Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:17])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(Cl)([Cl:20])=O>>[C:1]([Cl:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCC(=O)Cl

Procedure:
Pentadecanoic acid (24.2g) was treated with thionyl chloride (13.1g) at 80°-90° C. Pentadecanoyl chloride, thus obtained, was added slowly under ice cooling into the mixture of β-phenoxyethylalcohol (13.8g), pyridine (10.3g) and benzene (100ml) with stirring. After having been stirred, the reaction mixture was treated with an ordinary method (washed with dilute hydrochloric acid, the benzene layer was dried over Glauber's salt, and then benzene was removed under reduced pressure, giving a crude product). Solid (33g) was obtained. The solid was recrystalized from n-hexane, from which it formed colourless crystals (26g), m.p. 45.0°-47.0° C., of β-phenoxyethyl pentadecanoate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32](O)=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:37](CC)CC>C(Cl)Cl.CC#N>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32]([NH2:37])=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1.25 h

Procedure:
To a solution of the title acid of Example 2 (200 mg) in CH2Cl2 (3 mL) and CH3CN (1 mL) at 0° C. was added Et3N (120 μL) followed by 2-chlorol-methylpyridinium iodide (220 mg). After stirring for 75 mins. at 0° C., an excess of NH3 was slowly bubbled into the mixture and the reaction was allowed to stir at RT for 12 h. It was then diluted with ethyl acetate and washed successively with aq. NH4OAc (x2) and brine. After drying, the organic solution was concentrated and the residue was purified on a column of silica to afford the title compound.
Reaction SMILES: C(NC1C=C(C=C(C2OC=CN=2)C=1)[C:13]([NH:15][C@@H:16]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.[CH2:59]([N:62]([CH2:79][CH2:80][CH3:81])[C:63]([C:65]1[CH:66]=[C:67]([CH:71]=[C:72]([C:74]2[O:75][CH:76]=[CH:77][N:78]=2)[CH:73]=1)C(O)=O)=[O:64])[CH2:60][CH3:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:18][C@H:17]([C@H:26]1[CH2:30][C@@H:29]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH2:28][NH:27]1)[C@@H:16]([NH:15][C:13](=[O:14])[C:67]1[CH:71]=[C:72]([C:74]2[O:75][CH:76]=[CH:77][N:78]=2)[CH:73]=[C:65]([C:63]([N:62]([CH2:59][CH2:60][CH3:61])[CH2:79][CH2:80][CH3:81])=[O:64])[CH:66]=1)[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)[C@H]2C[C@@H](S(=O)(=O)CCC)CN2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
Step 17 (F): (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. To a solution of 3-(dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic acid (prepared as reported in WO 2002/02512, 20 mg, 0.062 mmol) in DCM is added HATU (28 mg, 0.073 mmol) and DIEA (33 mg, 0.26 mmol). After the solution is stirred at rt for 5 min, a 28 mg portion of the compounds of step 17 (E) (0.052 mmol) is added. The reaction solution was stirred 16 h at rt, and then the reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a step gradient of 20% to 50% to 70% ethyl acetate in hexanes to provide 40 mg (98%) of the desired amide. MS (ESI) (M+H-Boc)+=739.34
Reaction SMILES: [OH-].[Na+].[Cl:3][O-].[Na+].[OH:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl>>[Cl:3][C:13]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:6])=[N:15][CH:14]=1
Reactant: [O-]Cl
Reactant: O=C(O)c1cccnc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Cl)cnc1O
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To an agitated solution of 216.0 g of sodium hydroxide pellets in 2.25 liters of 5% (1.51 moles) of sodium hypochlorite solution was added 150.4 g of 2-hydroxynicotinic acid. Temperature of the reaction mixture was 19° C. Three hours later 750 ml (0.50 mole) of sodium hypochlorite was added and stirring was continued overnight. The reaction mixture was mixed with 12N hydrochloric acid in an agitated vessel in such a manner that the receiving solution was always strongly acid and temperature was kept below 20° C. with an ice bath. The amount of 12N acid used was 600 ml. The mixture was readily filtered on a sintered glass suction funnel. The crystalline filter cake was washed with 600 ml of water followed by 800 ml of 1:1 isopropyl ether/isopropyl alcohol. Weight of the dry crystals was 143.5 g (76.6% yield). Analysis by 1HNMR analysis showed the dried product contained no starting material and about 5% 3,5 -dichloro-2-hydroxypyridine. See Example 3 for method of computing impurity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH2:14]>C(Cl)(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of 4-methoxybenzene-1-sulfonyl chloride (2.4 g, 12 mmol) in CHCl3 (20 mL) was added methanamine (5 mL, 40 mmol) in EtOH. The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The resulting solid was washed with H2O (5 mL), ether, and air-dried to give 4-methoxy-N-methylbenzenesulfonamide (1.12 g, 48% yield) as a white solid. MS (ESI positive ion) m/z: 202 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br.Cl>ClCCCl.O>[Br:17][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2
Reactant: BrBr
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: Cc1ccc2c(Br)c(F)ccc2n1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A solution of 12.1 kg (75 mole) of 6-fluoro-2-methylquinoline in 33 liters of 1,2-dichloroethane was chilled to 5° C., and 15.0 kg (113 mole) of aluminum chloride was added thereto in portions over 15 minutes. The mixture was purged with nitrogen and then heated to 75° C. A solution of 13.2 kg (82.6 mole) of bromine in 2 liters of 1,2-dichloroethane was added over a period of 5.5 hours. The reaction was maintained at 75° C. during the addition and for an additional 15 minutes after the addition was completed. The reaction was stirred at 70° C. for 23 hours and was then cooled to 10° C. and slowly added to a mixture of 8 kg of 30% hydrochloric acid, 41 liters of water and 31.75 kg of ice. The mixture warmed to 50° C. during the addition. The mixture was heated in reflux and the 1,2-dichloroethane was removed by azeotropic distillation. The remaining aqueous solution was cooled to 60° C. and 12 kg of 10% hydrochloric acid was added. The solution was treated with Celite® (available from Johns-Manville Corp.) and filtered. The filtrate was cooled to 25° C. and 18 kg of 30% hydrochloric acid and 10.22 kg of zinc chloride were added. The resulting slurry was chilled to 5° C. and allowed to stir for several days. The solid was collected and then reslurried with 10 gallons of water. The slurry was chilled to 5° C. and 22 kg of chilled ammonium hydroxide was added. The resulting slurry (pH 10-11) was diluted with 25 gallons of water and the solid was collected, rinsed with water and dried in vacuo at 60° C. to give crude 5-bromo-6-fluoro-2-methylquinoline (84.5% pure by gas chromatography analysis). The material was recrystallized from hexane to give 99.2% pure 5-bromo-6-fluoro-2-methylquinoline.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]([CH2:9][C:10]([F:12])([F:11])[F:13])[C:23]([C:19]1[CH:18]=[C:17]([Cl:16])[N:22]=[CH:21][N:20]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)CNCc1ccccc1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N(Cc1ccccc1)CC(F)(F)F
Reaction time: 2 h

Procedure:
1.04 g (5.50 mmol) benzyl-(2,2,2-trifluorethyl)-amine and 5.50 mL (5.50 mmol) of a 1M sodium hydroxide solution were added dropwise while cooling with a bath of ice/ethanol to 1.00 g (5.65 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane. The mixture was first stirred for 2 h while being cooled and then for a further 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water (1×30 mL) and 1M hydrochloric acid (1×50 mL), dried on sodium sulphate, filtered and evaporated down i. vac. The product was reacted further without any further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C=O)C.[H-].[Na+].CS(O[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)(=O)=O>O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A 1 L, 1-neck flask was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.0 g, 103 mmol), and DMF (250 mL). The reaction mixture was cooled to 0° C. and NaH (2.73 g, 108 mmol) (95%) was added. The reaction mixture was stirred at 0° C. for 1 hour. tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (30.2 g, 108 mmol; prepared as in WO 06/021881) was added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with EtOAc, and the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified on a Biotage 40S column eluting with EtOAc/Hexane 10% to 25% EtOAc. The product was isolated as a white solid (11.3 g, 29%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][C:12]([CH3:18])([CH2:16][OH:17])[C:13]([OH:15])=[O:14]>CN(C1C=CN=CC=1)C.CCOCC>[C:1]([O:17][CH2:16][C:12]([CH3:18])([CH3:11])[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (4.52 g, 58.2 mmol) was added dropwise to a cold (0° C.) pyridine solution (10 ml) of 2,2-dimethyl-3-hydroxypropionic acid (5.5 g, 46.5 mmol) and 4-DMAP (0.57 g, 4.65 mmol). After stirring overnight at ambient temperature, the reaction was poured into ether (200 ml). This mixture was washed with 10% HCl (2×20 ml), and saturated brine (2×25 ml) and the resulting ethereal solution was dried (MgSO4). Evaporation gave the title compound as a pale yellow solid which was used in the next step without further purification. NMR (CDCl3) δ4.13 (2H, s), 2.08 (3H, s), 1.26 (6H, s).
Reaction SMILES: Br[CH:2]([CH:8](Br)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.COC1C=C(C(=O)C#CC(OC)=O)C=CC=1OC>C(Cl)Cl>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:9](=[O:10])[C:8]#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: CCOC(=O)C(Br)C(Br)C(=O)c1ccc(OC)c(OC)c1
Agent: COC(=O)C#CC(=O)c1ccc(OC)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C#CC(=O)c1ccc(OC)c(OC)c1
Yield: 81.7 %

Procedure:
A solution of ethyl 2,3-dibromo-4-(3,4-dimethoxyphenyl)-4-oxobutanoate (4.76 g, 11.2 mmol), prepared above, in methylene chloride (20 ml) and a solution of triethylamine (4 g) in methylene chloride (5 ml) were subjected to reaction and treatment in the same manner as described above in connection with Intermediate 1. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate) to give the title compound (2.4 g, 82%) as a yellow crystal.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(Cn2cncn2)cc1
Reaction time: 20 h

Procedure:
A mixture of 1 g of 4-bromobenzyl bromide, 0.41 g of 1,2,4-triazole, 0.55 g of potassium carbonate and 33 mg of potassium iodide in 30 ml of acetone is stirred at 50° for 20 hours. The solid is removed by filtration and the solution is concentrated by evaporation. The resulting crude precursor (1) is purified by column chromatography (SiO2, hexane/ethyl acetate 1:1) and crystallised from ether; m.p. 77°-79°; 1H-NMR (CDCl3): δ=5.3 (2H,s), 7.15 and 7.5 (4H,m), 7.95 (1H,s), 8.08 (1H,m).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][OH:21])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>C(Cl)Cl>[C:12]([O:16][C:17]([NH:18][CH2:19][CH2:20][O:21][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[O:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.7 %

Procedure:
Tosyl chloride (1.50 g, 7.87 mmol) was added to a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (0.84 g, 5.2 mmol) and Et3N (1.23 mL, 8.82 mmol) in CH2Cl2 (26 mL), and the solution was stirred at room temperature for 17 h. The solution was washed with H2O (15 mL), and the aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (20% EtOAc/hexanes) gave yellow crystals (1.29 g, 79%). 1H NMR (CDCl3) δ 1.41 (s, 9H), 2.45 (s, 3H), 3.38 (m, 2H), 4.07 (m, 2H), 4.82 (br s, 1H), 7.35 (d, 2H, J=8.1 Hz), 7.79 (d, 2H, J=8.1 Hz).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[K+]>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][N:12]=[C:11]([C:23]([OH:25])=[O:24])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 11.8 g (28 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, phenylmethyl ester in 115 ml of tetrahydrofuran were added 16 ml water and 35 ml of 1N potassium hydroxide. After stirring overnight at room temperature, 115 ml water was added and the pH was adjusted to 2.5 with 1N hydrochloxic acid. The acid was filtered off, washed with water and dried in vacuo. Yield: 8.6 g; melting point 203.6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(CC(=O)C)(=O)C.C(OCCOC(=O)C)(=O)C>C([O-])(=O)CC.[Pd+2].C([O-])(=O)CC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=3[C:6]=2[CH:7]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2)cc1
Agent: [Pd+2]
Agent: CCC(=O)[O-]
Solvent: CC(=O)OCCOC(C)=O
Solvent: CC(=O)CC(C)=O
Product: Cc1ccc2oc3ccc(C)cc3c2c1
Yield: 18.7 %

Procedure:
This example was carried out under the same conditions as in Example 1 except that 15.0 g of 4,4'-dimethyldiphenyl ether, 0.038 g (0.15 m. mole) of palladium propionate, 0.015 g (0.15 m. mole) of acetylacetone and 5 ml of ethylene glycol diacetate were employed. As a result, 2.78 g (14 m. moles) of 2,8-dimethyldibenzofuran and 0.78 g (2.0 m. moles) of the dimer also obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C1C(=O)N([Br:19])C(=O)C1.O>CC(O)=O>[Br:19][C:3]1[C:2]([Cl:1])=[CH:8][C:6]([NH2:7])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (6.0 g, 34.88 mmol) and NBS (6.06 g, 34.0 mmol) in HOAc (240 mL) was stirred at 130° C. for 1 h. The reaction mixture was poured into water. The precipitate was collected by filtration and washed with petroleum ether to give 4-bromo-5-chloro-2-nitroaniline as a light brown solid (8.25 g, 96.5%). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.62 (br s, 2H), 7.29 (s, 1H). LCMS (ESI) m/z 251 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH:22]=O.O>CO>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:22][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: CO
Product: C[C@H](NCc1cc(Cl)cc(Cl)c1)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
To a solution of the amine (4) (105 mg, 0.40 mmol) and 3,5-dichlorobenzaldehyde (95 mg, 0.52 mmol) in methanol (4 mL) was added borane-pyridine complex (130 μL, 1.21 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (7) as a white solid (76 mg, Yield: 45%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Br)cccc1C=O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a 500 mL two-neck round flask charged with 3-bromo-2-hydroxybenzaldehyde (D98) (13 g, 64.7 mmol) was added DMF (300 mL). Then K2CO3 (17.88 g, 129 mmol) was added, followed with methyl iodide (18.36 g, 129 mmol) at room temperature. The resulted mixture was stirred at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered through celite and washed with EtOAc. The resulted filtration was concentrated under reduced pressure. The residue was dissolved in EtOAc (250 mL), and washed with water (100 mL), 1N HCl (100 mL×2) and brine (100 mL×2). The organic layers was dried with sodium sulphate and concentrated. The residue was purified with ISCO column chromatography to afford 3-bromo-2-(methyloxy)benzaldehyde (D99) (4.05 g) as pale yellow oil. MS (ES): C8H7BrO2 requires 213.9. found 215.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][S:10][C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C[S-]
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cnc(N)cn1
Temperature: 60 °C
Yield: 40.9 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (3.32 g, 2.87 mmol) and 2-amino-5-bromopyrazine (5.00 g, 28.73 mmol) in N,N-dimethylformamide (144 mL) was treated with 95% sodium thiomethoxide (4.24 g, 57.47 mmol). The resulting reaction mixture was heated at 60° C. for 10 h. The reaction mixture was allowed to cool to 25° C. and then was poured into a saturated aqueous sodium bicarbonate solution (500 mL). The product was extracted with ethyl acetate (5×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/7 ethyl acetate/hexanes) afforded 5-methylsulfanyl-pyrazin-2-ylamine (1.66 g, 40.9%) as an orange solid: mp 65–67° C.; EI-HRMS m/e calcd for C5H7N3S (M+) 141.0361, found 141.0357.