Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].[CH3:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14]>C1(C)C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH2:12][C:13](=[O:14])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 5 °C

Procedure:
118 g of oxalic acid dimethyl ester, warmed to 60° C., are added dropwise to a suspension of 59.4 g (1.1 mols) of sodium methylate in 200 g of toluene, cooled to 5° C., in the course of 1 hour, whilst stirring. 100 g (1 mol) of technical grade pinacolin are allowed to run rapidly into the mixture. The mixture is subsequently stirred for 15 minutes and 90 g of a methanol/toluene mixture are then distilled off, at boiling point760 : 67° to 100° C., over a packed column in the course of 3 hours. The bottom product is cooled to 40° C. and 258 g of 20.9% strength by weight aqeuous sulphuric acid are added. Phase separation is effected after thorough stirring for 1 hour. Distillation of the organic phase at boiling point0.4 : 75° C. gives 163.5 g of pivaloylpyruvic acid methyl ester (87.0% of the theoretical yield) with a purity of 99.0% (by analysis by gas chromatography).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[CH:2].[CH3:11][NH:12][CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClCCCl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:12]([CH3:13])[CH3:11])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C#Cc1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
Glacial acetic acid (3 drops) was added to a mixture of 4-ethynylbenzaldehyde (250.7 mg, 1.93 mmol), dimethylamine (2M in THF, 1.5 mL, 3.0 mmol) and NaBH(OAc)3 (617 mg, 2.91 mmol) in DCE (6.5 mL). The resulting mixture was stirred for 2.5 h at rt. The reaction was quenched with saturated aqueous NaHCO3 (˜40 mL). The product was extracted into CH2Cl2 (100 mL, then 2×50 mL), and the combined organic layer was washed with brine (25 mL), dried (Na2SO4) and evaporated in vacuo. Purification on Biotage Isolera (silica, 0-3% 2M NH3-methanol/CH2Cl2) gave 1-(4-ethynylphenyl)-N,N-dimethylmethanamine (280.1 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8 Hz, 2H), 7.28 (d, J=8 Hz, 2H), 3.42 (s, 2H), 3.07 (s, 1H), 2.24 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])=[CH2:2].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CCOCC>[C:17]([O:10][C:6]1[CH:5]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:9]=[CH:8][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)c1cccc(O)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(C)c1cccc(OC(C)=O)c1
Yield: 94.6 %

Procedure:
250 g (1.86 mol) m-isopropenylphenol and 15 mL (0.19 mol) pyridine were placed in a four-neck flask equipped with a stirrer, reflux condenser, addition funnel, and thermometer. While stirring with cooling on a water bath, 200 mL (2.12 mol) acetic anhydride was dripped in. The reaction mixture was then diluted with ether and washed with water to neutrality. Drying and distillation afforded 310 g (1.76 mol) of the target material. The yield was 94%. The properties of this product are reported below.
Reaction SMILES: [CH3:1][CH:2]([O:12][C:13](=[O:32])[C:14]1[C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:17]([O:28][CH3:29])=[CH:16][C:15]=1[O:30][CH3:31])[CH2:3][CH2:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[Cl-].[Li+].[CH:35]([Sn](CCCC)(CCCC)CCCC)=[CH2:36].O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][CH:2]([O:12][C:13](=[O:32])[C:14]1[C:19]([CH:35]=[CH2:36])=[CH:18][C:17]([O:28][CH3:29])=[CH:16][C:15]=1[O:30][CH3:31])[CH2:3][CH2:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCC(=O)CCC(C)OC(=O)c1c(OC)cc(OC)cc1OS(=O)(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCC(=O)CCC(C)OC(=O)c1c(C=C)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
A mixture of 2,4-dimethoxy-6-trifluoromethanesulfonyloxy-benzoic acid 1-methyl-4-oxo-non-8-enyl ester (0.041 g, 0.085 mmol), PdCl2(PPh3)2 (0.007 g, 0.01 mmol), lithium chloride (0.052 g, 1.2 mmol), and vinyltributyltin (50 μL, 0.17 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 24 hours. After addition of water (10 mL), extraction, and chromatography afforded 2,4-dimethoxy-6-vinyl-benzoic acid 1-methyl-4-oxo-non-8-enyl ester as a clear oil (23 mg).
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH3:12]O>>[ClH:1].[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8]
Reactant: CO
Reactant: N[C@@H](CCCCO)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)CCCCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Hydrogen chloride gas was bubbled in a slurry of 6-hydroxy-L-norleucine [prepared as described by Bodanszky et al., J. Med. Chem., 21, p. 1030-1035 (1978), 1.00 g., 6.9 mmol.] in dry methanol (35 ml.) until the mixture became homogeneous and began to reflux. The solution was then let cool and was stirred at room temperature for 2.5 hours. The methanol was removed by rotary evaporation and the residue was azeotroped twice with toluene to give crude 6-hydroxy-L-norleucine, methyl ester hydrochloride as a gum. Meanwhile, the dicyclohexylamine salt product from part (a) (3.506 g., 6.8 mmol.) was partitioned between 5% potassium bisulfate and ethyl acetate. The ethyl acetate extract was washed with additional 5% potassium bisulfate and brine, then dried (sodium sulfate), filtered and stripped to give N-phthalimido-L-tryptophan as the free acid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[C:10]([F:16])[C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[F:15][C:11]1[C:10]([F:16])=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: C1CCNCC1
Reactant: O=C(CCl)Nc1n[nH]c2c(F)c(F)ccc12
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1n[nH]c2c(F)c(F)ccc12

Procedure:
The process is performed as in Example 75, starting with 8.5 g of 2-chloro-N-(6,7-difluoro-1H-indazol-3-yl)acetamide, 200 cm3 of acetonitrile and 8.8 cm3 of piperidine. The reaction medium is refluxed for 1 hour, the precipitate formed is then filtered off on a sinter funnel and the crystals are taken up in 200 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is recristallized from a mixture of 50 cm3 of cyclohexane and 16 cm3 of ethyl acetate, filtered off and dried (90 Pa; 45° C.) to give 3.2 g of N-(6,7-difluoro-1H-indazol-3-yl)-1-piperidineacetamide in the form of white crystals melting at 158° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[NH:4][N:3]=1.S(Cl)([Cl:13])(=O)=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:13][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[N+:7]([O-:9])=[O:8]
Reactant: Cc1cc([N+](=O)[O-])[nH]n1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c([N+](=O)[O-])c1Cl
Temperature: 115 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
Nitropyrazole 9 (10.0 g, 78.68 mmol) was dissolved in a mixture of chloroform (500 mL) with 1 drop DMF. To this was added sulfuryl chloride (9.60 mL, 14.33 g, 118.0 mmol) and the mixture heated to reflux for 20 hour at 115° C. external temperature. After additional 48 hours stirring at ambient temperature the mixture was evaporated to dryness in vacuo, dichloromethane (250 mL) added and the solution again evaporated in vacuo. Crude 15 was purified by column chromatography (1 kg SiO2, 0-10% methanol in DCM) yielding pure 15 (11.7 g, 72.42 mmol, 92%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.O[CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:35]1[CH2:36][CH2:37][CH:32]([O:13][C:14]2[CH:30]=[CH:29][C:17]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:19])=[CH:16][CH:15]=2)[CH2:33][CH2:34]1
Reactant: OC1CCOCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCOCC2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Diethyl azodicarboxylate (1.47 g, 8.4 mmol) was slowly added dropwise to a solution of 4-(4-hydroxybenzoyl)-nitrobenzene (1.7 g, 7 mmol) (prepared as described in Example 1, steps), 4-hydroxytetrahydropyran (0.78 g, 7.7 mmol) and triphenylphosphine (2.2 g, 8.4 mmol) in dry tetrahydrofuran (20 mL) while stirring at room temperature under inert atmosphere. The reaction mixture was stirred for an additional hour then quenched with water (1 mL) and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed on silica gel (25% ethyl acetate/hexanes) and crystallized from hexanes to give 4-(4-tetrahydropyran-4-yloxybenzoyl)-nitrobenzene (1.4 g, 61%) as a white solid, m.p. 105-106° C.; Analysis for C18H17NO5: Calc.: C, 66.05; H, 5.23; N, 4.28; Found: C, 65.95; H, 5.14; N, 4.38. MS m/e (%): 283 (M+; 100). Proceeding as in Example 1, steps 4 and last step, but replacing 4-(4-isopropoxybenzoyl)-nitrobenzene with 4-(4-tetrahydropyran-4-yloxybenzoyl)-nitrobenzene, gave 2-[4-(4-tetrahydropyran-4-yloxybenzyl)phenyl]amino-imidazoline, m.p.169-170° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](O)(=[O:27])[C:18]1[CH:26]=[CH:25][C:24]2[O:23][CH2:22][O:21][C:20]=2[CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([C:18]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=2)[OH:27])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc3c(c1)OCO3)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and piperonylic acid (benzo[1,3]dioxole-5-carboxylic acid)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].I[CH3:18]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(C#N)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 2-(4-cyanophenyl)acetate (0.8 g, 4.101 mmol) in anhydrous dimethylformamide were added 60% sodium hydride (180 mg, 4.511 mol) and Iodo methane were added after 10 min with an ice bath. The reaction mixture was stirred for 1 h hours, quenched with water and extracted with ethylacetate which is washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The residue was purified by column chromatography. Ethyl 2-(4-cyanophenyl)propanoate (453 mg) was obtained as 48%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]2[CH:32]=[N:33][C:34](Cl)=[CH:35][CH:36]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]2[CH:32]=[N:33][C:34]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[CH:35][CH:36]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Product: CC(C)C(=O)Nc1ccc2c(ccn2-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using N-(1H-indol-5-yl)isobutyramide (intermediate 10) and tert-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (intermediate 29).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13]1([C:29]3[CH:28]=[CH:27][C:26]4[CH:30]=[C:31](O)[CH:32]=[CH:33][C:25]=4[C:24]=3[O:23][C:22]3[CH:21]=[C:20]([N:35]([CH3:37])[CH3:36])[CH:19]=[CH:18][C:17]1=3)[O:12][C:11]2=[O:38])([OH:7])=[O:6].C(OC(=O)C)(=O)C>O>[C:1]([O:4][C:31]1[CH:32]=[CH:33][C:25]2[C:24]3[O:23][C:22]4[CH:21]=[C:20]([N:35]([CH3:36])[CH3:37])[CH:19]=[CH:18][C:17]=4[C:13]4([C:14]5[C:10](=[CH:9][C:8]([C:5]([OH:7])=[O:6])=[CH:16][CH:15]=5)[C:11](=[O:38])[O:12]4)[C:29]=3[CH:28]=[CH:27][C:26]=2[CH:30]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CN(C)c1ccc2c(c1)Oc1c(ccc3cc(O)ccc13)C21OC(=O)c2cc(C(=O)O)ccc21
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc2c3c(ccc2c1)C1(OC(=O)c2cc(C(=O)O)ccc21)c1ccc(N(C)C)cc1O3
Reaction time: 8 h

Procedure:
To prepare the acetate from 8, 300 mg 5'-carboxy-10-dimethylamino-3-hydroxy-spiro[7H-benzo[c]xanthene-7,1'(3'H)-isobenzofuran]-3'-one was added 5 ml acetic anhydride and the solution refluxed for 2 hours. The solution was poured into water and stirred overnight to hydrolyze excess actic anhydride. The resulting solid was collected and purified by silica gel chromatography with 10% methanol with chloroform to give 0.16 g dark violet solid, Rf =0.37 with methanol:chloroform (1:9). Absorbance maxima in potassium phosphate buffer at pH 7.0 at 511 and 540 nm; extinction coefficients of 24,100 and 21,700 cm-1M-1 respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[C:21]([C:22]4[CH:23]=[C:24]([C:30]5[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:31]=5[CH3:40])[CH:25]=[CH:26][C:27]=4[O:28][CH3:29])=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=3)[C@H:10]2[CH3:45])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:46]1[CH2:49][CH2:48][CH2:47]1>C1COCC1>[N:46]1([C:18]2[N:17]=[C:16]([CH2:15][N:11]3[C@@H:10]([CH3:45])[C@@H:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)[O:13][C:12]3=[O:14])[C:21]([C:22]3[CH:23]=[C:24]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:31]=4[CH3:40])[CH:25]=[CH:26][C:27]=3[O:28][CH3:29])=[CH:20][N:19]=2)[CH2:49][CH2:48][CH2:47]1
Reactant: C1CNC1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Yield: 100 %

Procedure:
To methyl 3′-[4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-(methylsulfonyl)pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (81 mg, 0.121 mmol) in THF (1.6 mL) was added azetidine (40.7 μL, 0.604 mmol). The reaction was subjected to microwave irradiation at 100° C. for 15 min. The reaction was concentrated, then dissolved in ethyl acetate and washed with water (2×), brine, dried (Na2SO4), filtered, concentrated. The crude reaction was purified by column chromatography to yield methyl 3′-[2-(azetidin-1-yl)-4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (78 mg, 0.121 mmol). LCMS calc.=647.2. found=647.4.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:33])[CH2:31][NH:32][C:19]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)=[O:21])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(=O)OC(C)(C)C)cn1
Yield: 81 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using glycine tert-butylester hydrochloride instead of 3-methoxypropylamine, to the title compound (111 mg, 81%) which was obtained as an off white foam. MS: m/e=424.3 [M+H]+.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:11]#[N:12].C[OH:21]>C(OCC)(=O)C>[ClH:19].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:11]([NH2:12])=[O:21]
Reactant: N#CC(NCCc1cccs1)c1ccccc1Cl
Reactant: CO
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)C(NCCc1cccs1)c1ccccc1Cl
Temperature: 47.5 °C
Reaction time: 0.33 h

Procedure:
Into 700 ml ethyl acetate at 0-10° C. 109.8 g (3 mol) of hydrogen chloride gas was introduced and to the solution 83 g (0.3 mol) of the [2-(2-thienyl)ethylamino](2-chorophenyl)acetonitrile of formula (I), prepared according to Example 1. or 2., and 15 ml (0.37 mol) of methanol are added and the mixture is slowly, in a period of 20 minutes, heated to 45-50° C. The reaction mixture is then stirred at 45-50° C. for 4 hours, the crystalline product is filtered off at room temperature, washed with ethyl acetate and dried. Weight: 90.4 g (91%) op.: 231-232° C. The quality of the product is identical with that of the product of Example 5.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[NH2:15][C:14]1[CH:16]=[CH:17][C:11]([F:10])=[CH:12][C:13]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc(F)cc1
Product: Nc1ccc(F)cc1C(=O)c1ccccc1
Yield: 37.9 %

Procedure:
The procedure was in the same manner as described in example 15, except that the starting material was benzoic acid instead of p-chlorobenzoic acid and 4-fluoroaniline instead of 4-chloroaniline. The title compound was obtained as yellow needle crystal, and yield 37.9%, m.p. 112-113° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11](OCC)=[O:12].[NH3:25]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11]([NH2:25])=[O:12]
Reactant: N
Reactant: CCOC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCO
Product: NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In 30 ml of ethanol was dissolved 3.0 g of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate. To the resulting solution was added 6 ml of concentrated aqueous ammonia. The resulting mixture was subjected to reaction at 20°-25° C. for 5 hours. Then, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 2.1 g of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:28])[CH3:27])[CH:19]=2)=[C:12]([I:29])[CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>CO.O>[I:16][C:14]1[CH:15]=[C:10]([OH:9])[CH:11]=[C:12]([I:29])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:27])[CH3:28])[CH:19]=1
Reactant: COc1ccc(Oc2c(I)cc(OC(=O)c3ccccc3)cc2I)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(Oc2c(I)cc(O)cc2I)cc1C(C)C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
A mixture of 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenyl benzoate (0.10 g, 0.16 mmol) and 1 N NaOH (0.81 mL, 0.81 mmol) in methanol (1.63 mL) was at room temperature for 24 h. The reaction mixture was neutralized with 2 N HCl, diluted with H2O and extracted with CH2Cl2 (10 mL×2). The organic layers were concentrated under reduced pressure and the crude product was purified preparatory TLC with acetone-hexanes (1:4) as mobile phase to afford 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenol as an off-white solid (0.079 g, 95%): 1H NMR (300 MHz, DMSO-d): δ 9.99 (s, 1 H), 7.28 (s, 2 H), 6.81 (d, J=12.0 Hz, 1 H), 6.67 (d, J=3.0 Hz, 1 H), 6.30 (m, 1 H), 3.72 (s, 3 H), 3.18 (m, 1 H), 1.11 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (7:3); Rf=0.42.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C)C=O>[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:9][C:8]2[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[O:6][CH3:7])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCCCCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCCCCc1ccccc1
Yield: 30.5 %

Procedure:
A solution of vanillin (12.49 g, 82.1 mmoles) in dimethylformamide was added with Na2CO3 (17.4 g, 164 mmoles) and KI (catalytic amount). The mixture was brought to 90° C. then slowly added with methansulfonic acid 5-phenyl-pentyl ester (24.87 g, 103 mmoles) obtained as described in example 11, in dimethylformamide (40 ml). After 1.5 hours the mixture was poured into 1N HCl and thrice extracted with pentane, anhydrified and dried. The residue was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1), so 7.46 g of the title product were obtained (yield: 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[NH:11]C(OCC1C=CC=CC=1)=O)=[CH:5]/[C@H:6]1[CH2:9][C@@H:8]([CH3:10])[CH2:7]1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:7][C@H:8]([CH3:10])[CH2:9]1
Reactant: [H][H]
Reactant: COC(=O)/C(=C/[C@H]1C[C@@H](C)C1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)C[C@H]1C[C@H](C)C1
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of (Z)-2-benzyloxycarbonylamino-3-(cis-3-methyl-cyclobutyl)-acrylic acid methyl ester (prepared in Example 214, 275 mg, 0.91 mmol), methanol (10 mL) and 10% palladium on activated carbon (50 mg) was placed in a Parr shaker bottle. It was then placed on the Parr hydrogenator apparatus and charged with hydrogen to 40 psi and shaken for 1 h. After such time, the catalyst was filtered through a plug of celite and the filterate was concentrated in vacuo to afford 2-amino-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (134 mg, 86%) as a pale yellow oil.