Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[NH:4]1)[CH3:2].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[CH2:1]([N:3]1[C:7]([O:8][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:6][C:5]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:4]1)[CH3:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(C=O)cc1

Procedure:
3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]benzonitrile was prepared from 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile and 4-fluorobenzaldehyde with a procedure similar to Example 1, Step 3. Calc'd (M+1) 318.1. Found: 318.0
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:21]2[CH:25]=[C:24]([C:26](=[O:29])[CH2:27][CH3:28])[N:23]([CH2:30][CH3:31])[CH:22]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[N:7]=1.C(OCC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[NH2:5][C:6]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:21]2[CH:25]=[C:24]([C:26](=[O:29])[CH2:27][CH3:28])[N:23]([CH2:30][CH3:31])[CH:22]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:7]=1
Reactant: CCC(=O)c1cc(C2(c3cccc(OC)c3)N=C(N)N(C)C2=O)cn1CC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CCC(=O)c1cc(C2(c3cccc(O)c3)N=C(N)N(C)C2=O)cn1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
Boron tribromide (1M in dichloromethane, 21 mL, 21.17 mmol) was added dropwise to a cold (−78° C.) suspension of 2-amino-5-(1-ethyl-5-propionyl-1-H-pyrrol-3-yl)-5-(3-methoxy-phenyl)-3-methyl-3,5-dihydro-imidazol-4-one (1.3 g, 3.52 mmol) in CH2Cl2. The mixture was allowed to warm to room temperature, stirred for 20 h, and poured slowly into cold (0° C.) ethyl ether, treated slowly with methanol over a 10 minute period, basified to pH 8 at 0° C. with saturated aqueous NaHCO3 and extracted with CHCl3. The combined CHCl3 extracts were washed with brine, dried over MgSO4 and evaporated to dryness. The resultant residue was purifiied by flash chromatography (ethyl acetate/methylene chloride/methyl alcohol/triethyl amine, 5/4.4/0.5/0.1) to give the title compound as a white solid (0.95 g, 72% yield), mp 101° C., 1H NMR (400 MHZ, DMSO-d6) δ 0.99 (t, 3H), 1.17 (t, 3H), 2.66-2.68 (q, 2H), 2.90 (s, 3H).4.19-4.21 (q, 2H), 6.5 (bs, 2H), 6.55 (m, 1H), 6.84-6.88 (m, 3H), 7.01 (m, 2H), 9.21 (bs, 1H), MS m/e (M−H)− 353.1.
Reaction SMILES: [Mg].[CH2:2]([CH:4]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:3].[N:18]1[C:25](Cl)=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>O1CCCC1>[Cl:20][C:19]1[N:21]=[C:22]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([CH2:2][CH3:3])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=2)[N:24]=[C:25]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([CH2:2][CH3:3])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=2)[N:18]=1
Reactant: CCCCC(CC)COc1ccc(Br)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc(-c2nc(Cl)nc(-c3ccc(OCC(CC)CCCC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
3.65 g (0.15 mol) of magnesium turnings are placed in a 100 ml sulfonating flask fitted with stirrer, condenser, dry pipe, dropping funnel and internal thermometer under inert gas (dry nitrogen), and etching of the turnings is initiated with a few crystals of iodine. 150 ml of anhydrous tetrahydrofuran are added, and a solution of 42.8 g (0.15 mol) of 4-(2-ethylhexyloxy)bromobenzene in 30 ml of tetrahydrofuran is added dropwise over the course of 45 minutes (room temperature). After gentle heating on the waterbath (40 C.) the Grignard reaction starts up (clouding, exothermic). The mixture is stirred at 40 C. for one hour and then under reflux (66 C.) until virtually all of the magnesium has dissolved (about 30 minutes). After cooling to room temperature, the Grignard solution is added dropwise at 0-C. over the course of 60 minutes to a solution of 9.2 g (0.05 mol) of cyanuric chloride in 40 ml of tetrahydrofuran (350 ml sulfonating flask, stirrer, condenser, dry pipe, dropping funnel, internal thermometer, inert gas). The mixture is stirred under reflux (66 C.) overnight and then evaporated to dryness. The residue is stirred with 100 ml of ice-cold 2N hydrochloric acid and then subjected to extraction with 200 ml of toluene. The organic phase is shaken twice with 10% brine, dried over sodium sulfate and concentrated by evaporation. The crude product (40.3 g, red oil) is still heavily contaminated (thin-layer chromatogram). To purify it, it is dissolved in 80 ml of toluene/hexane (1/1) and the solution is chromatographed over silica gel (5 cm×45 cm). 18.2 g (69.5%) of 2-chloro-4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazine are isolated as a yellow resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[O:17].[CH:18]([Mg]Cl)=[CH2:19].CCOCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH:18]=[CH2:19])[OH:17]
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (3.0 g, 9.66 mmol) at −78° C. in THF (48 mL) was added dropwise of vinylmagnesium chloride (17.51 mL, 28.0 mmol). After 30 min, the reaction was allowed to slowly warm to rt, then the reaction was quenched with 60 mL of saturated aqueious NH4Cl. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield 3.2 g of crude product as orange foam. This material was added ˜4 mL of Et2O and precipitate was formed and filtered through Bucher funnel to yield 7-bromo-3-chloro-5-vinyl-5H-chromeno[2,3-c]pyridin-5-ol (2.70 g, 7.97 mmol) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[NH2:21].C(O)(=O)C.[C-:26]#[N:27].[K+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([NH:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)[C:26]#[N:27]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: [C-]#N
Reactant: Nc1ccc2ccccc2c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred mixture of 43.8 parts of 2,6-dichlorobenzaldehyde, 41 parts of 2-naphthalenamine and 500 parts of glacial acetic acid is added dropwise a solution of 20.3 parts of potassium cyanide in 35 parts of water. The whole is stirred for 40 hours at room temperature. The precipitated product is filtered off, washed on the filter with glacial acetic acid, with 2-propanol and petrleum ether, and dried, yielding 60 parts of 2,6-dichloro-α-[(2-naphthalenyl)amino]benzeneacetonitrile; mp. 94.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[C:4]([F:18])[CH:3]=1.P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:16]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:18])[N:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2
Solvent: ClC(Cl)Cl
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCCC2

Procedure:
10.0 Parts of 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7 -hexahydro-3H-indazol-3-one and 7.3 parts of phosphorous oxychloride were mixed and heated to 130°-150° for six hours. The reaction mixture was dissolved in 100 parts of chloroform. The organic solution containing the product was washed successively with three portions of 25 parts each of 10% sodium hydroxide and then washed with 50 parts water. The chloroform solution was dried with 2-10 parts of anhydrous sodium sulfate and then filtered. The solvent was removed under a reduced pressure on a rotary evaporator. The resulting thick oil was purified by sublimation at 100°-120° at 0.5-1.5 mm. pressure to yield 7.8 parts of white crystalline material with m.p. 88°-89.5°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[CH2:30]([N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.6 %

Procedure:
A mixture of 9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 8.3 g of potassium carbonate, 20 g of benzyl bromide and 200 ml of acetone is stirred at room temperature for 3 days. Then, the reaction mixture is treated in the same manner as described in Example 1-(2). 9.3 g of tert.-butyl (4S)-1-benzyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless syrup. Yield: 75.6%
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][NH:24][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)(C)(C)C.C(N(C(C)C)CC)(C)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>CN(C)C=O>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([C:39]([NH:38][CH2:36][CH3:37])=[O:40])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCN=C=O
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc21
Temperature: 60 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
4-(3-t-Butoxyphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (20 mg, 0.056 mmol) was dissolved in dimethylformamide (1 mL), and diisopropylethylamine (29 μL, 3 equivalents) and ethyl isocyanate (13 μL, 3 equivalents) were added, followed by stirring at 60° C. for 2 days. The reaction mixture was poured onto water, followed by extraction with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtering off the drying agent, concentration was carried out under reduced pressure, and the resulting residue was stirred at room temperature for 30 minutes in trifluoroacetic acid. Concentration was carried out under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane), to obtain the desired compound (colorless powder, 1.7 mg, 9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:17][CH2:16][N:15]([CH3:21])[C:14]3=[O:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1NCCN1c1nc(-c2ccc(Br)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3ccc(Br)cc3)cs2)C1=O
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
1-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]imidazolidin-2-one (0.155 g, 0.480 mmol), prepared in step 2 of Example 75, was dissolved in 2.4 mL of anhydrous tetrahydrofuran and sodium hydride (60% suspension in mineral oil, 20 mg, 0.53 mmol) was added. The mixture was stirred for 20 min and then methyl iodide (0.03 mL, 0.48 mmol) was added and stirring was continued for 4 h. The reaction was quenched with saturated aqueous NH4Cl and diluted with ethyl acetate. The mixture was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (20% acetone/hexane) afforded the title compound (146 mg, 90%) as a white solid. HRMS: calcd for C13H12BrN3OS+H+, 337.99572; found (ESI, [M+H]+), 337.9954. Analytical HPLC: retention time 10.1 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: Cl.[NH2:2][OH:3].[N:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=4)[NH:19][C:18]=3[N:17]=[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=O)[C:39]([F:42])([F:41])[F:40])[CH:33]=3)[N:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CO.N1C=CC=CC=1>[N:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=4)[NH:19][C:18]=3[N:17]=[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[N:2][OH:3])[C:39]([F:40])([F:41])[F:42])[CH:33]=3)[N:15]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Temperature: 60 °C
Yield: 100.1 %

Procedure:
Hydroxylamine hydrochloride (0.08 g, 1.2 mmol) was added to methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (compound of Example 33) (0.285 g, 0.515 mmol) in MeOH (4.00 mL) and pyridine (0.666 mL) to give a yellow solution. After heating at 60° C. 5 days, the mixture was concentrated to dryness and the residue was dissolved into DCM (75 mL) and MeOH (15 mL) and this solution was washed with sat. NaHCO3 (20 mL). The aqueous layer was extracted two time with a mixture of CH2Cl2 (50 mL) and MeOH (10 mL) and the combined organic layers were dried over anh. MgSO4, filtered and concentrated to dryness to give methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (293 mg, 100% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.43 (m, 2H) 1.44-1.56 (m, 4H) 1.76-1.87 (m, 2H) 2.23-2.44 (m, 6H) 3.57-3.67 (m, 2H) 3.88 (s, 3H) 4.04-4.12 (m, 2H) 7.25-7.33 (m, 1H) 7.34-7.46 (m, 2H) 7.50 (m, J=7.6, 4.1 Hz, 1H) 7.55 (d, J=7.4 Hz, 1H) 7.81 (dd, J=8.2, 1.2 Hz, 1H) 7.99 (d, J=1.2 Hz, 1H) 8.36 (d, J=8.2 Hz, 1H) 12.07 (d, J=3.5 Hz, 1H); MS m/z 569.2 (M+H)+; HPLC >95%, RT=1.88 minutes.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)n2ccnc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)cc2nccn12
Yield: 62 %

Procedure:
A solution of 5-bromo-7-methylimidazo[1,2-a]pyridine (2 g, 0.01 mol) and sodium methoxide (25%, 10 mL) in methanol (10 mL) is heated under reflux for 48 h. The solvent is removed and the residue diluted with ethyl acetate (200 mL) and water (150 mL). The organic layer is separated and washed with water and brine, and dried over sodium sulfate. Evaporation of the solvent gave 5-methoxy-7-methylimidazo[1,2-a]pyridine (lg, 62%) as a white semi-solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])(C)(C)C.[Br:26]Br>C1COCC1.CCCCC>[Br:26][C:8]1[C:7]([O:9][CH3:10])=[CH:6][N:5]=[C:4]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(C#Cc2ncc(OC)cc2OC)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(C#Cc2ncc(OC)c(Br)c2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To a solution of 3,5-dimethoxy-2-(4-methoxyphenylethynyl)pyridine M (120 mg, 0.446 mmol) in dry THF (2.5 ml) at −78° C. was added t-butyllithium (0.49 mmol, 0.30 ml of a 1.6M solution in pentane) and the reaction stirred for 10 minutes. After this time bromine (25 μL, 0.50 mmol) was added neat and the reaction was allowed to warm to room temperature and quenched by the addition of water (10 ml) and ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica-gel, eluted with hexanes:EtOAc, 3:1) to afford the product as a white solid (45 mg, 29%). 1HNMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[CH3:12][NH:13]O.C(=O)([O-])[O-].[Na+].[Na+].[OH2:21].C(O)C>>[OH:21][N:13]([CH3:12])[C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: O
Reactant: COc1ccccc1C#N
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1C(=N)N(C)O
Temperature: 80 °C
Reaction time: 28 h

Procedure:
To a stirred solution of 2-methoxybenzonitrile (2.66 g, 20 mmol) and N-methylhydroxylamine hydrochloride (3.341 g, 40 mmol) in 2:1 water/ethanol (30 mL) was added sodium carbonate (2.332 g, 22 mmol) in small portions and the resulting pink solution stirred at 80° C. for 28 h. The reaction mixture was then concentrated and the residue stirred with CH2Cl2, filtered and concentrated to give crude product as a purple solid (3.3 g), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].Br.Br[C:13]1[S:17][C:16]([NH2:18])=[N:15][CH:14]=1.CCOCC>CN(C)C=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:13]1[S:17][C:16]([NH2:18])=[N:15][CH:14]=1
Reactant: Oc1ccccc1Cl
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1ncc(Oc2ccccc2Cl)s1
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
2-Chloro-phenol (1.7 mL, 16.0 mmol) was dissolved in a mixture of 36 mL of tetrhydrofuran (THF) and 4 mL of N,N-dimethylformamide (DMF). Sodium hydride (60% dispersion in oil, 0.700 g, 17.5 mmol) was added and the reaction was stirred for 5 minutes under an atmosphere of nitrogen. A solution of 5-bromo-thiazol-2-ylamine hydrobromide (2.1 g, 8.0 mmol) in 18 mL of THF and 2 mL of DMF was slowly added to the reaction mixture. The mixture was allowed to stir for 10 minutes and then 100 mL of ether was added. The reaction mixture was washed with 1N sodium hydroxide. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified on silica gel using a gradient of 50-99% ethyl acetate in hexanes to yield the product as a brown solid (0.3546 g, 1.564 mmol, 19%)
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][CH2:37][OH:38]>CN(C)C=O>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:36][CH2:37][OH:38])=[CH:26][CH:27]=2)=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: OCCCl
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(O)cc3)nc3ccccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3ccc(OCCO)cc3)nc3ccccc3c2=O)cc1

Procedure:
To a solution of 2-amino-N-(4-sec-butylphenyl)-benzamide (0.500 g, 1.86 mmol) in N,N-dimethylformamide (9 mL) under nitrogen atmosphere was added 4-hydroxy-benzaldehyde (0.450 g, 3.73 mmol) followed by iodine (0.560 g, 2.23 mmol) and potassium hydroxide (0.120 g, 2.23 mmol). The resulting mixture was heated at 110° C. overnight, then the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, washed with water and dried over sodium sulfate. The crude oil (0.97 g) was purified by column chromatography (silica gel 230-400 mesh; 1/1 hexanes/EtOAc as eluent) to give pure 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one as a yellow solid. Yield: 0.33 g (47.8%). To a mixture of 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one (0.11 g, 0.31 mmol) and potassium carbonate (0.13 g, 0.93 mmol) in N,N-dimethylformamide (3.5 mL) under nitrogen atmosphere was added 2-chloroethanol (0.032 mL, 46 mmol). The reaction mixture was heated at reflux for 14 hours, then the solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with 5% aqueous solution of sodium hydroxide, brine, and dried over sodium sulfate. The crude solid (0.13 g) was purified by column chromatography (silica gel 230-400 mesh; 10/0 to 1/1 hexanes/EtOAc, then 10/0 to 9.4/0.6 methylene chloride/MeOH as eluent) and triturated with Et2O to give the pure title compound as a light brown solid. Yield: 60 mg, (46.3%). MP 172.8-174.9° C. 1H-NMR (400 MHz, CDCl3): δ 8.35 (d, 1H), 7.80 (d, 2H), 7.50 (m, 1H), 7.28 (d, 2H), 7.14 (d, 2H), 7.05 (d, 2H), 6.72 (d, 2H), 4.00 (m, 2H), 3.95 (m, 2H), 2.58 (m, 1H), 1.95 (s, OH), 1.65-1.48 (m, 2H), 1.20 (d, 3H), 0.75 (t, 3H). MS (ES+) m/z: 415.09 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12](C(OC(C)(C)C)=O)[C:11]=1[Br:29])[NH:5][C:6](=[O:8])[CH3:7].FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]=1[Br:29])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1c(Br)n(C(=O)OC(C)(C)C)c2cc(Br)c(OC)cc12)NC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1c(Br)[nH]c2cc(Br)c(OC)cc12)NC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.6 %

Procedure:
To a solution containing 18.3 mg (0.03 mmol) of (S)-(+)-N-acetyl-2,6-dibromo-1-t-butoxycarbonyl-5-methoxytryptophan methyl ester (9) dissolved in 3.2 mL of chloroform, 0.8 mL of trifluoroacetic acid was added under ice cooling to prepare a 10% solution. Furthermore, the solution was stirred at room temperature for 12 hours. The reaction solution was charged with chloroform. The organic phase was washed with saturated sodium bicarbonate water. The resulting phase was further washed with a saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain colorless oil. Column chromatography using silica gel as a carrier and a chloroform-methanol (99:1, v/v) mixed solvent as an elution solvent was performed to obtain 10.3 mg (70%) of compound (2).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (163 mg, 1.45 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (300 mg, 1.03 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (15 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 70° C. for 14 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 120 mg, 33%).