Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[CH2:39][O:38][B:37]([OH:40])[C:36]=2[CH:41]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:29])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:30][CH2:31][C:32]5[CH:33]=[CH:34][C:35]6[CH2:39][O:38][B:37]([OH:40])[C:36]=6[CH:41]=5)=[O:25])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: NCc1ccc2c(c1)B(O)OC2
Product: O=C(NCc1ccc2c(c1)B(O)OC2)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12

Procedure:
The title compound can be prepared from 5-(5-(3,5-dichlorophenyl)-5-(trifluoro-methyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid and 6-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol as shown by the following scheme:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH:6]1[C:11]2=[CH:12][CH:13]=[C:14]3[C:18]([N:17](C(OCC)=O)[CH2:16][CH2:15]3)=[C:10]2[CH2:9][CH2:8][CH2:7]1>Cl>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH:6]1[C:11]2=[CH:12][CH:13]=[C:14]3[C:18]([NH:17][CH2:16][CH2:15]3)=[C:10]2[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CCc2ccc3c(c21)CCCC3C1=NCCN1
Agent: Cl
Product: c1cc2c(c3c1CCN3)CCCC2C1=NCCN1
Temperature: 0 °C

Procedure:
A solution of the product from Example 119 (0.38 g) in 6N hydrochloric acid (40 ml) was refluxed for 14 hours. The reaction mixture was cooled to 0° C., basified to pH 11 and extracted with methylene chloride. The organic layer was separated, dried and evaporated to afford the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([CH3:20])=[C:6]2[CH2:21][C:22]([NH:24]N)=[O:23]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([CH3:20])=[C:6]2[CH2:21][C:22]([NH2:24])=[O:23]
Reactant: CCCCCCCCn1c(C)c(CC(=O)NN)c2cc(OC)ccc21
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCn1c(C)c(CC(N)=O)c2cc(OC)ccc21
Yield: 84.7 %

Procedure:
A mixture of 1.27 g (3.68 mmol) of 5-methoxy-2-methyl-1-octyl-1H-indole-3-acetic acid hydrazide and 1 g of Raney Ni in 60 mL of ethanol was heated to maintain reflux for 3 hours, cooled, the solvent poured off the settled catalyst, treated with filter aid and filtered. The filtrate was concentrated to give 1.03 g (85% yield) of 5-methoxy-2-methyl-1-octyl-1H-indole-3-acetamide, mp, 96-98° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@H:8]([N:11]=[N+:12]=[N-:13])[C@@H:7]1[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+].COC1C=C(OC)C=CC=1C=O>C(#N)C.O>[CH3:19][O:18][CH:15]([O:16][CH3:17])[CH2:14][C@H:7]1[C@@H:8]([N:11]=[N+:12]=[N-:13])[C:9](=[O:10])[NH:6]1
Reactant: COc1ccc(CN2C(=O)[C@H](N=[N+]=[N-])[C@@H]2CC(OC)OC)c(OC)c1
Agent: COc1ccc(C=O)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COC(C[C@@H]1NC(=O)[C@@H]1N=[N+]=[N-])OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a stirred solution of 1.15 g (3.28 mmole) of cis-1-(2,4-dimethoxybenzyl)-2-(2,2-dimethoxyethyl)-3-azido-4-azetidinone in 120 ml of degassed acetonitrile was added at 80°, a solution of 11.8 g (43.7 mmole) of potassium persulfate and 4.05 g (23.3 mmole) of potassium monohydrogenphosphate in 135 ml of degassed water in 6 portions over a 1 hour period. The pH of the mixture was adjusted to 6.5-7.0 with potassium monohydrogenphosphate after each addition. After one hour, the mixture was cooled to room temperature, the acetonitrile removed in vacuum and the pH adjusted to 8.0. Extraction with ethyl acetate (4 × 75 ml) afforded a mixture of product and 2,4-dimethoxybenzaldehyde which was chromatographed over silica gel with benzeneethyl acetate to give 0.51 g (77%) of the title compound as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:19])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(O)c(Br)c1
Yield: 85 %

Procedure:
A solution of 3-bromo-4-hydroxybenzoic acid (50.4 g, 232 mmol) and conc. sulfuric acid (17 mL) in methanol (330 mL) was heated under reflux for 24 hrs. The reaction mixture was neutralized with aqueous sodium hydroxide solution. Methanol was removed under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether/hexane to give the title compound (45.5 g, yield 85%) as pale-pink crystals.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=1.CI>C(#N)C>[CH3:1][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 5 h

Procedure:
A 2 L round bottom flask equipped with a stir bar and reflux condenser was charged with acetonitrile (1 L), K2CO3 (263 g, 1.9 mol) and 4-hydroxy-2-fluoro-1-nitrobenzene (100 g, 0.64 mol). Methyl iodide (271 g, 1.9 mol) was added to the reaction mixture and heated at reflux temperatures with vigorous stirring for 5 h. The acetonitrile was removed and ethyl acetate (1 L) and H2O (700 mL) were added. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×200 mL). The organic phases were combined and washed with H2O (2×500 mL), brine (500 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as a slightly yellow solid (107 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC[O:11][C:12]([CH:14]1[C:18](=O)[CH2:17][CH2:16][CH2:15]1)=O>C(C1C=CC=CC=1CC)C>[OH:8][C:7]1[C:2]2=[N:1][C:15]3[CH2:16][CH2:17][CH2:18][C:14]=3[C:12](=[O:11])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: Nc1ncccc1O
Agent: CCc1ccccc1CC
Product: O=c1c2c(nc3c(O)cccn13)CCC2
Reaction time: 1 h
Yield: 55.4 %

Procedure:
A solution of 22.0 g of 2-amino-3-pyridinol, 62.4 g of ethyl cyclopentanone-2-carboxylate, and 200 ml of diethylbenzene is stirred and heated by means of oil bath maintained at ca. 150° for 1 hour, then gradually raised to 195°, and kept at 195° for 1 hour. Some tarry products are formed; hence the diethylbenzene solution is decanted from the tar and the diethylbenzene solution concentrated in vacuo. The residue, 29.8 g is recrystallized from 1400 ml of Skellysolve E to give 22.4 g of product, mp 136°-142°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2N=[N:11][CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].[CH2:16](OC(=O)C1C=CN=CC=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[CH:16][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccncc1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2cnccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 3-chloroisonicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](=[O:29])N(OC)C)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=2[CH:8]=1)=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: Fc1cccc2occc12
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2c(F)cccc2o1

Procedure:
The title compound (500 mg) was prepared from 4-fluoro-benzofuran (450 mg) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (900 mg) according to a procedure similar to that for Description 2.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:18][CH2:17]3)[CH3:15])=[N:11][NH:10][C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CI>CC#N>[CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:18][CH2:17]3)[CH3:15])=[N:11][N:10]([CH3:31])[C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(C(C)Cc2n[nH]c(=O)n2CC2CCCCC2)CC1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CI
Solvent: CC#N
Product: COc1ccccc1N1CCN(C(C)Cc2nn(C)c(=O)n2CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 48 %

Procedure:
To a slurry of 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-2,4-dihydro-3H-1,2,4-triazol-3-one D14 (50 mg, 0.121 mmol) and PS-BEMP (83 mg, 0.1820 mmol, 2.2 mmol/g) in MeCN (2 mL), MeI (11.5 μL, 0.182 mmol) was added and the mixture was shaken at room temperature for 64 h. The resin was filtered and the filtrate was evaporated under reduced pressure. The resulting yellow oil was purified by flash chromatography (Biotage Isolute SI, 1 g column, gradient DCM to 1% MeOH in DCM) and afforded 25 mg (48%) 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one E37 as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.O1CCCC1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([Cl:15])[CH:17]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: COc1ccc(CN)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1)-a) A mixture of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine 1.0 g, (3-chloro-4-methoxyphenyl)methylamine 0.81 g, triethylamine 0.66 ml and tetrahydrofuran 12 ml is stirred for 4 hours at room temperature. The reaction mixture is diluted with an aqueous 10% citric acid solution and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent; hexane:ethyl acetate=5:1) and concentrated in vacuo to give a colorless oil. The oil is left overnight at room temperature to give 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine as crystals, 1.58 g. mp 82-83° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C1(C)C=CC=CC=1>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:3]([O:10][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: BrCCCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: BrCCCCOCc1ccccc1
Yield: 66.4 %

Procedure:
To a warm mixture of sodium hydroxide (240 g, 6 mol) in 260 mL water there is added benzylalcohol (174 g, 1.61 mol), 1,4-dibromobutane (624 g, 2.88 mol), 10 g aliquat 336, and 150 mL toluene with good stirring. The temperature of the reaction mixture rises slowly to about 60° C. and is kept below this temperature by slight cooling. When the temperature of the mixture drops the cooling bath is removed and the reaction mixture is stirred for an additional hour, then poured in 500 mL water. The product is extracted with 750 mL toluene and the organic layer is washed with 3×500 mL water, then dried, evaporated and purified by bulb-to-bulb distillation at 0,2 mmHg. This gives first 1,4-dibromobutane, then an intermediate fraction and then the product. After redistillation of the intermediate fraction there is obtained a total of 260 g of the product (1.07 mol, 66% yield, probably contaminated with some 1,4-dibenzyloxycompound) with bp 130° C. (0.2 mmHg). The product is used as such in the next step. 1H-NMR (CCl4): δ 1.4-2.1 (m, 4H), 3.3 (2t, 4H), 4.3 (s, 2II), 7.2 (s, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12](=[O:29])[N:11]([CH2:30][CH2:31][CH3:32])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]#[C:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=1>CC(C)=O>[CH2:26]([N:13]1[C:14](=[O:25])[C:15]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:40][C:41]#[C:42][C:43]4[CH:44]=[CH:45][C:46]([O:49][C:50]([F:51])([F:52])[F:53])=[CH:47][CH:48]=4)=[CH:7][CH:6]=3)=[N:9][C:10]=2[N:11]([CH2:30][CH2:31][CH3:32])[C:12]1=[O:29])[CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2c(nc(-c3ccc(O)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: FC(F)(F)Oc1ccc(C#CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(=O)c2c(nc(-c3ccc(OCC#Cc4ccc(OC(F)(F)F)cc4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 80 °C
Yield: 36.7 %

Procedure:
A mixture of 8-(4-hydroxy-phenyl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.22 mmol) and potassium carbonate (0.076 g, 0.53 mmol), 1-(3-bromo-prop-1-ynyl)-4-trifluoromethoxy-benzene (prepared as given in example E1) (0.073 g, 0.26 mmol) in acetone (10 ml) was heated at 80° C. for 2 hours. The mixture was cooled to room temperature, filtered and washed with acetone. Solvent was evaporated to obtain a residue which was purified by preparative TLC to obtain 1,3-dipropyl-8-{4-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyloxy]-phenyl}-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione as a pale yellow solid (0.053 g, 37%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.Cl.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].CS(C)=O.C(N(CC)CC)C>CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CCCN
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)CCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.142 g (0.925 mmol) of gamma amino butyric acid, methyl ester hydrochloride were placed into a 10 ml round bottom flask with a magnetic stirring bar and 2 ml dimethylsulfoxide. To this solution was added 0.100 g (0.988 mmol) of triethylamine. The solution immediately turned green and was stirred at room temperature for one hour. Then 5 ml of acetone was added and the solution was filtered. The mother liquor was treated with ether (approximately 35 ml) to precipitate the product. Upon filtration and washing with ether, 232 mg of a white solid 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]butanoic acid, methyl ester (AIT-0092) was obtained. Yield: 83%.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:44])[CH:31]([NH2:43])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([OH:44])[CH:31]([NH:43][C:7]([C:3]2[CH:2]=[C:1]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)=[O:9])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:28][CH:29]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 3-biphenylcarboxylic acid (127 mg, 0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (147 mg, 69%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: COc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-methoxyaniline (Aldrich) according to the method described in Example 1c. Melting Point: 144-146° C. (diethylether)
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[C@@H:12]([C:13](=[O:15])[NH2:14])[N:11]([O:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:10]1=[O:31])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.Cl.[Cl:48][CH2:49][C:50]([NH:52][C:53]1[S:54][CH:55]=[C:56](/[C:58](=[N:62]/[O:63][CH2:64][C:65]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][C:72]([N+:75]([O-:77])=[O:76])=[CH:71][CH:70]=2)=[O:66])/C(Cl)=O)[N:57]=1)=[O:51]>ClCCl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:13]([C@H:12]1[N:11]([O:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[C:10](=[O:31])[C@H:9]1[NH:8][C:6](=[O:5])/[C:58](/[C:56]1[N:57]=[C:53]([NH:52][C:50](=[O:51])[CH2:49][Cl:48])[S:54][CH:55]=1)=[N:62]\[O:63][CH2:64][C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][C:72]([N+:75]([O-:77])=[O:76])=[CH:71][CH:70]=1)=[O:66])(=[O:15])[NH2:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1C(N)=O
Reactant: O=C(CCl)Nc1nc(/C(=N/OCC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)Cl)cs1
Agent: Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(NC(=O)CCl)n2)C(=O)N1OCC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 87 %

Procedure:
In 20 ml of dichloromethane is suspended 550 mg of (3S,4S)-3-(tert-butoxycarbonylamino)-4-carbamoyl-1-(p-nitrobenzyloxycarbonylmethoxy)-2-azetidinone, and 2 ml of anisole and 10 mL of trifluoroacetic acid are added to the suspension under ice-cooling with stirring. After the stirring under ice-cooling for 2 hours, 20 ml of toluene is added to the reaction solution, and the mixtuere is concentreated under reduced pressure. 20 ml of dichloromethane is added to the residue, and 1.06 ml of triethylamine and 964 mg of 2-(2-chloroacetamidothiazol-4-yl)-(Z)- 2-(p-nitrobenzyloxycarbonylmethoxyimino)acetyl chloride hydrochloride (prepared by the method as described in the Japanese Unexamined Patent Publication No. 131758/1982) are added, followed by stirring under ice-cooling for 2 hours. The solvent is distilled off under reduced pressure, and 15 ml of tetrahydrofuran and 15 ml of water are added to the residue. The mixture is adjusted to pH 7 with aqueous sodium hydrogen carbonate solution, and stirred under ice-cooling for 1 hour. The tetrahydrofuran is distilled off under reduced pressure, and crystals which separate out are recovered by filtration, and washed with aqueous sodium hydrogen carbonate solution, water, ether, ethyl acetate andeether successively to give 848 mg (83.0%) of (3S,4S)-4-carbamoyl-3-[2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-(p-nitrobenzyloxycarbonylmethoxyimino)acetamido]-1-(p-nitrobenzyloxycarbonylmethoxy)-2-azetidinone as yellow crystals, which is shown by TLC to contain a slight amount of impurities but used as crude crystals in the substituent reaction, m.p. 147°-153° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)=[CH:7][CH:6]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:11](=[C:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17]2)[C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][CH:7]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(CC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of methyl{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetate (153) (0.20 g, 0.51 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration and trituration with hot hexanes (containing 1% methanol), the title compound 154 was obtained as a white solid (0.185 g, 96%). mp 220-221° C. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.87 (s, 2H), 1.89 (s, 2H), 3.49 (s, 2H), 6.64 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 9.24 (s, 1H), 12.26 (s, 1H). LCMS (ESI): m/z 401 (M+Na)+, 377 (M−H)−. Anal. Calcd for C25H30O3. ⅙H2O: C, 78.71; H, 8.01; Found: C, 78.73; H, 7.98.