Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)on2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)on2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A mixture of methyl 3-[5-(4-trifluoromethylphenyl)-3-isoxazolyl]benzoate (1.04 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (30 ml) and methanol (30 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (20 ml) was added. The crystals were collected by filtration and recrystallized from ethanol to give 3-[5-(4-trifluoromethylphenyl)-3-isoxazolyl]benzoic acid (0.876 g, yield 88%) as a colorless crystalline powder. melting point: 276–277° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[N:7]1
Reactant: COC(=O)CCc1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)O)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ester 7 (0.31 g, 0.65 mmol) in THF (5 mL) was added a solution of LiOH (0.06 g, 1.40 mmol) in water (2 mL) and the resulting mixture was stirred at RT overnight. The volatiles were removed in vacuo. The residue was diluted with water (5 mL) and acidified to pH 1 with 2 M HCl. The acid 8 was isolated by filtration as a white solid and washed with water and dried overnight over KOH in a dessicator to yield 0.09 g (34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([OH:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([OH:12])[C:9]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:33]=[CH:34][C:35]=3[CH3:36])[CH2:26][CH2:25]2)=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Example 156 was prepared from bis(4-fluorophenyl)(hydroxy)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 9.44 (s, br, 1 H), 8.18 (s, 1 H), 7.62–7.48 (m, 4 H), 7.32 (s, 1 H), 7.07–7.00 (m, 1 H), 7.00–6.89 (m, 4 H), 6.72–6.53 (m, 1 H), 5.96–5.71 (br, 1 H), 3.55–3.44 (m, 2 H), 3.14–3.02 (m, 2 H), 2.83–2.66 (m, 1 H), 2.63–2.49 (m, 2 H), 2.39–2.22 (m, 1 H), 2.29 (s, 3 H), 2.17–1.98 (m, 4 H), 1.78–1.59 (m, 4 H), 0.92 (d, 6 H, J=6.8 Hz); ESMS m/e: 564.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C@H:6]([CH2:15][OH:16])[NH:7]C(OC(C)(C)C)=O)[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O.C(Cl)Cl>CCOCC>[CH2:1]([O:4][C:5](=[O:17])[C@H:6]([CH2:15][OH:16])[NH2:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCOC(=O)[C@@H](N)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
N-tert-butoxycarbonyl-L-serine allyl ester (27.2 g) was placed in a 500 ml r. b. flask and cooled to 0° C. To this yellow oil, 50% TFA/CH2Cl2 (100 ml) was added under positive N2 pressure. The reaction mixture was stirred at 0° C. (30 min), warmed to room temperature, and stirred for 2 h. TFA and CH2Cl2 were removed by rotoevaporation to yield a yellow oil. The yellow oil was dissolved in ether (200 ml). After 3 h at 4° C., the product completely precipitated. The precipitated product was collected by filtration and washed with ether (50 ml) and hexane (20 ml). The white precipitate was dried in a vacuum oven overnight. Dry L-serine allyl ester (3) was obtained (15.6 g, 100% yield). TLC in CH2Cl2/CH3OH/H2O (65:25:4) showed a pure product (Rf=0.58). FTIR: (thin film, cm−1) 2994.54, 2960.64, 2891.49, 1747.28, 1674.06, 1201.52, 11.45.92. 1H NMR (300 MHz, CDCl3, δ ppm): 5.86 (1H, m), 5.30 (2H, m), 4.59 (2H, d, J=6.43 Hz), 4.09 (2H, m), 3.77 (1H, m). FAB-MS [M+H+] calcd for C6H11NO3 146.2, found 146.0.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]2[O:10][C:11](=[O:13])[N:12]=[C:8]2[CH:7]=[C:6]([N:14]2[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]2)[N:5]=1.[CH3:20][O:21][C:22](N1C2C=CC=CC=2N=C1)=[O:23].C(O)(=O)C>CN(C)C=O>[N:14]1([C:6]2[N:5]=[C:4]([NH:3][C:22]([O:21][CH3:20])=[O:23])[N:9]3[O:10][C:11](=[O:13])[N:12]=[C:8]3[CH:7]=2)[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]1
Reactant: COC(=O)n1cnc2ccccc21
Reactant: Nc1nc(N2CC=CCC2)cc2nc(=O)on12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc(N2CC=CCC2)cc2nc(=O)on12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.2 g of sodium hydride are added portionwise to a solution, cooled to 15°, of 4.66 g of 5-amino-7-[3,6-dihydro-1(2H)-pyridyl]-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidin-2-one in 200 ml of dimethylformamide. The mixture is stirred vigorously at room temperature for 30 minutes. Thereafter, 5.28 g of 1-methoxycarbonylbenzimidazole in 50 ml of dimethylformamide are added thereto. After 2 hours, the mixture is treated with ice-cold water and adjusted to pH 5 with glacial acetic acid. The precipitate which results is recrystallized from methylene chloride/methanol, and there is obtained methyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate, m.p. 212°-214°
Reaction SMILES: [F:1][C:2]1[C:3]([OH:24])=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:25]12[O:30][CH:29]1[CH2:28][O:27][CH2:26]2.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[F:1][C:2]1[C:3]([O:24][C@H:29]2[C@H:25]([OH:30])[CH2:26][O:27][CH2:28]2)=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C1OCC2OC12
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@H]1O)C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 21.2 %

Procedure:
27B (680 mg, 2.034 mmol) was mixed with 3,6-dioxabicyclo[3.1.0]hexane (876 mg, 10.17 mmol), and K2CO3 (1546 mg, 11.19 mmol) in acetonitrile (1 mL) and H2O (1 mL) in a sealed tube. The mixture was stirred at 100° C. for 20 h. The reaction was quenched with H2O then extracted with EtOAc (2×) and concentrated. The residue was purified by flash column chromatography (0-90% EtOAc/hexanes) to give a mixture of diastereomers as yellow oil. The diastereomers were further separated by a prep chiral HPLC equipped with a OJ Column to give the first peak 27C (181 mg, 0.431 mmol, 21.17% yield). The relative stereochemistry of hydroxyether is trans however absolute stereochemistry is undetermined MS (ESI) m/z: 421.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:6](=[O:8])[CH2:7][C:2]([CH3:9])([CH3:1])[C:3]([OH:5])=[O:4])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[O:34])[CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2)c1
Reactant: CC1(C)CC(=O)OC1=O
Product: CC(C)(CC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1)C(=O)O

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperazin-1-yl}-2,2-dimethyl-4-oxo-butyric acid was prepared from 2,2-dimethylsuccinic anhydride and N-(3-tert-butyl-phenyl)-4-piperazin-1-yl-benzamide. HRMS m/z calcd for C27H35N3O4 [M+H]+: 466.2701. Found: 466.2698.
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CN=C(C(N)=O)C=1.Cl.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=2)=[CH:33][CH:32]=1
Reactant: Nc1ccc(O)cc1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Agent: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Product: COC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Methyl 4-(4-aminophenoxy)pyridine-2-carboxylate was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from the product of step 1 and 4-aminophenol.
Reaction SMILES: Cl[CH2:2]CCC(Cl)=O.[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24]N=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([F:39])[CH:33]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([NH:36][C:35]1[CH:37]=[CH:38][C:32]([O:31][C:22]2[C:21]3[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=3)[N:25]=[CH:24][CH:2]=2)=[CH:33][C:34]=1[F:39])=[S:16])=[O:13]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(Cl)CCCCl
Agent: O=C(CCCCl)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCCCl)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
4-Chlorobutanoyl isothiocyanate was prepared using commercially available 4-chlorobutanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Chlorobutanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 67%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:34]3[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=3[CH:28]=2)O1>>[CH3:37][C:33]1([CH3:38])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]2[CH:28]=[C:27]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[CH:36]=[CH:35][C:34]1=2
Reactant: OCCNC1CCCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS102 starting from 79 mg (0.245 mmol) of 2-[1-(6-bromopyridin-2-yl)azepan-4-ylamino]ethanol and 96 mg (0.257 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane. The product is purified by means of preparative HPLC and converted into the hydrochloride using methanolic HCl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[H-].[Na+]>C1COCC1>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1Sc1ccc(F)cc1
Reaction time: 18 h
Yield: 82.3 %

Procedure:
To a solution of 4-fluorothiophenol (1.0 g, 7.8 mmol) and 2-chloronitrobenzene (1.2 g, 7.8 mmol) in THF (10 mL) at 0° C. was added NaH (60% dispersion in oil, 390 mg, 9.4 mmol). The reaction was brought to room temperature and allowed to stir for 18 h. Ice was added and the layers separated. The aqueous layer was extracted three times with EtOAc (3×50 mL). The combined extracts were washed with water (50 mL) and dried (Na2SO4) and evaporated affording 4-fluorophenyl 2-nitrophenyl sulfide (1.6 g, 82%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.24 (dd, 1H, J=1.5, 8 Hz), 7.58-7.63 (m, 2H), 7.38 (dt, 1H, J=1.5, 7.4 Hz), 7.15-7.25 (m, 3H), 6.82 (dd, 1H, J=1.1, 8.1 Hz) ppm.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([Mg]Cl)([CH3:11])([CH3:10])[CH3:9].Cl>CCOCC>[C:8]([C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)C(=O)C1CCC1

Procedure:
To a mixture of 118.5 g. (1.0 mole) of cyclobutylcarbonyl chloride and 99 g. (1.0 mole) cuprous chloride in 1000 ml. of dry ether under a nitrogen atmosphere is added dropwise 478 ml. (1.0 mole) of 2 M t-butylmagnesium chloride in the same solvent. The addition is carried out at -5° to -15° C. The resulting mixture is poured into 500 ml. of 3 M hydrochloric acid and 700 g. ice, the organic layer is separated and washed successively with water, sodium bicarbonate solution, brine and dried (MgSO4). The dried ether extract is evaporated at reduced pressure and the residue distilled to provide t-butylcyclobutylketone.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.CO>N.[Ni]>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCc1ccc(OC(F)(F)F)cc1
Yield: 80 %

Procedure:
Using analogous conditions as described for the preparation of Intermediate I-17b, 2-(4-(trifluoromethoxy)phenyl)acetonitrile (I-51a: 3.8 g) in methanolic ammonia (50 mL) was reacted with raney nickel (7 g) and methanol (40 mL) to afford 3.1 g of the product (80% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[Cl:61]C1C=CC(N=C=S)=CC=1>>[Cl:61][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 264 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-chlorophenyl isothiocyanate. The compound of example 264 was used directly without isolation for the preparation of compound of example 265.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([C:12]([O:14]C)=[O:13])=[CH:9][CH:8]=2)[N:3]=1.Cl>[OH-].[Na+].CO.O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc(-c2noc(C)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccc(C(=O)O)s2)no1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A mixture of methyl 5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-thiophenecarboxylate, prepared according to Example 22, (86 mg, 0.38 mmoles) in 3 ml of 2N sodium hydroxide was diluted with 1 ml of methanol and warmed to 60° C. for 10 minutes. The solution was cooled to room temperature, diluted with 2 ml of water and acidified to pH 2 with concentrated hydrochloric acid. After standing for 30 minutes the fluffy crystalline solid which slowly separated was collected by filtration and dried in vacuo to furnish the title compound (45 mg, 56%), m.p. 218-20° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 85 %

Procedure:
10 g (0.05 mol) of 2-(4-nitrophenyl)propanoic acid were dissolved in a mixture of 5 ml of water and 100 ml of methanol and 0.65 g of Pd/C 5% were added. The mixture was submitted to hydrogenation at 60 psi for 2 hours at room temperature. After the separation of the catalyst by filtration on celite the methanol was evaporated under vacuum and the title compound was crystallised from water on cooling (7 g; 85 % yield).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:22]([CH2:21][Cl:20])=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Yield: 85.8 %

Procedure:
A solution of 4-benzylpiperidine (17.5 g, 100 mmol) in THF (250 mL) was treated with K2CO3 (14 g, 101 mmol) and chloroacetylchloride (11.3 g, 100 mmol) at rt for 2 hours. The reaction mixture was filtered. The filtrate was concentrated, and then dissolved in EtOAc and water. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the product (21.6 g, 91.5%). 1H NMR (CDCl3) δ 7.32-7.12 (m, 5H), 4.09 (s, 2H), 3.79-3.76 (m, 2H), 2,56 (d, J=7.0 Hz, 2H), 1.89-1.80 (m, 1H), 1.79-1.71 (m, 4H), 1.28-1.12 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:28][CH2:27]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: c1cc(C2(CN3CCNCC3)CCOCC2)ccc1OCCCN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.3 %

Procedure:
To a stirred solution of 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine (160 mg, 0.41 mmol) and N,N-diisopropylethylamine (180 μl, 1.03 mmol) in dichloromethane (2 ml) at 0° C. was added dropwise acetic anhydride (47 μl, 0.49 mmol). The reaction was allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (20 ml) and aqueous sodium carbonate solution (20 ml). The layers were separated and the aqueous layer was extracted again with dichloromethane (20 ml). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 90:10:1 by volume) to provide the title compound (34 mg, 19%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.78-1.81 (m, 4H), 1.83-1.89 (m, 2H), 1.99 (s, 3H), 2.01-2.03 (m, 2H), 2.06-2.11 (m, 3H), 2.15-2.18 (m, 3H), 2.40 (s, 2H), 2.51-2.53 (m, 4H), 2.63 (t, 2H), 3.22 (t, 2H), 3.42-3.44 (m, 2H), 3.52 (t, 2H), 3.73-3.76 (m, 2H), 4.02 (t, 2H), 6.86 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 430.3052 [MH]+.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(OCC)(=O)C.O>[CH2:20]([O:19][C:17]([NH:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A suspension of ethyl 1-aminocyclopropanecarboxylate hydrochloride (9.5 g, 57.3 mmol) in 450 mL of ethyl acetate was cooled to 0° C., a solution of NaHCO3 (39.5 g, 470.3 mmol) in 325 mL of water was added slowly. Then benzyl chloroformate (13.3 g, 78.2 mmol) was added drop-wise. The cold bath was removed and the mixture was stirred at room temperature for 16 hours. The organic phase was washed with 1N HCl (100 mL), saturated NaHCO3 solution (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated to give a white solid. The solid was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:3, v/v) to give ethyl 1-(benzyloxycarbonylamino)cyclopropanecarboxylate (13.7 g, 91%) as a white solid. MS: (M+H)+=286.1; 1H NMR (300 MHz, CDCl3): δ 7.37-7.32 (m, 5H), 5.13 (s, 2H), 4.70 (s, 1H), 4.13 (brs, 2H), 1.59-1.53 (m, 2H), 1.23-1.19 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][CH:35]([O:38][CH3:39])[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][CH:35]([O:38][CH3:39])[CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: COC1CCN(C2CCN(c3ccc(N)cc3C#N)CC2)CC1
Product: COC1CCN(C2CCN(c3ccc(NC(=O)c4cnn(-c5ccc(Cl)cc5)c4C)cc3C#N)CC2)CC1
Yield: 23.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.4 g) and 5-amino-2-[4-(4-methoxypiperidin-1-yl)piperidin-1-yl]benzonitrile (0.5 g), the title compound (0.2 g) was obtained, melting point: 245° C. decomposition.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:12]2)=[N:8][C:7]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:3][CH2:4][C:6]1[S:10][C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:15][CH2:16]2)=[N:8][C:7]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1
Reactant: CCOC(=O)c1sc(N2CCN(CCCCO)CC2)nc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(N4CCN(CCCCO)CC4)sc3CO)ccc21

Procedure:
The preparation was carried out as already described starting from 2-[4-(4-hydroxybutyl)piperazin-1-yl]-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazole-5-carboxylic acid ethyl ester by reduction using a lithium aluminium hydride solution in THF.