Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:12]2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>CO.CC(O)C.Cl>[C:25]1([CH2:24][CH:13]2[CH2:12][CH:11]([N:8]3[CH2:7][CH2:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:10][CH2:9]3)[CH2:16][CH2:15][NH:14]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)NC1(c2ccccc2)CCN(C2CCN(C(=O)OC(C)(C)C)C(Cc3ccccc3)C2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CC(=O)NC1(c2ccccc2)CCN(C2CCNC(Cc3ccccc3)C2)CC1
Yield: 7.9 %

Procedure:
A mixture of intermediate 19 (0.081 mol) in CH3OH (300 ml) and 2-propanol in HCl (30 ml) was stirred and refluxed for 2 hours. The solvent was evaporated The residue was taken up in water/DIPE and the mixture was separated into its layers. The aqueous layer was alkalized with NaOH and CH2Cl2 was added. The combined organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). Two pure fractions were collected and their solvents were evaporated, yielding 3 g of fraction 1,2 g fraction 2 and 2.5 g of (±)-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinyl]acetamide (intermediate 20). Fraction 1 was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:2) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 0.24 g (±)-cis-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinyl]acetamide dihydrochloride. dihydrate (intermediate 21). Intermediate 20 was repurified by column chromatography oversilica gel (eluent: CH2Cl2/(CH3OH/NH3)95/5). The pure fractions were collected and the solvent was evaporated The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:2) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 0.44 g of (±)-trans-N-[4-phenyl-1-[2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-4-piperidinyl]acetamide dihydrochloride dihydrate (intermediate 22). Less pure fractions (20 g) were repurified by HPLC over silica gel (eluent: CH2Cl2/(CH3OH/NH3)95/5). Two pure fraction groups were collected and their solvent was evaporated, yielding 6.5 g (±)-cis-N-[4-phenyl-1-[2-(phenylmethyl)-4-piperidinyl]-4-piperdinyl]acetamide (intermediate 23) and 7.2 g (±)-trans-N-[1-[2-(phenylmethyl)-4-piperidinyl]-4-phenyl-4-piperidinyl]acetamide (intermediate 24).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=O)[CH:6]=[CH:7][CH:8]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([O-])(=O)C.[NH4+:38].[OH-].[NH4+:40]>C(O)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[NH:38][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:40]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cccc(C(=O)C(=O)c2ccncc2)c1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cccc(-c2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2ccncc2)c1
Temperature: 25 °C

Procedure:
1-(3-Methoxyphenyl)-2-pyridin-4-ylethane-1,2-dione (1.93 g, 8.0 mmol), 4-formylpiperidine-1-carboxylic acid tert-butyl ester (1.7 g, 8.0 mmol) and ammonium acetate (6.2 g, 80 mmol) were dissolved in acetic acid (20 mL) and heated to reflux for 2 hours, then allowed to cool to ambient temperature. The reaction mixture was poured over an ammonium hydroxide (50 mL) and ice mixture, extracted with ethyl acetate (3×125 mL) and the combined organic layers dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was chromatographed on silica gel eluting with ethyl acetate to give the imidazole as a foam (1.2 g), which was used without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([CH:21]=O)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][O:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][O:25]/[N:24]=[CH:21]/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1
Reactant: O=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NOCCO
Agent: Cl
Product: OCCO/N=C/c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 45 %

Procedure:
The title compound was prepared from 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbaldehyde and 2-(aminooxy)ethanol hydrochloride in 45% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CD3OD), ppm 9.27 (s, 1H), 8.84 (m, 1H), 8.36 (s, 1H), 8.34 (d, 1H), 8.01 (d, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.39 (t, 2H), 3.87 (t, 2H). LCMS (method B): [MH]+=350, tR=1.94 min.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([S:12][CH2:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:15](O)=[O:16])(=[O:11])[CH3:10].OC1C2N=N[NH:32]C=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:9]([S:12][CH2:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:15]([C@H:3]1[CH2:4][CH2:5][CH2:6][NH:7][C:1](=[O:8])[CH:2]1[NH2:32])=[O:16])(=[O:11])[CH3:10]
Reactant: O=C1CCCCCN1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)[C@H]1CCCNC(=O)C1N
Reaction time: 18 h

Procedure:
Combine 3(S)-amino-:-caprolactam (0.28 g,2.2 mmol), 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (0.50 g,2.0 mmol) and hydroxybenzotriazole (HOBT) (0.33 g,2.2 mmol) in DMF (10ml). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC) (0.42 g,2.2 mmol). Stir 18hr, partition between EtOAc and H2O, dry and concentrate. Chromatograph on silica, eluting with diethyl ether (Et2O) to obtain the title compound as a foam,[α]D26 =-31.3° (EtOH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:20](O)=[O:21])[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].S(Cl)(Cl)=O.Cl[CH2:28][CH2:29]Cl>CN(C)C=O>[CH2:12]([N:8]([CH2:7][C:29]1[CH:28]=[CH:4][CH:6]=[CH:10][CH:9]=1)[C:20]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCl
Reactant: CCOC(=O)C1(C(=O)O)CC(=O)N([C@@H](C)c2ccccc2)C1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(RS)-3-Ethoxycarbonyl-1-((S)-α-methylbenzyl)-5-oxopyrrolidine-3-carboxylic acid (30.5 g) was dissolved in 1,2-dichloroethane (92 ml), and thionyl chloride (11 ml) and one drop of N,N-dimethylformamide were added. The mixture was refluxed for 2 hours and the reaction mixture was concentrated under reduced pressure. The obtained oil was dissolved in toluene (39 ml) and the mixture was dropwise added to a solution of dibenzylamine (23.7 g) and triethylamine (12.2 g) in toluene (130 ml) under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, a sodium hydrogencarbonate-10% aqueous hydrochloric acid solution and water, and dried over anhydrous magnesium sulfate to give the object compound.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[NH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1.[OH-].[Na+]>ClCCl.O>[NH2:7][C:8]1[C:12]([S:3][C:2]([F:6])([F:5])[F:1])=[CH:11][N:10]([CH3:13])[N:9]=1
Reactant: FC(F)(F)SCl
Reactant: Cn1ccc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(SC(F)(F)F)c(N)n1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfenyl chloride (11.6 g, 85.0 mmol) was added to a solution of 3-amino-1-methylpyrazole (8.0 g, 82.4 mmol) in 150 mL of dichloromethane with stirring at a rate such that the temperature did not rise above 5° C. When the addition was complete the mixture was allowed to warm to ambient temperature and stir for 18 hours and was then purged with nitrogen gas for 1 hour to remove any unreacted trifluoromethanesulfenyl chloride. The solid that formed during the reaction was collected by filtration and the filtrate was concentrated by evaporation under reduced pressure to obtain additional solids. The combined solids were dissolved in water and the solution was basified with 1N aqueous sodium hydroxide. The resulting mixture was extracted with dichloromethane (2×100 mL) and the extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a solid residue that appeared to be a mixture of two compounds. This solid was recrystalized from methylcyclohexane to obtain 16.2 g (40 percent of theory) of the title compound as a yellow solid melting at 138°-140° C. The impurity was identified as 1-methyl-3-((trifluoromethanesulfenyl)amino)-4-(trifluoromethythio)pyrazole.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:23][C:22]=3[Cl:36])=[CH:11]2)(=O)=O)C=CC=CC=1.CO.[OH-].[K+]>C(O)(=O)C>[Cl:36][C:22]1[N:23]=[C:24]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[S:25][C:21]=1[CH2:20][C:12]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)[NH:10][CH:11]=1
Reactant: COc1ccc(CNc2nc(Cl)c(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)s2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNc2nc(Cl)c(Cc3c[nH]c4ncc(Cl)cc34)s2)cn1
Temperature: 80 °C

Procedure:
[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine 619 was combined with methanol: potassium hydroxide (1M) (1:1, 0.5 mL). The mixture was heated at 80° C. for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50 mm×10 mm ID) eluting with 0.1% trifluoroacetic acid in water and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0190. MS (ESI) [M+H+]+=419.9.
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[N:12]=[CH:11]1.[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:27]2=[O:38])[S:21][C:22]=1[C:23](O)=[O:24]>>[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:27]2=[O:38])[S:21][C:22]=1[C:23]([NH:16][CH2:15][C:13]1[N:12]=[CH:11][O:10][CH:14]=1)=[O:24]
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Reactant: NCc1cocn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1cocn1
Yield: 48 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-4-ylmethanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 48% yield: 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.65 (s, 1H), 6.16-6.12 (m, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.15-4.10 (m, 2H), 3.63-3.57 (m, 2H), 3.43-3.38 (m, 2H), 2.60 (s, 3H), 2.20-2.11 (m, 2H), 1.91-1.83 (m, 2H); 13C NMR (75 MHz, CDCl3) δ162.4, 157.3, 155.5, 152.8, 151.3, 151.2, 135.9, 135.8, 128.6, 124.9, 117.5, 42.9, 42.3, 41.9, 35.5, 31.7, 31.3, 30.9, 30.5, 20.2, 20.1, 17.2; MS (ES+) m/z 417.7 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:7]([C:6]([OH:13])=[O:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
315 mg of L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine tert-butyl ester was dissolved in 2 ml of dry dichloromethane, and 1 ml of TFA was added thereto. The mixture was stirred at room temperature for three hours. The solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 267 mg of L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][NH2:47])[CH2:40][CH2:39]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:47][CH2:46][CH2:45][CH2:44][N:41]3[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]3)=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: CN1CCN(CCCN)CC1
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCCN4CCN(C)CC4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl -1H-pyrrole-3-carboxylic acid and 3-(4-methylpiperazin-1-yl)propylamine using diethyl cyanophosphonate as a coupling reagent Mass: 648.20 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Product: Fc1ccc(-c2ccccc2)cc1
Yield: 93 %

Procedure:
From 4-fluoro-bromobenzene and phenyl boronic acid, yield 93%; mp 73-75° C. (lit.,9 73-75° C.); IR: 1599, 1519, 1487 and 1196; 1H NMR (400 MHz; CDCl3): 7.56-7.53 (4H, m), 7.43 (2H, d, J 7.8), 7.34 (1H, t, J 8) and 7.15-7.1 (2H, m); rr/z (EI) 172 (70%, M+), 119 (30) and 69 (100) (Found: M+, 172.068. C12H9F requires M, 172.068).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCC)ccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 17 h
Yield: 75 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (16 mg, 0.045 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 17 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:8) to furnish IV as a colourless oil (12 mg, 75%).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[CH:8]1([CH2:16][N:17]2[CH2:22]C[C:20](=O)[CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CI.C([O:29][CH2:30][CH3:31])(=O)C>>[CH:8]1([CH2:16][N:17]2[CH2:22][CH:31]([CH3:3])[C:30](=[O:29])[CH:19]([CH3:20])[CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCN(CC2CCCCCCC2)CC1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC1CN(CC2CCCCCCC2)CC(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride of 105 mg was added to a dimethylformamide 6 ml solution of 1-cyclooctylmethyl-4-piperidone of 300 mg, and the solution was stirred at a room temperature for 30 minutes. Then, methyl iodide of 160 μl was added thereto, and the solution was further stirred for 8 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine, followed by drying on anhydrous sodium sulfate. Then, the solvent was distilled off, and the resulting residue was separated and refined by means of silica gel column chromatography (ethyl acetate/hexane=1/20), whereby the captioned compound of 45 mg was obtained in the form of colorless liquid. Further, 1-cyclooctylmethyl-3,5-dimethyl-4-piperidone of 42 mg was obtained in the form of colorless liquid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([OH:35])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)=[O:35])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH2:16]1[O:18][C@H:17]1[CH2:19][OH:20]>C(Cl)Cl.CCOCC>[C:1]([Si:5]([CH3:7])([CH3:6])[O:20][CH2:19][C@H:17]1[CH2:16][O:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OC[C@H]1CO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CO1
Temperature: 23 °C
Reaction time: 17 h
Yield: 79.3 %

Procedure:
tert-Butyl-chloro-dimethylsilane (12.9 g, 85.5 mmol) followed by Et3N (19 mL, 136 mmol) was added to a 0° C. solution of (S)-(+)-glycidol (5.0 g, 67 mmol) in CH2Cl2 (200 mL). The solution was allowed to warm to 23° C. with stirring over 17 h. The resulting pink solution was diluted with Et2O (800 mL) and stirred an additional 30 min. The Et2O layer was washed with saturated aqueous NaHCO3 (200 mL), H2O (2×100 mL), brine (100 mL), dried over Na2SO4 and concentrated. Purification by column chromatography (silica, 5-10% Et2O/hexanes) gave (R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane (10.01 g, 79%). TLC (silica, 10% Et2O/hexanes): Rf=0.5. 1H NMR (CDCl3, 400 MHz): 3.85 (dd, J=11.9, 3.2 Hz, 1H), 3.66 (dd, J=11.9, 4.8 Hz, 1H), 3.09 (m, 1H), 2.77 (dd, J=5.0, 4.2 Hz, 1H), 2.64 (dd, J=5.2, 2.7 Hz, 1H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:21]([N:23]([CH3:37])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:43]([O-:47])([O-])(=[O:45])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:43]([C:15]1[C:16]([C:21]([N:23]([CH3:37])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:36])([F:35])[C:31]([F:32])([F:34])[F:33])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:47])=[O:45])[CH3:3]
Reactant: CCSc1cccnc1C(=O)N(C)c1ccc(C(F)(F)C(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1C(=O)N(C)c1ccc(C(F)(F)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.18 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.12 g of 3-ethylsulfanyl-N-methyl-N-(5-pentafluoroethylpyridin-2-yl)picolinamide (Compound of Present Invention 31) and 5 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.13 g of 3-ethylsulfonyl-N-methyl-N-(5-pentafluoroethylpyridin-2-yl) picolinamide (hereinafter, referred to as Compound of Present Invention 30).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCBr
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)CCn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 4.97 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.86 mL, 12.43 mmol) and 1-bromo-3-methyl butane (0.715 mL, 5.96 mmol) in N,N-dimethylacetamide (20 mL) was heated at 65° C. for 5 days. The solution was cooled to about 25° C. and partitioned between 10% aqueous ammonium chloride and dichloromethane, the organic layer separated and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 1% methanol in dichloromethane to provide the title compound (0.569 g, 42%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]=[CH:18][C:19]1[CH:47]=[CH:46][C:22]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:29]=[CH:28][C:27]=2[OH:45])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]=[CH:18][C:19]1[CH:47]=[CH:46][C:22]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][CH2:34][S:35]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)(=[O:37])=[O:36])[CH:29]=[CH:28][C:27]=2[O:45][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
Under ice-cooling, ethyl bromoacetate (87 mg, 0.52 mmol) was added dropwise to a mixture of 4-[2-(2-benzothiazolyl)vinyl]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzanilide (307 mg, 0.52 mmol), potassium carbonate (145 mg, 1.05 mmol) and dimethylformamide (10 ml), and the resulting reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution and the product formed was extracted with ethyl acetate. The resulting extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=hexane:ethyl acetate=4:1) to give ethyl 2-[4-[2-(2-benzothiazolyl)vinyl]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (219 mg, 0.32 mmol, 62%) as colorless solid.