Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](C1C=CC=CC=1)(=[O:17])C.C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]1([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:15]=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccccc1
Reactant: C=C(c1ccccc1)c1ccccc1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=CC=C(c1ccccc1)c1ccccc1

Procedure:
First, a Grignard's reagent prepared from methyl chloride and magnesium is reacted with p-amino substituted benzophenone (2), followed by dehydration, to obtain 1,1-diphenylethylene derivative (3). Alternatively, the 1,1-diphenylethylene derivative (3) can be synthesized by reacting a Grignard's reagent, prepared from p-amino substituted bromobenzene, with an acetophenone compound (5), followed by dehydration. Next, a Vilsmeier reagent prepared from phosphorus oxychloride and N,N-dimethylformamide is reacted with the 1,1-diphenylethylene derivative (3) to obtain a 3,3-diphenylacrolein derivative (6). This 3,3-diphenylacrolein derivative (6) which is a mixture of a cis-isomer and a trans-isomer is subjected to a treatment using column chromatography or recrystallization treatment or a combination of these treatments to obtain a 3,3-diphenylacrolein derivative (7) embracing excess trans-isomers. The compound (7) and a diethyl 1,1-diphenylmethyl phosphonate derivative (9) are condensed by a Wittig-Horner reaction to synthesize 1-(p-aminophenyl)-1,4,4-triphenylbutadiene derivative (1) embracing excess tans-isomers (the ratio of trans-isomer≥0.6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:21])=[O:20]
Reactant: OCCc1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccccc1Cl
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 5.26 mL (40 mMol) 2-(2-chlorophenyl)ethanol and 8.36 mL (60 mMol) triethylamine in 100 mL tetrahydrofuran were added dropwise 3.25 mL (42 mMol) methanesulfonyl chloride with cooling. The reaction mixture was stirred 4 hours at ambient and was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed sequentially with water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 9.22 gm (98.3%) of the title compound as a yellow oil. The product was used without further purification.
Reaction SMILES: [OH:1][C:2](C)([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[CH3:21]C(C)([O-])C.[K+].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>CS(C)=O.O>[N:4]1([CH:3]([CH3:21])[CH:2]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[O:1][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(COCC(C)(O)Cn2ccnc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCCCCOC(COCc1ccc(OC)cc1)C(C)n1ccnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-[2-hydroxy-2-methyl-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (3.2 g, 0.0116 mol) in dimethylsulphoxide (20 ml) at 10° C., potassium tert butoxide (2.1 g, 0.018 mol) was added in portions over 10 min. CAUTION (see, L. Bretherick, Royal Society of Chemistry, Hazards in the Chemical Laboratory, 3rd Ed. p. 307). After stirring for 5 mins. a solution of ethyl 6-bromohexanoate (2.58 g, 0.0116 mol) in dimethyl sulphoxide (5 ml) was added, the reaction mixture warmed to room temperature, and stirring continued for a further 45 min. The mixture was poured into water, neutralised with 1N hydrochloric acid and extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4) and solvent removed at reduced pressure. The title compound was isolated by column chromatography (silica gel, 3% ethanol in chloroform) as a yellow oil.
Reaction SMILES: [CH2:1]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[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].[C:23](=[O:26])([O-])[O-:24].[K+].[K+].Cl[CH2:30]Cl>ClC(OC)=O.O>[CH3:30][O:24][C:23](=[O:26])[NH:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:1][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])=[CH:22][CH:21]=1
Reactant: ClCCl
Reactant: CCCCCCCCCCCCCCCc1ccc(N)cc1
Reactant: O=C([O-])[O-]
Agent: COC(=O)Cl
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCCCCc1ccc(NC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To the solution of 4-pentadecanylaniline (3.4 g) in dichloromethane (60 mL), methyl chloroformate (1.1 mL) and the solution of potassium carbonate (7.8 g) in water (110 mL) were added at 0° C., followed by stirring at room temperature for 14 hours. The reaction solution was poured to water, followed by extraction with dichloroethane. The organic layer was washed sequentially with 2N hydrochloric acid, water and an aqueous saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The reaction solution was concentrated under reduced pressure to obtain the title compound (3.9 g) having the following physical property values.
Reaction SMILES: [CH2:1]([C:5]([CH2:7][CH:8]([CH3:10])C)=[O:6])[CH:2](C)C.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl[C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3Cl)[C:24](=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[O:17]([C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[O:6][C:5]3[CH:1]=[CH:2][CH:10]=[CH:8][CH:7]=3)[C:24](=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Reactant: Oc1ccccc1
Reactant: CC(C)CC(=O)CC(C)C
Product: O=C1c2cccc(Oc3ccccc3)c2C(=O)c2c(Oc3ccccc3)cccc21
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
A stirred pressure reactor is charged with 183 ml of diisobutyl ketone. With stirring, 86.3 g of phenol (90%) are added. Then 103.8 g of 1,8-dichloroanthraquinone are added over 5 minutes and the reaction mixture is heated to boiling point. Distillation of water commences at 155° C. After 1.5 hours at this temperature, the reaction mixture is cooled to 35° C. and then 67 g of potassium carbonate are added. The batch is then heated to 160° C. over 90 minutes and allowed to react at this temperature for 1 hour. The reactor is then closed, heated to 175°-176° C. and kept at this temperature for 5 hours. After cooling to 30° C., the pressure in the reactor is reduced and the solvent is removed by distillation. To the reaction mixture are added 3 ml of 50% sodium hydroxide solution and the resultant 1,8-diphenoxyanthraquinone is isolated by filtration and vacuum dried, to give 141.0 g of a product with a titre of 86.2%, corresponding to a yield of 89.0%. The conversion is 99.9%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13](=[O:25])[NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[OH:24])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[OH:24])=[O:25]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)C(N)C(=O)NC1c2ccccc2CC1O

Procedure:
Compound 61 was kept in DCM-TFA 2:1 (2 mL) for 60 min at RT. The solution was co-evaporated with toluene to dryness.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[C:2]([NH:3][N:4]1[CH2:8][C:9]([CH3:10])=[N:14][NH:13][C:5]1=[O:7])(=[O:6])[CH3:1]
Reactant: CC(=O)Cn1nc(C)oc1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(=O)NN1CC(C)=NNC1=O

Procedure:
312 g of 2,3-dihydro-5-methyl-2-oxo-l,3,4-oxadiazol-3-ylacetone in 4 l of ethanol are stirred together with 200 g of hydrazine hydrate for 16 hours at 35° C. The solvent and the excess of hydrazine hydrate are evaporated in vacuo, and the residue is recrystallised from isopropanol to give 148 g (87% of the theoretical amount) of the title compound having a melting point of 197°-199° C.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]2[C:10](=[O:24])[NH:11][C:12](=[O:23])[N:13]([CH:22]=2)[C@@H:14]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37](Cl)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CO>[CH:1]1([CH:7]=[CH:8][C:9]2[C:10](=[O:24])[NH:11][C:12](=[O:23])[N:13]([CH:22]=2)[C@@H:14]2[O:21][C@H:18]([CH2:19][O:20][C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:54][CH:53]=3)[C@@H:16]([OH:17])[CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C=CC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C=CC4CCCCC4)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 54.7 %

Procedure:
Compound (2b) (320 mg, 0.95 mmol) was azeotroped three times with anhydrous pyridine. The mixture was added with anhydrous pyridine (1.5 ml) and 4,4′-dimethoxytrityl chloride (380 mg, 1.12 mmol), and subsequently with DMAP (41 mg, 0.34 mmol). Finally, triethylamine (160 μl, 1.14 mmol) was added and the mixture was stirred for 21 hours at room temperature. After characterization by TLC (CHCl3:MeOH=9:1), the product was purified using a silica gel column with the development solvent of CHCl3 and MeOH while varying the ratio of CHCl3:MeOH from 98:2 to 95:5 to obtain the target Compound (3b) as a pale yellow solid (329 mg, 0.52 mmol, yield 54%). The target compound was determined by 1H NMR for identification. Further, mass analysis was carried out by MALDI-TOF MS and it was identified as the target compound (calcd. for C38H43N2O7 [M+H]+ 639.306, found 639.496).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][CH:13]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[N:16]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:15]2[S:14]1>C(Cl)(Cl)Cl>[CH3:12][CH:13]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[N:16]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:15]2[S:14]1=[O:9]
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 1.5 h

Procedure:
A solution of 3-chloroperbenzoic acid (0.44 g.) in chloroform (5 ml.) was dropwise added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (0.92 g.) in chloroform (10 ml.) and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the precipitating crystals were filtered off and the filtrate was washed in turn with a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, followed by drying over magnesium sulfate, and then the solvent was distilled off. The residue was crystallized using a small amount of ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate-1-oxide, mp 173° to 175° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([I:9])[C:4]=1[CH2:10]Br.[C:12]1([C:18]([NH2:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[I:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]2[C:4]=1[CH2:10][N:31]([C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:2]2
Reactant: BrCc1cccc(I)c1CBr
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Ic1cccc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2 (b) from 1,2-Bis-bromomethyl-3-iodo-benzene and triphenylmethylamine. White solid.
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[CH:4]=1>ClCCl>[ClH:21].[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:14][CH2:13][CH2:12][NH:11][C@@H:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1)[CH3:1]
Reactant: COc1cccc([C@@H](C)NCCCc2ccccc2Cl)c1
Solvent: ClCCl
Product: C[C@@H](NCCCc1ccccc1Cl)c1cccc(O)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NPS R-568 (30.3 g 100 mmol) in dichloromethane at −78° C. was treated dropwise with borontribromide (50 g, 200 mmol). The reaction 40 was stirred 1 hr at rt and poured over ice. The hydrobromide was extracted from the aqueous phase with chloroform. The chloroform solubles were then washed (4×100 ml) with 50% HCl. The chloroform wash was dried over anhydrous magnesium sulfate and concentrated to afford (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride as a solid. A solution of sodium hydride (0.48 g, 20 mmol) in dimethylformamide was treated with (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride (3.25 g, 10 mmol) and the reaction stirred 1 hr at rt. The reaction was treated with iodoethane (1.71 g, 11 mmol) and stirred 16 hr at rt. Work-up and chromatography through silica using 3% methanol in chloroform afforded (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-ethoxyphenyl)ethylamine, 6T, as an oil; m/z (rel. int.) 316 (M+, 1), 302 (100), 282 (11), 196 (5), 178 (7), 149 (74), 121 (34), 103 (25), 91 (28), 77 (29).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:12]2[C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[OH:20])=[O:6])[CH:2]=[CH2:3].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)C=1.C(=O)([O-])[O-].[K+].[K+].O.C[N:43](C)C=O>>[CH2:1]([O:4][C:5]([C:7]1[C:12]2[C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[O:20][C:25]1[N:43]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[N:26]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)c1
Reactant: C=CCOC(=O)c1c(O)ccc2oc(C)c(C(=O)O)c12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=O)O)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture comprising 54.2 g of 4-allyloxycarbonyl-5-hydroxy-2-methylbenzofuran-3-carboxylic acid, 47 g of 4,6-dimethoxy-2-methylsulfonylpyridine and 65 g of potassium carbonate in 200 ml of N,N-dimethylformamide, was heated and stirred at 70° C. for two hours. The mixture was returned to room temperature, and then the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Crystals obtained by concentration under reduced pressure, were washed with isopropyl ether to obtain 79.2 g (yield: 98%) of the desired compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([F:15])=[CH:7][C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1CO)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:31]CN(C(C)C)C(C)C.C1COCC1>CCOC(C)=O>[C:10]([C:9]1[C:8]([O:13][CH3:14])=[CH:7][C:6]([F:15])=[C:5]([C@@H:3]2[O:4][CH2:31][C@H:25]3[CH2:24][N:23]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:28][CH2:27][N:26]3[CH2:2]2)[CH:12]=1)#[N:11]
Reactant: COc1cc(F)c(C(=O)CBr)cc1C#N
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 250 mL flask was added 5-(bromoacetyl)-4-fluoro-2-methoxybenzonitrile (2.00 g, 7.35 mmol), (R)—N-Boc-2-hydroxymethyl-piperazine (3.18 g, 14.7 mmol), DIEA (2.57 mL, 14.7 mmol) and THF (50 mL) and stirred at rt for 1 h; LC analysis of the reaction mixture indicated completion of the reaction. The solution was treated with EtOAc (100 mL), washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The residue was then purified over silica gel with the solvent systems of 5% MeOH in DCM to furnish the desired product. LC/MS: [(M+1)]+=408.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[CH3:14][CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].[C:21]([C:25]1[N:26]=[C:27]([C:30]2[O:31][C:32]3[CH:38]=[CH:37][C:36]([CH2:39]Cl)=[CH:35][C:33]=3[CH:34]=2)[S:28][CH:29]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[C:21]([C:25]1[N:26]=[C:27]([C:30]2[O:31][C:32]3[CH:38]=[CH:37][C:36]([CH2:39][C:15]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[CH3:14])=[CH:35][C:33]=3[CH:34]=2)[S:28][CH:29]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C(C)C
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: COC(=O)C(C)(C)Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled suspension of lithium diisopropylamide {(1.45 mM tetrahydrofuran and n-hexane solution), 3.7 ml} and methyl 2-methylpropionate (0.6 g), a dried hexamethylphosphoric triamide (0.5 ml) was added at -65 to -57° C. Subsequently, 4-tert-butyl-2-(5-chloromethylbenzofuran-2-yl)thiazole was added to the mixture in small portions. After being stirred for 30 minutes at the same temperature, additive hexamethylphosphoric triamide (1.5 ml) was added to the mixture. The reaction mixture was gradually elevated to -10° C. for 1 hour. The resulting mixture was poured into ice-water and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (20:1). The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-[5-(2-methyl-2-methoxycarbonylpropyl)benzofuran-2-yl]thiazole (0.43 g).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH3:26])=[O:11]
Reactant: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](OCC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO200687543, 1.18 g, 6.15 mmol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.33 g, 6.15 mmol) in dichloromethane (170 mL) were added HOBT (941 mg, 6.15 mmol) and N-methyl morpholine (2.02 mL, 18.45 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (2.11 g, 11.07 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight. The reaction was quenched with the addition of 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by flash column chromatography (silica, 35% ethylacetate in pet ether) afforded ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate 1.9 g (49%) as solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH3:17])=[CH:9][O:8]1)[CH3:5])[CH3:2].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@H:11]2[C@@H:10]([CH3:17])[CH2:9][O:8]1)[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@H](C)[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@@H]1OC[C@H](C)[C@@H]2CC[C@H](C)[C@@H]12
Yield: 69.4 %

Procedure:
28.0 g of (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran was dissolved in 500 mι of ethyl acetate, and after 90 mg of 10% palladium carbon was added, the reaction mixture was stirred at room temperature for 48 hours in a hydrogen gas atmosphere of 1 atm. The catalyst was filtered by celite, and the solvent was distilled off under a reduced pressure. There was thus obtained a colorless oily substance, (1S, 4R, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran. 28.0 g of this (1S, 4R, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran was dissolved in 400 mι of tetrahydrofuran without purification, and after 50 mι of 2N hydrochloric acid solution wad added, the reaction mixture was stirred for 12 hours while being cooled by ice. 300 mι of saturated sodium hydrogen carbonate solution was added to the reaction mixture, extraction was made with ethyl acetate (500 mι×3). The joined organic layer was dried by magnesium sulfate, and after filtration, the solvent was distilled off under a reduced pressure. The residue was purified by column chromatography using 200 g of silica gel, and 13.5 g of a colorless oily substance (yield=69.4%) was obtained from the hexane:ether=1:1 eluent. Since various spectral data of this colorless oily substance were in agreement with the data described in the reference ("Tetrahedron Lett.", 5325, 1968), it was determined as (4R, 4aR, 7S, 7aR)-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran-1-ol.