Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[C:14]=3[Cl:22])[C:5]2=[N:4][C:3]=1[CH3:23].N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>ClCCl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:31]([O:33][C:34]4[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=4)=[O:32])[C:14]=3[Cl:22])[C:5]2=[N:4][C:3]=1[CH3:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)Oc4ccc([N+](=O)[O-])cc4)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 3-bromo-8-(2,6-dichloro-3-methylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine (68 mg) and pyridine (0.5 ml) in dichloromethane (2 ml) was added 4-nitrophenyl chloroformate (40 mg) at ambient temperature. After stirring for 1 hour, the mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane twice. The organic layers were combined, washed with water twice and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(4-nitrophenoxycarbonyl) amino]benzyloxy]-2-methylimidazo-[1,2-a]pyridine (84 mg) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[N:13]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Yield: 98.9 %

Procedure:
2-Amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (7.96 g, 15.4 mmol) and hydrazine hydrate (3.85 g, 77.0 mmol) in ethanol (250 ml) was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the solid residue was extracted with diethyl ether (3×200 ml). The fractions were combined and the solvent removed in vacuo to give 5.9 g (100%) of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15].[C:17]([O-])(O)=O.[Na+]>CO>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[Br:6]
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccccc1Br
Temperature: 25 °C

Procedure:
2 mL H2SO4 is added to (2-bromo-phenyl)-acetic acid (15 g, 70 mmol) in 150 mL methanol. The reaction mixture is refluxed 16 hours and cooled to room temperature. 100 mL saturated NaHCO3 (aq) is added. Methanol is removed in vacuo. The resulting mixture is extracted with Ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:9][CH:10]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-(4-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:11]([OH:13])=O)[NH:9][N:10]=1.[NH2:14][C@@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:11]([C:8]3[NH:9][N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[O:13])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2ccco2)n[nH]1
Yield: 16.97 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 5-(2-furyl)-2H-pyrazole-3-carboxylic acid (3.42 g, 19.18 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (5 g, 19.18 mmol). The product was purified by flash chromatography and recrystallization from acetonitrile, respectively. Yield 16.97%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 4.30 (dd, 1H), 4.42 (dd, 1H), 4.53-4.63 (m, 1H), 6.50 (dd, 1H), 6.62 (d, 1H), 6.67 (d, 1H), 6.94 (s, 1H), 7.48 (dd, 1H), 7.53 (d, 1H), 7.68 (d, 1H), 7.73-7.84 (m, 2H), 8.02 (s, 1H), 13.70 (broad s, 1H).
Reaction SMILES: Cl(O)(=O)=O.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6]>[Zn].C(O)(=O)C>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[Cl:18])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Cl
Agent: [O-][Cl+2]([O-])O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(N)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To an acetic acid (7 ml) and conc. chloric acid (2 ml) solution of 1-tert-butyl-2-chloro-4-nitrobenzene (1.67 g, 7.8 mmol) was added zinc powder (4.1 g, 62 mmol) at 60° C. The reaction mixture was stirred at 60° C. for 1 hour. Zinc powder was filtered off and washed with H2O. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and then the organic layer washed with saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=¼ to furnish 0.7 g (48% yield) of the title compound as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[C:26]12([NH2:36])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:36][C:26]34[CH2:27][CH:28]5[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]5)[CH2:35]3)[CH2:33]4)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NC34CC5CC(CC(C5)C3)C4)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.078 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:9][C:5]1[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=1)(=[O:21])=[O:20]
Reactant: COc1nc(Cl)c(Cl)nc1N
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1ccccc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g0 and 2-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.096 g.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1.N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)c1cc(N)no1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)c2ccccc2)no1

Procedure:
To a solution of 3-amino-5-t-butylisoxazole in benzene, benzoyl chloride and pyridine are added, whereby the reaction is carried out. Thus 3-benzoylamino-5-t-butylisoxazole is obtained as crystals melting at 192° to 193° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:36])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[N:24][C:23]=3[Cl:35])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.Cl>[Cl-].C([N+](CC)(CC)CC)C.CCOC(C)=O>[C:42]([C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:36])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[CH:25]=[N:24][C:23]=3[Cl:35])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1)(=[O:44])[CH3:43]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (500 mg, 0.814 mmol), tetraethylammoniumchloride (409 mg, 2.442 mmol) and dichlorobistriphenyl phosphinepalladium(II) (57.1 mg, 0.081 mmol) was added tributyl[1-(ethyloxy)ethenyl]stannane (0.302 mL, 0.894 mmol) and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to RT, diluted with EtOAc and washed with water. The solvent was evaporated and the residue was dissolved in THF (7.00 mL) and HCl (1.0 M solution) (4 mL, 4.00 mmol) was added. The resulting mixture was stirred for 4 hours at RT. EtOAc was added and the organics were separated. The solvent was removed and the crude material was purifed via silica gel chromatography to give N-({3-[(3-acetyl-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (384 mg, 0.665 mmol, 82% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.08 (s, 1H), 7.90 (s, 1H), 7.70 (s, 1H), 7.33-7.49 (m, 3H), 5.59 (s, 2H), 4.61 (s, 2H), 3.49 (t, 2H), 2.60 (s, 3 H), 0.83 (t, 2H), −0.12-0.01 (m, 9H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[NH3:17]>CC(C)=O>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13]([NH2:17])(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Reactant: N
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25.3 g (0.1 mol) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfonyl chloride are dissolved in a little acetone and slowly added dropwise to 100 ml of concentrated ammonia solution at room temperature. The mixture is stirred at room temperature for 30 minutes and then poured onto ice-water. After acidification with concentrated hydrochloric acid, the product is filtered off with suction. Isopropanol is used for recrystallization. White crystals of melting point 156°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=3[N+:22]([O-])=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.O1CCCC1>[Pd].C(OCC)(=O)C>[NH2:22][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
A mixture of 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-nitrobenzoic acid (0.600 g), 5% palladium on carbon (0.600 g), tetrahydrofuran (30 ml) and ethyl acetate (30 ml) was stirred under a hydrogen atmosphere at room temperature and normal pressure for 30 min. Palladium on carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1, volume ratio) to give 3-amino-4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (0.15 g, yield 28%). Recrystallization from hexane-tetrahydrofuran gave yellow prism crystals. melting point: 294–296° C. (decomposition).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:20][C:21]1([F:29])[CH2:25][NH:24][C@@H:23]([C:26]([NH2:28])=[O:27])[CH2:22]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([N:24]3[CH2:25][C:21]([F:29])([F:20])[CH2:22][C@H:23]3[C:26]([NH2:28])=[O:27])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: NC(=O)[C@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 719267-96-6) as starting materials and isolated (33 mg, 44%); MS (ESI, m/z): 394.5 (M+H+).
Reaction SMILES: [OH-].[K+].Cl.[C:4]([NH2:12])(=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:12]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C(C=Cc1ccccc1Br)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccccc1-c1cc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
23 g (409 mmol) of potassium hydroxide are dissolved in 500 ml of ethanol, 40 g (255 mmol) of benzamidine hydrochloride 2 and 129 g (452 mmol) of (3-(bromophenyl)-1-phenyl-2-propen-1-one 1, dissolved in 500 ml of ethanol, are added at room temperature, and the mixture is stirred under reflux for 3 h. After cooling to room temperature, the precipitated solid is filtered off with suction, washed with a little ethanol and dried, leaving 55 g (129 mmol), 50%, of the product in the form of colourless crystals.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:28][O:29][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14]([CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:13]3=[O:27].[OH-].[Li+].Cl>O1CCCC1.O>[O:27]=[C:13]1[C:12]2([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[CH:7][C:8]=3[O:29][CH2:28]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][O:23]1
Reactant: COC(=O)COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of methyl({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)acetate (0.51 g, 1.25 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was added lithium hydroxide (0.05 g, 1.62 mmol). The reaction mixture was stirred at ambient temperature for 16 h. To the reaction mixture was added 1 N HCl to adjust pH<2, then extracted with ethyl acetate (2×50 mL). The combined organic solution was washed with water and brine, then dried over sodium sulfate, filtered and concentrated to afford ({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)acetic acid (0.42 g, 85%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 1H), 7.15-7.00 (m, 3H), 6.64 (d, J=8.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 6.40-6.34 (m, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.59 (s, 2H), 4.35-4.24 (m, 1H), 3.99-3.68 (m, 4H), 2.10-1.86 (m, 3H), 1.79-1.65 (m, 1H); MS (ES+) m/z 396.0 (M+1), 417.9 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CN(C=O)C.O>[C:16]([O:20][C:21](=[O:22])[NH:23][CH2:24][C:25](=[O:26])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a mixture of 4-fluoro-2-phenylaminoaniline (3.0 g, 14.85 mmol), tert-butoxycarbonyl glycine (2.4 g, 15 mmol) and HOAt (0.68 g, 5 mmol) in DCM (20 mL) and DMF (1 mL) at 0° C. was added EDCI (2.88 g, 15 mmol). The mixture was stirred at 0° C. for 1 h. To the reaction mixture was added a saturated aqueous solution of NaHCO3 (20 mL), saturated aqueous solution of Na2CO3 (10 mL) and water (10 mL). The mixture was extracted with DCM (2×20 mL) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% MeOH in DCM) to afford the title compound as a brown gum, (4.79 g, 89%). 1H NMR δ (ppm) (CHCl3-d): 7.95 (1H, s), 7.50 (1H, dd, J=8.83, 5.91 Hz), 7.32-7.22 (2H, m), 6.98-6.97 (4H, m), 6.68 (1H, dt, J=8.6, 2.7 Hz), 6.05 (1H, s), 5.06 (1H, s), 3.89 (2H, d, J=5.92 Hz), 1.42 (9H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C)[C@@H](N1CC2C(=CC(C3C=CC([N+]([O-])=O)=CC=3)=CC=2)C1=O)C(OC)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Product: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 539 was prepared analogous to the compound of example 6 by reduction of the compound of example 538.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20].[Cl-]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-aminophenylacetic acid (3.0 g, 19.8 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (4.00 g, 1.74 mL, 19.8 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the chloride was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water. The resulting precipitate was filtered, washed with water, add then dried in a vacuum dessicator overnight to afford 2.75 (51%) of the title compound as a pale yellow crystals, mp 168°-171° C.: 1H NMR (DMSO-d6) δ12.28 (bs, 1H), 10.36 (s, 1H), 7.50 (d, J=8.8, 2H), 7.20 (d, J=8.4, 2H), 4.02 (s, 2H), 3.51(s, 2H); 13C NMR (DMSO-d6) δ172.70, 164.65, 137.12, 130.45, 129.76, 119.12, 40.12, 30.40; MS (EI, m/z) 271 (M+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:16]=1)[CH2:12][CH3:13])(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH2:12][CH3:13]
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1cccc(-c2nc(Cl)ncc2F)c1
Reactant: NCCc1ccc(O)cc1
Product: CCN(CCCN)Cc1cccc(-c2nc(NCCc3ccc(O)cc3)ncc2F)c1

Procedure:
Intermediate 78 was coupled with tyramine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 424. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.29 (d, 1H), 8.19 (s, 2H), 7.66 (m, 2H), 7.05 (d, 2H), 6.68 (d, 2H), 4.49 (s, 2H), 3.58 (t, 2H), 3.24 (m, 4H), 2.98 (t, 2H), 2.80 (t, 2H), 2.07 (m, 2H), 1.36 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[O:14][CH2:15][C:16](=[O:23])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1.N1CCCCC1>CC(O)C>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27]([CH:34]=[C:15]2[O:14][C:13]([NH:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:24])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:26]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2OCCN(C)C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(Nc2ccccc2OCCN(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 21.6 %

Procedure:
To a solution of ethyl 2-({2-[2-(dimethylamino)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.010 g, 0.031 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0042 g, 0.029 mmol) in 2-propanol (0.3 mL), piperidine (0.00028 mL, 0.0028 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.0029 g, y. 22%).