Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]#[N:25])[CH:3]=3)[O:8][CH:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:10]2)[N:12]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CC(c3ccncc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccncc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 14.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (20 mg, 0.053 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (14.8 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (3 mg, 10%). 1H-NMR (MeOD): 2.24 (m, 1H), 3.01 (m, 1H), 3.39 (t, 3H), 5.54 (d, 1H), 7.19 (m, 1H), 7.60 (m, 1H), 7.62 (t, 1H), 7.69 (m, 1H), 7.89 (m, 3H), 8.02 (, 2H), 8.70 (s, 2H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([OH:20])[CH:19]=1.[CH:24]1(O)[CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH:29]1([O:20][C:18]2[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[N+:21]([O-:23])=[O:22])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1
Reactant: OC1C=CCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1C=CCCC1
Temperature: 25 °C

Procedure:
1.89 ml DEAD were added to an ice-cooled solution of the 1.57 g 5-Fluoro-2-nitrophenol, 1.18 ml 2-cyclohexenol and 3.15 g triphenylphosphin in methylene chloride. The reaction mixture was stirred and allowed to warm to rt overnight. The solvent was removed in vacuo. Purification is achieved by silica gel column chromatography with iso-hexane/EtOAc (gradient: 100% i-hexane→10:1 i-hexane/EtOAc).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH:6]([NH:8][C:9](=[O:14])[C:10]([O:12]C)=O)[CH2:5][C:4]([CH3:16])([CH3:15])[NH:3]1.[C:18]([C:22]1[CH:23]=[C:24]([CH2:33][CH2:34][C:35]([NH:37][NH2:38])=[O:36])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])([CH3:20])[CH3:19]>CO>[CH3:17][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9](=[O:14])[C:10]([NH:38][NH:37][C:35](=[O:36])[CH2:34][CH2:33][C:24]2[CH:25]=[C:26]([C:29]([CH3:30])([CH3:32])[CH3:31])[C:27]([OH:28])=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:23]=2)=[O:12])[CH2:5][C:4]([CH3:16])([CH3:15])[NH:3]1
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: COC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NNC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC(C)(C)N1

Procedure:
Into a 3-necked 100 ml flask was introduced methyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate (4.85 g, 0.02 mole) and 50 ml of methanol. The flask was equipped with a magnetic stirrer, a thermometer and a reflux condenser. The mixture was stirred until all of the solid material dissolved, following which 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionhydrazide (5.85 g, 0.02 mole) was added and the mixture was refluxed for 2 hours. The solid material was filtered off and air dried. The product weighed 2.7 g and had a melting range of 255°-257° C. The infrared scan of the product contained strong carbonyl bands at 1655, 1620, 1590 and 1490 cm-1.
Reaction SMILES: C(O[C:6](=[O:24])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29](C(OCC)=O)[C:30](OCC)=[O:31])[CH3:26]>>[CH2:25]([O:27][C:28]([C:29]1[C:6](=[O:24])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:30]=1[OH:31])=[O:40])[CH3:26]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(C(F)(F)F)c2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from starting materials (3-trifluoromethyl-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 381 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N

Procedure:
Prepared from (2′,4′-difluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B15) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a light yellow solid (1.77 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:18]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:19])[CH2:13][CH2:12]1.[CH:32]1([N:38]=[C:39]=[S:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCCl>[CH:32]1([NH:38][C:39](=[S:40])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH2:15][CH2:16]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCCc3ccccc3N)CC2)cc1
Reactant: S=C=NC1CCCCC1
Solvent: ClCCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCCc3ccccc3NC(=S)NC3CCCCC3)CC2)cc1
Yield: 43.7 %

Procedure:
To a solution of N-[1-[3-(2-aminophenyl)propyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (0.42 g) dissolved in 1,2-dichloroethane (5 mL) was added cyclohexyl isothiocyanate (0.42 g) at room temperature. The solution was then heated under reflux for 8 hours. The solution was purified by chromatography [silica gel, dichloromethane-methanol-aqueous ammonia (97:3:0.2-95:5:0.3)] to give the title compound (0.2458 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH2:15]([O:17][C:18](=[O:40])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[CH:36]=[C:35]3[C:31]([CH2:32][CH2:33][NH:34]3)=[C:30]([O:37][CH3:38])[CH:29]=2)=[O:27])=[CH:21][C:20]=1[F:39])[CH3:16].N1C=CC=CC=1>ClCCl>[CH2:15]([O:17][C:18](=[O:40])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[CH:36]=[C:35]3[C:31]([CH2:32][CH2:33][N:34]3[S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=3)(=[O:11])=[O:10])=[C:30]([O:37][CH3:38])[CH:29]=2)=[O:27])=[CH:21][C:20]=1[F:39])[CH3:16]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc3c(c(OC)c2)CCN3)cc1F
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
3-Trifluoromethylbenzenesulphonyl chloride (45.1 mg, 0.18 mmol, 1.1 equiv.) was added to a mixture of crude 2-fluoro-4-[(4-methoxy-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester (60 mg, 0.24 mmol, 1 equiv.) and pyridine (0.11 mL, 1.34 mmol, 8 equiv.) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by preparative HPLC to afford 2-fluoro-4-{[4-methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, 14.4 mg (33% yield). LC @215 nm; Rt 1.73: 100%, m/z (ES+): 567 (M+H+.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:28])[N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[CH:19])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:28])[N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccccc1F
Reactant: Brc1ccccn1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1ccccc1F
Yield: 75.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (136 mg, 0.86 mmol) and (2-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (250 mg, 0.86 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 240 mg (0.65 mmol, 76%) of (2-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid-tert-butyl ester as a white solid.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:17])=[CH:15][CH:14]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a stirring solution of 4-bromobenzoic acid-2,5-dioxo-pyrrolidin-1-yl ester (3.5 g, 11.7 mmol) [CAS: 80586-82-9] in tetrahydrofuran (0.15M), is added (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.9 mL, 11.7 mmol) and the mixture heated to reflux for 4 h. The reaction is allowed to cool to room temperature and washed with water while extracting with 10% isopropanol/dichloromethane. The organic portion is dried with sodium sulfate, filtered; and concentrated in vacuo. The resulting residue is purified on a silica gel column, eluting with 2M ammonia in methanol and dichloromethane to obtain 2.80 g (71%) of the title compound. MS (ES+) m/e 337.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][CH2:13][O:14][CH2:15][C:16]([OH:18])=O)=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.N1C=CN=C1.S(Cl)(Cl)=O.[CH3:28][NH:29][CH2:30][CH2:31][OH:32].Cl>C(Cl)Cl.O.C(N(CC)CC)C>[OH:32][CH2:31][CH2:30][N:29]([CH3:28])[C:16](=[O:18])[CH2:15][O:14][CH2:13][CH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1
Reactant: COc1cc2sccc2cc1CCOCC(=O)O
Reactant: CNCCO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc2sccc2cc1CCOCC(=O)N(C)CCO
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In 8 mL of methylene chloride is dissolved 0.80 g of 2-[2-(6-methoxybenzo[b]thiophen-5-yl)ethoxy]-acetic acid, to which are added 1.38 mL of triethylamine and 0.22 g of imidazole. The mixture is cooled to 5° C., to which is dropwise added a mixture of 0.24 mL of thionyl chloride and 8 mL of methylene chloride. The resulting mixture is stirred at the same temperature as above for one hour. The reaction mixture is cooled to −60° C., 0.47 mL of triethylamine and 0.31 mL of 2-(methylamino)-ethanol are added thereto, and the resulting mixture is stirred at the same temperature as above for one hour and the at ambient temperature for 1.5 hours. Water is added to the reaction mixture, pH is adjusted to 1.0 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.93 g of N1-(2-hydroxyethyl)-N1-methyl-2-[2-(6-methoxybenzo[b]thiophen-5-yl)ethoxy]-acetamide is obtained as an oily product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([NH:24][C:25]1[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:26]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:16]([NH:24][C:25]1[CH:37]=[C:36]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[CH:35]=[CH:34][C:26]=1[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
0.031 mL of indoline, 0.12 g of cesium carbonate, 1.7 mg of tris(dibenzylideneacetone)dipalladium(0), 0.8 mg of palladium acetate and 4.4 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate -10:1] to obtain 77 mg of tert-butyl 2-(benzamido)-4-(indolin-1-yl)benzoate as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)(=[O:14])[CH3:13]
Reactant: Oc1cccc2ncccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-hydroxyquinoline (5.1 g) in pyridine (100 ml) was added acetic anhydride (4.0 ml) and then the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated. The residue was diluted with water. The diluted solution was extracted with ethyl acetate. The extracted solution was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and then concentrated. The residue was azeotropled with toluene to give the title compound (7.7 g) having the following physical data. The obtained compound was used without purification in the subsequent reaction.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=1
Reactant: CC(C)(C)c1ccccc1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2-(tert-butyl)phenol (20 g, 133 mmol) in dry DCM (200 mL) was added tetrabutyl ammonium tribromide (64.3 g, 133 mmol) at 0° C. and the solution was stirred at rt for 2 h, concentrated and redissolved in Et2O, washed by brine (3×), dried over Na2SO4, filtered and concentrated to give compound P9a (36.6 g, 95%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C(=O)O)cnc1-c1ccccc1
Yield: 56.9 %

Procedure:
2.2 g of ethyl 1-methyl-2-phenyl-1H-5-imidazolecarboxylate was dissolved in 20 ml ethanol and 2 ml of 5N sodium hydroxide was added, followed by heating under reflux for 1 hour. The reaction solution was ice-cooled and neutralized with 2N hydrochloric acid, followed by extracting with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 1.1 g of 1-methyl-2-phenyl-1H-5-imidazolecarboxylic acid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][CH2:22][CH2:21]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:26][C:25]=3[Cl:27])[CH2:21][CH2:22]2)[C:3](=[O:16])[N:4]([CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][O:12][CH3:13])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CCC(CCOC)n1cc(Cl)nc(Cl)c1=O
Product: CCC(CCOC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 95–97° C.; 1H NMR (300 MHz, CDCl3): δ 7.16 (d, J=2.2 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.78 (s, 1 H), 4.89–4.82 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.39–3.27 (m, 2 H), 3.25 (s, 3 H), 3.11 (t, J=7.9 Hz, 2 H), 2.01–1.93 (m, 2 H), 1.84–1.72 (m, 2 H), 0.86 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C18H21N3O2Cl3 (M+H)+: 416.0699; found m/z 416.0717.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:12][CH3:13])[CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH2:3][CH:2]=[O:1])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: COc1cc(CCO)ccc1C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(CC=O)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 4-(2-hydroxyethyl)-2-methoxybenzonitrile (1.5 g, 8.5 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added Dess-Martin periodinane (3.6 g, 8.5 mmol) in one portion. The mixture was stirred for 12 h at rt and quenched with a 1:1 mixture of saturated Na2S2O3 (40 mL) and saturated NaHCO3 (40 mL). The resulting mixture was diluted with CH2Cl2 (70 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 2-methoxy-4-(2-oxoethyl)benzonitrile. The residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 7.52 (d, 1H, J=8.8 Hz), 6.86 (dd, 1H, J=1.1 Hz), 6.79 (s, 1H), 3.92 (s, 3H), 3.76 (s, 2H); LCMS: [(M+1)]+=176.26; tR=1.98 min.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:37](O)(=[O:40])[CH2:38][CH3:39]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:37](=[O:40])[CH2:38][CH3:39])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and propionic acid (9.0 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]Br.C1(C)C=CC=CC=1.CC(C)=O.N1C=CC=CC=1>[CH2:12]([O:14][C:15]([C:17]1[N:18]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=2)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: COc1ccc(Br)cc1OC
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccccc2n1-c1ccc(OC)c(OC)c1
Temperature: 25 °C

Procedure:
4-Bromoveratrole (8.8 g, 40 mmol), indole-2-carboxylic acid ethyl ester (1.9 g, 10 mmol), potassium carbonate (1.9 g), copper- (I) bromide (o.2 g), pyridine (2 ml) and nitrobenzene (10 ml) were stirred at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture was applied onto a silica gel flash chromatography column (silica gel: 140 g). The column was subsequently eluted with toluene (500 ml), toluene/acetone (95:5, 500 ml) and toluene/acetone (90:10, 500 ml). 1-(3,4-Dimethoxyphenyl)indole-2-carboxylic acid ethyl ester was eluted with toluene/acetone (90:10) and gave colorless crystals upon evaporation of the solvent. The crystals were triturated with diisopropyl ether, collected by vacuum filtration and dried in the air. Yield: 3.0 g. (92% of theoretical yield) M.pt.: 126°-128° C. Rf (toluene/acetone, 9:1)=0.53.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]3([C:16]([CH3:19])([CH3:18])[CH3:17])[O:15][CH2:14][CH2:13][O:12]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].C([Li])CCC.[CH:27](=[O:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[C:16]([C:11]1([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH:27]([OH:29])[CH3:28])[N:3]=3)[NH:8][CH:9]=2)[O:15][CH2:14][CH2:13][O:12]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC=O
Reactant: CC(C)(C)C1(c2c[nH]c3ncc(Br)nc23)OCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cnc2[nH]cc(C3(C(C)(C)C)OCCO3)c2n1
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
2-bromo-7-(2-tert-butyl-[1,3]dioxolan-2-yl)-5H-pyrrolo[2,3-b]pyrazine (0.2 g, 0.61 mmol) was dissolved in 6 ml tetrahydrofuran. Sodium hydride (49 mg, 1.22 mmol, 60% mineral oil dispersion) was added and the mixture stirred for 15 min. The mixture was cooled in a dry ice/acetone bath and butyl lithium (0.37 ml, 0.92 mmol, 2.5M hexanes solution) was added slowly. After 5 min, acetaldehyde (85 ul, 1.52 mmol) was added. After a further 1 hr, ammonium chloride solution was added, then water and ethyl acetate. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined ethyl acetate layers were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation the residue was purified by silica gel chromatography(methanol/dichloromethane) to give 109 mg (61%) of 1-[7-(2-tert-butyl-[1,3]dioxolan-2-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-ethanol. (M+H)+=292.