Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.S(OC)(OC)(=O)=O.[O:28]1[CH2:33]COC[CH2:29]1.[OH-].[Na+]>O>[CH3:29][O:28][CH3:33].[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: C1COCCO1
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC
Reaction time: 1 h

Procedure:
Into a mixture of 1 g of estrone, 0.5 ml of dimethyl sulfate and 5 ml of dioxane, 5 ml of 10% NaOH aqueous solution was added over a period of one hour. The reaction temperature was maintained at 15° - 20°C. The resulting mixture was stirred for one hour. Then, 30 ml of water was added and the resulting cyrstals were filtered, washed with water and dried to obtain 1.040 g of the 100% purity methyl ether of estrone in a 98.9% yield.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.Cl[C:15]([O:17][CH3:18])=[O:16].O>CCOC(C)=O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: Fc1cccc(Cl)c1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An oven-dried round bottom flask successively purged and evacuated with N2 was charged with anhydrous THF (84 ml) and placed in a −78° C. dry ice/acetone bath. To this was added n-butyllithium (2.5 M in hexanes) (18 ml, 46 mmol) and the mixture was stirred for 10 min before adding 1-chloro-3-fluorobenzene (5.48 g, 42.0 mmol) neat. The solution was stirred for 2 hrs before adding neat methyl chloroformate (4.0 ml, 50 mmol). The resultant solution was stirred at −78° C. for 3 hrs and then allowed to warm to RT. Water was added followed by EtOAc. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a clear liquid.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=O)[C:4]([O:6]CC)=[O:5].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])([O-:21])=[O:20].[OH-].[Na+]>C(O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[NH:26][C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)=[N:2][C:3]=2[C:4]([OH:6])=[O:5])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1cccc(OC)c1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)c1

Procedure:
Ethyl 5-(3-methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate obtained by reacting and treating ethyl 2-hydroxyimino-3-(3-methoxyphenyl)-3-oxopropionate and 3-nitrobenzylamine in the same manner as in Starting Material Synthetic Example 1 is dissolved in ethyl alcohol and 1 M aqueous sodium hydroxide solution is added. The mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(3-methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(C2C=CC=CN=2)=NN([CH2:61][C:62](O)=[O:63])C1=O.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:62]([O:63][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:61]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccn2)c2ccccc21
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 5, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.63 (1H, m), 8.36 (1H, m), 8.02 (1H, m), 7.81 (1H, t), 7.36 (2H, m), 7.23 (3H, m), 7.11 (4H, m), 5.05 (1H, br s), 4.72 (2H, m), 4.36 (2H, m), 3.61 (2H, s), 1.27 (9H, s).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][O:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: OCc1cccs1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccs3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A toluene solution (1.74 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), 2-thiophenemethanol (0.237 ml), triphenyl phosphine (984 mg), and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred overnight at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(2-thienylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (620 mg, yield: 56%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH:16]=[C:15]([CH:17]=O)[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:21][OH:22].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH:16]=[C:15]([CH:17]=[N:21][OH:22])[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2sc(C=O)cc2c1=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2sc(C=NO)cc2c1=O
Yield: 80 %

Procedure:
In 50 ml of warm ethanol was dissolved 0.5 g of 4,7-dihydro-7-ethyl-2-formyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. The solution was cooled to room-temperature, then 0.2 g of hydroxylamine hydrochloride was added followed by 2 ml of a 5%-solution of sodium hydroxide. After filtration, 4,7-dihydro-7-ethyl-2-hydroxyiminomethyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was obtained in a yield of 80%.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([SH:10])[CH3:9].C(N(CC)CC)C>C(OCC)C>[C:2](=[O:3])([S:10][CH2:8][CH3:9])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CCS
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCSC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A solution of 1-chloroethyl chloroformate (71.5 g, 0.5 mol) in diethyl ether (600 mL) was cooled to 0-4° C. in an ice-water bath and a solution of ethanethiol (37 mL, 0.5 mol) and triethylamine (69.3 mL, 0.5 mol) in diethyl ether (200 mL) was added dropwise over 1 h. The reaction mixture was removed from the ice bath and stirred at ambient temperature for 4 h. Triethylamine hydrochloride was removed by filtration, the filtrate concentrated under reduced pressure and the residue purified by vacuum distillation (67-68° C. at 240 mTorr) to afford the title compound (2) as a colorless liquid (75 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 1.35 (t, 3H), 1.8 (d, 3H), 2.9 (dq, 2H), 6.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36](C([O-])=O)[N:35]=[CH:34]2.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.O>CS(C)=O>[F:29][C:19]1[CH:18]=[C:17]([C:10]2[N:9]=[C:8]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][N:35]=[CH:34]4)[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)[CH:6]=3)[N:11]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCl
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCN(C)CC1
Temperature: 85 °C

Procedure:
A mixture of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.35 g, 0.55 mmol) and 4-methyl piperazine in DMSO (1.5 mL) was heated at 85° C. for 3 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound. The lower running spot was isolated and then taken up in CH2Cl2 (6 mL) and TFA (5 mL). The mixture was stirred for 2.5 h at RT. The volatiles were removed in vacuo to give a solid which was triturated with Et2O, filtered and dried under vacuum to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-amine (0.111 g, 0.184 mmol, 33%). MS 604.5 (M+1). HPLC retention time 5.10 mins.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH4+:27]>C(O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:27])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3cccc(CN4CCCC4)c3)oc12
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccc(CN4CCCC4)c3)oc12
Temperature: 30 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
Methyl 2-(3-(pyrrolidin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate (56 mg, 0.18 mmol) and ammonium water (50.4 mg, 1.44 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-(pyrrolidin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide (14 mg, yield 22%). 1H-NMR (400 MHz, DMSO-d6) δ 1.92 (s, 4H), 3.19 (s, 4H), 4.42 (s, 2H), 7.49 (s, 1H), 7.70-7.94 (m, 6H), 8.35-8.43 (d, J=32 Hz, 2H); LC-MS (ESI) m/z 322 [M+1]+.
Reaction SMILES: [NH:1]1CC(=O)N[C:2]1=[O:3].[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11].N1CC(=O)NC1=O.N[C@@H](C(O)=O)[C@H](CC)C>>[C:2]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])(=[O:3])[NH2:1]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C1CNC(=O)N1
Agent: CC[C@H](C)[C@@H](N)C(=O)O
Product: CC[C@H](C)[C@@H](NC(N)=O)C(=O)O

Procedure:
When this racemization occurs in the presence of a D-hydantoinase, the L-isoleucine hydantoin establishes an equilibrium with the D-allo-isoleucine hydantoin, and the D-allo-isoleucine hydantoin is selectively hydrolyzed by the D-hydantoinase to form the N-carbamoyl-D-allo-isoleucine. As the D-allo-isoleucine hydantoin is depleted from the mixture by D-hydantoinase-catalyzed hydrolysis, the equilibrium between the L-isoleucine hydantoin and the D-allo-isoleucine hydantoin is re-established under the epimerizing conditions, continuously generating additional D-allo-isoleucine hydantoin for stereoselective hydrolysis by the D-hydantoinase enzyme. This continual supply of the hydantoin of D-allo-isoleucine occurs during the course of the reaction until substantially all of the L-isoleucine hydantoin has been converted to N-carbamoyl-D-allo-isoleucine. In this way, the reaction can be carried out to substantial Jun. 7, 2002 completion so that L-isoleucine hydantoin is converted to N-carbamoyl-D-allo-isoleucine. By the term “substantial completion” is meant that at least about 75%, preferably at least about 85%, and most preferably at least about 95%, of the L-isoleucine hydantoin is converted to N-carbamoyl-D-allo-isoleucine. The yield of N-carbamoyl-D-allo-isoleucine produced by the method of the present invention can approach 100% of theoretical, given sufficient reaction time and/or sufficient hydantoinase enzyme. The reaction can be monitored, if desired, by any method known in the art. An example of a method useful for monitoring the extent of reaction in the D-hydantoinase-catalyzed hydrolysis is thin layer chromatography on silica gel. Alternatively, high performance liquid chromatography can be used to monitor the extent of reaction.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[C:9]1([CH3:8])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[NH:17][C:18]([N:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7])=[O:19]
Reactant: CN1CCCC1=N
Reactant: Cc1cc(C)c(N=C=O)c(C)c1
Solvent: c1ccccc1
Product: Cc1cc(C)c(NC(=O)N=C2CCCN2C)c(C)c1
Temperature: 25 °C

Procedure:
The hydrochoride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 L mole) is converted to free base (4.0 g.; 0.05 mole) by adding 10 ml. of 50% NaOH to an aqueous slurry (minimal amount of water) of the salt and benzene extraction. After drying over K2CO3, the benzene solution is stirred at room temperature and 8.06 g. (0.05 mole) of 2,4,6-trimethylphenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added. The reaction mixture is stirred at room temperature for 11/2 hours and then the solvent is evaporated in vacuo leaving an oily residue, which crystallizes on cooling. Recrystallizaton from acetone yields the pure product, 1-mesityl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 121°-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)Cl

Procedure:
A suspension of 4-bromo-2-methylbenzoic acid (4.9 g, 22.8 mmol) in dichloromethane containing a few drops of N,N-dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (2.4 mL, 27.5 mol). After gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes and then evaporated to dryness in vacuo to provide the crude 4-bromo-2-methylbenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([Sn](CCCC)(CCCC)C#CC)[CH2:26][CH2:27]C>C1(C)C=CC=CC=1.O>[CH3:8][C:6]1[CH:7]=[C:2]([C:25]#[C:26][CH3:27])[CH:3]=[C:4]([CH3:24])[C:5]=1[C:9]1[C:10](=[O:23])[CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][C:13]=1[O:14][CH3:15]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(Cc2ccccn2)C1
Solvent: Cc1ccccc1
Solvent: O
Product: CC#Cc1cc(C)c(C2=C(OC)CC(Cc3ccccn3)C2=O)c(C)c1
Temperature: 130 °C

Procedure:
To a degassed solution of rac-2-(4-bromo-2,6-dimethylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone (1.0 g, 2.5 mmol) in toluene (10 ml) is added tributyl(1-propynyl)tin (1.55 ml, 5.18 mmol) and tetrakistriphenylphosphine palladium(0) (0.5 g, 0.5 mmol) under a nitrogen atmosphere. The reaction mixture is heated at 130°C. for 40 minutes under microwave irradiation, then diluted with distilled water (20 ml) and extracted with ethyl acetate (50 ml×2). The combined organic fractions are washed with distilled water, brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo to afford rac-2-(2,6-dimethyl-4-prop-1-ynylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone. This material is used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9]([CH3:12])([CH3:11])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[C:20]#[N:21]>>[F:25][C:23]1[CH:22]=[C:19]([CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9]([CH3:12])([CH3:11])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=3[CH:15]=2)[CH:24]=1)[C:20]#[N:21]
Reactant: CC1(C)Nc2ccc(Br)cc2C(C)(C)O1
Reactant: N#Cc1cc(F)cc(Br)c1
Product: CC1(C)Nc2ccc(-c3cc(F)cc(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared using the coupling procedure for Example 13 starting with 6-bromo-2,2,4,4-tetramethyl-1,4-dihydro-2H-3,1-benzoxazine and 3-bromo-5-fluorobenzonitrile. A white solid: 1H-NMR (DMSO-d6) δ 8.03 (s, 1H), 7.87 (d, 1H, J=10.7 Hz), 7.65 (d, 1H, J=10.7 Hz), 7.57 (d, 1H, J=1.98 Hz) 7.45 (dd, 1H, J=8.33, 1.98 Hz), 6.65 (d, 1H, J=8.33 Hz), 6.42 (s, 1H), 1.52 (s, 6H), 1.34 (s, 6H); MS (ES) m/z 311 ([M+H]+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][CH2:10]/[C:11](/[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][O:20]C2CCCCO2)=[O:18])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>CO>[OH:20][NH:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]/[CH:12]=[C:11](\[CH2:27][O:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)/[CH2:10][NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C(CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12)NOC1CCCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12)NO
Yield: 52.8 %

Procedure:
(Z)-8-(2-morpholinoethylamino)-7-((naphthalen-1-yloxy)methyl)-N-(tetrahydro-2H-furan-2-yloxy)oct-6-enamide (63 mg, 0.09 mmol) obtained in Example (3-1-3) was dissolved in methanol (1.5 ml), and trifluoroacetic acid (0.04 ml, 0.45 mmol) was slowly added thereto at room temperature. The resulting mixture was reacted for 8 hours to conduct a deprotection reaction of THP. After the completion of reaction, the reaction solution was concentrated under reduced pressure. The residue thus obtained was purified by a preparative HPLC to obtain 21 mg of the title compound as pale orange oil (yield 53%), which was used in the subsequent analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:21]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[CH:19]=[C:20]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:21]=[C:16]([Br:15])[CH:17]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: CC(C)COc1cc(Br)cc(B(O)O)c1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1ccc(Oc2cc(Br)cc(OCC(C)C)c2)cc1C

Procedure:
(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (215 mg; 1.1 mmol), 3-Bromo-5-isobutoxy-phenylboronic acid (523.4; 1.9 mmol), copper(II) acetate (199 mg; 1.1 mmol), crushed molsieves (about 1 g) and triethylamine (0.46 ml; 3.3 mmol) was dissolved in dichloromethane (40 ml) and stirred over night. The reaction mixture was filtered through celite and evaporated to dryness. The crude product was purified by preparative HPLC (method B). Yield: 300 mg; 65%. HPLC-MS: m/z: 423.5 (M+); Rt: 2.71 min
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([CH2:21][NH:20][C:19](=[O:22])[CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:31])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][CH3:36]>C1COCC1>[CH2:35]([N:20]1[C:19](=[O:22])[CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][C:14]2([CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:31])[CH:7]=3)[CH2:12][CH2:13]2)[CH2:21]1)[CH3:36]
Reactant: CCBr
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNC(=O)C(c2ccccc2)O3)ccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)OC(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one (65 mg, 0.15 mmol) in THF (1 mL) at 0° C. was added NaH (6 mg, 0.15 mmol) and the reaction mixture was stirred for 30 minutes. Bromoethane (34 mg, 23 μL, 0.31 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give 2-ethyl-9-(4-isopropoxy-3-methyl-benzoyl)-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.48-7.43 (m, 2H), 7.39-7.29 (m, 3H), 7.23-7.17 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 5.11 (s, 1H), 4.56 (dt, J=12.1, 6.0 Hz, 1H), 3.63 (d, J=12.4 Hz, 1H), 3.59-3.19 (m, 5H), 3.09 (d, J=12.4 Hz, 1H), 2.92 (d, J=28.7 Hz, 1H), 2.22 (s, 1H), 2.23-2.16 (m, 3H), 1.59 (s, 3H), 1.35 (d, J=6.0 Hz, 6H), 1.14 (t, J=7.2 Hz, 3H). ESI-MS m/z calc. 450.3. Found 451.1 (M+1)+; Retention time: 1.76 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[S:29]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][NH:30]1>>[O:34]=[S:29]1(=[O:35])[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)nc1C
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)nc1C
Yield: 52.8 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (370 mg) described in Preparation Example 122 and isothiazolidine 1,1-dioxide (96 mg) and by the reaction and treatment in the same manner as in Example 4, the title compound (212 mg) was obtained.