Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]2[CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=[C:18]2[CH:23]=1
Reactant: Cc1ccnc(N)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Yield: 19 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-4-methylpyridine instead of 2-amino-3-methylpyridine, to the title compound (22 mg, 19%) which was obtained as a yellow solid. MS: m/e=290.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@H:6]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)C.[OH-].[Na+].Cl.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC>C1COCC1.CCO.CN(C=O)C.CCOC(C)=O>[C:25]([O:24][C:22](=[O:23])[NH:21][C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)[CH2:5][C:4]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:3])([CH3:28])([CH3:27])[CH3:26]
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NS(C)(=O)=O)Cc1ccc(-c2cccc(Cl)c2)cc1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
(R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-butyric acid ethyl ester (250 mg, 0.598 mmol) is treated with 2M NaOH aqueous solution (1 mL) in THF (1 mL) and EtOH (2 mL). After being stirred for 1 h, the reaction mixture is acidified with 1M HCl and extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo. To a solution of this residue in DMF (2 mL) are added methylsulfonamide (85 mg, 0.897 mmol), EDC (172 mg, 0.897 mmol), HOAt (98 mg, 0.718 mmol), and Et3N (0.125 mL, 0.897 mmol). After being stirred at room temperature overnight, the reaction mixture is diluted with EtOAc, washed with 1M HCl and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent: DCM/10% MeOH in DCM=100:0 to 0:100) to give [(R)-1-(3′-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-carbamic acid tert-butyl ester (244 mg). HPLC retentions time=1.30 minutes (condition B); MS (m+1)=467; 1H NMR (400 Mz, DMSO-d6) δ ppm 1.30 (s, 9 H), 2.41-2.48 (m, 2 H), 2.70-2.78 (m, 2 H), 3.18 (s, 3 H), 3.99-4.11 (m, 1 H), 7.28 (d, 2 H, J=8.34 Hz), 7.38-7.44 (m, 1 H), 7.48 (t, 1 H, J=7.83 Hz), 7.59-7.66 (m, 3 H), 7.69 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:25][N:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:23])([F:1])[F:24])=[N:4][N:5]=3)[CH:8]=2)=[CH:17][CH:16]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1)S(C)(=O)=O

Procedure:
N-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)methanesulfonamide (10 mg) was dissolved in DMF (1 mL) and heated with potassium carbonate (39 mg) and methyl iodide (40 mg) for 2 h at 85° C. The reaction mixture was filtered, concentrated, and purified by chromatography using 2% MeOH in methylene chloride as eluent. N-methyl-N-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)methanesulfonamide was obtained as white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Br[C:34]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:37]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([C:34]2[N:38]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[C:37]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:36][CH:35]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1ccc(Br)n1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.73 g, 18.9 mmol) synthesized in Example (1e) and 1-t-butyl 2-ethyl 5-bromo-1H-pyrrole-1,2-dicarboxylate (8.37 g, 26.3 mmol) synthesized in Example (17b) were dissolved in a mixed solvent of toluene (180 mL) and ethanol (77 mL), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (770 mg, 0.94 mmol) and an aqueous potassium carbonate solution (2M, 23.7 mL, 47.2 mmol) were added, and stirring was carried out at 100° C. for 1 hour under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (400 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (9.44 g, yield 84%) as a pale yellow oil.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].OO>O>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C@@H:7]([CH2:8][S:9][S:9][CH2:8][C@H:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[C:10]([OH:12])=[O:11])[C:10]([OH:12])=[O:11])=[O:5]
Reactant: CC(C)C(=O)N[C@@H](CS)C(=O)O
Agent: OO
Solvent: O
Product: CC(C)C(=O)N[C@@H](CSSC[C@H](NC(=O)C(C)C)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-Isobutyryl-L-cysteine (9.5 g, 50 mmol) was dissolved in 50 mL of water. Hydrogen peroxide (30%, 3.1 mL, 30 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. After evaporation of the solvent under reduced pressure, a white crystallised oil (9.8 g) was obtained. Recrystallisation from ethyl acetate furnished the title compound as a white solid which was dried in vacuo.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][N:22]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][N:26]=3)=[CH:19][CH:20]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.01 m of p-(trifluoromethyl)-benzoyl chloride is added dropwise with stirring to a solution of 0.01 m of 2-p-hydroxyphenyl-5-nonylpyrimidine in 20 ml of pyridine at 0°-5°, the mixture is stirred for 20 hours at room temperature, and worked up as usual. p-(5-Nonylpyrimidin-2-yl)-phenyl p-(trifluoromethyl)-benzoate is obtained.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[CH3:8][N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32][CH3:33])=[C:25](N)[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12]>ClCCl>[CH3:8][N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32][CH3:33])=[C:25]([F:1])[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COc1c(N)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: ClCCl
Product: COc1c(F)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of nitrosonium tetrafluoroborate (55 mg, 0.47 mmol) in dichloromethane (5 mL) was cooled to 0° C. and methyl-N-[3,5-dichloro-4-(3-amino-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine (189 mg, 0.43 mmol) was added. The reaction mixture was further stirred at 0° C. for 1 h. Dichloromethane was removed from nitrogen and o-xylene (10 mL) was added to the reaction mixture. The reaction mixture was refluxed for 1 h and the solvent was removed. The crude reaction mixture was purified on column (silica gel, n-heptane/ethyl acetate, gradient elution from 98:2 to 60:40) to give 50 mg (26%) of methyl-N-[3,5-dichloro-4-(3-fluro-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH3:20][O:21][C:22]1[C:27]2[N:28]=[C:29]([CH2:31][O:32][CH3:33])[NH:30][C:26]=2[C:25]([C:34](OC)=[O:35])=[CH:24][CH:23]=1>O1CCCC1.CCCCCC>[CH3:20][O:21][C:22]1[C:27]2[N:28]=[C:29]([CH2:31][O:32][CH3:33])[NH:30][C:26]=2[C:25]([C:34](=[O:35])[CH2:19][C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COCc1nc2c(OC)ccc(C(=O)OC)c2[nH]1
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1nc2c(OC)ccc(C(=O)Cc3ccncc3)c2[nH]1
Temperature: -78 °C
Yield: 25.1 %

Procedure:
A solution of diisopropylamine (1.51 g) in tetrahydrofuran (15 ml), under nitrogen, cooled to −10° C. was treated with butyl lithium in hexane (6 ml, 2.5M). The solution was cooled to −78° C. then treated dropwise with a solution of 4-picoline (1.40 g) in tetrahydrofuran (10 ml) followed by a solution of methyl 7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [1.25 g, Reference Example 3(a)] in tetrahydrofuran (15 ml). The brown solution was allowed to warm to room temperature and the resulting yellow suspension was filtered. The insoluble material was washed with a little tetrahydrofuran then air dried. The yellow solid (2.3 g) was dissolved in water (75 ml) and the solution extracted three times with dichloromethane (25 ml). The combined extracts were dried over magnesium sulphate and then evaporated. The resulting yellow solid (1.53 g) was subjected to flash chromatography on silica eluting initially with a mixture of methanol and dichloromethane (5:95, v/v) to give 1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone (0.39 g) recrystallised from toluene as a yellow solid, m.p. 218-220° C. with decomposition. [Elemental analysis:—C,66.58; H,5.53; N,13.76%. Calculated:—C,66.45; H,5.50; N,13.5%]; then eluting with a mixture of methanol and dichloromethane (1:9, v/v) to give 1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-propan-2-ol (0.4 g) recrystallised from methanol as a white solid, m.p. 210° C. with decomposition. [Elemental analysis:—C,68.40; H,5.94; N,13.85%. Calculated:—C,68.30; H,5.98; N,14.00%].
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O)[CH2:3][CH2:2]1.[NH2:23][OH:24].[OH-].[K+]>C1COCC1>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:23][OH:24])=[O:21])[CH2:3][CH2:2]1
Reactant: NO
Reactant: COC(=O)CCCCCCc1nc2ccccc2n1C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCc1nc2ccccc2n1C1CC1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of methyl 7-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)heptanoate (80 mg, 0.27 mmol) in THF at 0° C. was added 50% hydroxylamine solution (0.16 mL, 2.6 mmol). To this was added KOH (0.80 mL, 1M in MeOH, 0.80 mmol) dropwise. The reaction was stirred at 0° C. for 2 hr, briefly concentrated and neutralized by adding 1 N HCl solution until pH was 7. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified by biotage column chromatography to give 7-(1-cyclopropyl-1H-benzo[d]imidazol-2-yl)-N-hydroxyheptanamide 24 (52 mg). MS (M+1=302)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
Ethyl-3-bromoproprionate (1.67 ml) was added to a suspension of tert-butyl-1-piperazine carboxylate (2.43 g) and potassium carbonate (2.16 g) in acetonitrile (30 ml). The reaction mixture was stirred for 56 hrs at room temperature, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl 4-(3-ethoxy-3-oxopropyl)-1-piperazinecarboxylate (2.44 g) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39](=[O:40])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:25])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH3:27])[CH3:28]
Reactant: CCCCCCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 13.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](4-octylphenyl)amine (1.1 g) and 2,6-diisopropylphenyl isocyanate (0.71 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-octylphenyl)urea (0.23 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C1COCC1>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCNc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in THF (30 mL) was added N1,N1-dimethylethane-1,2-diamine (310 mg, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, the residue was dissolved in dichloromethane and washed with 1 N HCl aq and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete as indicated by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (280 mg, 50%) as a purple solid: ESI MS m/z 181 [C9H16N4+H]+.
Reaction SMILES: C([Sn](CCCC)(CCCC)C1C=CC(OC)=CC=1[N+]([O-])=O)CCC.C([O:32][C:33]1[CH:54]=[CH:53][C:36]2[CH:37]=[C:38]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=3[N+:50]([O-])=O)[CH2:39][CH2:40][CH2:41][C:35]=2[CH:34]=1)C1C=CC=CC=1>>[NH2:50][C:43]1[CH:44]=[C:45]([O:48][CH3:49])[CH:46]=[CH:47][C:42]=1[CH:38]1[CH2:39][CH2:40][CH2:41][C:35]2[CH:34]=[C:33]([OH:32])[CH:54]=[CH:53][C:36]=2[CH2:37]1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3CCC2)c([N+](=O)[O-])c1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Product: COc1ccc(C2CCCc3cc(O)ccc3C2)c(N)c1
Yield: 72.3 %

Procedure:
Synthesized from 6-benzyloxy-3,4-dihydro-2H-naphthalen-1-one according to an analogous synthetic method to Preparation Example 91, 2-benzyloxy-5,7,8,9-tetrahydrobenzocyclohepten-6-one (7.2 g) was used according to an analogous synthetic method to Preparation Example 82 to provide 2-benzyloxy-8,9-dihydro-7H-benzocyclohepten-6-yl trifluoromethanesulfonate (6.7 g). Synthesized from this compound and tributyl(4-methoxy-2-nitrophenyl)tin according to an analogous synthetic method to Preparation Example 77, 3-benzyloxy-8-(4-methoxy-2-nitrophenyl)-6,7-dihydro-5H-benzocycloheptene (4.7 g) was used according to an analogous synthetic method to Example 30 to provide the title compound (2.4 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:12])[CH:4]1[OH:13])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:12])[C:4]1=[O:13])[CH3:2]
Reactant: CCC1Cc2c(C)cccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1Cc2c(C)cccc2C1=O

Procedure:
The non-purified 2-ethyl-4-methyl-1-indanol was treated on a steam bath in 700 ml of toluene in the presence of 0.75 g of p-toluenesulfonic acid monohydrate for 2 hours. The solvent mixture was removed in vacuo, the residue was taken up in ether, and the mixture was washed with saturated NaHCO3 solution and NaCl solution and dried over MgSO4. The solvent was removed in vacuo and the residue was distilled (62° C./0.2 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([F:30])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:31])[CH:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([F:30])[CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:33]\[OH:34])=[C:4]([CH3:31])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OC(C)C)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OC(C)C)c(F)c1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-isopropoxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=457.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl:6][C:7]1[C:8]([O:30][CH3:31])=[N:9][C:10]([C:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH:27]3[CH2:29][CH2:28]3)=[CH:22][CH:21]=2)=[CH:14][C@H:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:11][CH:12]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:20]2[CH:21]=[CH:22][C:23]([S:26][CH:27]3[CH2:28][CH2:29]3)=[CH:24][CH:25]=2)=[CH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:16]2)=[N:9][C:8]=1[O:30][CH3:31]
Reactant: COc1nc(C(=C[C@H]2CCNC2)c2ccc(SC3CC3)cc2)ccc1Cl
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)N1CC[C@H](C=C(c2ccc(SC3CC3)cc2)c2ccc(Cl)c(OC)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Propionyl chloride (58 μL) was added to a solution of 3-chloro-6-{1-[4-(cyclopropylsulfanyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]ethenyl}-2-methoxypyridine (EZ mixture) (235 mg) and triethylamine (83 μL) in tetrahydrofuran (6 mL) under ice-cooling, and the mixture was stirred at room temperature for four hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:5) to give 1-[(3R)-3-{2-(5-chloro-6-methoxypyridin-2-yl)-2-[4-(cyclopropylsulfanyl)phenyl]ethenyl}pyrrolidin-1-yl]propan-1-one (EZ mixture) as a crude product (363 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O>[N:18]1([C:11]2[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[C:24]([CH3:27])([CH3:25])[CH3:26])=[CH:13][C:12]=2[F:17])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Yield: 67.2 %

Procedure:
This ester 400 mg (1.06 mmoles) was suspended in 1 mL water, 1,9 mL 1N aqueous sodium hydroxide was added. The suspension was refluxed 30 minutes. The solution was cooled and adjusted to pH 7.5 with 1N hydrochloric acid. The precipitate was filtered and washed with water. The crude product was recrystallized in water to give 248 mg of titled compound. MP>270° C.
Reaction SMILES: [NH2:1][C:2]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:9]=1)=[O:5].[CH3:26][NH2:27]>CS(C)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:24]=[C:23]([NH:27][CH3:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:9]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccn(Cc2cccc(F)c2)c1
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1ccc(C(=O)NCc2ccn(Cc3cccc(F)c3)c2)c(N)n1
Temperature: 135 °C
Yield: 15 %

Procedure:
2-Amino-6-chloro-N-(1-(3-fluoro-benzyl)-1H-pyrrol-3-ylmethyl)-nicotinamide described in Preparation Example A+-5 (50 mg, 0.14 mmol) was dissolved in a mixture solution of dimethylsulfoxide (1 mL) and N,N-diisopropylethylamine (0.5 mL), methylamine (2.0 M tetrahydrofuran solution) (1 mL, 2 mmol) was added thereto, and the solution was heated in a sealed tube for 15 hours (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (7.3 mg, 0.021 mmol, 15%) was obtained.