Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:35][O:36][C:37](=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:22][NH:23][C:24](=[O:34])[CH2:25][NH:26]C(OC(C)(C)C)=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([O:20][CH:21]([CH2:35][O:36][C:37](=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:22][NH:23][C:24](=[O:34])[CH2:25][NH2:26])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CNC(=O)CNC(=O)OC(C)(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CNC(=O)CN)OC(=O)CCCCCCC/C=C\CCCCCCCC
Reaction time: 0.5 h

Procedure:
15.20 g (19.56 mmol) 20 was taken up in 200 ml CH2Cl2 /TFA (3:1 v/v) and stirred for 30 min. Afterwards the solution was diluted with 200 ml CH2Cl2 and shaken out with 200 ml sat. NaHCO3 solution. The organic phase was dried over MgSO4 and rotary evaporated. Yield: 11.64 g (88%) 21 as an oil.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4[N:19]([CH2:28][CH2:29]O)[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.S(Cl)([Cl:42])=O>ClC(Cl)Cl>[Cl:42][CH2:29][CH2:28][N:19]1[C:18]2[CH:31]=[CH:32][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][N:8]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:13][CH2:12]3)=[CH:16][C:17]=2[N:21]=[C:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCn1c(-c2ccccc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCCn1c(-c2ccccc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reaction time: 0.33 h

Procedure:
A stirred mixture of 5.03 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-2-phenyl-1H-benzimidazole-1-ethanol and 75 parts of trichloromethane is acidified by the introduction of gaseous hydrogen chloride. Then there are added dropwise 2.4 parts of thionyl chloride at room temperature. Upon completion, stirring is continued for 20 minutes at reflux. The reaction mixture is evaporated. 100 Parts of water are added to the residue and the whole is alkalized with sodium hydrogen carbonate. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 3.1 parts of 1-(2-chloroethyl)-5-[4-(diphenylmethyl)-1-piperazinylmethyl]-2-phenyl-1H-benzimidazole; mp. 173.8°-179.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(Cl)cc1
Product: CN(C)C=CC(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 10.0 g. of p-chloroacetophenone and 25 ml. of dimethylformamide dimethylacetal is refluxed for 3 hours. Evaporation gives a thick oil which crystallized with the addition of hexane, to give the product, m.p. 78.5°-80.5° C. Recrystallization from methylene chloride and hexane provides the product of the Example as crystals, m.p. 83°-84° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:45](O)[CH2:46][OH:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CO.C(Cl)Cl>[CH:27]1[C:28]2[N:16]([C@@H:10]([CH2:11][CH2:12][C:13]([O:15][CH2:45][CH2:46][OH:47])=[O:14])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:29])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: OCCO
Reactant: O=C(O)CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: O=C(CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCO
Temperature: 0 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a solution of 22 (1.2 g, 3.10 mmol) in CH2Cl2 (20 mL) were added DCC (0.703 g, 3.40 mmol) and catalytic amount of DMAP (0.057 g, 0.46 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0° C. and ethylene glycol (0.770 g, 0.680 mL, 12.4 mmol) in CH2Cl2 (5 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The solid DCU was removed by filtration and the filtrate was evaporated under reduced pressure. The crude residue obtained was dissolved in CH2Cl2 (100 mL), washed with water (40 mL×2), brine (40 mL×2), dried over Na2SO4, filtrated and then concentrated to get a yellow residue. A flash chromatography using CH3OH:CH2Cl2 (1:99) as eluent afforded (S)-1-benzyl 5-(2-hydroxyethyl) 2-(9H-carbazol-9-yl)pentanedioate 23 (0.950 g, 71%) as a yellow gummy liquid.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Na+].[I-].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24]C1CCCCO1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1C=CC=CC=1>[CH:12]1[C:13]2[N:14]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])[C:15]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: ClCCOCCOC1CCCCO1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [I-]
Solvent: c1ccccc1
Product: OCCOCCn1c2ccccc2c2ccccc21

Procedure:
To a flask containing 100 ml benzene, 100 ml 50% NaOH, was added carbazole (2) (20 g, 0.12 mmol), 4 g benzyltriethylammonium chloride (TEBA), 1 g of NaI and 2-[2-(2-chloroethoxy)-ethoxy]-tetrahydropyran (3) (38 g, 0.12 mmol) under N2. The mixture was refluxed for 6 h.
Reaction SMILES: Cl.[Br:2][C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.[C:12]([C:14]1[CH:48]=[CH:47][C:17]([CH2:18][C@@:19]2([CH3:46])[N:23]3[C:24]([C:27]([NH:29][C:30]4([C:33](O)=[O:34])[CH2:32][CH2:31]4)=[O:28])=[CH:25][N:26]=[C:22]3[N:21]([C:36]3[CH:41]=[C:40]([Cl:42])[C:39]([F:43])=[C:38]([Cl:44])[CH:37]=3)[C:20]2=[O:45])=[CH:16][CH:15]=1)#[N:13].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Br:2][C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:33]([C:30]2([NH:29][C:27]([C:24]3[N:23]4[C@@:19]([CH2:18][C:17]5[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:48][CH:47]=5)([CH3:46])[C:20](=[O:45])[N:21]([C:36]5[CH:41]=[C:40]([Cl:42])[C:39]([F:43])=[C:38]([Cl:44])[CH:37]=5)[C:22]4=[N:26][CH:25]=3)=[O:28])[CH2:32][CH2:31]2)=[O:34])[CH3:10])=[CH:5][CH:4]=1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Reactant: C[C@@H](N)c1ccc(Br)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108 %

Procedure:
To a solution of the above (R)-1-(6-bromo-pyridin-3-yl)-ethylamine HCl salt (500 mg, 1.82 mmol) in DMF (10 mL) was added 1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (900 mg, 1.66 mmol) and diisopropylethylamine (1.45 mL, 8.30 mmol). The mixture was stirred at room temperature for 5 min. HATU (694 mg, 1.83 mmol) was added to the mixture and the clear yellow mixture was stirred for 17 h. The mixture was diluted with ethyl acetate (35 mL) and washed with water (8 mL). The organic phase was washed with 5% aqueous NaCl solution (2×10 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to pale yellow oil. The crude oil was purified via flash chromatography on silica gel, eluting with 1-6% MeOH/CH2Cl2, to afford 1.3 g of the title compound as a yellow foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C@@H:8]([CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:9](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:10])([CH3:4])([CH3:3])[CH3:2].OO.[Li+].[OH-].S([O-])([O-])=[O:36].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:30])[CH2:7][C@@H:8]([CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:9]([OH:10])=[O:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=S([O-])[O-]
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)O
Temperature: 0 °C
Yield: 73 %

Procedure:
4-(4-(S)-Benzyl-2-oxo-oxazolidin-3-yl)-3-(R)-cyclopentylmethyl-4-oxo-butyric acid tert-butyl ester (620 mg, 1.49 mmol, 1.0 eq.) was dissolved in THF (35 mL) and cooled in a 0° C. ice-water bath. Hydrogen peroxide (31 w/w %) (654 μL, 5.97 mmol, 4.0 eq.) and LiOH (72 mg, 2.98 mmol, 2.0 eq.) in water (7.5 mL) was added to the reaction mixture. The reaction stirred at 0° C. and judged to completion by LC/MS. Saturated sodium sulfite (18 mL) and sodium bicarbonate (18 mL) is added to the reaction. THF was evaporated by rotary evaporation and extracted the aqueous layer with CH2Cl2 (3×75 mL) to remove the chiral auxiliary. The aqueous layer was acidified at 0° C. with 6M HCl to pH ˜1 and extracted with ethyl acetate (4×75 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to provide 281 mg (1.10 mmol, 73%) of 2-(R)-Cyclopentylmethyl-succinic acid 4-tert-butyl ester as clear oil and used directly in Step B. HPLC-MS calcd. for C14H24O4 (M+Na+) 279.3. found 279.3.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl.[Cl-].[Na+].O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2ccc3ccccc32)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(-n2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
To 2.90 g (13 mmol) 1-(4-methoxyphenyl)-1H-indole in 80 ml anhydrous DCM at −78° C. was added 2.27 ml (24 mmol) BBr3. The solution was allowed to gradually warm to room temperature overnight. The solution was poured into a slurry of ice and water. Brine was added and the product was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated. The crude product was chromatographed on SiO2 to afford 0.73 g 1-(4-hydroxyphenyl)-1H-indole as an oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[S:9](=O)(=[O:12])([OH:11])[OH:10].C(C(CCCC)C([O-])=O)C.[K+:24]>C(OCC)(=O)C>[K+:24].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: Oc1ccc(O)cc1
Reactant: O=S(=O)(O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 77.9 %

Procedure:
Hydroquinone (10 g, 0.09 mol) was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. Temperature was slowly raised to 50-60° C. then stirred for 3-8 h. The reaction mass was then cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 16 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:69][S:70]([N:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1)(=[O:72])=[O:71]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][NH:8][C:5]1[CH:6]=[N:7][C:2]([N:76]2[CH2:77][CH2:78][N:73]([S:70]([CH3:69])(=[O:72])=[O:71])[CH2:74][CH2:75]2)=[CH:3][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CNc1cnc(N2CCN(S(C)(=O)=O)CC2)cc1-c1ccccc1C
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
6-Chloro-N-methyl-4-o-tolylpyridin-3-amine (58 mg, 0.25 mmol, prepared as described in WO2005/002577), sodium tert-butoxide (72 mg, 0.75 mmol), palladium acetate (5.6 mg, 0.025 mmol, CAS RN 3375-31-3) and BINAP (47 mg, 0.075 mmol, CAS RN 76189-55-4) were dissolved in toluene (3 mL) and stirred under an argon atmosphere for 10 minutes. 1-(Methylsulfonyl)piperazine (82 mg, 0.5 mmol, CAS RN 55276-43-2) was added and the reaction mixture was sealed and heated to 150° C. under microwave irradiation for 30 min. The reaction mixture was loaded directly onto a silica gel column (elute with EtOAc) to yield the desired compound (39 mg, 43%) as a brown oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([Cl:10])=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc(Cl)c1Cl
Yield: 115.7 %

Procedure:
1 g (6.1 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 5 ml of DMF. To this solution was added 0.98 g (7.32 mmol) of N-chlorosuccinimide. The solution was poured onto 100 ml of cool water. The formed precipitate was filtered, washed with water and dried to yield 1.4 g (80%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])[CH:22]=[C:21]([Cl:31])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:19][OH:20])[C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:32][O:20][N:19]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:24][C:23]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])=[CH:22][C:21]=2[Cl:31])=[CH:10][CH:11]=1)[C:16](=[O:18])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)C(=NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(C)=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
0.8 g of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-propane-1,2-dione 1-oxime, 0.43 g of potassium carbonate and 0.26 g of methyl iodide are stirred in 10 ml of dimethylformamide at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phase and purification over silica gel, the title compound is obtained. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 2.51 (s, 3H), 4.08 (s, 3H), 4.15 (t, 2H), 4.29 (t, 2H), 4.59 (d, 2H), 6.11 (t, 1H), 6.83 (s, 2H), 6.95 (d, 2H), 7.30 (d, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([OH:13])[CH:9]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:13][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:12][N:11]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1cc(-c2ccccc2Cl)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2Cl)on1
Yield: 87.9 %

Procedure:
5-(2-Chlorophenyl)-3-hydroxy-isoxazole (0.23 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.35 g, 88%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:25])=[C:7]([CH3:24])[N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][C:3]=1[CH3:26].Cl[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29]>>[CH2:31]([O:30][C:28]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:25])=[C:7]([CH3:24])[N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][C:3]=1[CH3:26])=[O:29])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOC(=O)Cl
Reactant: COC(=O)c1ccc(Cn2c(C)c(C)c3cc(C)c(N)cc32)c(OC)c1
Product: CCCCOC(=O)Nc1cc2c(cc1C)c(C)c(C)n2Cc1ccc(C(=O)OC)cc1OC
Yield: 99 %

Procedure:
Similarly, starting from methyl 4-(6-amino-2,3,5-trimethylindol-1-ylmethyl)-3-methoxybenzoate and butyl chloroformate, methyl 4-[6-(butoxycarbonyl)amino-2,3,5-trimethylindol-1-ylmethyl]-3-methoxybenzoate (Example 39) was obtained in 99% yield as a white solid; partial NMR: 0.9 (t, 3H, CH2CH3), 1.3 (m,2H,CH2CH3), 1.5 (m,2H, CH2OCH2 0), 4.1 (t,2H,CH2O), 4.1 (t,2H,CH2O).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH2:11]([C:13]1[NH:17][N:16]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])[CH:14]=1)[CH3:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:17]1[C:13]([CH2:11][CH3:12])=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])=[N:16]1)=[O:10]
Reactant: CCc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Potassium carbonate (0.72 g, 5.2 mmol) and methyl isocyanate (0.29 g, 5.0 mmol) were added to a solution of 5-ethyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (1.58 g, 5.2 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellow solid of N-methyl-5-ethyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.68 g, yield: 38.0%). mp: 89-91° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.29 (t, J=7.4 Hz, 3H), 2.91 (d, J=5.0 Hz, 3H), 3.09 (q, J=7.4 Hz, 2H), 5.92 (s, 1H), 6.55-6.85 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.85 (dd, J=2.1 and 8.7 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][CH2:16][C:15]=2[N:14]=1>C(Cl)(Cl)Cl>[C:26]([O:25][C:23]([N:18]1[CH2:17][CH2:16][C:15]2[N+:14]([O-:6])=[C:13]([Cl:12])[CH:22]=[CH:21][C:20]=2[CH2:19]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cl)ccc2C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2c(ccc(Cl)[n+]2[O-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
3-Chlorobenzoperoxoic acid (241 mg, 1.4 mmol) was added to a solution at 0° C. of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (250 mg, 0.93 mmol, see Example 1 procedure) in CHCl3 (3 mL). The reaction mixture thus obtained was warmed to room temperature and stirred overnight. After concentration, the residue was purified by flash chromatography on silica gel eluting with 0% to 80% EtOAc in hexane to give the title compound (150 mg, 56.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (9H, s), 3.11 (2H, m), 3.77 (2H, t, J=6.16 Hz), 4.60 (2H, s), 6.99 (1H, d, J=8.41 Hz), 7.40 (1H, d, J=8.41 Hz) ppm; LC/MS m/z: 285 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][CH:9]=1)(=[O:3])[CH3:2].[Na].[CH2:12]([OH:14])[CH3:13]>>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:14][CH2:12][CH3:13])[S:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)Nc1csc(Br)n1
Agent: [Na]
Product: CCOc1nc(NC(C)=O)cs1

Procedure:
Following the procedure of Example 1 4-acetamido-2-bromothiazole is treated with sodium in absolute ethanol to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>CCOC(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:7]=[CH:6][C:5]([C:8]4([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: OC1(c2ccc(I)cc2)CCNCC1
Solvent: CCOC(C)=O
Product: OC1(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)CCNCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 4-(4-iodophenyl)piperidin-4-ol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.78 g (61% of theoretical); C24H21ClN2O (M=388.889); calc.: molpeak (M+H)+:389/391 (Cl); found: molpeak (M+H)+:389/391 (Cl); Rf value: 0.86 (silica gel, EtOAc/cyc 4:1).
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1.Cl.O1CC[CH2:24][CH2:23]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C[CH2-].C[CH2-].[Zn+2]>[CH2:23]([C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1)[CH3:24]
Reactant: Cn1c(=O)cc(Cl)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: C1CCOC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [CH2-]C
Product: CCc1cc(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 56) (1.12 g) in THF (tetrahydrofuran) (30 ml) were added under nitrogen atmosphere bis(tri-tert-butyl phosphine)palladium (188 mg) and zinc diethyl (1.1 M hexane solution, 10 ml) and the resulting mixture was stirred at room temperature for twenty minutes. The reaction solutions were added into 1 N (normality) of hydrochloric acid and the resulting mixture was extracted with ethyl acetate (50 ml×2). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-ethyl-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (0.94 g).