Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:21])[CH2:10][C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)([CH2:11][CH:12]=C)[CH2:8][CH2:7][O:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:4][C:5]1([CH3:21])[CH2:10][C:9]([CH2:11][CH:12]=[O:1])([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7][O:6]1
Reactant: C=CCC1(c2ccc(C)cc2)CCOC(C)(C)C1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(C2(CC=O)CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52 %

Procedure:
O3 gas was passed through a solution of 2,2-dimethyl-4-(4-methylphenyl)-4-(prop-2-en-1-yl)oxane (1.21 g, 5 mmol) in CH2Cl2 (50 ml) at −78° C. until the solution turned light blue (about 5 min). After additional 5 minutes, the reaction mix was purged with oxygen gas for 15 min before adding triphenylphosphine (2.62 g, 10 mmol). The reaction was stirred at rt for 4 h and concentrated. Purified by normal phase SiO2 chromatography (10 to 60% EtOAc/hexanes) to give 2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]acetaldehyde as a colorless oil (641 mg, 52%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[C:5](=[O:23])[CH:4]=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)=[N:7]3)=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(OCCn3nc(-c4ccsc4)ccc3=O)ccnc2c1
Temperature: 120 °C
Yield: 72.2 %

Procedure:
To a solution of 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (0.090 g, 0.27 mmol) and 3-thiopheneboronic acid (0.069 g, 0.54 mmol) in 4 mL of dioxane was added 1 mL of 1N Na2CO3 followed by 30 mg of FibreCat, in a microwave vial. The reaction was heated to 120° C. for 30 minutes. The mixture was then diluted with 40 mL of NaHCO3 and 60 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtAOc to 10% MeOH/EtOAc) to give a white solid (0.074 g, 72% yield). MS (ESI pos. ion) m/z (MH+): 380.1. Calc'd Exact Mass for C20H17N3O3S: 379.1.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH:8]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>COCCOC>[C:21]([C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:18]=1[OH:25])[N:8]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(N(C(=O)CCC(=O)O)c2ccccc2)cc(C(C)(C)C)c1O
Yield: 93.1 %

Procedure:
1.5 g (0.015 mole) of succinic anhydride, 4.5 g (0.010 mole) of 4-anilino-2,6-di-t-butylphenol, and 10 ml of 1,2-dimethoxyethane were combined and heated at reflux for 48 hours. 1.5 g of succinic anhydride and 5 ml of 1,2-dimethoxyethane were added and the reaction was heated for an additional 24 hours. The reaction mixture was cooled in an ice bath. The resulting precipitate was collected, rinsed with a small amount of cold 1,2-dimethoxyethane, and recrystallized from a mixture of ethanol and water to give 3.7 g of off-white 4-(3,5-di-t-butyl-4-hydroxy-N-phenylanilino)-4-oxobutanoic acid, m.p. 205°-208° C. Analysis: Calculated for C24H31NO4 : % C, 72.5; % H, 7.9; % N, 3.5: Found: % C, 72.4; % H, 7.8; % N, 3.3.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([C:10](OC)=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: COC(=O)c1ncn2cc(Br)sc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1ncn2cc(Br)sc12
Temperature: -100 °C
Reaction time: 0.83 h
Yield: 93 %

Procedure:
A solution of methyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (31 mg, 0.12 mmol) in dichloromethane (8 ml) was cooled to −100° C. Thereafter, a toluene solution of diisobutylaluminium hydride (1.01 M solution; 0.4 ml, 0.4 mmol) was added dropwise to the cooled solution. The mixture was stirred at −100° C. for 50 min and then at −80° C. for 15 min. After the completion of the reaction, a saturated aqueous potassium sodium tartrate solution was added to the reaction solution, and the mixture was stirred at room temperature for one hr and was extracted with ethyl acetate (8 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 2-bromo-7-hydroxymethylimidazo[5,1-b]thiazole (26 mg, 95%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[C:4]=1[CH3:11])=[O:2].C(O)C.[BH4-].[Na+]>O>[OH:2][CH2:1][C:3]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[C:4]=1[CH3:11]
Reactant: CC1=C(C=O)C(C)(C)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(CO)C(C)(C)CC1=O

Procedure:
42 g. of 1-formyl-3-oxo-2,5,5-trimethyl-cyclopentane, prepared according to either Example 2 or 3 are heated to boiling together with 2.1 g. of p-toluenesulfonic acid, 60 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 600 ml. of toluene for 4 hours under reflux conditions. After cooling, the mixture is filtered. The filtrate is washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. There is obtained crude 1-formly-3-oxo-2,5,5-trimethyl-cyclopent-1ene as an oil, whose 2,4-dinitrophenylhydrazone has a melting point of 216°-218°C. 38 g. of the crude 1-formyl-3-oxo-2,5,5-trimethyl-cyclopent-1-ene are dissolved in 1000 ml. of ethanol. The solution is treated at 0°-5°C. within 1 hour with 2.1 g. of sodium borohydride, stirred for a further 30 minutes, introduced into water and extracted with ether. The ether is dried over sodium sulfate and evaporated under reduced pressure. There is obtained 1-hydroxymethyl-3-oxo-2,5,5-trimethyl-cyclopent-1-ene which, after recrystallization from hexane, has a melting point of 38°-39°C. 8.3 g. of the 1-hydroxymethyl-3-oxo-2,5,5-trimethyl-cyclopent-1-ene are dissolved in 170 ml. of ether. After the addition of 1 ml. of pyridine, the solution is treated dropwise at 0°C. with a solution of 2.21 ml. of phosphorus tribromide in 30 ml. of ether, stirred for 1 hour, introduced into water and extracted with ether. The ether extract is dried and evaporated. The residue is taken up in 120 ml. of ethyl acetate. The solution is treated dropwise with 14.4 g. of triphenylphosphine in 120 ml. of ethyl acetate and heated to boiling for 1 hour under reflux conditions. The methyl-(3-oxo-2,5,5-trimethyl-cyclopent-1-en-1 -yl-triphenylphosphonium bromide which crystallizes out in the cold has a melting point of 264°C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C@@H:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([F:31])=[CH:23][CH:22]=3)[CH3:20])[CH2:14]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C(O)C>[F:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([C@H:19]([NH:18][C@H:15]2[CH2:16][CH2:17][C@@H:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][CH:9]=3)[CH2:14]2)[CH3:20])=[CH:22][CH:23]=1
Reactant: CCOC(=O)COc1ccc([C@@H]2CC[C@H](N[C@H](C)c3ccc(F)c4ccccc34)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCC(=O)O)cc2)C1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
{4-[(1R,3S)-3-{[(1R)-1-(4-Fluoronaphthalen-1-yl)ethyl]amino}cyclopentyl]phenoxy}acetic acid ethyl ester (800 mg, 1.8 mmol) was dissolved in ethanol (5 mL), followed by addition of 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred for 30 minutes at room temperature. 1N hydrochloric acid was added dropwise to the reaction mixture to make the reaction solution acidic, and the solvent was distilled off under reduced pressure. The aqueous phase was extracted with chloroform, the extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give the title compound (742 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].Br[CH2:32][CH2:33][CH2:34][Cl:35].O>CN(C)C=O>[Cl:35][CH2:34][CH2:33][CH2:32][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: ClCCCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCl)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
814 mg (2.09 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 15 ml of dimethylformamide under argon atmosphere, 256 mg of sodium hydride (60% oil dispersion) and 0.42 ml of 1-bromo-3-chloropropane were added under ice-cooling and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to give 193 mg (20%) of 5-(3-chloropropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:15])[C@H:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:14])[NH2:13])[NH2:7].O.O.O.O.O.O.O.O.O.O.O.O.OP([O-])([O-])=O.[Na+].[Na+]>O.[OH-].[Na+]>[NH2:7][C@H:6]([C:5]([OH:15])=[O:4])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:13])[NH2:14]
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Agent: *CCO*
Agent: CCCCCCCCCCCCOCCCCCCCCCCCC
Agent: Cl
Solvent: O
Product: N=C(N)NCCC[C@H](N)C(=O)O
Temperature: 110 °C

Procedure:
2.61 Grams (10 mmol) of L-arginine methyl ester dihydrochloride, 1.11 g (3.1 mmol) of disodium phosphate 12 hydrate and 0.1 g of polyoxyethylene lauryl ether (“Newcol 1100”, nonionic surfactant produced by Nippon Nyukazai Co., Ltd.) were dissolved in 5.0 ml of water to prepare a treating agent solution. A cotton cloth (150 mm×170 mm, 4.8 g) was in advance treated to be immersed in 25% aqueous sodium hydroxide solution for an hour at room temperature, washed with water and dried. This treated cotton cloth was allowed to uniformly absorb the total amount of the above treating agent solution and then air-dried for 3 hours at room temperature. The dried cloth was heat-treated for 40 minutes at 150° C. in a batch type hot air oven (“IPHH-2000”, an inert oven manufactured by Tabaiesbeck Co., Ltd.) and washed with water. It was further washed with 5% aqueous sodium bicarbonate solution and rinsed three times with water and subsequently was washed with 10% aqueous citric acid solution and rinsed three times with water, and finally washed with household washing detergent solution, rinsed with water and air-dried. The identification of L-arginine cellulose ester was conducted by the following method. A part of the cloth was cut and a solution of ninhydrin in butanol was sprayed on it. Thereafter, it was heated for 10 minutes in an oven of 110° C. to cause coloring thereby the presence of the amino acid was confirmed. Also, a part of the cloth was cut and subjected to an infrared spectroscopic analysis whereby there was confirmed a peak based on ester bond at 1720–1740 cm−1. As a result of determination for the amount of the bonded L-arginine, it was 0.08 mmol based on 1 g of the cloth. The degree of esterfication was 0.013.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC.C1CCCCC1.CCOCC>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(c1ccccc1)c1ccccc1Cl
Reactant: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Temperature: 15 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a stirred, ice-cooled solution of 2-chlorobenzophenone (21.6 g, 100 mmol) in 150 mL of dry Et2O under N2 was added 60 mL (120 mmol) of 2.0 M phenyllithium solution in cyclohexane-Et2O (7:3), keeping T<15° C. After stirring for a further 1 h at 15° C., the solution was poured onto crushed ice and extracted with Et2O. The organic solution was washed with 0.2 M H2SO4, water (until neutral), brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from hexanes containing a few per cent EtOAc to give 23.1 g (78%) of (2-chlorophenyl)diphenylmethanol as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH3:32].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH2:31][CH3:32])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid(500mg), potassium carbonate(310 mg), iodoethane(350mg) and N,N-dimethylformamide(10 ml) was stirred at room temperature for 16 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated and the 15 crystals thus precipitated were collected by filtration. These were recrystallized from acetone-hexane to give colorless of ethyl 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionate(495mg, 91%). mp 70-71° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C:30]1([CH3:37])[C:34]([CH3:36])([CH3:35])[O:33][BH:32][O:31]1.[C:38]([NH:41][C:42]([CH:54]1[CH2:59][CH2:58][N:57]([C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:61])[CH2:56][CH2:55]1)([CH2:50][CH2:51][CH:52]=[CH2:53])[C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])(=[O:40])[CH3:39]>C1COCC1.[Ir+].ClC1CCC=CCCC=1>[C:38]([NH:41][C:42]([CH:54]1[CH2:55][CH2:56][N:57]([C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:61])[CH2:58][CH2:59]1)([CH2:50][CH2:51][CH2:52][CH2:53][B:32]1[O:33][C:34]([CH3:36])([CH3:35])[C:30]([CH3:37])([CH3:29])[O:31]1)[C:43]([NH:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])(=[O:40])[CH3:39]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC1(C)OBOC1(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
While under an argon atmosphere, a solution of 1,2-bis(diphenylphosphino)ethane (306 mg, 0.77 mmol) and chloro-1,5-cyclooctadiene iridium (I) dimer (258 mg, 0.39 mmol) in anhydrous THF (30 mL) was treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.48 g, 1.67 mL, 11.6 mmol) in one portion. After stirring for 15 minutes the solution was cooled to 5° C. (ice-water batch) and treated with benzyl 4-(2-acetamido-1-(tert-butylamino)-1-oxohex-5-en-2-yl)piperidine-1-carboxylate (3.42 g, 7.70 mmol) in one portion. After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. After 2 hours of stirring the reaction was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted using ethyl acetate (2×150 mL). The organic layer was dried over MgSO4, filtered and concentrated. MPLC purification (100 g column, 40-80% ethyl acetate in heptane) gave benzyl 4-(2-acetamido-1-(tert-butylamino)-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-yl)piperidine-1-carboxylate as a colorless oil (3.10 g, 71% yield). 1H NMR (CDCl3, 300 MHz) δ 7.36-7.30 (m, 5H), 6.94 (bs, 1H), 5.46 (s, 1H), 5.10 (s, 2H), 4.36-4.10 (m, 2H), 2.86-2.60 (m, 3H), 2.40-2.28 (bt, J=12.3 Hz, 1H), 1.98 (s, 3H), 1.78-1.61 (m, 2H), 1.49-1.17 (m, 5H), 1.33 (s, 9H), 1.20 (s, 8H), 1.12-0.94 (m, 2H), 0.73 (t, J=7.8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc(Oc2cc(Br)cnc2Nc2nc(CCc3ccccc3)cs2)cc1
Yield: 102.2 %

Procedure:
Following the procedure in Example 7 Step E, 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (740 mg, 2.163 mmol), 1-bromo-4-phenylbutan-2-one (687.6 mg, 3.028 mmol) and triethylamine (0.5014 mL, 3.676 mmol) afforded 5-bromo-3-(4-fluorophenoxy)-N-(4-phenethylthiazol-2-yl)pyridin-2-amine (1040 mg, 102.2% yield) as a white solid after drying. 1H NMR (CDCl3) δ 8.71 (bs, 1H), 8.13 (d, 1H), 7.28 (m, 2H), 7.20 (m, 3H), 7.13 (m, 2H), 7.06 (m, 3H), 6.43 (s, 1H), 3.05-2.92 (m, 4H), Mass spectrum (apci) m/z=470.2, 472.2 (M+H).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[S:16][C:17]2[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][C:21]([CH3:28])([CH3:27])[C:18]=2[C:19]=1[CH3:20])\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[CH:32][CH:31]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[S:16][C:17]2[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][C:21]([CH3:28])([CH3:27])[C:18]=2[C:19]=1[CH3:20])\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1sc2c(c1C)C(C)(C)CCC2(C)C
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1sc2c(c1C)C(C)(C)CCC2(C)C
Yield: 2.16 %

Procedure:
Compound 106 was synthesized from (4-{[(2E)-2-(methoxyimino)-2-(3,4,4,7,7-pentamethyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)ethyl]oxy}phenyl)methanol (0.3 g, 0.7 mmol) and methyl 3-(4-hydroxyphenyl)propanoate (0.135 g, 0.7 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 2.16%); Purity: 97.59%.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([NH:14][C:13]1[CH:15]=[CH:16][N:9]([C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)[C:10](=[O:11])[N:12]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.2 %

Procedure:
To 61.29 g (270 mmol) of the material of Example I dissolved in 1300 ml of anhydrous N,N-dimethylformamide ("DMF") (Aldrich; Cat. No. 22, 70506), was added 28 ml (296 mmol) of acetic anhydride (Aldrich; Cat. No. 11,004-3), and the resulting mixture was stirred at room temperature for 20 hrs. DMF was removed under reduced pressure, and the resulting residue was treated with the excess of 100 ml dimethyl ether; 71.4 g (98% yield) of a crystalline product was obtained and collected by filtration, washed thoroughly with dimethyl ether, and dried over P2O5 for 3 hrs. This product had a melting point of 150°-170° C.; the published melting point for this product 154°-176° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[C:7]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[S:28][C:29]3[N:30]=[CH:31][N:32]=[C:33]([O:36][CH3:37])[C:34]=3[N:35]=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:37][O:36][C:33]1[C:34]2[N:35]=[C:27]([NH:26][C:25]([N:12]3[CH2:11][CH2:10][C:9]([OH:15])([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[N:8]=4)[CH2:14][CH2:13]3)=[O:24])[S:28][C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: OC1(c2cccc(C(F)(F)F)n2)CCNCC1
Reactant: COc1ncnc2sc(NC(=O)Oc3ccccc3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ncnc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)n4)CC3)nc12
Yield: 17.5 %

Procedure:
A mixture of 6-trifluoromethyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol (320 mg, 1.30 mmol) in acetonitrile (15 mL) was treated with (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-carbamic acid phenyl ester (360 mg, 1.18 mmol). The mixture was stirred at reflux for 2 h. At this time, the reaction was poured into a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with methylene chloride. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 methylene chloride/methanol) afforded 4′-hydroxy-6-trifluoromethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (94 mg, 17%) as a white solid; LRMS for C18H17F3N6O3S (M+H)+ at m/z=454. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([NH2:17])(N)=O.OO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>>[CH:2]1[C:1]2[CH2:7][C:8]3[C:14](=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:17][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: OO
Product: c1ccc2c(c1)Cc1ccccc1N2
Reaction time: 0.17 h

Procedure:
Chemiluminescent HRP detection limit using a reagent composition containing 0.05 mM 2′,3′,6′-trifluorophenyl 3-methoxy-10-methylacridan-9-carboxylate (compound 13), 0.1 mM 4-phenylphenol, 0.5 mM urea peroxide, 1 mM EDTA, and 0.025% TWEEN 20 in 0.01 M tris buffer, pH 8.0 was obtained on a Labsystems Luminoskan microtiter plate reader. White Microlite 1 FB 12-well strips (Dynatech Laboratories) containing 100 μL of the reagent in each well were reacted with 10 μL of HRP dilutions. Light intensity was measured at 10 min.