:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=2)=[N:23][N:22]=1
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Reactant: O=C1NCC[C@H]1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@H]2CCNC2=O)c1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a stirring mixture of Methyl 3-hydroxy-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (7 g) (Intermediate 7) and (R)-(+)-3-hydroxy-2-pyrrolidinone (Intermediate 16) (2.4 g) in dry THF (200 mL) taken in round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (11.3 g) was added. Diisopropyl azodicarboxylate (DIAD) (6.2 mL) in dry THF (10 mL) was added drop wise to the above reaction mixture. The reaction was stirred at room temperature. Reaction was monitored by TLC for completion. After completion, reaction mixture was concentrated under vacuum to remove the solvents. Diluted with DCM and coated over silica gel and chromatographed to furnish the product as white solid (6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH2:10][OH:11].[N+]([O-])(O)=O>[N+](C)([O-])=O.O>[Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH:10]=[O:11]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CO
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=Cc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 50.5 %

Procedure:
100 g of 5-(2-chloro-4-trifluoromethyl-phenoxy)-2-nitrobenzyl alcohol were dissolved in 370 ml of nitromethane. A mixture of 86.4 g of 65% strength nitric acid and 43.2 g of water was then added dropwise in the course of 90 minutes to this solution, at 60° to 65° C., and the mixture was stirred for 8 hours at 60° to 65° C. It was then diluted with 4 liters of water, and the product was filtered off. 50.2 g (50% of theory) of 5-(2-chloro-4-trifluoromethyl-phenoxy)-2-nitro-benzaldehyde, of melting point 95° C., were obtained.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[O:21][C:20]=2[CH2:34][O:35][CH3:36])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[O:21][C:20]=2[CH2:34][O:35][CH3:36])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methanol (553 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoate as an amorphous compound. The obtained methyl 4-(cyclohexyl{2-(methoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methoxy)benzoate was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (195 mg, 27%) as an amorphous compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(OCC)(=O)C>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N)C(=O)O
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
3.46 g (15 mmoles) of BOC-Leu-OH are dissolved in 50 ml of ethyl acetate, 2.1 ml (15 mmoles) of triethylamine are added, and the solution is cooled to -15° C. The mixture is stirred at the same temperature, and 1.97 ml (16 mmoles) of pivaloyl chloride are added dropwise, followed by 1.65 ml (16.5 mmoles) of piperidine. The mixture is stirred for 10 minutes between the introduction of the two reactants. When the addition is complete, the mixture is stirred for additional 30 minutes at -10° C., and then it is allowed to stand in a refrigerator overnight. The separated precipitate is filtered off, the filtrate is washed thrice with 10 ml of n hydrochloric acid, each, thrice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated. The oily residue is dissolved in 15 ml of a 4 n solution of hydrochloric acid in ethyl acetate, the mixture is allowed to stand for one hour, then it is diluted with ether and stored in a refrigerator overnight. The precipitate is filtered off to obtain 2.0 g (57%, calculated for BOC-Leu-OH) of H-Leu-piperidine.HCl; m.p.: 123°-125° C., Rf5 =0.45.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][PH:4](=[O:6])[OH:5].[C:12]([OH:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OOC(CC)(C)C)(CC)(C)C>[OH:6][P:4]([CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])([CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([OH:31])=[O:30])=[O:5]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC(C[PH](=O)O)CC(C)(C)C
Agent: CCC(C)(C)OOC(C)(C)CC
Product: CCCCCCCCC(CCCCCCCCC(=O)O)P(=O)(O)CC(C)CC(C)(C)C
Temperature: 140 °C
Yield: 82.8 %

Procedure:
6.31 g (0.0354 moles) of 2,4,4-trimethylpentyl phosphinic acid, 10 g (0.0354 moles) of oleic acid and 0.25 mL (0.0012 moles) of di-tert-amylperoxide are mixed in a 50 mL single neck flask. The mixture is purged with argon to remove oxygen and is heated under argon for 6 hours at 140° C. Tert-amyl alcohol is removed by distillation and 13.5 g (83% yield) of 10-[hydroxy-(2,4,4-trimethyl-pentyl)-phosphinoyl]-octadecanoic acid is obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:24][C@H:25]2[O:27][CH2:26]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:24][C@@H:25]2[CH2:26][O:27]2)=[CH:6][N:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OC[C@@H]2CO2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Methyl-pyridin-3-ol (0.218 g, 2.0 mmol) was placed in a flask with DMF (10 mL) and NaH (60% dispersion in oil, 77 mg, 2.0 mmol) and stirred for 30 min. at room temperature. (S)-glycidyl 3-nitrobenzene sulfonate (0.52 g, 2.0 mmol) was then added to the reaction mixture, which was then stirred at room temperature for 14 hours. The reaction was quenched with NaHCO3 (saturated) and then extracted three times with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to yield crude product which was purified by silica gel chromatography (60% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(NC(C(O)=O)C(C)C)(=O)C1C=CC=CC=1.Cl.ClC1C=CC(C2CCNCC2)=CC=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:27][CH2:28][N:29]([C:16](=[O:18])[CH:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:13]([CH3:14])[CH3:15])[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
Example 213 was prepared in a similar manner as described for the preparation of Example 208 with the exceptions that Cbz-DL-valine and 4-(4-chlorophenyl)-4-hydroxypiperidine were substituted for benzoyl-DL-valine and 4-(4-chlorophenyl)piperidine hydrochloride, respectively. MS found: (M+H)+=446.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Si]([C:14]#[N:15])(C)(C)C.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CO>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([CH:8]([C:14]#[N:15])[CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=CCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[Si](C)(C)C#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)CC2CCCCC2)CC1

Procedure:
A solution of cyclohexaneacetaldehyde (8.45 g, 66.96 mmol) and TMSCN (17.9 mL, 133.92 mmol) in MeOH was stirred for 2 h at 23° C. and N-BOC-piperazine (13.72 g, 73.66 mmol) was added. After 24 the solvent was evaporated to give the title compound.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C.Cl>O.CN1CCCC1=O>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a flask was added methyl 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]benzoate (1.0 eq) and N-methylpyrrolidinone (7.6 vols). The contents of the flask were cooled to 10° C. Water (3.9 vols) was added, and the mixture then cooled to approximately −15° C. Sodium hydroxide (1.5 eq) was dissolved in water (2.3 vols), and the sodium hydroxide solution added slowly to the flask over one hour, maintaining the reaction temperature below −10° C. The sodium hydroxide was line washed with water (0.5 vols). The reaction mixture was held for approximately 4 hours. Acetic acid (1.25 eq) was added to the mixture at −10° C. The mixture was allowed to warm to 5° C. Acetic acid (2.37 eq) was added to the mixture, the acetic acid line washed with water (3.5 vols) and the mixture allowed to warm to 22° C. The mixture was seeded, then water (5 vols) was added to the mixture. 2N hydrochloric acid (1.5 eq) was added to the mixture until pH4 was reached. The reaction mixture was stirred for at least 14 hours, then cooled to 10° C., stirred for 1 hour at 10° C. The mixture was filtered. The solid was slurry washed with water (3×2.5 vol). The isolated solid was dried at 25° C. under vacuum to afford the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH3:13])=[C:11]([NH:14][CH3:15])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:14][CH3:15])[C:12]=1[CH3:13]
Reactant: CCOC(=O)c1cnc(Cl)c(C)c1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1c(CO)cnc(Cl)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 6-chloro-5-methyl-4-(methylamino)nicotinate (2.0 g, 8.8 mmol) in tetrahydrofuran (60 mL) was added lithium aluminium hydride at 0° C., and the mixture was stirred at RT for 1.5 h. LCMS monitored the reaction was completed. The reaction was quenched by sodium sulfate decahydrate (1.5 g) and filtrated. The filtrate was concentrated to get the title compound (1.4 g, crude) as a white solid. MS (ES+) C8H11ClN2O requires: 186, 188. found: 187, 189 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][NH:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1)=[O:9])C.[NH3:23]>>[C:16]1([C:13]2[N:14]=[CH:15][C:10]([C:8]([NH:7][NH:6][CH2:5][C:4]([NH2:23])=[O:22])=[O:9])=[CH:11][N:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CNNC(=O)c1cnc(-c2ccccc2)nc1
Reactant: N
Product: NC(=O)CNNC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 46 %

Procedure:
A mixture of [N′-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetic acid ethyl ester (0.37 mmol) in 25% ammonia solution (25 mL) is stirred at rt over night. The solid is collected by filtration and dried to afford 2-[N′-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetamide (46%). MS: 272 (M+H); 1H NMR (300 MHz, CD3OD): δ 4.45 (s, 2H), 7.45-7.56 (m, 3H), 8.40-8.50 (m, 2H), 9.18 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Br[CH2:32][CH2:33]Cl.[OH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[OH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:32][CH2:33][N:20]2[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]4)/[S:22][C:21]2=[O:23])[CH2:40][CH2:39]1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: ClCCBr
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CCN(CCO)CC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-{2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethyl}-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8), 1-bromo-2-chloroethane and 1-(2-hydroxyethyl)piperazine following General Procedure G.