Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13]Br)=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20].[OH2:21]>CS(C)=O.[Cu-]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:21])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Reactant: O
Agent: O=[Cu-]
Solvent: CS(C)=O
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CO)ccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-bromomethylpyrazole (0.6 g, 1.72 mmol) in DMSO (10 mL) was added copper (I) oxide (0.52 g, 3.62 mmol) and water (3 mL). The reaction was stirred at 60° C. overnight. The next day the reaction mixture was filtered through celite. The filtrate was partitioned between ethyl acetate and water. The organic was washed three times with water, brine, dried over sodium sulfate, filtered and concentrated to leave 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxymethyl pyrazole (0.45 g, 92% yield) as pure compound: MS (CI): 286 (M+H)+ (100%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16](/[C:21](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=2)=[CH:22]/[C@@H:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:26](=[O:39])[CH2:25][CH2:24]2)=[N:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16](/[C:21](/[C:40]2[CH:41]=[CH:42][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:44][CH:45]=2)=[CH:22]/[C@@H:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:26](=[O:39])[CH2:25][CH2:24]2)=[N:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(/C=C/CCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Yield: 61.8 %

Procedure:
10% palladium-activated carbon (50 mg) and zinc(II) bromide (25 mg) were added to a solution of (5R)-5-[(E)-2-{5-[(1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-en-1-yl]-6-methoxypyridin-2-yl}-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (226 mg) in methanol (5 mL), and the mixture was stirred at room temperature for five hours in a hydrogen atmosphere. The reaction solution was diluted with ethyl acetate and filtered through celite. The filtrate was sequentially washed with water and brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:9) to give (5R)-5-[(E)-2-[5-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-methoxypyridin-2-yl]-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (140 mg, 62%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8](=O)[CH2:9][CH3:10])[C:6](=[O:12])[CH2:5][CH:4]([C:13]#[N:14])[CH2:3]1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCCC1>[O:1]=[C:2]1[CH:7]([C:8](=[N:18][CH:15]([CH3:17])[CH3:16])[CH2:9][CH3:10])[C:6](=[O:12])[CH2:5][CH:4]([C:13]#[N:14])[CH2:3]1
Reactant: CC(C)N
Reactant: CCC(=O)C1C(=O)CC(C#N)CC1=O
Solvent: C1CCOC1
Product: CCC(=NC(C)C)C1C(=O)CC(C#N)CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.2 g (0.006 mol) of 3,5-dioxo-4-propionylcyclohexanenitrile were dissolved in 40 ml of dry tetrahydrofuran, and 0.4 g (0.006 mol) of isopropylamine was added. The mixture was stirred for 16 hours at room temperature, the solvent was stripped off under reduced pressure and the residue was filtered under suction over a little silica gel using methylene chloride/methanol. The solvent was stripped off to give 1.3 g 92% of theory) of 3,5-dioxo-4-(1-isopropyliminopropyl)-cyclohexanenitrile.
Reaction SMILES: CO.[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O:29]C)=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:14])=[O:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=1.C[O-].[Na+:39]>CCOCC>[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O-:29])=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:13])=[O:14])=[C:10]([CH3:11])[C:6]=2[CH:5]=1.[Na+:39].[Na+:39].[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O-:29])=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:13])=[O:14])=[C:10]([CH3:11])[C:6]=2[CH:5]=1
Reactant: COC(=O)c1coc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(C(=O)[O-])co3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
Into 30 mL of methanol was dissolved 290 mg of Compound 23, followed by addition of 77 mg of sodium methoxide. After 8 hours of stirring at room temperature, ether was added and the precipitated crystals were collected by filtration and washed with ether to obtain 300 mg of the title compound as colorless powder.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.O.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([O:24][C:25]([NH:8][C@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C=CC[C@@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of D-2-amino-4-pentenoic acid (500 mg) in Dioxane (20 mL) at RT was added triethylamine (1.09 g), water (0.5 mL), and N-(benzyloxycarbonyloxy)succinimide (2.27 g). The reaction mixture was stirred overnight at RT, concentrated in vacuo, diluted with saturated NaHCO3 and extracted with ether (3×). The basic aqueous layer was acidified to pH 2 with 2N HCl and extracted with EtOAc (3×). The combined EtOAc layer was washed with brine, dried (Na2SO4), filtered and concentrated to give a clear viscous oil (1.17 g, quantitative).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:11])[CH3:10]>C(OCC)(=O)C>[C:9]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: O=c1cc(O)cc[nH]1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc[nH]c(=O)c1
Yield: 60 %

Procedure:
A 5.00 g quantity of 4-hydroxy-2-pyridone and 3.84 ml of acetyl chloride were reacted for 5 hours in the same manner as in Example 2. The title compound was isolated in an amount of 4.15 g from the reaction mixture in the same manner as in Example 2 except that ethyl acetate was used as extraction solvent. Yield was 60%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:37]=2)=[O:31])[CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.COCCOC.O>[C:38]1([C:36]2[CH:37]=[C:32]([C:30]([NH:29][C:18]3[CH:17]=[C:16]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[O:31])[CH:33]=[N:34][CH:35]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccs2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
Water (0.60 mL), 2-thiopheneboronic acid (34 mg), sodium carbonate (70 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) suspension of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-85% hexane/ethyl acetate] to obtain tert-butyl 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-2-yl)benzoate.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]1[C:10](=[O:22])[NH:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:14]=1[CH3:15].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)(Cl)Cl>[CH3:8][C:9]1[C:10]([O:22][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:13][C:14]=1[CH3:15]
Reactant: Cc1nc(-c2ccccc2)[nH]c(=O)c1C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1nc(-c2ccccc2)nc(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a mixture of sodium hydride (about 60% oily, 1.0 g) and dimethylformamide (80 ml) is added 5,6-dimethyl-2-phenyl-4(3H)-pyrimidinone (5.0 g) while the temperature of the mixture is kept at 0-5° C., and the mixture is stirred at 0° C. for 30 minutes. To the mixture is added dropwise ethyl bromoacetate (4.2 g) at the same temperature. After addition, the mixture is stirred at 80° C. for three hours, and thereto are added ice-water and chloroform. The chloroform layer is collected by filtration, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from isopropanol to give ethyl 2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)acetate (6.2 g), m.p. 90-91° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>C(O)(=O)C.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)N1CCc2cc(Oc3ccnc(N)c3)ccc21
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 60.7 %

Procedure:
5-(2-Aminopyridin-4-yloxy)-2,3-dihydro-1H-indole-1-carboxylic acid methylamide (40 mg, 0.14 mmol) was dissolved in acetic acid (0.9 ml), manganese (III) acetate (29 mg, 0.17 mmol) was added thereto and the reaction mixture was stirred at 70° C. for 3.5 hours. Manganese (III) acetate (29 mg, 0.17 mmol) was further added, and the reaction mixture was further stirred at 70° C. for 0.5 hours. After naturally cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in diethyl ether:acetone=3:1, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (24 mg, 0.085 mmol, 61%) as colorless crystals.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](C#N)(C)C.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([S:23](Cl)(=[O:25])=[O:24])=[C:18]([CH3:27])[C:17]=1[CH3:28].CO>C(#N)C>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([S:23]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])(=[O:24])=[O:25])=[C:18]([CH3:27])[C:17]=1[CH3:28]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: N[C@H](CO)C(=O)O
Agent: C[Si](C)(C)C#N
Solvent: CO
Solvent: CC#N
Product: COc1cc(C)c(S(=O)(=O)N[C@H](CO)C(=O)O)c(C)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a suspension of D-serine (6.95 g, 66.1 mmol) in acetonitrile (100 mL) was added trimethylsilyl cyanide (40 mL, 298 mmol) and the resulting solution was heated to 80° C. After 1 h, 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (17.3 g, 69.4 mmol) was added and the heating was continued. After 12 h, the reaction mixture was cooled to room temperature. Methanol (15 mL) was added, and the organics were removed in vacuo. The residue was diluted with diethyl ether (300 mL) and after cooling the reaction mixture to 0° C., the pH was adjusted to 8 with 6 N aqueous sodium hydroxide solution. The organic layer was collected and the aqueous layer was extracted with diethyl ether. The aqueous layer was adjusted to pH 4 and again extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to afford 2(R)-(4-methoxy-2,3,6-trimethylbenzene-sulfonylamino)-3-hydroxypropionic acid (20.5 g) as a brown foam which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:13]([C:16]2[CH:21]=[CH:20][C:19](OCCCC)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH3:12][N:9]1[CH2:10][CH2:11][C:6]([S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[O:3][CH2:4][CH2:6][CH2:7][CH3:8])(=[O:15])=[O:14])([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccccc1S(=O)(=O)C1(C(=O)O)CCN(C)CC1

Procedure:
1-Methyl-4-(butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-methyl-4-(4butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (7.6 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). The resulting reaction mixture was worked up outlined in example 83. Yield 6.0 (84%); white solid; mp 195° C.; MS:356.4 (M+H)+
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C[C@@H]([C@@H]1[C@@]2(C)CCC/C(=C\C=C3\C[C@@H](O)CCC\3=C)/[C@@H]2CC1)CCCC(O)(C)C>C(O)C>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:25]4([CH3:26])[CH2:24][CH2:23][C@H:22]([OH:27])[CH2:21][C:20]4=[CH:19][CH:18]=[C:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]12
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
For the treatment with vitamin D metabolites, stock solutions of 2 mM 7-Dehydrocholesterol (7-DHC, Sigma St. Louis, Mo., USA), 2 μM cholecalciferol (D3, Sigma St. Louis, Mo., USA), and 2 μM 25-Hydroxyvitamin D (25-D3, Sigma St. Louis, Mo., USA) were prepared in absolute ethanol and filtered with a 0.22 mm pore size filter before use. Fourteen different groups were prepared; eight were non irradiated: 7-DHC at different doses (20 nmols, 2 nmols, 0.2 nmols, 2×10−2 nmols, and 2×10−3 nmols), 2×10−2 nmols D3, 2×10−2 nmols 25-D3 and ethanol. And six were UV-irradiated: 7-DHC at the same different doses (20 nmols, 2 nmols, 0.2 nmols, 2×10−2 nmols, and 2×10−3 nmols) and ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:39])([F:38])[C:27]1[CH:28]=[C:29]([OH:37])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:37][C:29]3[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:27]([C:26]([F:25])([F:38])[F:39])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 65.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (30 mg, 0.08 mmol) was reacted with 3,5-bis(trifluoromethyl)-phenol (30 mg, 0.13 mmol) to give the title compound (30 mg, 65%) after purification by flash chromatography on silica gel (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([CH2:16][CH2:17][S:18][CH:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][C:32]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][C:40]([Cl:46])=[CH:41][CH:42]=4)[N:37]=3)=[CH:33][C:20]1=2)(O)=[O:14].N.O>O1CCCC1>[C:13]([CH2:16][CH2:17][S:18][CH:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][C:32]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][C:40]([Cl:46])=[CH:41][CH:42]=4)[N:37]=3)=[CH:33][C:20]1=2)(=[O:14])[NH2:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
0.98 g of 1,1'-carbonyldiimidazole was added to 1.99 g of 11-(2-carboxyethylthio)-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Example 2 dissolved in 33 ml of tetrahydrofuran and the mixture was stirred at room temperature for 4 hours. Then, 4 ml of conc. aqueous ammonia was added to the mixture and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was condensed under reduced pressure, water was added to the residue, crystals were collected by filtration and the crystals were dissolved in chloroform. After this chloroform solution was washed with water and dried over anhydrous sodium sulfate, solid obtained by removing the solvent was washed with an acetone-hexane mixed solution to obtain 1.99 g of the title compound.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:40])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:18](OCCO)=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO.CC[O:45][C:46]([CH3:48])=[O:47].CC[O:51]C(C)=O.[K+].[Br-]>C(O)=O>[CH2:1]([NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:33]2[C:34]([F:39])([O:51][CH2:48][C:46]([OH:45])=[O:47])[CH2:35][CH:36]=[CH:37][CH:38]=2)[CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:20]=1)=[O:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(-c2ccc(OC)cc2)c(OCCO)c(-c2ccccc2F)c1
Reactant: CCOC(C)=O
Agent: [Br-]
Agent: [K+]
Solvent: O=CO
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)c1cc(C2=CC=CCC2(F)OCC(=O)O)cc(-c2ccc(OC)cc2)c1

Procedure:
The title compound was prepared, as a white solid (0.229 g, 47%) from N-dodecyl-3-(2-fluorophenyl) 5-(4-methoxyphenyl)-4-(2-hydroxyethoxy)benzamide using a procedure similar to step 3 of example 1. The product was purifed by preparatory plate chromatography (4% Methanol/EtOAc) followed by flash chromatography (15% EtOAc/Hex and 20% EtOAC/Hex, both with 1% formic acid); 1H NMR (400 MHz, DMSO-d6) δ 0.84 (t, J=6.8 Hz, 3H), 1.17-1.27 (m, 18H), 1.44-1.51 (m, 2H), 3(dd, J=6.8, 13.0 Hz, 2H), 3.78 (s, 3H), 3.81 (s, 2H), 6.99-7.02 (m, 2H), 7.23- (m, 2H), 7.42-7.47 (m, 2H), 7.50-7.57 (m, 2H), 7.71 (d, J=2.2 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 8.47 (t, J=5.5, 1H), 12.48 (broad s, 1H); IR (KBr) 3375, 2925, 2850, 1730, 1615, 1200 cm−1; mass spectrum [(+)ESI], m/z 564 (M+H)+; Anal. Calcd. for C34H42FNO5: C, 72.44; H, 7.51; N, 2.48, Found, C, 72.48; H, 7.67; N, 2.46.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C1C(=O)N([Br:28])C(=O)C1>O>[C:1]([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[Br:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(COC(=O)c2ccccc2)on1
Solvent: O
Solvent: CC(=O)O
Product: Cc1noc(COC(=O)c2ccccc2)c1Br
Temperature: 110 °C

Procedure:
To a resealable vial was added (3-methylisoxazol-5-yl)methyl benzoate (907 mg, 4.18 mmol), AcOH (3.5 mL, 61.1 mmol), and NBS (892 mg, 5.01 mmol). The reaction was heated to 110° C. overnight. The reaction was cooled to room temperature and diluted with water. The aqueous was extracted with EtOAc and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-bromo-3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z 296 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C([Li])CCC.Br[CH2:23][C:24]1[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=1.O>O1CCCC1>[F:1][C:2]1[C:3]([CH2:16][CH2:23][C:24]2[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[N:6][CH:7]=1
Reactant: CC(C)c1csc(CBr)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ncc1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1csc(CCc2cc(NC(=O)OC(C)(C)C)ncc2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
The tert-butyl N-(5-fluoro-4-methyl-2-pyridyl)carbamate (75.6 mg, 0.334 mmol) obtained in (F) was dissolved in tetrahydrofuran (2 ml) and added dropwise with n-butyl lithium (1.5 M solution in hexane, 0.468 ml, 0.702 mmol) at −78° C. under argon atmosphere. The reaction mixture was warmed to room temperature, stirred for 1 hour, cooled to −78° C. again, added dropwise with a solution of 2-(bromomethyl)-4-isopropyl-1,3-thiazole (84.6 mg, 0.384 mmol) in tetrahydrofuran (2 ml), and then warmed to room temperature. The reaction mixture was added with water and extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:ethyl acetate=100:1) to obtain the title compound (40.0 mg, 33%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[C:13][CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[C:7]([O:10][CH3:11])=[N:8][CH:9]=1)(=O)[CH3:2].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH:1]([C:4]2[CH:5]=[C:6]([C:12]#[C:13][CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[C:7]([O:10][CH3:11])=[N:8][CH:9]=2)[CH3:2])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: COC(=O)NCC#Cc1cc(C(C)=O)cnc1OC
Product: COC(=O)NCC#Cc1cc(C(C)NC2CC2)cnc1OC

Procedure:
Methyl [3-(5-acetyl-2-methoxypyridin-3-yl)prop-2-yn-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxypyridin-3-yl}prop-2-yn-1-yl)carbamate [Ex(296-3)] as a colorless oil.