Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[CH2:11]([C:19]1[CH2:33][C@@H:32]([O:34][Si](C(C)(C)C)(C)C)[C@H:31](/[CH:42]=[CH:43]/[C@@H:44]([O:52][Si](C(C)(C)C)(C)C)[CH2:45][C@H:46]([CH3:51])[CH2:47][CH2:48][CH2:49][CH3:50])[C:20]=1[S:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:11]([C:19]1[CH2:33][C@@H:32]([OH:34])[C@H:31](/[CH:42]=[CH:43]/[C@@H:44]([OH:52])[CH2:45][C@H:46]([CH3:51])[CH2:47][CH2:48][CH2:49][CH3:50])[C:20]=1[S:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(CCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(CCc2ccccc2)C[C@H]1O
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a solution of ice-cooled acetonitrile (1 ml) and pyridine (0.1 mL) was added hydrogen fluoride-pyridine (0.1 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-phenethyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (52 mg, 0.072 mmol) in pyridine (0.1 mL). The ice bath was removed and the solution was agitated for 15 hours wile returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution by ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromotography (40 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-phenethyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (32 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.O(CCCCBr)C1C=CC=CC=1.[OH:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=1.OC1C=CC(CCO)=CC=1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:25][C:26]2[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCCCBr)cc1
Reactant: OCCc1cccc(O)c1
Agent: BrCCCCOc1ccccc1
Agent: OCCc1ccc(O)cc1
Product: OCCc1cccc(OCCCOc2ccc(F)cc2)c1
Yield: 95 %

Procedure:
By following the procedure of example 9 and using 3-(4-fluorophenoxy)propyl bromide rather than 4-phenoxybutyl bromide and 2-(3-hydroxyphenyl)ethanol rather than 2-(4-hydroxyphenyl)ethanol, the title compound was prepared.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cccn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.Cl.[CH3:16][NH:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:17]([CH3:18])[CH3:16])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 4-Fluoro-3-nitro-benzoic acid methyl ester (Bioorg. Med. Chem.; 6; 8; 1998; 1185-1208) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 11a was obtained in 69% yield (3.48 g, 15.5 mmol).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18](I)([CH3:20])[CH3:19]>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([F:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)I
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(F)nc21
Reaction time: 5 h
Yield: 43.8 %

Procedure:
A mixture of 2-fluoro,6-chloro-purine (2 g, 11.7 mmol), and powdered potassium carbonate (4 g, 28 mmol) was vigorously stirred in 30 ml DMF. Isopropyliodide (6 ml, 60 mmol) was added very slowly over 2 h. The reaction was stirred for a further 5 h. DMF was removed and the crude taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel column chromatography (30% ethyl acetate in hexane) to provide the pure product as a white solid (1.1 g, 44%). δH (CD3OD, 250 MHz) 1.65 [6 H, d, J 7.5, CH(CH3)2], 4.92 [1 H, m, CH(CH3)2], 8.66 (1 H, s, ArH); δC (CD3OD, 250 MHz) 154.7 (C), 153.88 (C), 152.2 (C), 147.65 (CH), 132.44 (C), 50.66 (CH), 22.72 (2×CH3); m/z 215.2 (M+H)
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH3:23][O:24][N:25]=[C:26]([C:30]([O:35][CH3:36])([O:33][CH3:34])[CH2:31][Br:32])[C:27](O)=[O:28].P(Cl)(Cl)(Cl)=O>C(Cl)Cl.CN(C)C=O>[CH3:23][O:24][N:25]=[C:26]([C:30]([O:35][CH3:36])([O:33][CH3:34])[CH2:31][Br:32])[C:27]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: CON=C(C(=O)O)C(CBr)(OC)OC
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12)C(CBr)(OC)OC
Yield: 79.8 %

Procedure:
7-Amino-3-hydroxycepham-4-carboxylic acid (2.18 g, purity 84.8%), trimethylsilylacetamide (10.5 g.), 2-methoxyimino-3,3-dimethoxy-4-bromobutyric acid (syn isomer, 3.24 g.), N,N-dimethylformamide (1.1 ml), phosphorus oxychloride (1.36 ml) and methylene chloride (50 ml.) were treated in a similar manner to that of Example 25 (1) to give 7-[2-methoxyimino-3,3-dimethoxy-4-bromobutyramido]-3-hydroxycepham-4-carboxylic acid (syn isomer, 3.75 g.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1>C(Cl)Cl>[OH:9][CH2:8][C:6]1[N:7]=[C:2]([NH:1][C:24]([NH2:23])=[S:25])[CH:3]=[CH:4][CH:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cccc(CO)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=S)Nc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(6-Amino-pyridin-2-yl)-methanol (6-2, 1.00 g, 8.06 mmol) was dissolved in 20 mL anhydrous CH2Cl2 and 5 mL anhydrous DMF under N2. Benzoylisothiocyanate (1.19 mL, 8.86 mmol) was added and the reaction was stirred at room temperature fro 16 h. The reaction was concentrated in vacuo and to the resulting residue was added 24 mL 1M NaOH (aq) and 24 mL THF. The resulting mixture was heated to reflux for 3 h. The THF was removed in vacuo and a white precipitate formed. The mixture was filtered and washed with water to provide the titled compound as a white solid. 1H NMR(DMSO-d6): δ 10.58 (bs, 1H), 10.48 (bs, 1H), 8.84 (bs, 1H), 7.74 (t, 1H, J=8.1 Hz), 7.06 (d, 1H, J=7.5 Hz), 7.01 (d, 1H, J=8.1 Hz), 5.47 (t, 1H, J=5.9 Hz), 4.47 (d, 2H, J=5.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([F:21])[CH:11]=1.[CH2:22](OC(OCC)OCC)C>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:22][N:9]([C:10]3[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([F:21])[CH:11]=3)[C:3]=2[CH:4]=1
Reactant: CCOC(=O)c1ccc(Nc2cc(Br)ccc2N)cc1F
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)c1ccc(-n2cnc3ccc(Br)cc32)cc1F

Procedure:
917 mg ethyl 4-(2-amino-5-bromo-phenylamino)-2-fluoro-benzoate (compound in Production Example 333) and 7 mL triethoxymethane were stirred at 140° C. for 3 hours. The solvent was evaporated, and the residue was purified by NH silica gel chromatography (ethyl acetate/hexane). By recrystallization from ethyl acetate/hexane, 734 mg of the title compound was obtained as pale pink crystals.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)[C:7]#[N:8].[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[OH:13][CH2:12][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([CH2:3][OH:2])[CH:11]=1)[C:7](=[NH:8])[O:16][CH2:14][CH3:15]
Reactant: N#Cc1cc(CO)cc(CO)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc(CO)cc(CO)c1
Reaction time: 5 h
Yield: 92 %

Procedure:
Hydrogen chloride gas was passed through a solution of 3,5-bis-hydroxymethyl-benzonitrile (50 mg, 0.23 mmol) in anhydrous ethanol (100 mL) at room temperature. After 5 h, hydrogen chloride gas was stopped. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford ethyl 3,5-bis-hydroxymethyl-benzimidate hydrochloride (52 mg, 92%). It was used without further purification.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][C:14]([Cl:18])=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[Cl:18][C:14]1[S:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[N:16][C:15]=1[CH3:17]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(Cl)s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc([C@H]2CC[C@H](C(=O)O)CC2)sc1Cl

Procedure:
A mixture of cis/trans-4-(5-chloro-4-methyl-thiazol-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:5) (209 mg, 0.726 mmol) in 1,4-dioxane (7.3 ml) and 2 M aqueous sodium hydroxide solution (3.6 ml, 7.3 mmol) was stirred for 12 h at room temperature. The reaction mixture was partitioned between ethyl acetate (25 ml) and 0.1 M aqueous hydrogen chloride solution (25 ml). The layers were separated. The aqueous layer (pH 2) was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were washed with one 10-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (170 mg, 90%) as white solid. MS m/e: 258 ([M−H]−)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C(O)(=O)C>[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Reaction time: 4 h

Procedure:
30 mL (0.162 Mol) 1-benzylpiperidone (L) and 16.1 mL (0.185 Mol) morpholine (M) are dissolved in 407 mL tetrahydrofuran at ambient temperature. While cooling, 1.0 g (5 mmol) of p-toluenesulphonic acid and 14.6 mL glacial acetic acid are added, whereupon a jelly-like precipitate is formed. 52.19 g (0.246 Mol) sodium triacetoxyborohydride are added while cooling with ice, during which time the reaction temperature rises to 30° C. After 4 hours at 20° C., 90 mL water are added dropwise. After another 30 minutes, 280 mL of 17% potassium carbonate solution are added. The mixture is stirred intensively, while gas is observed to be given off. After separation of the phases the organic phase is dried and evaporated down.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[CH:37][C:38]([CH:41]=[C:1]([Br:5])[Br:2])=[CH:39][CH:40]=2)=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCc1ccc(-c2ccc(C=O)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCc1ccc(-c2ccc(C=C(Br)Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
60 g of carbon tetrabromide was dissolved in 185 ml of dichloromethane, and 100 g of triphenylphosphine was added at 0° C. or less. Next, 22 g of 4'-butyl-4-biphenylaldehyde was dissolved in 93 ml of dichloromethane, which then was added dropwise to the first dichloromethane solution over a period of one hour. The combined solutions were then agitated at room temperature for one hour. After completion of the reaction, the dichloromethane was distilled off, and 500 ml hexane was added to the residue. The resulting crystals were filtrated and further washed with hexane three times. The residue was recrystallized with hexane to obtain 9.6 g of 4-(4'-butylphenyl)-β,β-dibromostyrene.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[B-](F)(F)(F)[F:15]>>[F:15][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: F[B-](F)(F)F
Product: COc1ccc(C(F)(F)F)cc1F

Procedure:
The 2-amino-4-trifluoromethylphenols (XI) required for the reaction sequence just described may be prepared by conventional methods. Thus, 2-amino-6-fluoro-4-trifluoromethylphenol may be prepared from 2-nitro-4-trifluoromethylchlorobenzene by reacting the latter with sodium methoxide to give 2-nitro-4-trifluoromethylanisole, and reducing this compound to 2-amino-4-trifluoromethylanisole. The latter compound may be diazotised and converted to its fluoborate salt and heated to give 2-fluoro-4-trifluoromethylanisole. This may then be nitrated to form 2-fluoro-6-nitro-4-trifluoromethylanisole, which is then reduced to give 2-amino-6-fluoro-4-trifluoromethylanisole. Finally the latter compound is heated with a demethylating agent, for example an excess of pyridine hydrochloride to give 2-amino-6-fluoro-4-trifluoromethylphenol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:22])[C@@H:12]3[C@H:15]([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:16])[C:9]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:45][N:46]=[C:47]=[O:48].C(OCC)(=O)C>ClCCl>[CH3:45][NH:46][C:47]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:22])[C@@H:12]3[C@H:15]([O:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[CH3:16])[C:9]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH:5]=[CH:6][CH:7]=1)=[O:48]
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cccc(O)c3)C[C@H]12
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)Oc1cccc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrobenzyl (5R,6S)-3-(3-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate prepared in the above step in dichloromethane (10 ml) was added N,N-diisopropylethylamine (catalytic amount), and thereto was added under ice cooling a solution of methyl isocyanate (57 mg) in dichloromethane (5 ml). After stirring under ice cooling for 2 hours, the temperature was raised to room temperature and the reaction mixture was poured into a mixture of ice water and ethyl acetate. The mixture was extracted and separated with a separating funnel. The organic layer was washed with cold water (twice) and a cold saturated aqueous sodium chloride solution in the order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 4-nitrobenzyl (5R,6S)-3-(3-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (276 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[NH2:22][CH2:23][C@H:24]([OH:34])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[OH:34][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:21]=[CH:20][C:11]([CH:12]=[C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:2][CH2:7]1
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and 4-[(2S)-3-amino-2-hydroxy-propoxy]-phenol (which was obtained in Example 5) according to the procedure of Example 73 as a pale yellowish solid; mp >208° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.05 (m, 2H), 2.70-3.50 (m, 5H), 3.80-4.10 (m, 5H), 6.90 (d, J=6.7 Hz, 2 H), 6.77 (d, J=6.7 Hz, 2H), 7.02 (d, J=8.9 Hz, 2H), 7.35 (s, 1H), 7.39 (d, J=8.9 Hz, 2H), 8.95 (brs, 1H); MS (ES) m/z: 469.9 (MH+); HRMS Calcd. for C24H28N305S(M+): 469.1671. Found: 469.1648.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:28])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:29])=[CH:10]2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31](O)[CH3:32].Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl.O.C(OCC)(=O)C>[CH2:31]([O:26][C:25](=[O:27])[CH2:24][CH:21]1[CH2:20][CH2:19][N:18]([C:17]2[CH:16]=[C:15]([CH3:28])[N:14]=[C:13]3[N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:30])[CH:10]=[C:11]([CH3:29])[C:12]=23)[CH2:23][CH2:22]1)[CH3:32]
Reactant: CCO
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of {1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetic acid (100 mg) in CHCl3 (4 mL) in an ice cooling bath was added ethanol (20 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg), and dimethylaminopyridine (26 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ethyl acetate and water, and separated. The organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=4/1) to obtain {1-[1-(4-bromo-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-4-yl}acetic acid ethyl ester (99 mg). {1-[1-(4-Bromo-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-4-yl}acetic acid ethyl ester was dissolved in ethanol (2 mL) and 4 M HCl in ethyl acetate solution (60 μL) was added into the solution with cooling in an ice bath. After stirring at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropylether (1 mL). The crystal was collected by filtration to obtain the title compound. (95 mg)
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(C)ccc2Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-methoxyphenylboronic acid (152 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using methanol-chloroform to give the title compound (64 mg, yield 80%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N:20][C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([CH:29]=2)[C:26]([OH:28])=[O:27])=[CH:15][CH:14]=1)=[N+:2]=[N-:3].[C:31](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]=[N:20][C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([CH:29]=2)[C:26]([O:28][CH3:31])=[O:27])=[CH:17][CH:18]=1)=[N+:2]=[N-:3]
Reactant: O=C([O-])[O-]
Reactant: [N-]=[N+]=NCCCCCCCCOc1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(N=Nc2ccc(OCCCCCCCCN=[N+]=[N-])cc2)ccc1O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a stirred solution of 5-((4-(8-azidooctyloxy)phenyl)diazenyl)-2-hydroxybenzoic acid (400 mg, 0.97 mmol) in acetone (20 mL) was added powdered anhydrous potassium carbonate (270 mg, 1.94 mmol). Dimethyl sulfate (92 mg, 0.97 mmol) was then added dropwise at room temperature. The reaction mixture was heated at reflux for 20 min and then allowed to cool to ambient temperature. Volatiles were removed in vacuo, the residue taken up in EtOAc (40 mL), the solution washed with water (2×20 mL), brine, dried over Na2SO4, and filtered. Volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel 60 (230-400 mesh) using EtOAc and hexanes (95:5) as the elutant to give 210 mg (0.49 mmol, 50%) of the product as a yellow solid, mp 58-60° C. 1H NMR (500 MHz, CDCl3) δ 1.39-1.51 (m, 8H), 1.64 (qt, 2H), 1.83 (qt, 2H), 3.28 (t, J=Hz, 2H), 4.02 (s, 3H), 4.05 (t, J=6.5 Hz, 2H), 7.88 (d, J=Hz, 2H), 8.07 (dd, J=Hz, 2.5 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 11.06 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 25.9, 26.7, 28.8, 29.1, 29.2, 51.5, 52.5, 68.2, 112.4, 114.7, 118.3, 124.5, 126.0, 128.7, 145.5, 146.7, 161.5, 163.3, 170.3; HRMS (ESI) calculated for C22H28N5O4 (M+H)+426.2135, observed 426.2141.