Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][N:25]1[C:33](Cl)=[O:34].Cl>O.CC(C)=O>[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][N:25]1[C:33]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:34]
Reactant: O=C(Cl)N1Cc2ccccc2C1=O
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccc(CCN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Reaction time: 2 h

Procedure:
3 g of N-(4-[2-amino-ethyl]-benzenesulfonyl)-N'-butyl-urea (melting point 210°-212° C., prepared by saponification of N-(4-[2-acetylamino-ethyl]-benzenesulfonyl)-N'-butyl-urea with sodium hydroxide solution) are dissolved with 0.4 g of sodium hydroxide in 50 ml of water and 50 ml of acetone and, while stirring, a solution of 2 g of 1-oxo-isoindoline-2-carboxylic acid chloride (melting point 119°-121° C., prepared from 1-oxo-isoindoline sodium and phosgene) in about 50 ml of acetone is added. The temperature of the mixture increases slightly. Stirring is continued for 2 hours at room temperature, whereupon the residue is acidified with dilute hydrochloric acid. The precipitate is reprecipitated from dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-butyl-urea melts at 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>N(CC)CC.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>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:34]=[C:33]([CH2:32][CH2:31][OH:35])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CCO)cc3cc(CC4CCOCC4)cc(c1=O)c32
Yield: 71 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide (0.16 g), PdCl2(PPh3)2, CuI (0.018 g) and 3-butyn-1-ol (0.03 mL) in 15 mL Et2NH is stirred at room temperature for 7 days. The solid in the reaction is filtered and rinsed with EtOAc. The filtrate is partitioned between EtOAc and H2O. The aqueous layer is extracted with EtOAc (3×). The organic layers and the solid previously filtered are combined, concentrated, adsorbed onto silica and chromatographed (gradient from CH2Cl2 to 4% MeOH in CH2Cl2). Product-containing fractions are combined and condensed to afford 101.6 mg (71%) of N-(4-chlorobenzyl)-2-(2-hydroxyethyl)-6-oxo-8-(tetrahydro-2H-pyran-4-ylmethyl)-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[OH:16])=[C:4]([F:20])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:8](=[O:17])[NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][C:4]=1[F:20])[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCc1ccc(Br)cc1F)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Yield: 93.8 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-4-chloro-2-hydroxy-benzamide (3.25 g, 9.06 mmol) in acetone (45 mL, 0.2 M) was treated with aq K2CO3 (2 M, 6.8 mL, 14 mmol) and ethyl bromoacetate (1.2 mL, 11 mmol). After being heated to 50° C. for 8 h, the solution was cooled to room temperature and concentrated under reduced pressure until most of the acetone was removed. The solution was acidified to pH 1–2 with 2 N HCl, diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by MPLC (10–60% ethyl acetate in heptane, 23 mL/min, 70 min) gave [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester as a white crystalline solid (3.78 g, 94%): mp 126–127° C.; Rf 0.61 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (t, J=6 Hz, 1 H), 7.82 (d, J=8.4 Hz, 1 H), 7.52–7.47 (m, 1 H), 7.39–7.31 (m, 2 H), 7.28 (d, J=1.8 Hz, 1 H), 7.14 (dd, J1=8.4 Hz, J2=1.8 Hz, 1 H), 5.00, (s, 2 H), 4.49 (d, J=6 Hz, 2 H), 4.16 (q, J=7.2 Hz, 2 H), 1.18 (t, J=6.6 Hz, 3 H). ESI-LC/MS m/z calcd for C18 H11BrClFNO4: 444.7; found 446.0 (M+1)+. Anal. calcd for C16H16BrClFNO4: C, 48.62; H, 3.63; N, 3.15; Cl, 15.95. Found C, 48.57; H, 3.63; N, 3.11; Cl, 16.00.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1.COC(=O)C1C=CC(O)=C([Cl:33])C=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[C:6]([Cl:33])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: COC(=O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
Following the procedure for the preparation of 4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting 3-Chloro-4-hydroxy-benzoic acid methyl ester provided the title compound. MS: (M+H m/z=328.0).
Reaction SMILES: CS([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[N:13]=[C:14]([CH2:24]OS(C)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[N:6]1)(=O)=O.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[N:30]1([CH2:24][C:14]2[C:15]3[C:20](=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)[CH:21]=[C:12]([NH:11][C:7]3[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=3)[N:13]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Product: COc1ccc2c(Cn3ccnc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in the example 369d was used, starting from Methanesulfonic acid 3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-ylmethyl ester and 1H-Imidazole to give 5 mg of (1-Imidazol-1-ylmethyl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 335 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.[CH:22]([N:25]([CH2:29][CH2:30]Cl)[CH2:26][CH2:27]Cl)([CH3:24])[CH3:23]>>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:30][CH2:29][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]2)(=[O:7])=[O:8])=[CH:14][CH:13]=1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: CC(C)N(CCCl)CCCl
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(C(C)C)CC2)cc1
Yield: 64 %

Procedure:
Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-isopropyl-4-piperidine carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (6 g, 20.3 mmol) and isopropyl [bis(2-chloroethyl)]amine hydrochloride (4.88 g, 22.3 mmol); 5.28 g brown oil. Yield 64%; MS: 408.2 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7]([CH3:18])=[C:8]([CH3:17])[C:9](=[O:16])[NH:10]2)C=C.C(Cl)(Cl)Cl.[OH-].[Na+].CN(C)[C:27]1[CH:32]=CC=C[CH:28]=1>>[CH2:32]([C:14]1[C:5]([OH:4])=[C:6]2[C:11](=[C:12]([CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[C:8]([CH3:17])=[C:7]2[CH3:18])[CH:27]=[CH2:28]
Reactant: C=CCOc1ccc(C)c2[nH]c(=O)c(C)c(C)c12
Reactant: CN(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=CCc1cc(C)c2[nH]c(=O)c(C)c(C)c2c1O
Temperature: 200 °C
Reaction time: 2 h

Procedure:
5-Allyloxy-3,4,8-trimethylcarbostyril (1.02 g, 420 mmol) was dissolved in N,N-dimethylaniline (20 ml), and the mixture was stirred in a bath of 200° C. for 2 hours. The reaction mixture was condensed under reduced pressure, to which chloroform and aqueous 2N-NaOH solution were added, then extracted into the aqueous phase. The aqueous phase was neutralized with conc. HCl solution, followed by extracting with chloroform--methanol (10:1), drying, and condensing. The resultant residue was recrystallized from chloroform--methanol--ether. As a result, 989 mg of the title compound was obtained as pale yellow needles (97.0%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].C>O.C(O)CO>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: O=C(O)c1ccccc1Nc1ccc(F)cc1
Temperature: 125 °C
Yield: 37.3 %

Procedure:
4-Fluoroaniline (1.86 gm; 20 mmol), 2-chlorobenzoic acid (1.56 gm; 10 mmol), ethylene glycol (5 ml) and anhydrous sodium carbonate (1.1 gm; 10 mmol) were placed in a reaction vessel and stirred until effervescence ceased. Cupric chloride (100 mg; 0.75 mmol) dissolved in 2 ml of water was added to the reaction mixture which was then heated to 125° C. for 6 hrs. The reaction was allowed to cool and water (30 ml) and charcoal were added. The mixture was filtered and then acidified to pH 2 with conc. hydrochloric acid. The precipitate was collected by filtration, washed with water and then re-dissolved in 1M sodium hydroxide solution. Material was re-precipitated by the addition of acetic acid, filtered off, washed with aqueous acetic acid, then water and finally dried under vacuum over phosphorous pentoxide to give 862 mg (37%) of N-(4-fluorophenyl)anthranilic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
The intermediate from step A (8.8 g, 37.6 mmol) was dissolved in toluene and to it was added PtO2 (0.5 g). The resulting mixture was stirred under hydrogen at atmospheric pressure overnight. The catalyst was filtered off and the filtrate was removed under reduced pressure. Flash chromatography on silica gel eluting with 5% and then 10% EtOAc in hexanes provided the title compound (8.6 g, 98%) as an oil. MS calculated (M+H)+ 237, found 237.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([OH:38])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:45][C:46]1[CH:47]=[N:48][C:49](Cl)=[N:50][CH:51]=1.Cl>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([O:38][C:49]4[N:50]=[CH:51][C:46]([Br:45])=[CH:47][N:48]=4)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(O)cn2)cc1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Oc3ncc(Br)cn3)cn2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 4-tert-butyl-N-{6-[2-(5-hydroxypyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (200 mg) in dimethylformamide (4 ml)is added potassium carbonate (154 mg), 5-bromo-2-chloropyrimidine (216 mg), and the mixture is stirred at 50° C. for two hours. The reaction mixture is acdified with cold hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and brine, and dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The oily residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=50:1), and the fractions are evaporated to remove the solvent. The resulting crude crystals are recrystallized from methylene chloride/isopropyl ether to give 4-tert-butyl-N-{6-[2-(5-(5-bromopyrimidin-2-yloxy)pyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (238 mg) as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S-:10][C:11]#[N:12].[Na+].BrBr.C(=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][C:11]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#CSc1ccc(N)c(C#N)c1
Yield: 70.9 %

Procedure:
To a solution of 2-aminobenzonitrile (4.00 g (33.9 mmol)) and sodium thiocyanate (3.00 g (37.0 mmol)) in methanol (20 ml), a solution of bromine (5.50 g (34.4 mmol)) in methanol (5.0 ml) was added dropwise over a period of 40 minutes under cooling with ice and with stirring. The mixture was then stirred under cooling with ice for 30 mitutes, and then neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography with chloroform as eluent to give 4.21 g (71%) of 2-amino-5-thiocyanobenzonitrile as pale yellow-white crystals.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([OH:17])[C:6]=2[CH:7]=1)[CH3:2].I[C:19]1[CH:29]=[CH:28][C:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1.[Cu]I>[CH3:26][N:25]([CH3:27])[C:23]([C:22]1[CH:28]=[CH:29][C:19]([O:17][C:8]2[C:6]3[CH:7]=[C:3]([CH2:1][CH3:2])[O:4][C:5]=3[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=2)=[CH:20][CH:21]=1)=[O:24]
Reactant: CCOC(=O)c1cc(O)c2cc(CC)oc2c1
Reactant: CN(C)C(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)cc2)c2cc(CC)oc2c1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
A mixture of ethyl 2-ethyl-4-hydroxy-1-benzofuran-6-carboxylate (0.8 g, 3.4 mmol), 4-iodo-N,N-dimethylbenzamide (0.9 g, 3.3 mmol), Cs2CO3 (1.12 g, 3.4 mmol) and CuI (400 mg, 2.1 mmol) in pyridine (30 mL) was heated to 100° C. for 24 hours. TLC (petroleum ether/EtOAc 4:1) indicated the complete consumption of the phenol. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via silica gel column chromatography using petroleum ether/EtOAc (20:1 to 1:1) to afford the desired compound (400 mg, 30%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.97 (s, 1H), 7.56 (s, 1H), 7.43 (d, 2H), 7.00 (d, 2H), 6.27 (s, 1H), 4.44-4.35 (q, 2H), 3.15-3.04 (d, 6H), 2.83-2.78 (q, 2H), 1.45-1.37 (t, 3H), 1.37-1.26 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[OH:25][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)=[CH:3][CH:4]=1)[CH2:15][O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCCc1ccccc1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(O)COCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenethyloxy-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropane carbonyl}-methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:11]=[N:12][NH:13][N:10]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc(Cc2nn[nH]n2)cc1
Temperature: 90 °C

Procedure:
To a solution of (4-fluorophenyl)acetonitrile (5.00 g, 37.0 mmol) in 100 mL of toluene was added sodium azide (7.22 g, 111 mmol), triethylamine (15.5 mL, 111 mmol), and concentrated aqueous HCl solution (9.25 mL, 111 mmol). The reaction was heated at 90° C. overnight. The solution was cooled to room temperature and extracted with water and 1N NaOH solution. The combined aqueous layers were washed with ether (3×), acidified with concentrated aqueous HCl solution, and the resulting precipitate was collected by filtration and rinsed with 0.1N HCL solution. The resulting solid was azeotroped from toluene to provide 5-(4-fluorobenzyl)-2H-tetrazole. ESI+MS: 178.9 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:18])[CH3:17]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)(Cl)Cl>[C:11]([C:7]1[CH:8]=[C:9]([C:16](=[O:18])[CH3:17])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
A mixture of 2,6-di-t-butylphenol (1 g) in trifluoroacetic anhydride (5 ml) is carefully treated with 0.28 ml of glacial acetic acid and the reaction mixture is stirred at 20°-25° for 1 hr. The reaction mixture is diluted with chloroform and is separated, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product (1.39 g) is chromatographed on 180 g of silica gel. The column is packed and eluted with chloroform/acetone (99/1). An initial fraction of 200 ml is collected, followed by 7 ml fractions. Based on their TLC homogeniety, fractions 20-55 are combined and concentrated. Recrystallized from hexane gives the tire compound, mp 148°-150°; IR (mineral oil) 3581, 3007, 2956, 2925, 2871, 2856, 1663, 1596, 1581, 1465, 1463, 1442, 1423, 1370, 1364, 1356, 1320, 1305, 1274, 1239, 1232, 1138, 1124, 1108 an 886 cm-1 ; NMR (CDCl3, TMS) 7.84, 5.73, 2.56, and 1.47δ; CMR (CDCl3, TMS) 197.6, 158, 4, 135.8, 129.1, 126.1, 34.4, 30.2 and 26.3δ; MS (m/z) M+ (found)=248; other ions at m/z 233, 217, 205, 189, 178, 115, 57 and 43.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][C:16]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(C(OCC)=O)[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COCCO>O>[CH2:3]([O:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][CH:16]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: O=C(O)C(CCCc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
2.00 g of potassium hydroxide was added to a mixture of 3.91 g of diethyl 2-(4-benzyloxybenzyl)-2-(3-phenylpropyl)malonate obtained in Reference example 12(a), 30 ml of 2-methoxyethanol and 3 ml of water, and the resulting mixture was stirred on an oil bath of 130° C. for 1.5 hours. After the reaction, the reaction mixture was concentrated, water and ethyl acetate were added to the concentrated mixture, and then 6N hydrochloric acid was added thereto to make it acidic. Then, the ethyl acetate layer was separated, washed with an aqueous NaCl solution and dried over anhydrous magnesium sulfate, followed by concentration. The residual syrup was dissolved in 20 ml of xylene, and the mixture was stirred for one hour and concentrated. The syrup-like 2-(4-benzyloxybenzyl)-5-phenylvaleric acid thus obtained was dissolved in 40 ml of ethanol, and 1 ml of conc. sulfuric acid was added thereto. The resulting mixture was stirred at 80° C. for 3 hours and allowed to stand at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and water, followed by separation of the ethyl acetate layer. The extract thus obtained was dried over anhydrous magnesium sulfate and concentrated to obtain 3.32 g of the desired compound as a syrup.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:5]2[N:6]=[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:20][CH:19]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-hydroxyphenyl)pyrazine (coelenteramine) (c-5) (prepared by the method described in Adamczyk, M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (303 mg, 1.09 mmol) was dissolved in pyridine (2 mL) and cooled to 0° C. To this was added acetic anhydride (133 μL, 1.40 mmol) and stirred for an hour after warming to room temperature. To the mixture was added saturated aqueous solution of sodium bicarbonate and ethyl acetate to stop the reaction. After separating the aqueous layer and organic layer, it was extracted 3 times with ethyl acetate. The organic layer was washed 3 times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography (50 g, n-hexane/ethyl acetate=1/1) to give 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) as a pale yellow solid (337 mg, 96.7%). Rf=0.31 (n-hexane/ethyl acetate=3/2). Mp. 183.5-185.5° C. 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 4.07 (s, 2H), 6.42 (s, 2H), 7.12-7.17 (AA′BB′, 2H), 7.19 (d, J=7.2 Hz, 1H), 7.27 (t, J=7.5 Hz, 2H), 7.33 (d, J=7.0 Hz, 2H), 7.90-7.95 (AA′BB′, 2H), 8.41 (s, 1H). IR (KBr, cm−1) 513, 596, 640, 654, 710, 746, 851, 910, 1016, 1136, 1167, 1198, 1217, 1373, 1423, 1452, 1466, 1493, 1508, 1535, 1630, 1746, 3148, 3289.