Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]([CH3:35])[S:30][C:31]=2[C:32](O)=[O:33])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]=[C:29]([CH3:35])[S:30][C:31]=2[C:32]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:33])=[CH:25][CH:26]=1
Reactant: Cc1nc(-c2ccc(F)cc2)c(C(=O)O)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc(-c2ccc(F)cc2)c(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic Acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 4-(4-Fluoro-phenyl)-2-methyl-thiazole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]=2)[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
To a solution of 6-bromo-2-naphthol (3.00 g, 13.5 mmol) in 67 ml of methylene chloride were added 4-dimethylaminopyridine (0.164 g, 1.34 mmol) and t-butyldimethylsilyl chloride (2.64 g, 17.5 mmol). The solution was cooled to 0° C. and triethylamine (2.60 ml, 18.7 mmol) was added. After 1.5 hours the reaction mixture was diluted with ethyl acetate and washed successively with saturated NH4Cl, H2O, and brine. Drying (MgSO4), evaporation, and purification by flash chromatography through 130 g of silica gel (1:4 CH2Cl2 /hexane) yielded 3.83 g (85%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.[C:24](OCC)(=[O:26])C>CO.CCCCCC>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:26][CH3:24])[CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(Br)cc2CN1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc2c(c1)CN(Cc1ccccc1)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 2-benzyl-5-bromo-2,3-dihydro-isoindol-1-one (0.065 g, 0.22 mmol), 30% sodium methoxide-methanol (0.06 mL, 0.33 mmol), and CuBr (0:004 g, 0.03 mmol) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-5-methoxy-2,3-dihydro-isoindol-1-one (0.03 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.86 (s, 3H), 4.22 (s, 2H), 4.78 (s, 2H), 6.82-7.29 (m, 7H), 7.79 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]2[C@@H:11]([CH2:12][CH3:13])[CH2:14][O:15][C:29]2=[O:31])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:19]([CH3:26])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=1[CH3:24]
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H]1COC(=O)N1c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester (106 mg, 0.27 mmol), triphosgene)27 mg, 0.090 mmol), triethylamine (27 mg, 0.27 mmol) in dry THF was stirred at room temperature for 2 hr. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 13.6 g of crude product as a white glass foam. The foam was triturated with hexane/diethyl ether to give a white solid, mp. 144–145.5° C., Anal. For C21H23ClN2O5 calc.: C, 60.22; H, 5.53; N, 6.69; found: C, 60.10, H, 5.79; N, 6.66.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([CH2:28][P:29](=[O:37])([O:33][CH:34]([CH3:36])[CH3:35])[O:30]CC)=[CH:26][C:25]=3[O:40][CH3:41])[N:14]=2)=[CH:4][CH:3]=1.[I-].[Na+]>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([CH2:28][P:29](=[O:30])([OH:37])[O:33][CH:34]([CH3:35])[CH3:36])=[CH:26][C:25]=3[O:40][CH3:41])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OC(C)C
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(O)OC(C)C)cc2OC)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of ethyl propan-2-yl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 72C, 550.0 mg, 0.83 mmol) in pyridine (5.50 mL) was charged with sodium iodide (748 mg, 4.99 mmol). The reaction was heated at 120° C. for 24 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:33]([CH3:34])[CH:8]2[CH2:9][C:10]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[CH:31][N:30]=[CH:29]5)=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])([CH3:12])[O:11][C:7]2=[C:6]([CH3:35])[C:5]=1[CH3:36])([O-])=O.C(O)C.C(O)(=O)C.[OH-].[Na+]>[C].[Pd].O>[NH2:1][C:4]1[CH:33]([CH3:34])[CH:8]2[CH2:9][C:10]([NH:13][C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[CH:31][N:30]=[CH:29]5)=[CH:24][CH:23]=4)[CH2:20][CH2:21]3)=[O:15])([CH3:12])[O:11][C:7]2=[C:6]([CH3:35])[C:5]=1[CH3:36]
Reactant: CC1=C2OC(C)(NC(=O)N3CCN(c4ccc(-n5ccnc5)cc4)CC3)CC2C(C)C([N+](=O)[O-])=C1C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC1=C(N)C(C)C2CC(C)(NC(=O)N3CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
In an autoclave, 0.88 g of (±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-yl)-[4-(4-imidazol-1-ylphenyl)-piperazin-1-yl]carboxamide and 0.5 g of 10% palladium carbon, 10 ml of ethanol and 5 ml of acetic acid were added, followed by stirring overnight under a hydrogen pressure of 10 kg/cm2. The reaction solution was poured into water, neutralized with a 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol=10:1) to obtain 0.56 g of the objective product (melting point: 189-191° C.).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>C(O)CCC>[CH3:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[NH:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1
Reactant: Clc1nncc2ccccc12
Reactant: Cc1cccc(N)c1
Agent: Cl
Solvent: CCCCO
Product: Cc1cccc(Nc2nncc3ccccc23)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Under a N2 atmosphere, 30 g (149 mmol) 1-chlorophthalazine hydrochloride in 0.6 l n-butanol is mixed with 16.2 ml (149 mmol) m-toluidine and stirred for 1 h at 65° C. The solution is concentrated by evaporation and the residue distributed between dichloromethane/MeOH 10:1 and Na2CO3 solution (80 g in 0.5 l H2O). The aqueous phase is extracted twice with dichloromethane/MeOH 10:1, the organic phases are washed with Na2CO3 solution (80 g in 0.5 l H2O) and brine, dried (Na2SO4) and evaporated. The residue is taken up in 200 ml boiling dichloromethane/acetone 1:1, filtered hot, and partly evaporated. Then addition of DIPE leads to crystallization of the title compound, which is filtered off and washed with DIPE: m.p. 176-177° C.; 1H-NMR (DMSO-d6) 9.12 (s, HN), 9.08 (s, 1H), 8.59 (m, 1H), 7.99 (m, 3H), 7.76 (s, 1H), 7.73 (d, 1H), 7.24 (t, 1H), 6.86 (d, 1H), 2.32 (s, 3H); FAB-MS (M+H)+=236; an. calc.(C15H13N3·0.05 H2O) C, 76.28%; H, 5.59%; N, 17.79%; meas. C, 76.04%; H, 5.53%; N, 17.68%.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:32][N:33]([CH:41]=[O:42])[O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C:8]([N:10]2[CH:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC=C)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCOCC1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:6][C@H:7]([CH2:32][N:33]([CH:41]=[O:42])[O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCOC(=O)N1CCC(C(=O)Nc2ncc(OC)cn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: COc1cnc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Pd(Ph3P)4 (23.77 mg, 0.021 mmol) was added to a solution of 2-propen-1-yl 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-({[5-(methyloxy)-2-pyrimidinyl]amino}carbonyl)-1-pyrazolidinecarboxylate (173 mg, 0.294 mmol) and morpholine (81 μl, 0.935 mmol) in dichloromethane (DCM) (4.1 ml). The mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure to give a crude product which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-N-[5-(methyloxy)-2-pyrimidinyl]-3-pyrazolidine carboxamide (67 mg, 0.133 mmol, 45% yield). MS (ES+) m/z 505.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.2 %

Procedure:
Methyl 4-hydroxysalicylate (20.0 g, 119 mmol) was dissolved in DMF (400 ml), then potassium carbonate (17.2 g, 125 mmol) and benzyl bromide (21.4 g, 125 mmol) were added, using additional DMF (400 ml) to aid the transfer. Potassium iodide (3.0 g) was added, and the reaction mixture was stirred at room temperature under nitrogen for 48 h. The DMF was removed in vacuo, the residue taken up in EtOAc, washed with water (3×), brine, and dried. The organic layer was concentrated in vacuo, and the crude product recrystallized from EtOAc:hexane to give 17.9 g (61.1%) of a white solid. A second recrystallization of material recovered from the filtrate yielded an additional 6.2 g (21.2%) of product.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:40]([NH:42][CH3:43])=[O:41])[CH:38]=5)[C:33]([CH3:44])=[CH:32][C:31]4=[O:45])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:46].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:40]([NH:42][CH3:43])=[O:41])[CH:38]=5)[C:33]([CH3:44])=[CH:32][C:31]4=[O:45])[CH2:24][CH2:23]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: CNC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 5.5 h

Procedure:
To 0.5 mL of methanol solution containing 58 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-7-((methylamino) carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 5.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.032 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-N-methyl-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxamide hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][C:3]=1[F:28].ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:48])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][C:3]=1[F:28]
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)c(F)c3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)c(F)c3)c[nH]c12

Procedure:
The title compound was prepared starting from 75 mg (0.18 mmol) of the compound from Example 283 in analogy to the synthesis of the compound from Example 296. 76 mg (98% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28]([O:34][CH3:35])[CH:27]=1>>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([F:1])[CH:3]=2)=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: NNC(=O)c1ccc(O)c(F)c1
Reactant: COc1cc(OCCN2CCc3ccccc3C2)ccc1C=O
Product: COc1cc(OCCN2CCc3ccccc3C2)ccc1C=NNC(=O)c1ccc(O)c(F)c1
Yield: 29.8 %

Procedure:
This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above 4-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.13 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([OH:20])=O)[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].[CH3:25]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:54][C:55]1[CH:56]=[CH:57][C:58]2[O:62][CH:61]([CH2:63][N:64]3[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[CH2:60][C:59]=2[CH:70]=1>ClCCl>[F:54][C:55]1[CH:56]=[CH:57][C:58]2[O:62][CH:61]([CH2:63][N:64]3[CH2:65][CH2:66][N:67]([CH2:25][C:18](=[O:20])[CH2:17][O:16][CH:13]4[CH2:12][CH2:11][CH:10]([NH:9][C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:21]([F:23])([F:22])[F:24])[CH:5]=5)[CH2:15][CH2:14]4)[CH2:68][CH2:69]3)[CH2:60][C:59]=2[CH:70]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Fc1ccc2c(c1)CC(CN1CCNCC1)O2
Reactant: N#Cc1ccc(NC2CCC(OCC(=O)O)CC2)cc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCC(OCC(=O)CN3CCN(CC4Cc5cc(F)ccc5O4)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (216 mg, 0.63 mmol, 1.5 eq) in dichloromethane (25 ml) was added EDAC.HCl (122 mg, 0.64 mmol, 1.5 eq), HOBt (86 mg, 0.64 mmol, 1.5 eq), triethylamine (128 mg, 1.26 mmol, 3 eq) and 1-[(5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (100 mg, 0.42 mmol) at room temperature. The solution was stirred at room temperature overnight, diluted with dichloromethane (150 ml), and washed with water (80 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 1-2% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 4-[[4-(3-[4-[(5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-oxopropoxy)cyclohexyl]amino]-2-(trifluoromethyl)benzonitrile as a white solid (0.18 g, 69%); (ES, m/z): [M+H]+ 561.20; 1H NMR (300 MHz, CDCl3): δ 7.56 (d, J=8.7 Hz, 1H), 6.81-6.92 (m, 3H), 6.64-6.71 (m, 2H), 5.13 (broad s, 1H), 4.29 (d, J=7.8 Hz, 1H), 4.21 (s, 2H), 3.67-3.77 (m, 3H), 3.34-3.47 (m, 3H), 2.92-2.99 (dd, J=˜8.1 Hz, ˜15.9 Hz, 1H), 2.51-2.89 (m, 5H), 2.15-2.25 (broadened d, J=9.9 Hz, 4H), 1.41-1.48 (m, 3H), 1.21-1.32 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=[CH:5]2.[CH:20]([B-](F)(F)F)=[CH2:21].[K+].C(N(CC)CC)C.O>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:20]=[CH2:21])[CH:8]=2)[CH:3]=1
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Reactant: C=C[B-](F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: C=Cc1ccc2cc(Br)ccc2c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester (2) (3.0 g, 8.45 mmol), potassium vinyltrifluoroborate (1.4 g, 11.83 mmol) in EtOH (84 mL) and a 1.0 M aqueous solution of cesium carbonate (17 mL) was purged with nitrogen, to the mixture was added tetrakis(triphenylphosphine)palladium (244 mg, 0.2 mmol) followed by triethylamine (2.3 mL, 17 mmol). The mixture was heated to 45° C. for 16 h under nitrogen and cooled to room temperature. To the mixture was added H2O (84 mL), the resulting suspension was stirred at room temperature for 30 min. and filtered. The wet cake was washed with H2O (30 mL) and dried in the vacuum oven at 45° C. for 16 h to give 1.9 g product. The product is used in the next step without further purification. 1H NMR (400 MHz, CDCl3) d 7.86 (d, 1H), 7.54–7.61 (m, 4H), 7.42–7.44 (dd, 1H), 6.73–6.80 (dd, 1H). 13C NMR (400 MHz, CDCl3) d 136.18, 135.12, 133.77, 131.62, 129.42, 129.32, 129.29, 126.93, 125.84, 124.00, 119.55, 114.54. [M+H]+ at m/z 233.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N+:26]([O-:28])=[O:27]>O>[N+:26]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:13]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[C:17]([O:19][CH3:20])=[O:18])([O-:28])=[O:27]
Reactant: COc1ccc(O)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(OC)cc2)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 65.6 %

Procedure:
To a 100 ml round-bottomed flask containing potassium hydroxide (4.7 g; 82.0 mmol) dissolved in water (20 ml) was successively added 4-methoxyphenol (10.0 g; 80.6 mmol) and methyl 4-chloro-3,5-dinitrobenzoate (20.2 g; 77.5 mmol). The flask was fitted with a reflux condenser and the reaction heated at 150° C. (oil bath) for 3 hours. After cooling to room temp, the reaction mixture was transferred to a large mortar and triturated with cold 2N NaOH (100 ml) to remove unreacted phenol. The solid was collected by filtration and air-dried to give 21.5 g of crude product. Crystallization from absolute ethanol gave 17.7 g (65.6%) of pure methyl 3,5-dinitro-4-(4-methoxyphenoxy)benzoate as light yellow needles. 300 MHz 1H NMR (CDCl3) d 3.77 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.82 (m, 4H, ArH), 8.70 (s, 2H, ArH).
Reaction SMILES: [Cl:1][O-].[Na+].[C:4]([C:7]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)(=[O:6])[CH3:5].C(O)(=O)C>CO.O>[C:4]([C:7]1[CH:16]=[C:15]([Cl:1])[C:14]([OH:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)(=[O:6])[CH3:5]
Reactant: CC(=O)c1ccc(O)c2ncccc12
Reactant: [O-]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)c1cc(Cl)c(O)c2ncccc12

Procedure:
350 ml of a 14% strength sodium hypochlorite solution are added dropwise to a suspension of 94 g of 5-acetyl-8-hydroxyquinoline in 1 litre of methanol and 1 litre of water at 10°-20°C, whilst stirring well. After stirring for a further hour, the mixture is acidified with 60 ml of glacial acetic acid and diluted with 1 liter of water, and the product is filtered off. The filter residue is washed with water and recrystallised, whilst still moist, from alcohol. 70 g of almost colourless 5-acetyl-7-chloro-8-hydroxyquinoline are obtained, melting point 163°-166° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([NH2:34])[N:28]=2)=[CH:22][CH:21]=1.N>O1CCOCC1>[NH2:34][C:29]1[N:28]=[C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:21][CH:22]=2)[CH:32]=[C:31]([CH3:33])[N:30]=1
Reactant: Cc1cc(Nc2ccc(N)cc2)nc(N)n1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2)nc(N)n1
Temperature: 50 °C
Yield: 46.7 %

Procedure:
4-Nitrobenzoyl chloride (11.00 g, 0.06 mol) and dry pyridine (9.08 mL, 0.11 mol) were sequentially added to a solution of amine E3 (4.85 g, 0.02 mol) in dry dioxane (200 mL), and the resulting solution heated at ˜50° C. for 5 d. After this time, the reaction mixture was cooled to room temperature, and then basified by addition of aqueous ammonia solution. The resulting suspension was filtered through a pad of Celite to afford amide E4 as an amorphous yellow solid (3.40 g, 41%). 1H NMR [(CD3)2SO]: 2.09 [s, 3H, ArCH3], 5.87 [s, 1H, ArNHAr], 6.08 [br s, 6.08, ArNH2], 7.68 [m, 4H, ArH], 8.18 [d, J=8.80 Hz, 2H, ArH], 8.36 [d, J=8.80 Hz, 2H, ArH], 8.95 [s, 1H, ArH], 10.45 [s, 1H, ArC(O)NHAr]. LCMS (APCl+): 365 (100%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.CN(C)C=O.Cl[CH2:17][Cl:18].[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[Cl:18][C:17]1[C:20](=[CH:19][OH:25])[CH2:21][CH2:22][CH2:23][C:24]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: O=C1CCCCC1
Reactant: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)C(=CO)CCC1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Dimethylformamide (40 mL) and 40 mL dichloromethane were mixed and cooled to 5° C. Phosphorous oxychloride (37 mL) was dissolved in 40 mL dichloromethane and added dropwise to the dimethylformamide/dichloromethane solution at rate to maintain the temperature below 25° C. Cyclohexanone (10 g, 0.102 mol) was added and the mixture heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was poured into 200 mL of ice and allowed to sit overnight. The quenched reaction mixture was filtered to collect 3.59 g solid, mp 127° C., λmax =325 nm (ε=14,000).