Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:53])([CH3:52])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25](/[CH:28]=[C:29]3\[C:30](=[O:50])[NH:31][C:32]4[C:37]\3=[CH:36][C:35]([S:38]([CH2:41][C:42]3[C:47]([Cl:48])=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:49])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[NH:24][C:23]=2[CH3:51])=[O:21])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>C(Cl)Cl.C(OCC)(=O)C>[NH2:7][C:8]([CH3:53])([CH3:52])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25](/[CH:28]=[C:29]3\[C:30](=[O:50])[NH:31][C:32]4[C:37]\3=[CH:36][C:35]([S:38]([CH2:41][C:42]3[C:43]([Cl:49])=[CH:44][CH:45]=[CH:46][C:47]=3[Cl:48])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[NH:24][C:23]=2[CH3:51])=[O:21])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)C(C)(C)N)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a mixture of (2-{4-[2-({5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (from the above reaction) in DCM (3 mL) was added 6N HCl in ethyl acetate. The mixture was stirred at 40° C. for 3 hours. The reaction was concentrated, basified to pH 7-8 with 2N NaOH, extracted with DCM and concentrated. The residue was purified on a silica gel column to give 40 mg the titled compound as a red solid.
Reaction SMILES: CO[C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[NH2:10])=[O:4].[O-:12][C:13]#[N:14].[K+]>C(O)(=O)C.O>[CH3:11][C:8]1[C:9]2[NH:10][C:13](=[O:12])[NH:14][C:3](=[O:4])[C:5]=2[S:6][CH:7]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1csc2c(=O)[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.4 %

Procedure:
To a stirred solution of methyl-3-amino-4-methylthiophene-2-carboxylate (530 mg, 3.1 mmol) in acetic acid (15.5 mL) and water (1.6 mL) was added a solution of potassium cyanate (754 mg, 9.3 mmol) dissolved in water (2.5 mL) dropwise via syringe. The reaction was stirred at room temperature for 15 h, upon completion of the reaction; the reaction mixture was concentrated to 75% and filtered off white solid. To the solid was added 6% aqueous sodium hydroxide (16 mL) and refluxed for 2 h. After cooling to room temperature, the solution was acidified using 12N HCl to pH=6. The resultant precipitate was filtered, washed with water and dried in vacuum oven overnight to give 403 mg (71%) of the title compound as a white solid which was used without any further purification:
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:21]3[C:22]([CH3:29])=[C:23]([OH:28])[C:24]([CH3:27])=[C:25]([CH3:26])[C:20]=3[O:19][C:18]=2[CH3:30])=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.O>C(Cl)(Cl)Cl>[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([O:28][C:23]2[C:24]([CH3:27])=[C:25]([CH3:26])[C:20]3[O:19][C:18]([CH3:30])=[C:17]([C:14]4[CH:15]=[CH:16][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:12][CH:13]=4)[C:21]=3[C:22]=2[CH3:29])=[O:38])=[CH:35][CH:34]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccc(C(C)C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)Oc2c(C)c(C)c3oc(C)c(-c4ccc(C(C)C)cc4)c3c2C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
Triethylamine (0.45 mL, 3.21 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,4,6,7-tetramethylbenzofuran-5-ol (0.90 g, 2.92 mmol) and 4-methoxybenzoyl chloride (0.55 g, 3,21 mmol) in chloroform (15 mL) at room temperature, and the mixture was stirred for 3 hours at 60° C. Water (30 mL) was poured into the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with 1 N hydrochloric acid and saturated sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain the title compound (0.52 g, yield 79).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26](O)C.C=O>O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=3)[CH2:26]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)cc1C(F)(F)F
Agent: C=O
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)cc1C(F)(F)F

Procedure:
2-Phenylamino-N-(3-trifluoromethyl-4-sulphamoylphenyl)-acetamide (11.2g) was added to ethanol (200 ml) and paraformaldehyde (1.3g) in water (400 ml) added thereto under reflux. The mixture was refluxed 11/2 hr, cooled and worked up as in Example 6(c) to yield 11,8 g, m.p. 235°-238°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: OCc1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ncccc2CO)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-methoxyphenyl)boronic acid (1.6 g, 10.53 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv), Pd(dppf)Cl2 (0.57 g, 0.10 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 1.5 h at 100° C., and then it was diluted with 20 mL of H2O. The resulting solution was extracted with 2×50 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:1) as eluent to furnish 1 g (67%) of [2-(4-methoxyphenyl)pyridin-3-yl]methanol as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[S:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=2[C:4]([NH:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)=[O:5])=[CH:22][C:21]=1[S:27][CH3:28]
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Reactant: CSc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1cc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)ccc1Cl
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxycyclohexyl)nicotinamide (150 mg, 0.55 mmol) was added to a solution of 4-chloro-3-(methylsulfanyl)phenol (96 mg, 0.55 mmol), caesium carbonate (358 mg, 1.1 mmol) in N,N-dimethylformamide (2 ml). The reaction was stirred under nitrogen at 55° C. for 18 h, cooled, and quenched with 1:1 water:sat. ammonium chloride solution and passed through a chemelute™ cartridge. The solvent. The residue was purified by flash column chromatography using dichloromethane:methanol (100:0 to 96:4) as eluant to afford 2-[4-chloro-3-(methylsulfanyl)phenoxy]-5-fluoro-N-(trans-4-hydroxycyclohexyl)nicotinamide as an amorphous glass (37 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]3)[CH:25]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][NH:16][C:17]4=[O:20])=[CH:13][CH:12]=3)[O:8][C:7]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)[CH:25]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][NH:16][C:17]4=[O:20])=[CH:13][CH:12]=3)[O:8][C:7]=12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(-c5ccc6c(c5)C(=O)NC6)cc34)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3ccc4c(c3)C(=O)NC4)oc12
Reaction time: 4 h

Procedure:
To a solution of 6-{7-amino-4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one in THF (2.4 mL) was added tetra-n-butylammonium fluoride (1.0 M in THF, 2.4 mL, 2.4 mmol). After 4 h, the reaction was diluted into EtOAc and washed with sodium bicarbonate and water. The aqueous layer was concentrated. The residual solid was rinsed with MeOH and EtOAc thoroughly, then purified by ISCO chromatography (0 to 10% 7 N NH3/MeOH:EtOAc) to afford 1.5 mg (3%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.44 (s, 1H), 8.34 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 7.92 (d, J=5.3 Hz, 2 H), 7.76 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 4.56-4.58 (m, 2H), 4.23-4.34 (m, 1H), 3.67-3.78 (m, 1H), 2.11-2.25 (m, 4H), 1.97-2.08 (m, 2H), 1.54 (m, 2H); MS (ESI): 430.17 [M+H]+; HPLC tR=0.90 min (TOF: polar—3 min).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: Cl.[NH2:2][OH:3].[N+:4]([C:7]1[CH:8]=[C:9]([C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]>O.N1C=CC=CC=1>[N+:4]([C:7]1[CH:8]=[C:9](/[C:13](=[N:2]\[OH:3])/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: CCOC(=O)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)/C(=N/O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 16.9 %

Procedure:
Ethyl (Z)-3-nitro-alpha-hydroxyiminophenylacetate can be obtained in the following manner: a solution of 62 g of hydroxylamine hydrochloride in 200 cm3 of water is added to a solution of 10 g of ethyl 3-nitrophenyl-glyoxylate in 250 cm3 of pyridine and the mixture is brought for 2 hours to a temperature near to 100° C. The reaction mixture is concentrated under reduced pressure (1.2 kPa). The residue is diluted with 250 cm3 of water and extracted with 250 cm3 of ethyl acetate. The organic phase is washed with a 1N aqeuous solution of hydrochloric acid, dried over magnesium sulphate, filtered and evaporated to dryness to give a white solid. This solid is purified by chromatography on a column of diameter 4 cm containing 500 cm3 of silica, eluting with a cyclohexane/ethyl acetate mixture and collecting fractions of 100 cm3. The fractions between 1 and 1.2 liters are combined and concentrated to dryness to give 1.8 g of ethyl (E)-3-nitro-alpha-hydroxyiminophenylacetate in the form of a colorless oil; the fractions between 1.4 and 1.6 liters are combined and concentrated to dryness to give 2.5 g of ethyl (Z)-3-nitro-alpha-hydroxyiminophenylacetate in the form of a solid which is used as such in the subsequent syntheses.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-]>CO.CCOC(C)=O>[NH2:1][CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:14][CH:15]=2)[CH:9]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Solvent: CCOC(C)=O
Solvent: CO
Product: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1

Procedure:
To a solution of 1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one prepared above (203 mg, 0.695 mmol) in MeOH (6 mL) and EtOAc (6 mL), SnCl22H2O (343 mg, 1.52 mmol) was added. After the mixture was heated to reflux for 1 h, it was concentrated in vacuo. The residue was purified by HPLC to give 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one (145 mg). MS 267 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27](Cl)=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O1CCCCC1[O:40][C@@H:41]([CH3:44])[CH2:42][OH:43]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27]([O:43][CH2:42][C@@H:41]([OH:40])[CH3:44])=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: C[C@@H](CO)OC1CCCCO1
Reactant: O=C(Nc1nc2cc(-c3ccc(C(F)(F)F)c(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Product: C[C@H](O)COc1ccc2nc(C(=O)Nc3nc4cc(-c5ccc(C(F)(F)F)c(Cl)c5)ccc4[nH]3)cn2n1

Procedure:
6-((S)-2-Hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (38 mg) was prepared from 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and (S)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol (100 μL) as described above in Example 122. LCMS (m/z): 532. 1H NMR (400 MHz, DMSO-d6): δ 12.5 and 11.5 (1H, brs) 8.85 (1H, s) 8.14 (1H, d) 8.02 (1H, brs) 7.85-7.93 (3H, m) 7.55-7.63 (2H, m) 7.07 (1H, d) 5.01 (1H, d) 4.17 (2H, d) 4.02-4.07 (1H, m) 1.19 (3H, d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C@H:9]1[C:16]([NH:18][C:19]1([C:22]#[N:23])[CH2:21][CH2:20]1)=[O:17].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([C:19]1([NH:18][C:16]([C@@H:9]2[CH2:10][C:11]([F:15])([F:14])[CH2:12][CH2:13][C@H:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:29]2[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=2)=[O:17])[CH2:21][CH2:20]1)#[N:23]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: N#CC1(NC(=O)[C@@H]2CC(F)(F)CC[C@H]2c2ccccc2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ccc(-c2ccccc2[C@@H]2CCC(F)(F)C[C@H]2C(=O)NC2(C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(1R,2R)-2-(2-Bromophenyl)-N-(1-cyanocyclopropyl)-5,5-difluorocyclohexanecarboxamide (518 mg, 1.35 mmol), 4-(methylthio) benzeneboronic acid (285 mg, 1.70 mmol), PdCl2(dppf).CH2Cl2 (61 mg, 0.075 mmol) and 2.0 M Na2CO3 aqueous solution (1.02 mL, 2.04 mmol) were heated at 85° C. in N,N-dimethylformamide (4.0 mL) under a nitrogen atmosphere. After 17 hours at this temperature, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water and the layers separated. The aqueous phase was extracted with additional ethyl acetate and the combined organics were washed with brine, and dried (Na2SO4). Concentration in vacuo and chromatography of the residue on silica eluting with 30/70 EtOAc/hexanes gave the title compound as a faint-yellow foam, [αD=−41° (c=0.95, CHCl3), MS (−ESI): 425.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:33])([F:32])[S:28](Cl)(=[O:30])=[O:29]>CC(C)=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][S:28]([C:27]([F:33])([F:32])[F:26])(=[O:30])=[O:29])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-1-indanone (20.93 g., 0.07 mole), anhydrous potassium carbonate (25.99 g., 0.188 mole) and dry acetone (350 ml) are stirred at room temperature and treated with trifluoromethane sulfonyl chloride (12.70 g., 0.0754 mmole) in portions. Reaction is complete in about 15 minutes after the completion of the addition. The mixture is filtered and evaporated to dryness. The residue is dissolved in methylene chloride, the solution dried (MgSO4) and evaporated under vacuum to an oil giving 28.45 g. (94%),
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:4]=1[C:5]#[N:6].Cl.N1C=CC=CC=1.O>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:4]=1[C:5]#[N:6]
Reactant: COc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1c(O)cccc1[N+](=O)[O-]
Temperature: 200 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-Methoxy-6-nitrobenzonitrile (Example 1290 (10.73 g, 60.2 mmol) and pyridine hydrochloride (16.0 g, 138 mmol) were mixed together as solids under nitrogen, and then heated in a preheated oil bath at 200° C. for 40 min. After cooling to room temperature, water (200 mL) and CH2Cl2 (200 mL) were added and stirred vigorously for 1 hour. Then, the precipitated product was collected by filtration and recrystallized from water, to give 8.2 g, (83%) of 2-hydroxy-6-nitrobenzonitrile as a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.13 (broad s, 1H), 7.68-7.79 (m, 2H), 7.39-7.44 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].ClC1C=CC=CC=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCCC1
Temperature: 145 °C
Reaction time: 20 h
Yield: 285.5 %

Procedure:
2-fluoro-4-nitrophenol (36.73 g, 0.234 mol) was added to a dried chlorobenzene (5 v/w, 250 mL). The mixture was heated to 145° C. Intermediate VII (12.5 g, 0.039 mol) was added to the reaction solution. The reaction was conducted at this temperature for 20 h. After completion of the reaction, the solvent was evaporated off to produce a grey solid. This solid was dissolved in CH2Cl2, and washed with a satureated saturated K2CO3 solution several times. The organic layer was collected. The solvent was dried off to produce a solid, which is recrystallized with ethanol to produce a yellow solid (49.16 g) in a yield of 71.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].I[CH:42]([CH3:44])[CH3:43]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([O:30][CH:42]([CH3:44])[CH3:43])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(C)C)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
0.28 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.25 g potassium carbonate are suspended in 5 ml of acetonitrile. 0.31 g of 2-iodopropane is added and the reaction mixture is heated to reflux under a blanket of nitrogen for about 16 h until the reaction is completed according to TLC analysis. The solvent is evaporated under reduced pressure, and the remaining residue is taken up in EA. The organic phase is washed with water, twice with 1 M aqueous sodium hydroxide solution and with brine, dried over MgSO4, and the solvent is removed under reduced pressure. Purification of the resulting crude product by crystallization from diethyl ether yields the title compound.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=O>>[CH3:2][O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1/[CH:6]=[CH:47]/[C:46]1[CH:45]=[C:44]([CH2:43][CH2:42][CH2:41][N:32]2[C:33](=[O:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]2=[O:30])[CH:51]=[CH:50][CH:49]=1
Reactant: COc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: COc1ccccc1/C=C/c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
2-Methoxybenzyltriphenylphosphonium bromide was coupled with phthalimide 29 to give (E)-2-(3-(3-(2-methoxystyryl)phenyl)propyl)isoindoline-1,3-dione as a white solid. Yield (0.5590 g, quant.), trans-/cis-isomer ratio 1:1. Trans-isomer: 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.88 (m, 4H), 7.52-7.65 (m, 5H), 6.69-7.41 (m, 4H), 6.57 (d, J=16.8 Hz, 1H), 3.76 (s, 3H), 3.52 (t, J=6.8 Hz, 2H), 2.48 (t, J=8.0 Hz, 2H), 1.91-1.99 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[Cl:30])=[CH:14][CH:13]=2)[C:9]#[N:10])=[C:4](F)[CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:23]([Cl:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=3[Cl:28])=[CH:16][CH:17]=2)[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3F)cc2)c(Cl)c1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(-c4ccccc4Cl)cc3)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution 2-(4-bromo-2-fluorophenyl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propanenitrile (1 eq.) from step 1 and 2-chlorophenylboronic acid (2 eq.) in tert-butanol (0.16M) at room temperature was added palladium acetate/triphenyl phosphine (1:3; 0.05 eq.) and aqueous Na2CO3 (2M; 4 eq.). The mixture was stirred at 80° C. for 12 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel, eluting with Hex/Tol (55 to 65%) afforded the desired compound.