Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(OC)=CC=1C(=O)CN1C(C(OCC)=O)=CC(C2C=NC=CC=2)=N1.[CH3:30][Si:31]([CH3:43])([CH3:42])[C:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34][N:33]=1.Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=1[O:56][CH3:57])=[O:47]>>[CH3:57][O:56][C:49]1[CH:50]=[C:51]([O:54][CH3:55])[CH:52]=[CH:53][C:48]=1[C:46](=[O:47])[CH2:45][N:34]1[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:32]([Si:31]([CH3:42])([CH3:43])[CH3:30])=[N:33]1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Agent: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Product: CCOC(=O)c1cc([Si](C)(C)C)nn1CC(=O)c1ccc(OC)cc1OC

Procedure:
This compound was prepared in a similar method to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethyl silyl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (purchased from Aldrich). 1H-NMR δ 9.92 (d, 1H), 7.02 (s, 1H), 6.57 (dd, 1H), 6.51 (d, 1H), 5.67 (s, 2H), 4.39 (quartet, 2H), 3.98 (s, 3H), 3.89 (s, 3H), 1.38 (t, 3H), 0.27 (s, 9H).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:27])=O>>[Cl:27][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC(F)(F)F
Yield: 97 %

Procedure:
Dimethylformamide (0.1 ml) was added dropwise to a solution of 6-methoxy-7-(2,2,2-trifluoroethoxy)-3,4-dihydroquinazolin-4-one (15.8 g, 57.7 mmol) in thionyl chloride (200 ml) and the reaction was heated at reflux for 6 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2×50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (2×250 ml) and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6-methoxy-7-(2,2,2-trifluoroethoxy)quinazoline (16.3 g, 97% yield) as a cream solid:
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH2:15][C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:37]=[C:38]([CH3:47])[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(O)(=O)C>O1CCCC1.C(OCC)C.O>[Si:1]([O:8][CH:9]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH:15]([C:38]([OH:37])([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:47])[C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCCC(C)(O)C1CC2C(/C=C/C(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CCC2C1=O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
(E)-2-(3-tert-Butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one, (65 mg), prepared as described in Reference Example 37 and in the form of (±)-(E)-2β-(3β-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one was dissolved in dry tetrahydrofuran (2.63 ml). The solution was cooled to to -70° C. under an atmosphere of argon and treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.212 ml; 1M), and the mixture was stirred at -70° C. for 10 minutes. The mixture was then treated with ethyl 5-oxohexanoate (55 mg) and stirred for a further period of 5 hours at -70° C. The solution was treated with a solution of glacial acetic acid (0.02 ml) in diethyl ether (0.175 ml) and the mixture was allowed to warm to the ambient temperature. The mixture was then treated with water (20 ml) and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residual oil was subjected to medium pressure, short column chromatography on silica gel, using a mixture of ethyl acetate and hexane (1:6 v/v) as eluant, to give 6-[(E)-3-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-(5-ethoxycarbonyl-2-hydroxypent-2-yl)bicyclo[3,3,0]octan-2 -one (22 mg), in the form of 6β-[(E)-3β-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-(5-ethoxycarbonyl-2-hydroxypent-2-yl)bicyclo[3,3,0]octan-2-one, otherwise known as (±)-ethyl(13E)-(9S,15R)-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-15-cyclohexyl-5-hydroxy-5-methyl-16,17,18,19,20-pentanorprosta-13-dienoate.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[C:9]([N+:20]([O-])=O)=[CH:10][CH:11]=[C:12]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH2:4][CH2:3]1.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:20][C:9]1[C:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]=2[C:12]([S:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1
Reactant: CN1CCc2c(Sc3ccccc3)ccc([N+](=O)[O-])c2CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCc2c(N)ccc(Sc3ccccc3)c2CC1
Reaction time: 30 h

Procedure:
To a solution of 15.7 g. (0.05 mole) of 3-methyl-9-nitro-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine in 350 ml. of ethanol and 125 ml. of water is added, in portions, 35 g. (0.2 mole) of sodium hydrosulfite. The mixture is stirred and refluxed for 16 hours, then an additional 52 g. (0.3 mole) of sodium hydrosulfite is added and refluxing is continued for 30 hours, allowing about one-half of the solvent to distill from the reaction during the last hour. The mixture is cooled, diluted with water, made alkaline with ammonium hydroxide and extracted with ethyl acetate. After being dried, the extract is concentrated to give 9-amino-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine which is purified by chromatography. A solution of the base in ethanol is treated with an excess of hydrogen chloride. Following addition of ether crystalline 9-amino-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine dihydrochloride is obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH:15]([CH2:18][CH:19]=[CH2:20])[CH2:16][OH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)(Cl)Cl>[Br:1][CH2:20][CH:19]1[CH2:18][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16][O:17]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCC(CO)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: BrCC1CC(c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
N-Bromosuccinimide (1.78 g) is added to a stirred solution of 1.6 g of 2-phenyl-4-penten-1-ol in 15 ml of chloroform at room temperature. The resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is then poured into 10 ml of water. The chloroform layer is separated and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant to give 1.67 g of 2-(bromomethyl)-4-phenyltetrahydrofuran as colorless oil.
Reaction SMILES: [Cl:1][CH:2]1[CH:16]([CH2:17][CH3:18])[C:6]2[C:7](=[O:15])[CH:8]=[C:9]([O:13]C)[C:10](=[O:12])[NH:11][C:5]=2[CH2:4][CH:3]1[Cl:19].B(Br)(Br)Br.C([O-])(O)=O.[Na+].[K+].[Br-]>C(Cl)Cl>[Cl:1][CH:2]1[CH:16]([CH2:17][CH3:18])[C:6]2[C:7](=[O:15])[CH:8]=[C:9]([OH:13])[C:10](=[O:12])[NH:11][C:5]=2[CH2:4][CH:3]1[Cl:19]
Reactant: CCC1c2c([nH]c(=O)c(OC)cc2=O)CC(Cl)C1Cl
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: CCC1c2c([nH]c(=O)c(O)cc2=O)CC(Cl)C1Cl
Reaction time: 1 h

Procedure:
To a stirred suspension of 6,7,8,9-tetrahydro-7,8-dichloro-6-ethyl-3-methoxy-1H-1-benzazepine-2,5-dione (525 mg, 1.73 mmol) in dry CH2Cl2 (60 mL, from CaH2) under N2, a solution of BBr3 in CH2Cl2 (10 mL, 1M, Aldrich) was added over 10 s. The suspension turned orange, then a yellow solution was observed which transformed to a yellow suspension. The suspension was allowed to stir under N2 for 1 h. The reaction was added to saturated NaHCO3 (200 mL) and was allowed to stir for 10 min. A pink emulsion was obtained. The emulsion was vacuum filtered (changed filter papers frequently, saved) to give a pink solution. The solution was washed with CH2Cl2 (2×50 mL). The pH of the aqueous portion was adjusted to 2 with concd HCl. The resulting precipitate was collected and washed with water (6×2 mL). The damp filter cake was crystallized from 95% EtOH (dissolved in boiling solvent (100 mL), hot filtered, coned to 40 mL, allowed to cool to rt) to give a pale beige solid (62 mg, 12%, a mixture of diastereomers by NMR (8:2)); mp 197° C. (dec, preheat to 195° C.); tH NMR (DMSO-d6 and D2O) δ0.75 (overlapping t, 3H), 1.22-1.77 (overlapping m, 2H), 2.94 (m, 1H), 3.11 (dd, J1 =4.8 Hz, J2 =17.1 Hz, 1H), 3.37 (overlapping m, 1H), 4.20 (dd, J1 =5.7 Hz, J2 =9.3 Hz, 1H), 4.34-4.61 (overlapping m, 1H), 6.32 and 6.33 (overlapping s, 1H), the spectrum without D2O displayed additional resonances at 10.45 (bs, 1H), 10.99 and 11.05 (overlapping s, 1H); IR (KBr) 3305, 3207, 3097, 2990, 1679, 1647, 1612, 1553, 1399, 1284, 1229, 912 cm-1.
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15]>>[O:15]=[C:7]1[NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:11][C:10]=2[O:6]1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: O=S(=O)(O)Cl
Product: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
Sulfurochloridic acid (70 g, 603.45 mmol) was cooled to 0° C. and benzo[d]oxazol-2(3H)-one (1.8 g, 13.33 mmol) was added in several batches, maintaining the temperature at about 0° C. The resulting solution was stirred at room temperature for 3 hours, then quenched by the addition 400 mL of iced water. The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:10 ethyl acetate/petroleum ether solvent system to afford 0.8 g (26%) of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride as a white solid. 1H NMR (CDCl3) δ 8.26 (s, 1H), 8.00 (d, 1H), 7.98 (d, 1H), 7.32 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH3:14][C@H:15]1[O:19][C:17](=[O:18])[CH2:16]1>O1CCCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[S:1][C@@H:15]([CH3:14])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: Sc1cccs1
Reactant: C[C@@H]1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)O)Sc1cccs1
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
To a magnetically-stirred 25 mL round-bottomed flask blanketed with nitrogen was charged 2-mercaptothiophene (0.73 g, 6.29 mmol) in tetrahydrofuran (7 mL, K.F. <0.1 mg/mL) at 25° C. Triethylamine (0.87 mL, 6.29 mmol) was injected and the reaction mixture was stirred for 10 minutes to complete salt formation. To this mixture was added (R)-(+)-β-methyl-β-propiolactone (0.54 g, 6.29 mmol) in one portion and the reaction mixture was stirred at 25° C. for approximately 3 hours. When complete, the mixture was stripped of solvent on a rotary evaporator at 25° C. and diluted with ethyl acetate (10 mL) and water (10 mL). The pH of the mixture was then adjusted to 2.0 with 5N hydrochloric acid and the layers separated. The upper ethyl acetate product layer was dried over sodium sulfate and concentrated to an oil on a rotary evaporator. Silica gel chromatography (10% ethyl acetate/hexanes) afforded 1.19 g of (S)-3-(2-thienylthio)butyric acid (94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]=[C:38]=[O:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[NH:37][C:38]([NH:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8])=[O:39]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.5 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene (62 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (125 mg, 64%) as a colorless powder.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1>C1COCC1>[CH2:2]=[C:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 65 %

Procedure:
A suspension of methyltriphenylphosphonium iodide (15.22 g, 37.6 mmol, Sigma-Aldrich) in THF (75 mL) was stirred at RT before addition of potassium t-butoxide (4.22 g, 37.6 mmol, Sigma-Aldrich) in one portion. The resulting bright yellow solution was stirred at RT for 30 minuets before adding tert-butyl 3-oxopiperidine-1-carboxylate (3 g, 15.06 mmol) and stirring for 3 h. It was poured into ice water, and the mixture was extracted with DCM (4×50 mL) before drying the combined organics over Na2SO4, filtering, and concentrating under reduced pressure. The crude material was purified by column chromatography (eluant: 0 to 10% EtOAc/hexanes), affording the product as a clear oil (1.93 g, 65%). 1H NMR (DMSO-d6) δ: 4.70-4.81 (m, 2H), 3.80 (s, 2H), 3.30-3.40 (m, 2H), 2.18-2.26 (m, 2H), 1.47-1.56 (m, 2H), 1.38 (s, 9H)
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)CO>[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5]
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: COc1ccc(N)c(OC)c1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1OC
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9 g, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.004 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1g (201 mg, 78%); mp: 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 10.30 (s, 1H), 8.25-8.21 (m, 2H), 7.73 (d, J=7.5 Hz 1H), 7.56 (s, 1H), 7.35-7.28 (m, 3H), 7.11 (t, J=7.5 Hz, 1H), 6.99-6.90 (m, 5H), 6.59-6.47 (m, 3H), 5.45 (s, 2H), 4.67 (d, J=5.2 Hz, 2H), 3.87 (s, 6H), 3.79 ppm (s, 3H); MS (ESI m/z): 537 [M+H]+. Yield: 78%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 40 °C
Reaction time: 48 h

Procedure:
3-Chloro-4-methoxycarbonylbenzoic acid (0.24 g) was dissolved in DMF (2.5 mL) under N2 then CDI (0.36 g) was added and the resulting mixture was stirred at 40° C. for 2 h. t-BuOH (0.54 mL) and DBU (0.33 mL) were added and the resulting mixture was stirred at 40° C. for 2 days. The mixture was evaporated and the residue was taken up with AcOEt, washed with 1N HCl and sat NaHCO3, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: toluene) to give 2-chloro-4-(tert-butoxycarbonyl)benzoic acid methyl ester (216 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH:28]([CH2:34][CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[Na+].[Na+].O>CN1CCCC1=O>[CH2:34]([CH:28]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[CH:25]=[N:24]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:35]
Reactant: CCOC(=O)C(Br)CC
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CC)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.05 mol), ethyl 2-bromobutanoate (0.055 mol) and Na2CO3 (0.15 mol) in 1-methyl-2-pyrrolidinone (250 ml) was stirred at 75° C. overnight. Ethyl 2-bromobutanoate (0.015 mol) was added again. The mixture was stirred at 75° C. for 6 hours, at room temperature for 48 hours, poured out into H2O and stirred for 30 minutes. The precipitate was filtered off and dissolved in CH2Cl2. The solution was filtered. The filtrate was dried, filtered and the solvent was evaporated. The residue was triturated in DIPE and ethyl acetate, filtered off and dried, yielding 10 g (43%) of (±)-ethyl α-ethyl-4,5-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-oxo-1H-1,2,4-triazol-1-acetate (interm. 9).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C([O:12][C:13](=[O:38])[C:14]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:32])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]2[CH2:29][NH:28][C:27](=[O:30])[N:26]2[CH3:31])=[CH:18][CH:17]=1)C.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:34]([O:33][C:14]([CH3:32])([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]2[CH2:29][N:28]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:27](=[O:30])[N:26]2[CH3:31])=[CH:18][CH:17]=1)[C:13]([OH:38])=[O:12])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOC(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)C(=O)OCC
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3ccc(Cl)cc3)C(=O)N2C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobenzyl chloride (0.04 g, 0.174 mmol) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.047 g, 0.116 mmol) and sodium hydride (0.012 g, 0.29 mmol, 60% suspension on mineral oil), pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature 48 h, diluted with ethyl acetate, and washed with 1N HCl and water. The organic layer is dried, concentrated, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.27 (d, 2H, J=8.7 Hz), 7.17 (d, 2H, J=8.7 Hz), 7.07 (d, 2H, J=8.7 Hz), 7.71 (d, 2H, J=8.7 Hz), 4.34, 4.32 (ABq, 2H, J=15.0 Hz), 3.95 (t, 3H, J=5.9 Hz), 3.69-3.62 (m, 1H), 3.61-3.55 (m, 1H), 3.51-3.45 (m, 1H), 3.38 (t, 1H, J=8.7 Hz), 3.04-2.93 (m, 3H), 2.84 (s, 3H), 2.26-2.18 (m, 1H), 1.92-1.84 (m, 1H), 1.62-1.54 (m, 2H), 1.49 (s, 3H), 1.42-1.33 (m, 3H), 0.93 (t, 3H, J=7.3 Hz). MS [EI+] 503 (M+H)+, [EI−] 501 (M−H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[CH:4][CH:3]=1.CS(O[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])=[O:11])=[CH:4][CH:3]=1)=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: CC(C)c1ccc(O[C@H](Cc2ccc(O)cc2)C(=O)OCC[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1ccc(O[C@H](Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1
Yield: 88 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using 2-trimethylsilylethyl (R)-3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionate (221 mg), which is the product of Reference example 30(e), t-butyl 2-methanesulfonyloxyethylcarbamate (330 mg) and potassium carbonate (381 mg) and the reaction mixture was treated to afford the desired compound (264 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C@@H:8]2[C@H:11]([NH:12]C(=O)OCC3C=CC=CC=3)[C:10](=[O:23])[NH:9]2)[N:6]=1>CCOC(C)=O.CO.[Pd]>[NH2:12][C@H:11]1[C@@H:8]([CH2:7][N:5]2[N:4]=[N:3][C:2]([CH3:1])=[N:6]2)[NH:9][C:10]1=[O:23]
Reactant: Cc1nnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nnn(C[C@H]2NC(=O)[C@H]2N)n1

Procedure:
Prepared in an analogous manner to example 4, step 3 using benzyl ((2R,3S)-2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (111 mg, 0.351 mmol) and Pd on C (10%, 50 mg) in EtOAc:MeOH (5:1, 7.0 mL) for 3 h. The crude residue was used as such in following step. LCMS: Rt=0.14 min, m/z=183.2 (M+1) Method 2m_acidic.