Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.CON(C)[C:17](=[O:31])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][Si](C)(C)C)=[C:21]([F:30])[CH:20]=1>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:30])[CH:20]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CON(C)C(=O)Cc1ccc(O[Si](C)(C)C)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)c(F)c1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of 45 ml of n-butyllithium (1.6M in hexane) is added dropwise to a suspension, cooled to -78 C., of 18.2 g of 1,4-dibromobenzene in 140 ml of THF. Then, 10 g of N-methoxy-N-methyl-2-(3-fluoro-4-trimethylsilanyloxy-phenyl)-acetamide (paragraph. Bb)) in 35 ml of THF are added dropwise at -78° C. The reaction mixture is stirred at -78 C. for 2 hours, then left to stand at room temperature for 1 hour while stirring. After dilution with ethyl acetate, the mixture is washed with 10% aqueous KHSO4 solution, saturated NaHCO3 solution and 10% aqueous NaCl solution. After extraction with ethyl acetate, the organic phases are dried and concentrated. Then, the silyl group is cleaved with 105 ml of THF, 11 ml of H2O and 5 drops of 1N HCl. Concentration, dissolution in methylene chloride, drying and column chromatography over silica gel with methylene chloride/0.5% methanol as the eluent, give 9.2 g of 1-(4-bromo-phenyl)-2-(3-fluoro-4-hydroxy-phenyl)-ethanone. MS: m/e 308 (M+,1 Br).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[S:6](=O)(=[O:9])([OH:8])[OH:7]>>[S:6]([OH:9])([O:5][CH:3]([CH3:4])[CH2:2][NH2:1])(=[O:8])=[O:7]
Reactant: O=S(=O)(O)O
Reactant: CC(O)CN
Product: CC(CN)OS(=O)(=O)O

Procedure:
FIG. 5 shows another synthetic reaction scheme for preparation of an mPEG-DTB-ligand compound in accord with the invention. The details of the reaction procedure are given in Examples 3A-3B. Briefly, cold 1-amino-2-propanol was reacted with sulfuric acid to form 2-amino-1-methylethyl hydrogen sulfate. This product was reacted with carbon disulfide and sodium hydroxide in aqueous ethanol to yield 5-methylthiazolidine-2-thione. An aqueous solution of hydrochloric acid was added to the 5-methylthiazolidine-2-thione and heated. After refluxing for one week, the product, 1-mercapto(methyl)ethyl ammonium chloride, was crystallized and recovered. This product was reacted with methoxy carbonylsulfenyl chloride to yield 2-(methoxycarbonyldithio)ethaneamine. Reaction of the 2-(methoxycarbonyldithio)ethaneamine with mPEG-chloroformate using the procedure described above with respect to FIG. 2 yields the desired mPEG-DTB-nitrophenyl compound suitable for reaction with a selected amine-containing lipid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27](O)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:20][CH:19]=2)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: COC(=O)Cc1cc(Cl)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Cl)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 42 %

Procedure:
To a mixture of [4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (1.0 g), methyl 2-(5-chloro-2-hydroxyphenyl)acetate (0.74 g), triphenylphosphine (1.08 g) and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 1.79 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give methyl 2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.68 g, 42%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[CH2:6][CH2:5]1.O>CO.CO.C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([OH:14])[CH2:6][CH2:5]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)CCC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of sodium borohydride (3.5 g, 93 mmoles) in dry methanol (50 ml) at 0° C. under a nitrogen atmosphere was added a solution of 4,4-dimethyl-1-tetralone (10 g, 57.4 mmoles) in dry methanol:toluene (1:3) dropwise over a 45 minute period. After this time the mixture was allowed to warm to room temperature, and then two volumes of water were added. After stirring for 1 hour, the organic layer was separated, dried over magnesium sulfate, filtered, and evaporated under reduced pressure to leave a light yellow oil. This was purified by silica gel column chromatrography eluting with ethyl acetate:hexane (1:9) to give 1,2,3,4-tetrahydro-4,4-dimethyl-1-naphthol as a colorless oil. (9.89 g, 98%).
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[O-][CH2:32][CH3:33].[Na+]>C(O)C>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([O:20][CH2:32][CH3:33])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 308.7 %

Procedure:
Single Aminoacid, Di- and Tripeptide-ketoesters (General Procedure). To a stirred solution of 8.53 g (15.0 mmol) of Z-Leu-Phe-EE in 40 ml anhydrous ethanol at room temperature was added dropwise a solution of sodium ethoxide (0.204 g; 3.0 mmol) in 20.0 ml anhydrous ethanol. The color of the reaction mixture change from colorless or pall yellow to deep yellow or orange dependent on enol-ester. Then the reaction mixture was stirred at room temperature for 4-5 hours, the ethanol was then evaporated in vacuo (rotavaporator) and the residue treated with 200 ml ethyl ether (or 200 ml ethyl acetate in the case of the tripeptide). The ether (ethyl acetate) solution was washed with 2×75 ml H2O, 2×75 ml satd. NaCl, decolorized with carbon and dried over MgSO4. After evaporation of solvent, the crude product 6.09 g (89.7%) was flash chromatographed on silica gel using CHCl3 : MeOH=50:1 v/v. Evaporation of solvent give pure Z-Leu-Phe-COOEt (4.08 g; 58.0%) as a thick oil. Single spot on TLC, Rf =0.60, A; 0.47, M. Mass spectrum, FB-MS [(M+1)/Z]=469.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
To a solution of ethyl 4-aminobenzoate (10 g) and 4-(dimethylamino)benzaldehyde (9.0 g) in methylene chloride (200 mL) is added sodium triacetoxyborohydride (18.9 g) and acetic acid (3.47 mL) under ice-cooling, and the mixture is stirred at room temperature for 2 days. To the reaction mixture is added a saturated sodium hydrogencarbonate solution and extracted with chloroform (×2). The extract is concentrated in vacuo and the residue is triturated in n-hexane/ethyl acetate to give ethyl 4-[4-(dimethylamino)benzylamino]benzoate (11.6 g, yield; 64%) as powder. MS (APCI) m/z; 299 [M+H]+
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.Br[CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1>CN(C=O)C.O>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[S:3][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: Cn1ccnc1S
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1SCCCOC1CCCCO1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
Sodium hydride (0.95 g of a 50% suspension in mineral oil, 20 mmol) was added to a solution of 2-mercapto-1-methylimidazole (2.26 g, 19 mmol) in DMF (100 ml) and the mixture stirred for 30 minutes. 2-(3-Bromopropoxy)tetrahydropyran (5.0 g, 22.5 mmol), (J. Chem. Soc. 1963, 3440), was added and the mixture heated at 100° C. for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)imidazole (2.5 g, 55%).
Reaction SMILES: S(Cl)([Cl:3])=O.COC1C=CC(COC([NH:15][CH2:16][C@@H:17]([C:19](O)=[O:20])[OH:18])=O)=CC=1.C(OCC)C.[CH2:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[ClH:3].[CH2:29]([O:36][C:19](=[O:20])[C@@H:17]([OH:18])[CH2:16][NH2:15])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(COC(=O)NC[C@H](O)C(=O)O)cc1
Solvent: CCOCC
Product: Cl
Product: NC[C@H](O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
At 0°-5°, add thionyl chloride (11.0 ml) dropwise to N-(4-methoxybenzyloxycarbonyl)-(S)-isoserine (10.0 g) in benzyl alcohol (100 ml), warm the mixture to room temperature, and stir for 20 hours. Pour the reaction mixture into diethyl ether (300 ml) and filter the solid. Wash the solid with diethyl ether and dry in vacuo to give the title compound, a tan solid, m.p. 127°-130° C., [α]D26 =-18.6° (MeOH).
Reaction SMILES: [O:1]=[C:2]([C:9]1[C:10]([C:15]([F:18])([F:17])[F:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:20][C:21]([C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([O:32][CH3:33])=[C:25]([O:34][CH3:35])[CH:24]=1)=O.Cl>N1C=CC=CC=1>[CH3:35][O:34][C:25]1[CH:24]=[C:23]([C:21]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([C:9]3[C:10]([C:15]([F:18])([F:16])[F:17])=[N:11][CH:12]=[CH:13][CH:14]=3)[O:1][CH:20]=2)[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]=1[O:32][CH3:33]
Reactant: CCOC(=O)CC(=O)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1OC
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2cc(OC)c(OC)c([N+](=O)[O-])c2)coc1-c1cccnc1C(F)(F)F
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of ethyl 3-oxo-3-(2-(trifluoromethyl)pyridin-3-yl)propanoate (1.305 g, 5 mmol) in pyridine (25 mL) was added 2-bromo-1-(3,4-dimethoxy-5-nitrophenyl)ethanone (1.67 g, 5.5 mmol). The reaction mixture was heated to 70° C. and stirred for 5 hours, then cooled to room temperature and poured onto 6 N aqueous HCl (100 mL). The precipitate was filtered off, washed with water and dried over P2O5 under vacuum. The solid was recrystallised from dichloromethane/ispropanol to give crude ethyl 4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)furan-3-carboxylate, 1.00 g (43%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:50][CH2:51][N:46]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=4)[CH2:47][CH2:48]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCN(c3ccccn3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 97.3 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 1-(pyridine-2-yl)piperazine (29.4 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyridine-2-yl)piperazine-1-yl]pyrimido[4,5-b][1,5]diazocine (95.7 mg, 97%).
Reaction SMILES: ClC([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]=1[NH2:27].[CH:28]1C(Cl)=CC=C(Cl)C=1>>[C:9]([C:8]1[CH:7]=[CH:6][C:5]([C:4]2[NH:14][C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]=3[N:27]=2)=[CH:13][CH:12]=1)([O:11][CH3:28])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Reactant: Clc1ccc(Cl)cc1
Reactant: O=C(Cl)Cc1ccc(C(=O)[O-])cc1
Product: COC(=O)c1ccc(-c2nc3cc([N+](=O)[O-])c([N+](=O)[O-])cc3[nH]2)cc1
Yield: 62 %

Procedure:
To a solution containing 10 g (45.8 mmole) of p-chlorocarbonylmethylbenzoate dissolved in 100 ml of dichlorobenzene was added 3.0 g (15.3 mmole) of 1,2-diamino-4,5-dinitrobenzene. After heating the resulting mixture to reflux under nitrogen (frothing), it was maintained at that temperature for 2 hours. The solution was then allowed to cool in ice for one hour, and the precipitate that formed was filtered by suction, washed with benzene and air-dried. Recrystallization from tetrahydrofuran (THF)-n-propanol by distillation to a small volume in vacuo yielded 3.2 g (62%) of 2-[p-carbomethoxyphenyl]-5,6-dinitrobenzimidazole as light yellow needles, m.p. 239°-240°.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].B(F)(F)F.CCOCC.[N+](=[CH:66][CH2:67][CH3:68])=[N-]>CCOCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:66][CH2:67][CH3:68])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC=[N+]=[N-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: FB(F)F
Solvent: CCOCC
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 38) in ether (6 ml) is added borontrifluoride etherate (10 μl) followed by freshly prepared 1-diazopropane (100 fold excess). The mixture is stirred at room temperature for 15 min and quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is separated, washed (sat'd aqueous NaCl) and dried over anhydrous magnesium sulfate. Removal of solvent followed by preparative tlc on silica gives the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Mg].CN(C)[CH:14]=[O:15].CCOC(C)=O>C1COCC1.BrCCBr>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:9][CH3:10])[CH:5]=1)[CH:14]=[O:15]
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)cc(Cl)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: BrCCBr
Product: COc1cc(Cl)cc(C=O)c1
Temperature: 0 °C
Yield: 54 %

Procedure:
3,5-Dichloroanisole (74.0 g, 419 mmol) in THF (200 mL) was added dropwise to magnesium metal (14.2 g, 585 mmol, pre-washed with 0.5 N HCl) in THF (100 mL) at 25° C. After the addition, 1,2-dibromoethane (3.9 g, 20.8 mmol) was added dropwise. The resultant dark brown mixture was heated at reflux for 3 h. The mixture was cooled to 0° C., and N,N-dimethylformamide (60 mL) was added in one portion. The mixture was partitioned with diethyl ether (3×400 mL) and 6N HCl (500 mL). The combined organic extracts were washed with brine (300 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash chromatography (2×) on silica gel eluting with Hex:EtOAc (4:1) afforded the sub-title compound (38.9 g, 54%/) as a yellow oil.
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6]1)(=O)C.O>O1CCCC1>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][CH:5]([OH:4])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Solvent: C1CCOC1
Solvent: O
Product: OC1CCc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.1 %

Procedure:
5.54 g of lithium hydroxide·hydrate was added to 24.2 g of 7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in 150 ml of tetrahydrofuran, and the mixture was stirred at room temperature for about 20 hours. After the reaction, water was added to the reaction mixture, and then the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then condensed. The obtained residue was applied to silica gel column chromatography to obtain 10.5 g of 4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine.
Reaction SMILES: COC([NH:5][C@H:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:19]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:17])[CH:12]=2)[CH2:7]1)=O.I[Si](C)(C)C.CO>C(#N)C>[NH2:5][C@H:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:19]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=4)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:17])[CH:12]=2)[CH2:7]1
Reactant: COC(=O)N[C@@H]1Cc2ccc(NC(=O)c3cccc(C)c3-c3ccc(C(F)(F)F)cc3)cc2C1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)C[C@H](N)C3)c1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(R)-6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylic acid (2-methoxycarbonylaminoindan-5-yl)-amide (6.5 g, 13.9 mmol) is dissolved in acetonitrile (325 mL) and cooled to 0° C. under nitrogen. Iodotrimethylsilane (11.1 g, 55.6 mmol) is added dropwise, the mixture is allowed to warm to room temperature and is stirred overnight. Methanol (100 mL) is added and the mixture is stirred for 1 hour and then concentrated in vacuo. The residue is dissolved in ethyl acetate (750 mL) and washed with saturated sodium bicarbonate (2×125 mL), water (125 mL), 5% Na2S2O3 solution (125 mL), water (125 mL), and brine (50 mL). The organic phase is dried over sodium sulfate and concentrated to afford (R)-N-(2-aminoindan-5-yl)-6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxamide.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([CH:17]([N:24]=[C:25]=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O:29]CC)C>>[CH2:1]([N:8]1[C:9](=[O:29])[S:10][N:24]([CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:25]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: S=C=NCc1ccccc1
Product: O=c1sn(C(c2ccccc2)c2ccccc2)c(=O)n1Cc1ccccc1

Procedure:
Reagents: Benzylisothiocyanate (6.5 mmol, 0.85 mL), diphenylmethyl-isocyanate (6.5 mmol, 1.23 mL) and SO2Cl2 (6.5 mmol, 0.52 mL) in diethyl ether (25 mL). Isolation: filtration of reaction mixture. Purification: recrystallization from MeOH.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:10]C(=O)OC(C)(C)C)=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:18](OCC)(=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].CC(C)([O-])C.[K+].Cl.[NH2:35]O>C1(C)C=CC=CC=1.O.C(O)C>[NH2:10][C:5]1[C:4]([C:1]2[O:3][N:35]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:2]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(=O)c1cccnc1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)OCC
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccnc2N)on1
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of tert-butyl (3-acetylpyridin-2-yl)carbamate (600 mg, 2.29 mmol) and diethyl oxalate (669 mg, 4.58 mmol) in toluene (5.0 mL) was added potassium tert-butoxide (514 mg, 4.58 mmol) at room temperature under a nitrogen atmosphere, which was stirred for two hours. After addition of toluene (5.0 mL) and stirring for one hour, potassium tert-butoxide (257 mg, 2.29 mmol) was added thereto and the solution was stirred for two hours. To the reaction mixture were added hydroxylamine hydrochloride (477 mg, 6.87 mmol) and ethanol (10 mL), which was stirred for one hour, water (1.0 mL) was added thereto and the solution was stirred overnight at room temperature. Water (30 mL) was added thereto and the solution was extracted with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and dried over anhydrous magnesium sulfate, the solution was concentrated. The concentrated residue was dissolved in N,N-dimethyl formamide (5 mL), triethylamine (192 mg) was added thereto, and the solution was stirred at 80° C. for six hours. After cooling, water was added thereto, and the solution was extracted with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure, so as to obtain the title compound (443 mg) as a white solid.