Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH3:2].[F:14][C:15]([F:26])([F:25])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C1(C)C=CC=CC=1.[Cu]I.CN[C@@H]1CCCC[C@H]1NC>[F:26][C:15]([F:14])([F:25])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:7][CH:8]=2)[N:17]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of ethyl-4-bromophenylacetate (875 mg, 3.60 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (570 mg, 3.00 mmol), potassium carbonate (842 mg, 6.10 mmol), copper (I) iodide (5 mol %, 29 mg, 0.15 mmol), and (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (20 mol %, 85 mg, 0.60 mmol) in toluene (2 ml) was stirred under an atmosphere of argon at 130° C. in a microwave reactor for 1 h. Further copper (I) iodide (10 mg, 0.05 mmol), and (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (30 mg, 0.21 mmol) was added and heating continued at 130° C. for a total of 4 h. The reaction mix was cooled and added to a 20 g pre-packed silica column and eluted with 0-20% ethyl acetate in petroleum ether to give the title compound as a brown oil (0.92 g, 87%).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:33]([OH:36])[C:34]#[CH:35]>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:35]#[C:34][CH2:33][OH:36])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCO
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(C#CCO)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 12, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with prop-2-yn-1-ol to give the title compound as light brown oil. MS: 477.3 (MH+).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([NH:28]CC(O)=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[NH2:28][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCC=Cc1ccccc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Product: NCC=Cc1ccccc1

Procedure:
Aminomethyl styrene resin was prepared from chloromethyl styrene resin (Polumer Laboratories, PL-CMS Resin, 1.0 meq/g) using the procedure of Weinshenker. Weinshenker, N. M.; Shen, C. M.; Wong, J. Y., Organic Synthesis, vol. 56, pp. 95-99. The aminomethyl resin was coupled with N-(Fmoc)glycine using a procedure similar to that described in Example 7. The Fmoc group was removed using a procedure similar to that described in Example 8. This sequence was repeated three times to give the title compound, which has three glycine residues attached to the polystyrene resin.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[CH2:11](OC(OCC)OCC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[O:10]1[C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=[CH:11]1
Reactant: Nc1ccc(O)cc1O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc2ncoc2c1

Procedure:
4-Aminoresorcinol hydrochloride (3.0 g, 18.5 mM), triethylorthoformate (9.1 g, 61.4 mM), and pyridinium-p-toluenesulfonate (PPTS, 250 mg, 1.0 mM) were refluxed in xylenes (200 mL) for about 18 hours. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (200 mL) and washed with H2O (3×150 mL). The combined aqueous layer was back extracted with ethyl acetate (200 mL) and the combined organic layer was dried over MgSO4. Filtration and concentration provided an oil that was filtered through a silica gel column eluted with 1% methanol/methylene chloride to provide a brown solid, 1.66 g; m.p., 118-121° C.
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:22][CH3:23])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12](Cl)=[O:13]>>[CH3:1][CH:2]([NH:6][C:12](=[O:13])[C:11]1[CH:10]=[C:9]([O:8][CH3:7])[C:17]([O:18][CH2:19][C:20]#[CH:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)N
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Product: C#CCOc1c(OC)cc(C(=O)NC(C)CCC)cc1OC

Procedure:
According to the same method as that of Production Example 1, 1-methylbutylamine was used in place of 2,2-dimethylpropylamine, 3,5-dimethoxy-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1-methylbutyl)-3,5-dimethoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 56 of the present invention) represented by the formula:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH:20]=[O:21])=[CH:16][CH:17]=1
Reactant: OCCCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 51.6 %

Procedure:
A solution of oxalyl chloride (1.32 mL, 15.1 mmol) in dichloromethane (40 mL) was stirred at −78° C. and treated dropwise with dimethyl sulfoxide (2.21 mL, 31.1 mL) over 5 minutes. The resulting solution was stirred for 35 minutes at −78° C. A solution of 3-(4-fluorophenyl)-propan-1-ol (1.50 g, 9.73 mmol) in dichloromethane (12 mL) was added over 5 minutes, and stirring continued at the same temperature for 50 minutes. Triethylamine (4.41 mL, 31.6 mmol) was added, and the cooling bath was replaced by an ice-water bath. The resulting slurry was stirred for one hour, then was diluted with dichloromethane. The resulting mixture was washed with half-saturated aqueous ammonium chloride, then with saturated sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The resulting orange oil was distilled in a short-path apparatus at 50° C. and 0.2 Torr pressure to provide a colorless liquid (764 mg, 50%). 1H NMR (300 MHz, CDCl3) δ9.83 (t, J=1 Hz, 1H), 7.17 (m, 2H), 6.99 (t, J=9 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.79 (tt, J=7, 1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][CH:18]([CH3:22])[C:19](Cl)=[O:20].Cl>O.COCCOC>[Cl:11][C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[CH:18]([CH3:22])[CH3:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reaction time: 2 h

Procedure:
4-Amino-2-chlorobenzoic acid was stirred in water (60 ml) and 1,2-dimethoxyethane (25 ml) with sodium bicarbonate (5.04 g) and the brown suspension cooled to 0°-5° C. 2-Methylpropionyl chloride (4.26 g) was added dropwise over 10 minutes with vigorous stirring, and the mixture was then stirred at 0°-10° C. for 2 hours. The mixture was poured into 2M hydrochloric acid and the pale brown precipitate washed with water and filtered and dried to give 2-chloro-4-(2'-methylpropionamido)benzoic acid as a pale brown crystalline solid (6.30 g), m.p. 206°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[NH2:17][OH:18]>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[N:17][OH:18])[CH2:7][CH2:6]1
Reactant: NO
Reactant: O=C1CCN(Cc2ccccc2Cl)CC1
Agent: Cl
Product: ON=C1CCN(Cc2ccccc2Cl)CC1

Procedure:
1-(2-Chlorobenzyl)-4-piperidone oxime is prepared from 1-(2-chlorobenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: C1O[CH:4]([C:5]2[C:6]([C:10]3[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)=[N:7][NH:8][CH:9]=2)OC1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>>[N+:15]([C:12]1[O:11][C:10]([C:6]2[C:5]([CH:4]=[N:20][OH:21])=[CH:9][NH:8][N:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]cc2C2OCCO2)o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-c2n[nH]cc2C=NO)o1
Yield: 94 %

Procedure:
Following the same procedure, react 2.5 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehye ethyleneacetal in a similar manner with 0.9 g of hydroxylamine hydrochloride and 0.8 g of sodium acetate to obtain a 94% yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehydeoxime.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl.C(OC(=O)C)C>C1COCC1>[CH3:26][C:20]1[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[CH2:18][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:12][CH2:13]1)=[O:27]
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(C(=O)O)cs3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a solution of 2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (10.46 g, 27.06 mmol) in THF (30 mL) is added aqueous solution of sodium hydroxide (2 M, 20.3 mL) at RT. After stirring 3 h at RT, the reaction mixture is acidified with aqueous solution of HCl (2 M) until pH 2-3, and ethylacetate (30 mL) is added to the reaction mixture, and layers are separated. The aqueous layer is extracted with ethyl acetate (20 mL) and the combined organic layers are washed with brine (10 mL), dried over sodium sulafte, filtered, and evaporated under reduced pressure to give 2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid (5.9 g, 60.8%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=1.55-1.65 (m, 2H), 2.01-2.12 (m, 2H), 2.15 (s, 3H), 2.22 (s, 3H), 2.77-2.86 (m, 1H), 3.18-3.29 (m, 1H), 3.65 (d, 2H), 3.98-4.07 (m, 1H), 4.45-4.53 (m, 1H), 6.90 (s, 1H), 6.92 (s, 1H), 6.93 (s, 1H), 7.04 (d, 1H), 8.49 (br, 1H), 12.95 (s, 1H). MS: m/z=359 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][CH3:31])[CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.I[CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:33]([CH3:35])[CH3:34])=[C:25]([O:30][CH3:31])[CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Trans-N—((R)-1-(4-Fluorophenyl)ethyl)-4-(4-hydroxy-3-methoxyphenylsulfonamido)cyclohexanecarboxamide (Example 2, 14 mg, 0.031 mmol), 2-iodopropane (4 ul, 0.037 mmol), K2CO3 (21 mg, 0.155 mmol) and tetrabutylammonium iodide (TBAI, 3 mg, cat) were dissolved in DMF (0.5 ml) and the reaction was stirred at room temperature for 15 hr under nitrogen. LCMS indicated that the reaction was complete, and the crude material was purified via reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA). Fractions containing the product were lyophilized to yield the title compound as a white solid (6.4 mg, 42%). MS MH+ 493.1
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[Si:1]([O:8][CH:9]1[CH2:13][NH:12][C@@H:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)cc1[C@H]1CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)cc1[C@H]1CC(O[Si](C)(C)C(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
To a solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylate (2.648 g, 6.222 mmol) in CH2Cl2 (26 mL) at 0° C. was added TFA (9.3 mL). The resulting mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was azeotroped with toluene-CH2Cl2 (2×) and dried under reduced pressure to provide (R)-4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetate (assumed to be a mixture of cis and trans isomers; 2.92 g, 106.8% yield), which was used directly without further purification. LC/MS (ES+APCI) m/z=326.3 (M+H).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5]Br.N1(N[C:19](=[O:27])[CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])CCCCC1.S(=O)(=O)(O)O>C(OCC)C>[CH2:22]([O:21][C:20]([O:24][CH2:25][CH3:26])([CH2:5][C:4]1[C:3]([Cl:2])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11])[CH:19]=[O:27])[CH3:23]
Reactant: CCOC(OCC)C(=O)NN1CCCCC1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(C=O)(Cc1c(Cl)cccc1Cl)OCC
Temperature: 25 °C

Procedure:
2.4 g of magnesium turnings are covered with 100 ml of dry diethyl ether. To that mixture is then added dropwise a solution of 24 g of 2,6-dichlorobenzylbromide in 50 ml of dry diethyl ether at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour, then is cooled to room temperature. The reaction mixture is then added dropwise, over a period of 2 hours, to a cooled (0°-5° C.) solution of diethyoxyacetic acid piperidinyl amide (21.5 g) in 100 ml of diethyl ether. After the addition is complete, the reaction mixture is stirred for an additional hour at 5° C. The mixture is then poured into cold sulfuric acid (400 ml of water containing 30 ml of concentrated sulfuric acid). The ether layer is separated and evaporated to dryness. The residue, which consists of crude 2,6-dichlorobenzylglyoxal diethylacetal, is distilled under reduced pressure (130°-140° C./1 mmHg) and used in Example 49(b) and 50(a) set forth below.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([S:13]([O-:16])(=[O:15])=[O:14])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+]>O=S(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1([S:13]([O:16][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:15])=[O:14])[CH2:11][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])C1(COCc2ccccc2)CC1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOS(=O)(=O)C1(COCc2ccccc2)CC1

Procedure:
A mixture of potassium 1-(benzyloxymethyl)cyclopropanesulfonate in SOCl2 (35 mL) and DMF (3.5 mL) was refluxed for 1.5 h and excess SOCl2 was removed under reduced pressure. Water was added carefully to the resulting mixture and extracted with ethyl acetate. The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% ethyl acetate/hexanes) to obtain 1-(benzyloxymethyl)cyclopropanesulfonyl chloride 2 in 97% yields (3.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[CH2:44](Cl)[CH:45]=[CH2:46]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:29]([CH2:46][CH:45]=[CH2:44])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: C=CCCl
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: C=CCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 7.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (+)-1-(3,4,5-trimethoxybenzoyl)-3-(2-hydroxyethyl)-3-phenylpyrrolidine) and allyl chloride to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:18]2[CH:17]=[C:16]([NH:15][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:30])[CH:21]=[CH:20][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Oc2ccc(F)cc2)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
4-[3-(4-fluoro-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (15 g, 0.036 mol) was dissolved in 4 N HCl in dioxane (160 mL) and stirred overnight at room temperature. The volume of the reaction was reduced to remove most of the dioxane and the residue was filtered to afford piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide hydrochloride (11.7 g, 96%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH:16][CH2:17][CH:18]=[CH2:19])[CH:14]=[CH2:15]>CN(C=O)C>[CH2:13]([N:16]([CH2:17][CH:18]=[CH2:19])[C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:14]=[CH2:15]
Reactant: C=CCNCC=C
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: C=CCN(CC=C)c1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
In DMF was dissolved 1.50 g (6.8 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then 1.56 9 (16.1 mmol) of diallylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:15) to give 1.17 g (yield: 61.1%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH3:29])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[O:11].O[C:31]1C=CC(C(=O)CCC)=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH2:29][CH3:31])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])=[CH:14][CH:13]=1)=[O:11]
Reactant: CCCC(=O)c1ccc(O)cc1
Reactant: CC(Sc1ccccc1O)C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Product: CCC(Sc1ccccc1O)C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1

Procedure:
The intended compound was obtained according to the method of Reference Example 1-1-(1), (2), (3), according to a method similar to it, and according to a combination of the method with an ordinary method, but using 4′-hydroxybutyrophenone as the starting material. 1HNMR (400 MHz, CDCl3, ppm): 1.02-1.19 (18H, m), 1.21-1.32 (3H, m), 1.80-2.05 (211, m), 4.36 (1H, t, J=6.9 Hz), 6.77-7.02 (4H, m), 7.22-7.37 (2H, m), 7.77-7.79 (2H, m)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](\C)/[CH:7]=[CH:8]/C1CCCC=1Br)[CH3:2].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.C(C1C(C)(C)CCCC=1C)#C.C#C>C1C=CC=CC=1.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.[Cu]I>[CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH:7]=[CH2:8])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C1=C(Br)CCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: C=CC=CC(=O)OCC
Reaction time: 4.5 h

Procedure:
(2E,4E)-5-(2-Bromo-cyclopent-1-enyl)3-methyl-penta-2,4-dienoic acid ethyl ester (1.43 g) was dissolved in 5 ml of benzene. At ambient temperature was added successively: 293 mg of Pd(Ph3P)4, 95 mg of CuI, 147 mg of (Ph)3P, and 8 ml of piperidine. To this mixture was added via dropping funnel within 1 hour 2-ethynyl-1,3,3-trimethyl-1-cyclohexene (745 mg) dissolved in 5 ml of benzene. After 4.5 hours, additional acetylene (350 mg) was added and stirring continued for 30 minutes. The mixture was then poured into crushed ice/HCI, extracted with EtOEt, washed twice with water, dried over Na2SO4, and evaporated to dryness. Medium pressure chromatography (SiO2, hexane/AcOEt=98/2) yielded 1.478 g of (2E, 4E)-3-Methyl-5-(2,6,6-trimethyl-cyclohex-1-enylethynyl)-cyclopent-1-enyl]-penta-2,4-dienoic acid ethyl ester as a yellow oil.
Reaction SMILES: Br.Br[C:3]1[CH:14]=[N:13][C:6]2[NH:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=2[CH:4]=1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>>[C:20]([O:19][C:15](=[O:18])[CH:16]=[CH:17][C:3]1[CH:14]=[N:13][C:6]2[NH:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=2[CH:4]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CN1CCNc2ncc(Br)cc2C1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Br
Product: CN1CCNc2ncc(C=CC(=O)OC(C)(C)C)cc2C1
Yield: 55 %

Procedure:
7-bromo-4-methyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine hydrobromide (2.0 g, 6.2 mmol) was subjected to Heck coupling with tert-butyl acrylate to give crude product. Purification by silica gel chromatography (CH2Cl2:MeOH:NH4OH/95:4.95:0.05) gave the title compound as a brown oil (970 mg, 55%), 1H NMR (300 MHz, CDCl3) 8.11 (d, J=2.1 Hz, 1H), 7.52 (d, J=2.2 Mz, 1H), 7.47 (d, J=16.0 Hz, 1H) 6.22 (d, J=16.0 Hz, 1H), 3.64 (s, 2H), 3.27-3.31 (m, 2H), 2.83-2.88 (m, 2H), 2.44 (s, 3H), 1.52 (s, 9H); MS (ESI) m/e 290 (C16H23N3O2+H)+.