Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH2:9][CH2:10][O:11]C(=O)C)[C:3]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.N>CO>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH2:9][CH2:10][OH:11])[C:3]=1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: CC(=O)OCCn1ccc(=O)c(O)c1Cc1ccc(F)cc1
Agent: N
Solvent: CO
Product: O=c1ccn(CCO)c(Cc2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 g of acetic acid 2-[3-hydroxy-2-(4-fluorobenzyl)-4-oxo-4H-pyridin-1-yl]-ethyl ester dissolved in 20 ml of methanol, and 5 ml of a 6M solution of ammonia in methanol are added. The reaction solution is stirred at room temperature for 18 hours, the product precipitating in the form of a thick crystal mass. Filtering, washing with methanol and drying yield 3-hydroxy-1-(2-hydroxy-ethyl)-2-(4-fluorobenzyl)-1H-pyridin-4-one in the form of colourless crystals. M.p.: 225°-231° C., decomp. from 190° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[CH3:24][C:23]1[N:19]([CH2:18][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)[CH2:12][CH2:13]2)=[O:29])[N:20]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:22]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (2.67 g, 6.2 mmol) in THF (20 mL) is added aqueous solution of sodium hydroxide (2 M, 4.65 mL, 9.3 mmol) at RT. After stirring 3 h at RT, the reaction mixture is acidified with 2M aqueous solution of HCl until pH 2-3, and the solution is extracted with ethylacetate (20 mL). The aqueous layer is re-extracted with ethylacetate (20 mL) and the combined organic layers are washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid (2.33 g, 94%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-acetone): δ=1.69-1.82 (m, 1H), 1.87-2.02 (m, 1H), 2.16-2.37 (m, 2H), 2.38 (s, 3H), 2.89-2.99 (m, 1H), 3.38-3.48 (m, 2H), 4.14-4.22 (m, 1H), 4.50-4.69 (m, 1H), 5.20-5.36 (2 d, 2H (diastereotopic)), 6.41, (s, 1H), 8.34 (s, 1H). MS: m/z=403 (M+1).
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:12]2=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.[Cl-].[CH2:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CO>[NH2:6][C:7]1[C:12]2=[CH:13][C:14]([CH2:16][OH:17])=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: Nc1ncnn2cc(CO)cc12
Reactant: C=[N+]1CCOCC1
Agent: [Cl-]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CN3CCOCC3)c(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of DMF (50 mL) was added (4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol (550 mg, 3.35 mmol) and 4-methylenemorpholin-4-ium chloride (Eur. J. Med. Chem. 1989, 24, 379-384) (636 mg, 4.69 mmol). The solution was stirred at rt for 1 h and then the solvent was evaporated. The oil was triturated with CH2Cl2 and a white solid was collected. The free based was obtained by stirring over a Dowex 66 solid support resin in MeOH. The material was filtered and evaporated yielding 794 mg (90%) of the desired product as a white solid. MS [M+H]+=264; LCMS RT=1.07.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[N:6][CH:7]=1.[NH:15]1[CH:19]=[C:18]([CH2:20][NH:21][C:22]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:23])[N:17]=[CH:16]1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:29][C:26]1[S:25][C:24]([C:22]([NH:21][CH2:20][C:18]2[N:17]=[CH:16][N:15]([C:2]3[CH:7]=[N:6][C:5]([N:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]4=[O:14])=[CH:4][CH:3]=3)[CH:19]=2)=[O:23])=[CH:28][CH:27]=1
Reactant: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Reactant: O=c1ccccn1-c1ccc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)nc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 15.7 %

Procedure:
A mixture of 1-(5-iodopyridin-2-yl)pyridin-2(1H)-one (75 mg, 0.25 mmol), N-((1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (60 mg, 0.17 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed with Argon before being charged with CuI (19 mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the title compound (11 mg). MS found for C19H14ClN5O2S: 412.0 and 414.0 (M+H, Cl pattern).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:23][CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH2:19]([O:18][C:16]([CH:15]1[CH2:21][CH2:22][CH2:23][N:13]([CH2:2][CH:3]2[O:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4]2)[CH2:14]1)=[O:17])[CH3:20]
Reactant: BrCC1COc2ccccc2O1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (3.0 g, 13.09 mmol) and ethyl nipecotate (2.65 ml, 17.02 mmol) in DMF (15 ml) was added DIPEA (7.5 ml). The reaction mixture was irradiated in the microwave reactor at 110° C. for 3 min. Water (20 ml) was then added. The reaction mixture was extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and evaporated to give the crude title compound, which was purified by column chromatography (DCM/MeOH, 95:5).
Reaction SMILES: O=C1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4](=[O:24])O1.Cl.[CH:26]1([CH2:31][O:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([CH2:31][O:32][NH:33][C:4](=[O:24])[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=2[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CS(=O)(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Reactant: NOCC1CCCC1
Agent: Cl
Product: CS(=O)(=O)Nc1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccn1

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (7 ml) was added methanesulfonyl chloride (280 mg) and the reaction mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The remaining solid yellow material was dissolved in a mixture of hot EtOAc (50 ml) and DMF (4 ml). On cooling a solid material formed, that was isolated by filtration and dried under vacuum, affording N-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-methanesulfonamide. Step 2: This anhydride intermediate was converted into the title compound by reaction with O-cyclopentylmethyl-hydroxylamine hydrochloride (see preparation 66), using general procedure 1A. 13C-NMR (DMSO-d6) δ 166.8, 152.9, 152.6, 148.3, 132.4, 127.9, 115.2, 114.8, 113.3, 111.4, 110.1, 79.4, 45.0, 41.5, 37.6, 28.9, 24.9.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)=[CH:21][N:20]=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34]C)=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:22]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)=[CH:21][N:20]=[CH:19][N:18]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ncncc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ncncc2-c2nnn[nH]2)cc1
Yield: 77 %

Procedure:
To a solution of methyl 2-butyl-1-[4-[5-(1H-tetrazol-5-yl)pyrimidin-4-yl]benzyl]-1H-benzimidazole-7-carboxylate (0.18 g, 0.4 mmol) in methanol (5 ml) was added 1N aqueous NaOH (0.9 ml) and the mixture was heated under reflux for 6 hours. After concentration to dryness, the residue was dissolved in water. After removal of insoluble materials by filtration, the filtrate was neutralized with aqueous hydrochloric acid. The resulting precipitates were collected by filtration to afford colorless powders (0.14 g, 77%), m.p. 181°-183° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=O)[C:9]([N:12]3[CH2:17][C@@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[NH:22]1[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]1=[O:30]>CC(O)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:9](=[C:10]([F:11])[C:5]=2[O:4][N:3]=1)[N:12]1[CH2:17][C@@H:16]([CH3:18])[O:15][C@@H:14]([CH3:19])[C@@H:13]1[C:26]1([C:25](=[O:29])[NH:24][C:23](=[O:30])[NH:22][C:27]1=[O:28])[CH2:20]3
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(Cl)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Yield: 26.5 %

Procedure:
A mixture of 3-chloro-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 535, 764 mg, 2.44 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (313 mg, 2.44 mmol) in iPrOH (3 ml) was heated at reflux for 3 days. Solvent was removed and the residue was recrystallized from methanol. The solids obtained were recrystallized from 1:1 EtOH-Water to afford 273 mg of product consistent with desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][CH2:15][CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=2)[CH2:17]1>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]2[C:23]([CH2:24][CH2:25][CH:16]([CH2:15][NH:14][C:6](=[O:8])[CH:5]([C:4]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=3)[OH:9])[CH2:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2c(c1)CC(CN)CC2
Reactant: O=C(O)C(O)c1ccc(Cl)c(Cl)c1
Product: COc1ccc2c(c1)CC(CNC(=O)C(O)c1ccc(Cl)c(Cl)c1)CC2
Yield: 81.5 %

Procedure:
By following the procedure of Example 1(i) but starting from 3,4-dichloromandelic acid (3.1 g, 0.014 mol) and 2-aminomethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene (2.67 g, 0.014 mol), N-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl) methyl]-3,4-dichloromandelamide (4.5 g) is obtained as an oily product characterised by the following IR absorption maxima 3380 (b): O--H, CON--H; and 1641: NHC=0 cm-1.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[CH:12]=O.Cl.[NH2:15]O.C([O-])=O.[Na+].C(O)=O>O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12]#[N:15]
Reactant: O=Cc1coc2ccccc2c1=O
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1coc2ccccc2c1=O

Procedure:
A mixture of 26.1 g. (0.15 mole) of 4-oxo-4H-1-benzopyran-3-carboxaldehyde, 13.1 g. (0.19 mole) of hydroxylamine hydrochloride, 18.4 g. (0.27 mole) of sodium formate and 250 ml of 99% formic acid was heated with stirring at reflux for 21/2 hours. Water was added to 1-liter volume. The separated solid was filtered from the cooled mixture, washed well with water and dried to give 13 g. (51%) of crude nitrile melting at 138°-145°C. Recrystallization from ethylacetate gave pure, white crystals melting at 174°-176°.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:18][CH2:19][O:20][CH3:21])=[C:7](B(O)O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33](I)[C:27]=2[CH:26]=1)(=[O:24])[CH3:23].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:22]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:7]3[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=3[O:18][CH2:19][O:20][CH3:21])[C:27]=2[CH:26]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cc2c(I)cccc2s1
Reactant: COCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCOc1c(-c2cccc3sc(C(C)=O)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 70 %

Procedure:
A mixture of 620 mg (2.1 mmol) 3,5-di-tert-butyl-2-methoxymethoxy phenylboronic acid, 377 mg (1.24 mmol) of 2-acetyl-4-iodo benzo[b]thiophene, 72 mg (0.105 mmol, 5%) Pd(PPh3)4 6 mL of ethanol, 1.25 mL of Na2CO3 in 8 mL of toluene was heated to reflux for 12 hours. After cooling and work-up, the crude product was purified over a short silica gel plug (eluent: ethyl acetate/hexane: 10/90) to give 368.6 mg (0.868 mmol, yield: 70%) of pure 2-acetyl-4-(2-methoxymethoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene as a clear oil. 1H-NMR (CDCl3), δ: 7.84 (d, J=7.9 Hz, 1H), 7.79 (s, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.46 (d, J=2.6 Hz, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 4.47 (d, J=4.5 Hz, 1H), 4.06 (dd, J=14.2, 7.0 Hz, 2H), 2.81 (s, 3H), 2.54 (s, 3H), 2.02 (s, 3H), 1.49 (s, 9H), 1.33 (s, 9H), 1.23 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][CH:2]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:4](=[O:5])[CH:3]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(CC(C)C(C(=O)O)c2ccccc2)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(C)C(c1ccccc1)C2=O
Temperature: 5 °C
Reaction time: 10 h

Procedure:
To a solution of 3-methyl-4-[3-(methyloxy)phenyl]-2-phenylbutanoic acid (4) (13 g, 45.7 mmol) in CH2Cl2 (300 mL) was added oxalyl chloride (12 mL, 137.1 mmol) at room temperature. The reaction mixture was stirred for 10 h and concentrated under reduced pressure to afford the crude acid chloride. The acid chloride was redissolved in CH2Cl2 (300 mL) and cooled to 5° C. Anhydrous aluminum chloride (9.2 g, 68.6 mmol) was added, portion-wise, over a period of 15 min. The resulting brown colored reaction mixture was stirred at 5° C. for 3 h under N2. The reaction mixture was poured onto 2 N HCl (400 mL), stirred for 15 min and the layers were separated. The aqueous phase was further extracted with CH2Cl2 (3×200 mL). The combined organic solution was washed with sat. NaHCO3 (1×150 mL), brine (1×100 mL), dried (Na2SO4) and then concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 flash column chromatography using hexanes:EtOAc (9:1 to 4:1) as an eluent to afford 5.62 g (46% over 3 steps) of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J1=8.00 Hz, 1H), 7.35-7.20 (m, 3H), 7.12 (d, J=8.00 Hz, 1H), 6.86 and 6.84 (dd, J1=12.0 Hz, J2=4.00 Hz, 1H), 6.73 (br.s, 1H), 3.87 (s, 3H), 3.34 (d, J=12.0 Hz, 1H), 3.03 and 3.0 (dd, J1=16.0 Hz, J2=4.0 Hz, 1H), 2.85 and 2.81 (dd, J1=16.0 Hz, J2=8.0 Hz, 1H), 2.53 (m, 1H), 0.95 (d, J=4.0 Hz, 3H). 6.84-6.78 (m, 3H), 4.32 (sextet, J=4.0 Hz, 1H), 3.82 (s, 3H), 3.25 and 3.21 (dd, J1=16.0 Hz, J2=8.0 Hz, 1H), 3.07 and 3.04 (dd, J1=16.0 Hz, J2=8.0 Hz, 1H), 1.71 (d, J=8.00 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].C(OCC)(=O)C.Cl>O1CCOCC1.O>[SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)Cc1csc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1csc(S)n1
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a solution of ethyl 2-mercapto-4-thiazole acetate (203 mg) in 1,4-dioxane (1.0 ml) was added 1N-sodium hydroxide solution (2.0 ml) at room temperature. After stirring at the same temperature for 2 hours, the solution was poured into a mixture of ethyl acetate and water, and adjusted to pH 8.0 with 1N-hydrochloric acid. The separated aqueous solution was adjusted to pH 3.0 with 1N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to give 2-mercapto-4-thiazole acetic acid (120 mg).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[CH3:22][C@:23]12[CH2:39][CH2:38][C@H:37]3[C@@H:28]([CH:29]=[CH:30][C:31]4[C@@H:36]3[CH2:35][CH2:34][C:33](=[O:40])[CH:32]=4)[C@@H:27]1[CH2:26][CH2:25][C:24]2=[O:41].C(O)(=O)C>O1CCCC1.[Cu]I>[CH3:16][Si:15]([CH3:17])([C:18]([CH3:21])([CH3:20])[CH3:19])[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:29]1[CH2:30][C:31]2[C@H:36]([CH2:35][CH2:34][C:33](=[O:40])[CH:32]=2)[C@@H:37]2[C@@H:28]1[C@H:27]1[C@@:23]([CH2:39][CH2:38]2)([CH3:22])[C:24](=[O:41])[CH2:25][CH2:26]1
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCBr
Agent: [Cu]I
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 1 h
Yield: 172 %

Procedure:
7.4 g of magnesium filings is placed into 31 ml of tetrahydrofuran and combined within 1.5 hours with a solution of 113 g of 11-bromoundecyl-tert-butyldimethylsilyl ether in 310 ml of tetrahydrofuran. After one hour at a bath temperature of 100°, the mixture is diluted with 157 ml of tetrahydrofuran, cooled to -30°, mixed with 29.5 g of copper(I) iodide, stirred for 0.2 hour at -30°, a solution of 25 g of 4,6-estradiene-3,17-dione [Kalvoda, J., and Anner, G., Helv. Chim. Acta 50 : 269 (1967)]in 220 ml of tetrahdyrofuran is added dropwise, and the mixture is further stirred for 1.5 hours at -30°. Then, 18.7 ml of glacial acetic acid is added, the mixture is concentrated under vacuum, poured on water, suctioned off through "Celite", rinsed with ethyl acetate, extracted twice with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 88.6 g of 7α-[11-(dimethyl-tert-butyl-silyloxy)undecyl]-4-estrene-3,17-dione, [α]D =54.4°, as an oil, as well as 55.2 g of 7β-[11-(dimethyl-tert-butylsilyloxy)undecyl]-4-estrene-3,17-dione, mp 65°.
Reaction SMILES: [C:1]([C:4]1[CH2:8][CH2:7][CH2:6][CH:5]=1)(=[O:3])[CH3:2].[OH:9]O.[OH-].[Na+]>CO.O>[C:1]([C:4]12[O:9][CH:5]1[CH2:6][CH2:7][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=CCCC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C12CCCC1O2
Reaction time: 1 h

Procedure:
A solution of 11.02 g of 1-acetyl-cyclopent-1-ene in 50 ml of methanol is cooled to -10°C and mixed with 28.8 ml of perhydrol within 5 minutes. In the course of 1 hour, while stirring and cooling, 8.25 ml of 6N-sodium hydroxide solution are added, the whole is stirred for 1/2 hour at room temperature, diluted with 125 ml of water and extracted with pentane. The pentane solution is washed neutral with sodium chloride solution and the pentane is distilled off through a Vigreux column. The residue is distilled under 10 mm Hg pressure, to yield 1-acetyl-1,2-epoxy-cyclopentane passing over at 62° - 63°C.
Reaction SMILES: ClC1C=CC2N=C(C)C=CC=2C=1C(O)=O.[Cl:16][C:17]1[C:18]([NH:37][C:38](=[O:46])[CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([NH:27][CH2:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH:21]=[CH:20]2.FC(F)(F)C(O)=O>>[Cl:16][C:17]1[C:18]([NH:37][C:38](=[O:46])[CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:21]=[CH:20]2
Reactant: CC(C)(C)OC(=O)CCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Agent: Cc1ccc2c(C(=O)O)c(Cl)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Yield: 29.7 %

Procedure:
Prepared according to the method of example 7 (b), using N-[6-chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-β-alanine, 1,1-dimethylethyl ester (Example 41 (a)) (150 mg) and trifluoroacetic acid (2 mL). Purification by HPLC (Symmetry—0.1% aqueous ammonium acetate/acetonitrile) afforded the title product (39 mg).
Reaction SMILES: C1(N[C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)CCCCC1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](Cl)=[O:33])[CH:28]=[CH:29][CH:30]=1>CCN(CC)CC>[CH:17]1([NH:9][C:32](=[O:33])[CH:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)[C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: CCN(CC)CC
Product: COc1cccc(C(C(=O)NC2CCCCC2)c2c3ccccc3nn2-c2ccccc2)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 3-methoxyphenyl acetyl chloride ([6834-42-0]) in the presence of Et3N to give the title compound as yellow foam. MS: m/e=440.4 [M+H+].
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[N:23]2[N:24]=[C:25]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[C:26]([C:27](=O)[C:28]#[CH:29])=[C:22]2[CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:17][C:18]1[N:23]2[N:24]=[C:25]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[C:26]([C:27]3[CH:28]=[CH:29][N:10]=[C:8]([NH:7][CH:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[N:9]=3)=[C:22]2[CH:21]=[CH:20][CH:19]=1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2ccco2)nn2c(Cl)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopentylguanidine hydrochloride (1.53 g, 9.38 mmol) and potassium carbonate (0.78 g. 5.63 mmol) were added to 80 mL of ethanol. The suspension was stirred at room temperature for 1 hour. 1-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (1.27 g, 4.69 mmol) was added to the resultant solution and stirred at room temperature for 24 hours. The reaction mixture was concentrated and ethyl acetate and water were added. The phases were separated, the organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (3:7 ethyl acetatehexanes). gave 4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (520 mg, 30%) as a yellow solid. 1H NMR (CDCl3): δ 8.28 (d, 1H), 8.22 (d, 1H), 7.58 (d, 1H), 7.23 (m, 1H), 7.04 (d, 1H), 6.92 (d, 1H), 6.62 (d, 1H), 6.53 (m, 1H), 5.16 (d, 1H), 4.35 (m, 1H), 2.07 (m, 2H), 1.77–1.52 (m, 6H). MS m/z 380 (M+1).