Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9]Cl)(=[O:4])[CH2:2][CH3:3].C1N2CN3CN(C2)CN1C3.C1N2S(=O)(=O)N3CN(C2)S(=O)(=[O:29])N1C3.ClCCCl>O>[C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH:9]=[O:29])(=[O:4])[CH2:2][CH3:3]
Reactant: O=S1(=O)N2CN3CN1CN(C2)S3(=O)=O
Reactant: CCC(=O)OCC=C(C)CCl
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)OCC=C(C)C=O
Temperature: 35 °C
Reaction time: 4 h
Yield: 26.8 %

Procedure:
The crude 4-propionyloxy-2-methyl-1-chloro-2-butene (64.0 g, 0.362 mol) obtained in the above (i) was added to a solution of hexamethylenetetramine (50.9 g, 0.363 mol) in water (345 ml), and the mixture was stirred at 35° C. for 4 hours to prepare a tetramine salt. 1,2-Dichloroethane (200 ml) was added to the reaction mixture, and compounds insoluble in water were removed by extraction. 1,2-Dichloroethane (400 ml) was further added to the aqueous layer that had been washed, and the mixture was stirred at 60° C. for 4 hours to hydrolyze the tetramine salt. After completion of the reaction, the 1,2-dichloroethane layer was separated, and 1,2-dichloroethane (250 ml) was further added to the aqueous layer for extraction. The 1,2-dichloroethane layers were combined and dried over anhydrous sodium sulfate. The 1,2-dichloroethane was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane (=1:5)) to give 4-propionyloxy-2-methyl-2-buten-1-al (15.2 g, 0.0973 mol, Yield: 26.8% ).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(Cl)ccc2n[nH]cc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(Cl)ccc2nn(C)cc12
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To a solution of methyl 5-chloro-2H-indazole-4-carboxylate (3.80 g, 18.0 mmol) in ethyl acetate (72 mL) was added trimethyloxonium tetrafluoroborate (3.47 g, 23.5 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (3.20 g, yield 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:14]=1)[CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>CC#N>[CH3:38][O:37][C:33](=[O:36])[CH:34]=[CH:35][C:16]1[CH:15]=[CH:14][C:13]([CH:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH:8]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)C2c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2c3ccc(OC)cc3CCC2c2ccccc2)cc1

Procedure:
Prepared by Heck coupling 6c and methyl acrylate in accordance with the general method described in Example IV. Yield (83%); APcI m/z: 440 (M+H+CH3CN+, 100%).
Reaction SMILES: Br[C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:23]([CH3:25])[CH3:24])[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>COCCOC>[F:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][CH2:5][C:6]([N:8]([CH:23]([CH3:25])[CH3:24])[NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]([F:37])([F:50])[F:49])[CH:29]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: COCCOc1ccc(C(=O)NN(C(=O)COc2ccc(F)cc2Br)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCOc1ccc(C(=O)NN(C(=O)COc2ccc(F)cc2-c2ccccc2OC(F)(F)F)C(C)C)cc1
Yield: 54.4 %

Procedure:
A solution of 4-(2-methoxy-ethoxy)-benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (202 mg, 0.42 mmol) in DME (5 ml)/2M Na2CO3 (0.731 ml, 1.46 mmol) was with 2-trifluoromethoxyphenylboronic acid (129 mg, 0.63 mmol) and Pd[PPh3]4 (96.5 mg, 0.084 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 45-60% ethyl acetate/hexane gradient to afford the product as a solid (129 mg, 55%). MS m/e 565.55 (M+H+)
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH:19][NH:20][C:21]([CH:23]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:26][CH2:25][N:24]1[S:39]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([F:57])[CH:55]=3)[N:50](S(CC[Si](C)(C)C)(=O)=O)[CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])=[O:40])=[O:22].C(O)(=O)C>O1CCCC1>[OH:19][NH:20][C:21]([CH:23]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:26][CH2:25][N:24]1[S:39]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([F:57])[CH:55]=3)[NH:50][CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])=[O:40])=[O:22]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)NO)CC2)c2cc(F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NO)C1CN(C(=O)OCc2ccccc2)CCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 45 °C
Yield: 71 %

Procedure:
Tetrabutylammonium fluoride (0.194 ml, 1M solution in tetrahydrofuran) was added to a solution of N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide (0.067 mg, 0.093 mmol), [prepared as described in Step 7 above] in tetrahydrofuran (1.6 ml). The reaction mixture was heated at 45° C. for approx. 20 min., and then quenched with glacial acetic acid (0.011 ml, 0.194 mmol). The reaction mixture was concentrated and the residue was chromatographed by preparatory TLC (10% methanol/methylene chloride) to give N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoroindol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide (71%), mp 85.7-89.7° C.
Reaction SMILES: [NH2:1][C:2]1[S:11][C:5]2[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([O:20][C:21](=O)C)(=O)[CH3:18]>C(OCC)(OCC)OCC>[CH2:17]([O:20][CH:21]=[N:1][C:2]1[S:11][C:5]2[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(N)sc2c1CCN(C)C2
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc2c(c1C(=O)OCC)CCN(C)C2
Yield: 97 %

Procedure:
40.0 g (167 mmol) of 2-amino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 250 ml of triethyl orthoformate were mixed with 3.2 ml of acetic anhydride and refluxed under nitrogen for 3 h. The mixture was then completely evaporated in a rotary evaporator at 80° C. 48.0 g (97%) of crude product were isolated as a dark oil which is sufficiently pure for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18](=[O:20])[CH3:19])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[CH:4][CH:3]=1.[CH2:37]([Mg]Br)[CH2:38]C.[CH2:42]1COCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([OH:20])([CH3:42])[CH2:19][CH2:37][CH3:38])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:32])[F:33])[CH:25]=2)=[CH:35][CH:36]=1
Reactant: C1CCOC1
Reactant: CC(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Reactant: CCC[Mg]Br
Solvent: O
Product: CCCC(C)(O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
7-(4-Chlorobenzyl)-3-methyl-1-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.48 mmol, example 348) was dissolved in THF (6 mL), cooled to 0° C. and 2.0 M propyl magnesium bromide in THF (0.36 mL, 0.72 mmol) was added drop wise. The reaction was stirred in the cold for 15 min then warmed to room temperature and stirred 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to a golden oil. The oil was purified using a 25 g silica gel flash column eluted with 20% ethyl acetate/hexanes to give 7-(4-chlorobenzyl)-1-(2-hydroxy-2-methylpentyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.88 g, 32% yield) as a clear oil. LCMS retention time=4.792 minutes and 98% purity, LCMS MH+=567. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8 Hz), 7.47-7.50 (m, 1H), 7.38-7.44 (m, 5H), 7.31 (d, 1H, J=8 Hz), 5.42 (s, 2H), 4.23 (s, 1H) 3.92-4.02 (dd, 2H, J=4 Hz and 16 Hz), 3.29 (s, 3H), 1.30-1.41 (m, 4H), 0.99 (s, 3H), 0.80 (t, 3H, J=8 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]1[O:23][C:22](=[O:24])[C:21]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:20]=1>CN1CCOCC1>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]([NH:20][C:21]1([C:22]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1)C(=O)O
Yield: 22.4 %

Procedure:
10 ml of N-methylmorpholine was added to 522 mg (3.5 mmol) of L-methionine and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 170 mg (22%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:21]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:21]=1
Reactant: Nc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2(=O)=O
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: Nc1ccc2c(c1)C=Cc1ccc(CO)cc1S2(=O)=O

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-amino-dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[C:31]([O-])([O-])=[O:32].[K+].[K+]>O1CCOCC1.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>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:31]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]3)=[CH:4][CH:3]=2)=[O:32])=[CH:24][CH:23]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=Cc2ccc(C(=O)c3ccc(C)cc3)cc2OC1C(F)(F)F
Temperature: 80 °C
Yield: 40.8 %

Procedure:
The ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 9a, Step 2 (3.0 g, 7.53 mmol), 4-methylphenylboronic acid (1.11 g, 8.26 mmol), K2CO3 (3.12 g, 22.59 mmol), and PdCl2(PPh3)2 (159 mg, 0.225 mmol) were mixed in dioxane (30 mL) in a sterling bomb. Carbon monoxide was bubbling to 40 psi. The reaction was heated to 80° C. for 5 h. After filtration, the reaction was quenched with NH4Cl and extracted with EtOAc. The organic layer was washed and dried over MgSO4. The filtrate was evaporated and dried in vacuo to afford yellow solid (1.2 g, 41%): LCMS m/z 391.10 (M+H). 1H NMR (CDCl3/400 MHz) 7.75 (s, 1H), 7.69 (d, 2H, J=8.0 Hz), 7.39(d, 1H, J=8.0 Hz), 7.36 (s, 1H), 7.31 (d, 1H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 7.25(s, 1H), 5.78 (q, 1H, J=6 Hz), 4.33 (m, 2H), 2.43(s, 3H), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:13]=[N:12][C:11](SC)=[N:10][C:9]=2[N:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)[CH:17]=1)=[O:5])[CH3:2].Cl[C:29]1C=C(C=CC=1)C(OO)=O.[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:13]=[N:12][C:11]([S:39]([CH3:29])(=[O:43])=[O:41])=[N:10][C:9]=2[N:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)[CH:17]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(SC)ncc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
To a solution of 8-indan-5-yl-2-methylsulfanyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.3 g, 0.79 mmol) in 5 mL of CH2Cl2, was added 3-chloroperoxybenzoic acid (m-CPBA, 69.5%, 431 mg, 1.73 mmol) portionwise. The solution was stirred at room temperature for 3 hours. An aqueous solution of 10% sodium thiosulfate was added to quench the reaction. After 30 minutes saturated sodium bicarbonate solution was added, and the aqueous solution was extracted with CH2Cl2. The combined CH2Cl2 fractions were washed with brine and dried over Na2SO4. Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:3-1:1.6, v/v) gave 0.22 g (67%) of the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.75 (s, 1H), 8.70 (s, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.24 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 4.38 (q, 2H), 3.19 (s, 3H), 3.00 (m, 4H), 2.10 (m, 2H), 1.40 (t, 3H).
Reaction SMILES: C1COCC1.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.[Cl:16][CH2:17][Si:18](Cl)([CH3:20])[CH3:19].C([Li])CCC>O.C(OCC)(=O)C>[Cl:16][CH2:17][Si:18]([CH3:20])([CH3:19])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: CCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc([Si](C)(C)CCl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
A mixture of 60 ml of THF, p-bromophenetole (9.7 gram) and chloromethyldimethylsilyl chloride (7.3 gram) was cooled in a dry ice/acetone bath. To the mixture was dropwise added 33 ml of 1.55M n-butyl lithium under an argon atmosphere. After stirring the mixture for additional 15 minutes at -78° C., the stirring was continued at room temperature for 30 minutes. The mixture was added with 6 ml of ethyl acetate and 30 ml of water, and extracted with ethyl ether. The ether extract was washed with saturated sodium chloride solution, dried, and concentrated. Distillation of the residue gave 5.5 gram of chloromethyldimethyl(4-ethoxyphenyl)silane. Physicochemical data of the product is listed in Table 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 68.6 %

Procedure:
To a solution of 1.38 g of p-chlorophenol and 0.585 g of sodium methoxide in 10 ml of methanol is added a solution of 3.53 g of methyl α-bromo-α-[p-(p-methylsulfonylphenoxy)phenyl]acetate in 15 ml of methanol. The mixture is refluxed for 20 hours, chilled and filtered to give 2.71 g of white crystals, mp 182°-183° C. Recrystallization by heating in 75 ml of acetone and adding 20 ml of dichloromethane, followed by adding hexane gives on chilling the product as white crystals, mp 182°-183° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2([CH3:17])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.C(OC(C1CCNCC1)=O)C.CC1(C(O)=O)CC1.O[Li].O>C1COCC1.CCO.O>[CH3:17][C:14]1([C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:13])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C)CC2)CC1
Agent: CC1(C(=O)O)CC1
Agent: CCOC(=O)C1CCNCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
First step: Using the general procedure I for the preparation of amide, 2.60 g of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester was prepared from 1.89 g of piperidine-4-carboxylic acid ethyl ester and 1.40 g of 1-methyl-cyclopropanecarboxylic acid as a light yellow oil. ES-MS m/e: 240.3 (M+H+). Second step: To a stirred solution of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (2.60 g, 0.011 mmol) in THF, EtOH, H2O (50 ml, 1/1/1) was added LiOH.H2O (686 mg, 16.3 mmol). After two hours at RT, the reaction mixture was concentrated under vacuo. The crude residue was diluted in CH2Cl2 and aqueous HCl (1N) was added until pH=2. The organic phase was collected, dried over Na2SO4 and concentrated under vacuo to afforded 1.98 g (86%) of the title product as a white powder. ES-MS m/e: 212.1 (M+H+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.Cl.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1)([O-:21])=[O:20]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:16]([O:15][C:13]([CH:4]1[CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][C:7]2[C:26]3[C:25](=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[NH:28][C:2]=2[CH2:3]1)=[O:14])[CH3:17]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C1CCC(=O)CC1C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCOC(=O)C1Cc2[nH]c3ccc([N+](=O)[O-])cc3c2CC1C(=O)OCC
Yield: 21 %

Procedure:
To 50 ml of acetic acid were added 2.4 g of diethyl 4-oxocyclohexane-1,2-dicarboxylate, 3.0 g of zinc chloride and 1.9 g of 4-nitrophenylhydrazine hydrochloride. The mixture was refluxed for 4 hours. Then, acetic acid was removed by distillation under reduced pressure. To the residue were added 100 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with diluted hydrochloric acid, an aqueous saturated sodium chloride solution, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from iso-propyl alcohol to obtain 750 mg (yield: 21%) of diethyl-6-nitro-1,2,3,4-tetrahydrocarbazole-2,3-dicarboxylate as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH-:9].[K+].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1OCCOCCOCCOCCOCCOC1>[CH2:17]([O:9][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1ccccc1
Reactant: [OH-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: Brc1cccc(OCc2ccccc2)n1

Procedure:
A stirred mixture of 2,6-dibromopyridine (3.55 g), benzyl. alcohol (1.63 g), potassium hydroxide (1.68 g), 18-Crown-6 (0.20 g) and toluene (25 ml) is heated under reflux for 30 minutes. The cool solution washed with water and brine, dried (MgSO4) and evaporated to give an oil which is vacuum-distilled (Kugelrohr) to give 3.85 g of 2-benzyloxy-6-bromopyridine, bp 220-225° C./1.0 mm.
Reaction SMILES: CO[C:3](=[O:33])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([OH:28])=[C:22]([O:29][CH3:30])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH2:44]>>[C:24]([OH:26])(=[O:36])[CH3:25].[CH3:27][O:26][C:24]1[CH:25]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:18])=[NH:15])=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:33])[N:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[N:44]=2)[CH:21]=[C:22]([O:29][CH3:30])[C:23]=1[O:28][CH2:23][CH2:24][O:26][CH3:27]
Reactant: COc1ccccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(O)c(OC)c1
Agent: Cl
Product: CC(=O)O
Product: COCCOc1c(OC)cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3OC)c(=O)[nH]2)cc1OC

Procedure:
The same procedure was carried out as in Example (6a), except that {2-(4-hydroxy-3,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (86a)) was used instead of the {2-(3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in Example (6a), and 2-methoxyphenylhydrazine hydrochloride was used instead of 2-hydrazinopyrimidine, to give the title compound.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][C:10](OC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C/C=C/c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC/C=C/c1ccccc1

Procedure:
In an analogous manner to that described in Example 5(b), by reducing methyl (E)-4-phenyl-but-3-enoate by means of lithium aluminium hydride in tetrahydrofuran there was obtained (E)-4-phenyl-but-3-en-1-ol, which was converted into (E)-4-phenyl-but-3-enyl methanesulphonate in analogy to the procedure described in J.Chem.Soc. Perk.Trans. 1 (1988), (6),1517-1519 for the preparation of the (Z) isomer.