Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[N:11]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:20]/[OH:21])/[CH2:9][C:10]2[N:11]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCCn1ccnc1CC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCn1ccnc1C/C(=N\O)c1ccc(N)cc1
Yield: 65.8 %

Procedure:
A solution of 1-(4-aminophenyl)-2-(1-propylimidazol-2-yl)ethanone (600 mg) and hydroxylamine hydrochloride (223 mg) in ethanol (20 ml) was refluxed for 1 day. After the mixture was allowed to be at room temperature, and saturated sodium bicarbonate solution was added to the mixture, the mixture was extracted with ethyl acetate and washed with water and saturated brine. The mixture was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate-diisopropyl ether to give (1E)-1-(4-aminophenyl)-2-(1-propylimidazol-2-yl)ethanone oxime (419 mg) as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH3:25])[N:19]=3)[O:12]2)=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[CH3:41][N:42]1[CH:46]=[C:45]([CH2:47][CH2:48][NH2:49])[N:44]=[CH:43]1.CS(C)=[O:52]>C(N(C(C)C)CC)(C)C>[CH:18]([OH:22])=[O:52].[C:35]1([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH:26][C:4]2[N:3]=[C:2]([NH:49][CH2:48][CH2:47][C:45]3[N:44]=[CH:43][N:42]([CH3:41])[CH:46]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH3:25])[N:19]=3)[O:12]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CS(C)=O
Reactant: CCCc1noc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: Cn1cnc(CCN)c1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1noc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCc5cn(C)cn5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 85 °C

Procedure:
A mixture of Intermediate 23 (0.075 g, 0.135 mmol), and 2-(1-methyl-1H-imidazol-4-yl)ethylamine (0.085 g, 0.677 mmol) in diisopropylethylamine (0.04 ml) and DMSO (0.04 ml), in a sealed vial (e.g. Reacti-vial™) was heated at 85° C. for 40 h. A further portion of 2-(1-methyl-1H-imidazol-4-yl)ethylamine (0.085 g, 0.677 mmol) was added after the first 20 h. Purification by Autoprep. HPLC afforded the title compound after freeze drying as a cream solid (0.037 g). LC/MS system B Rt=2.71 mins, m/z=651 MH+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1C=CCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1CC[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
A mixture of 3,4-dichlorophenylboronic acid (488 mg, 2.56 mmol), bis(norbornadiene)rhodium tetrafluoroborate (14.6 mg, 0.0390 mmol) and S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25.8 mg, 0.0410 mmol) in dioxane (6.6 mL) was sparged with Ar three times and stirred at rt for 2 h. To the reaction mixture was added water (1.015 mL) followed by the addition of cyclopent-2-enone (200 mg, 2.44 mmol) and TEA (0.340 mL, 2.44 mmol). The reaction mixture was stirred at room for 18 h. The reaction mixture was diluted with DCM, washed with H2O, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography 40 g using hexanes/EtOAc (0-100% over 15 min, flow rate 40 mL/min) to give Intermediate 41A (585 mg, 2.55 mmol, 100% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.86-2.02 (1H, m), 2.18-2.38 (2H, m), 2.38-2.55 (2H, m), 2.67 (1H, dd, J=18.2, 7.4 Hz), 3.28-3.49 (1H, m), 7.09 (1H, dd, J=8.0, 2.5 Hz), 7.34 (1H, d, J=1.8 Hz), 7.41 (1H, d, J=8.3 Hz).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:25])([F:23])[F:24])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 38.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), 1-amino-2-methylpropan-2-ol (12.43 mg, 0.139 mmol), 4-methylmorpholine (37.6 mg, 0.372 mmol), and HATU (45.9 mg, 0.121 mmol) were dissolved in DMF (1 mL). It was stirred for 20 min and was then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% methanol to 100% methanol over 10 min, 20 mL/min, 220 nM, product retention=11.2 min) to provide (R/S)-2-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.036 mmol, 39.2% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.48 (1 H, s), 8.13 (2 H, d, J=8.35 Hz), 7.52-7.76 (7 H, m), 5.16 (1 H, s), 3.25 (2 H, s), 1.17 (3 H, s), 1.14 (3 H, s); HPLC peak RT=7.3 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[Cl:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:25][CH2:26][CH2:27][C:28]([NH:7][C:6]1[C:2]([Cl:1])=[N:3][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=1)=[O:29]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCCl)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 5 °C
Yield: 95.5 %

Procedure:
A 100 mL, three-neck round bottom flask was charged with 3-chloro-1-(pyridine-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) and ethyl acetate (10 mL). Sodium bicarbonate (1.08 g, 6.17 mmol) was added and the reaction mixture was cooled to 5° C. 3-Chloropropanoyl chloride (0.783 g, 6.17 mmol) was added dropwise at <20° C. The reaction was allowed to warm up to 20° C. and stirred for 2 hours, at which point thin layer chromatography analysis (Eluent: ethyl acetate) indicated that the reaction was complete. The reaction was diluted with water (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a white solid (1.40 g, 96%): mp 152-154° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.07 (d, J=2.7 Hz, 1H), 8.89 (s, 1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.23 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7, Hz, 1H), 3.90 (t, J=6.2 Hz, 2H), 2.94 (t, J=6.2 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 167.90, 147.50, 139.47, 135.46, 133.47, 125.51, 124.20, 122.47, 119.87, 40.63, 37.91; ESIMS m/z 285 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:44]1([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.C(#N)C>[F:28][C:4]1[CH:3]=[C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[S:55])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCC4)CC3)ncn2)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC#N
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h
Yield: 57.4 %

Procedure:
After dissolving 4-(azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (40 mg) in ethanol (1 ml) under a nitrogen atmosphere, D-10-camphorsulfonic acid (22.3 mg) was added and the mixture was stirred for 5 minutes. Phenylacetyl isothiocyanate (34.1 mg)-acetonitrile (0.5 ml×3) was added thereto, and the mixture was stirred for 30 minutes. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (1.5 ml) and hexane (1.5 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (33.5 mg, 61.8%) as white powder.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=O)[CH:8]=2)[CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=1.P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1.O>[OH:1][C:2]1[C:11]([C:12]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][C:21]=2[CH3:26])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][C:21]=3[CH3:26])=[O:17])[CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: Cc1ccc(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3cc(O)c(C(=O)Nc4ccc(C)cc4C)cc3c2)c(C)c1
Temperature: 90 °C
Yield: 58.9 %

Procedure:
2-Hydroxy-3,6-dihydroxycarbonylnaphthalene (11.6 g) and m-xylidine (13.3 g) were dispersed in xylene (232.2 g), followed by heating to 90° C. Phosphorous trichloride (6.0 g) was added dropwise at 90 to 100° C., and then the mixture was reacted at 140° C. for 3 hours. After the completion of the reaction, water (116.1 g) was added and the reaction solution was neutralized with sodium carbonate at 80 to 90° C. The solution was filtered at room temperature and washed in turn with xylene (116.1 g) and water (116.1 g). The resultant crystal was subjected to reflux washing using acetone (80 g) and then filtered. This operation was repeated three times, followed by drying to obtain 12.9 g of 2-hydroxy-3,6-bis(2,4-dimethylphenylaminocarbonyl)naphthalene as a white powdered crystal (melting point: 284.5-286° C.).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cu][C:14]#[N:15].[C-]#N.[Na+].C(OCC)(=O)C>O>[C:14]([C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])#[N:15]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)cc1C#N
Temperature: 195 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), copper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 123a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:46]1([CH:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:53](O)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CC#N.O>[OH:14][C:3]1[C:2]([NH:1][C:53](=[O:54])[CH:52]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:4]=1
Reactant: Nc1cnc(-c2ccccn2)nc1O
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cnc(-c2ccccn2)nc1O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-amino-2-(pyridin-2-yl)pyrimidin-4-ol (10-e) (120 mg, 0.64 mmol) in MeCN (5 ml) were added HATU (254 mg, 0.67 mmol), Et3N (130 mg, 1.28 mmol) and 2,2-diphenylacetic acid (135 mg, 0.64 mmol). The resulting mixture was stirred at room temperature for 1 hour. Then the mixture was diluted with water and followed by extraction with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC to provide compound 10-1. 1H NMR (DMSO-d6, 300 MHz): δ 12.50 (br, 1H), 9.85 (br, 1H), 8.73 (m, 2H), 8.10 (m, 1H), 8.00 (m, 1H), 7.60 (m, 1H), 7.35 (m, 10H), 5.75 (s, 1H). (M+H)+=383.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23]Cl)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:27][NH:28][CH3:29].[CH3:30][N:31](C)[CH:32]=O>>[CH3:27][N:28]([CH3:29])[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23][N:31]([CH3:32])[CH3:30])[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CNC
Reactant: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Reactant: CN(C)C=O
Product: CN(C)CC(=O)Nc1cccc2c1C(=O)c1c(NC(=O)CN(C)C)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Add 0.4 g, 1.0 mmol 1,8-bis(chloroacetamido)anthraquinone (compound 3) with 0.5 ml TEA, and 0.4 ml, 6 mmole Dimethylamine, dissolved in 20 ml dehydrated dimethylformamide (DMF). The mixture is reacted in a mini-reactor. The reaction temperature is 120° C. in the oil bath and the reaction time is 30 minutes. The reacted mixture is poured into 50 ml ice water and is filtered to collect precipitate. The precipitate is recrystallized from ethanol to get yellow compound 3m.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (47%).
Reaction SMILES: [N:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[C:18]1([CH2:24][C:25]([Cl:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[ClH:27].[N:10]1[CH:11]=[CH:12][C:7]([N:6]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[C:25](=[O:26])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccn(Nc2ccncc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cl
Product: O=C(Cc1ccccc1)N(c1ccncc1)n1cccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
To a solution of N-(1H-pyrrol-1-yl)-4-pyridinamine (6 g) in 400 ml of dichloromethane containing sodium bicarbonate (6.3 g) was added a solution of phenylacetyl chloride (6.7 g) in 50 ml of dichloromethane. After stirring four hours at ambient temperature, the reaction mixture was evaporated, stirred with water and extracted with ether. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 11 g of an oil. This oil was purified by flash chromatography (silica, 25% ethyl acetate in dichloromethane) to give 10 g of an oil. This oil was converted to the hydrochloride salt in ethanol to give 10.4 g of crystals, d 203°-205°. A 3 g sample was recrystallized from ethanol-ether to give 2.8 g of needles, d 203°-204°.
Reaction SMILES: Cl[C:2]1C(O)=C(NC(=O)C2C=C(OC)C=C(OC)C=2)C=C(Cl)C=1C.Cl.Cl.[CH2:26]([N:28]([CH2:37][CH3:38])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([CH3:36])N=1)[CH3:27].C(N(CC)CC)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.CO>[CH3:27][CH2:26][N:28]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([CH3:2])[CH:36]=1)[CH2:37][CH3:38]
Reactant: COc1cc(OC)cc(C(=O)Nc2cc(Cl)c(C)c(Cl)c2O)c1
Reactant: CCN(CC)c1ccc(N)c(C)n1
Agent: Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)c1ccc(N)c(C)c1
Temperature: 5 °C

Procedure:
Into a 250 ml erlenmeyer flask was placed 4 g (11.4 mmoles) of N-(3,5-dichloro-2-hydroxy-4-methylphenyl)-3,5-dimethoxybenzamide, 3.15 g (12.5 mmoles) N2,N2-diethyl-6-methyl-2,5-pyridinediamine dihydrochloride and 100 ml of methanol. A suspension resulted. To this suspension was added 7.84 g (77.5 mmoles) of triethylamine. The suspension became a solution. The reaction flask was cooled via an ice/water bath to about 5° C. While the reaction mixture was cooling, 5.7 g (25 mmoles) of ammonium persulfate was dissolved in 12 mL of water. This solution was added dropwise to the reaction vessel. The mixture got so thick during the addition that an additional 100 ml of methanol needed to be added. After complete addition of the ammonium persulfate, the mixture was stirred at 5° C. for 2½ hours. The solid was collected on a medium sintered glass funnel, rinsed with methanol then 2 times with 45° C. water and finally ligroin and then air dried by sucking air through the funnel overnight. 5.2 g of desired product was collected. The collected product was returned to a 125 ml erlenmeyer flask 75 ml of ethanol was added. The mixture was heated to reflux on a hot plate for 5 minutes and allowed to cool to 45° C. A solid was then collected on a medium sintered glass funnel and dried by sucking air through the funnel overnight. The yield was 4.8 g (85% purified yield) of desired dye, with an absorbance maximum of 630 nm, and an extinction coefficient of 24,565.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Cl.Cl[C:13]1[CH:33]=[CH:32][CH:31]=[C:30](C)[C:14]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([OH:28])=[O:27])[CH:23]=2)[C:18]([CH3:29])=[N:17]1>>[CH3:29][C:18]1[C:19]2[C:24](=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)[N:16]([CH2:4][C:3]2[C:2]([CH3:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=2[CH3:11])[N:17]=1.[CH2:15]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([OH:28])=[O:27])[CH:23]=2)[CH:18]=[CH:29]1)[C:14]1[CH:13]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Product: Cc1cc(C)c(Cn2nc(C)c3ccc(CC(=O)O)cc32)c(C)c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1

Procedure:
The titled compound (10.3 mg) as a white solid was prepared from the compound [102-4] obtained in the process (4) of Example 102 (21.2 mg) and 2,4,6-trimethylbenzyl chloride according to the method of the process (5) of Example 102.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH2:25][O:26][CH2:27][C:28]#[CH:29])=[C:15]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:35](=[O:37])=[O:36]>CCCCCC.O1CCCC1>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH2:25][O:26][CH2:27][C:28]#[C:29][C:35]([OH:37])=[O:36])=[C:15]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: O=C=O
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1=C(COCC#CC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
A 1.6M solution of n-butyllithium in hexane (45 ml) was added dropwise to a solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (132 g) in tetrahydrofuran (1 l.) keeping the temperature below -40°. The mixture was stirred at -60° for 2 hours and then carbon dioxide gas was passed through the solution for 30 minutes with cooling in an acetone/cardice bath. The mixture was allowed to warm to 0° while the passage of carbon dioxide gas was continued and then quenched with water (1 l.) and the layers separated. The aqueous layer was extracted into ether (500 ml) and the combined organic layers were washed with water, diluted with dichloromethane, washed with 1M HCl, dried over MgSO4 and evaporated. The residue was triturated with methanol and the resulting solid collected, washed with cold (-20°) methanol and dried to give 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}but-2-ynoic acid, (83.7 g), m.p. 150°-152°.