Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)C(C)C)(C)C.CN(C=O)C>C1COCC1.CN(C)C1C=CN=CC=1>[F:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[F:12])[O:5][CH2:4][CH:3]([OH:14])[CH2:2][NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCC(O)COc1ccc(F)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCC(O)COc1ccc(F)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 of rac-1-amino-3-(3,4-difluorophenoxy)propan-2-ol (4.9 mmol, 1 equivalent) was dissolved in 16 ml of THF, and 0.76 ml of benzyl chloroformate (0.9 g, 5.4 mmol, 1.1 equivalents) and then 2.6 ml of N,N-diisopropylethylamine (1.9 g, 14.8 mmol, 3 equivalents) and 0.12 g of 4-dimethylaminopyridine were added. The mixture was stirred at RT for 30 min. 2 ml of DMF were then added, and the mixture was stirred at RT overnight. The mixture was concentrated and the residue was then taken up in ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. This gave 2.2 g (96% of theory, purity 73%) as a crude product which was reacted without further purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]([C:12]#N)=[C:5]([C:10]#N)[C:6](=O)[C:7]=1Cl.[C:15]([O:18][C:19]1C=C2C(=C[C:28]=1[O:29][CH3:30])CCCC2)(=[O:17])[CH3:16]>O1CCOCC1>[C:15]([O:18][C:19]1[CH:12]=[C:4]2[C:5]([CH2:6][CH2:7][CH2:2][C:3]2=[O:14])=[CH:10][C:28]=1[O:29][CH3:30])(=[O:17])[CH3:16]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1cc2c(cc1OC(C)=O)CCCC2
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC(C)=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 454 mg of 2,3-dichloro-5,6-dicyanobenzoquinone in 4 mL of dioxane was added dropwise over a period of 5 minutes to a stirred solution of 6-acetoxy -7-methoxytetralin in 1 mL of 5% aqueous dioxane at 25° C. under an atmosphere of nitrogen. The resulting solution was stirred at 25° C. for 20 hours. Thereafter the reaction mixture was filtered through a sintered glass funnel and the solid residue of 2,3-dichloro-5,6-dicyaniodihydroquinione was washed with 2 mL of dioxane. The residue wash solution was combined with the filtrate. Thereafter the dioxanie was evaporated from the combined filtrate at reduced atmospheric pressure. The resulting residue was stirred with a mixture of 10 mL of 5% aqueous sodium bicarbonate and 80 mL of ethyl acetate. The ethyl acetate layer was separated and washed successively once with 5 mL of 5% aqueous sodium bicarbonate, once with 5 mL of water, and twice with 5 mL of brine. The ethyl acetate extract was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the ethyl acetate was evaporated from the filtrate at reduced atmospheric pressure. The resulting residue was chromatographed on a column of silica gel eluted by a solution of ethyl acetate and hexane in a ratio of 3 to 5 under a moderate positive pressure to obtain 146 mg of 7-acetoxy-6-methoxytetralin-1-one having m.p. 118.5-119.5° C. MS [M+]234.
Reaction SMILES: [F:1][C:2]1[C:28]([F:29])=[C:27]([F:30])[C:5]2[N:6]([C@@H:13]3[O:25][C@H:24]([CH3:26])[C@@H:19]([O:20]C(=O)C)[C@H:14]3[O:15]C(=O)C)[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[F:1][C:2]1[C:28]([F:29])=[C:27]([F:30])[C:5]2[N:6]([C@@H:13]3[O:25][C@H:24]([CH3:26])[C@@H:19]([OH:20])[C@H:14]3[OH:15])[C:7]([NH:9][CH:10]([CH3:11])[CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2cc(F)c(F)c(F)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CC(C)Nc1nc2cc(F)c(F)c(F)c2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 46.8 %

Procedure:
5,6,7-Trifluoro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine (0.41 g, 0.99 mmol), ethanol (10 mL), sodium carbonate (0.19 g, 1.79 mmol), water (2 mL), and methanol (5 mL) were used according to general procedure III. The title compound was purified by silica gel chromatography using 10:1 dichlormethane-methanol as eluant to provide a white solid (0.16 g, 47%); m.p. 175-178° C.: 1H NMR (DMSO-d6) δ: 7.17 (m, 1H, Ar—H), 6.78 (d, J=7.4, Hz, 1H, NH), 5.69 (dd, J=6.3, 1.8 Hz, 1H, CH), 5.26 (d, J=6.5 Hz, 1H, OH), 5.21 (d, J=5.2 Hz, 1H, OH), 4.15 (m, 1H, CH), 4.07 (m, 1H, CH), 3.86-3.74 (m, 2H, overlapping CH), 1.34 (d, J=6.3 Hz, 3H, CH3), 1.23 (d, J=6.5 Hz, 6H, overlapping CH3).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:13]1[CH:14]=[N+:15]([O-])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20].C([OH:25])C>>[C:1]1([NH+:11]([O-:25])[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[N+:19]([O-:21])=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: Nc1cccc2ccccc12
Product: O=[N+]([O-])c1ccncc1[NH+]([O-])c1cccc2ccccc12
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To 1-naphthylamine (5.43 g) in 100 ml of absolute ethanol was added 3-fluoro-4-nitropyridine-N-oxide (6.0 g) in 25 ml of ethanol and this mixture was heated to 70° C. and stirred for six hours. The mixture was filtered to yield a solid (6.6 g) which was recrystallized from ethanol to yield a solid (2.6 g), m.p. 200°-201° C. (decomp.).
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Cu])#[N:11].C(N)CN>CC(N(C)C)=O>[NH2:8][C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([C:10]#[N:11])=[CH:7][N:6]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Solvent: NCCN
Product: Cc1cc(N)ncc1C#N
Temperature: 170 °C
Reaction time: 20 h
Yield: 86.9 %

Procedure:
A mixture of 5-bromo-4-methyl-pyridin-2-ylamine (500 mg, 2.67 mmol), CuCN (478 mg, 5.34 mmol) and DMA (2 mL) was stirred under nitrogen for 20 h at 170° C. The reaction mixture was cooled and added to 50 mL of a 20% aqueous solution of ethane-1,2-diamine. The layers were separated and the aqueous layer was extracted 3× with EtOAc. The combined organics were washed with water followed by brine and dried over MgSO4. Concentration in vacuo afforded compound 851A (309 mg, 87%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([C:26]3([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27]3)=[O:25])=[C:16]2[N:15]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([C:26]3([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]3)=[O:25])=[C:16]2[N:15]=1
Reactant: COC(=O)C1(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
(R)-methyl 1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)cyclopropanecarboxylate (Example 33; 24 mg, 0.054 mmol), was dissolved in a mixture solvent of THF/MeOH/water (0.3/0.3/0.2 mL), followed by addition of lithium hydroxide monohydrate (6 mg, 0.14 mmol). After stirring at ambient temperature for five hours, the reaction mixture was diluted with water (15 mL), acidified with 1 N HCl (aq.) to pH ˜3, and filtered, giving the final product as a fine white solid (19 mg, 82% yield). MS (apci) m/z=428.2 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=3)=[CH:9][CH:10]=2)[O:5][CH2:4][C@@H:3]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[C:35]([O:34][C:33](=[O:39])[NH:32][C@H:3]1[C@@H:2]([OH:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:9][CH:10]=2)[O:5][CH2:4]1)([CH3:38])([CH3:36])[CH3:37].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2[C@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2[C@@H]1O

Procedure:
tert-Butyl (3S,4R)-4-hydroxy-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylcarbamate (500 mg) was dissolved in 30% TFA solution in DCM (3673 μl). After 2 h the reaction mixture was concentrated to give (3R,4S)-tert-butyl-4-hydroxy-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylcarbamate, TFA salt (quant.): LCMS=445.0 [M+H]+; 1H NMR and HPLC as in Ex. 1.
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([OH:27])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:32][N:33]([CH3:42])P(N(C)C)(N(C)C)=O>O1CCCC1>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:33]([CH3:42])[CH3:32])=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1C(=O)N(C)C)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a mixture of 10 ml of tetrahydrofuran and 0.1 ml of hexamethylphosphoramide was dissolved 0.50 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, and 0.2 ml of thionyl chloride was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, the residue was dissolved in 10 ml of tetrahydrofuran, and 2 ml of 50% aqueous dimethylamine solution was added dropwise with stirring. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3) to give 0.49 g of N-acetyl-N-(2-dimethylaminocarbonylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([O:14]CC)=[O:13])[NH:5][N:4]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC.[OH-].[Na+]>CC(C)=O.O>[CH3:19][N:5]1[C:6]([C:12]([OH:14])=[O:13])=[C:7]([C:8]([F:11])([F:10])[F:9])[C:3]([C:2]([F:18])([F:17])[F:1])=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(F)(F)F
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: Cn1nc(C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (10.9 mmol) of ethyl 3,4-bis(trifluoromethyl)-1H-pyrazole-5-carboxylate and 4.5 g (32.6 mmol) of potassium carbonate are suspended in 70 ml of acetone, and 1.35 ml of iodomethane (21.7 mmol) are added. The reaction mixture is stirred at room temperature overnight. 54 ml (108 mmol) of 2 N aqueous sodium hydroxide solution are added to the suspension. The solution is then stirred at room temperature overnight. The reaction mixture is diluted with water, and most of the acetone is removed on a rotary evaporator under reduced pressure. The residue is adjusted to pH 2-3 using 1 M hydrochloric acid. The aqueous reaction solution is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure on a rotary evaporator. This gives 2.7 g of 1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (84%; purity 88%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[O:21][CH3:22])[C:6]=2[CH:23]=1.N1C(C)=CC=CC=1C.Cl[C:33]([O:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34]>ClCCl>[CH:36]1([O:35][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH2:10][C:11]4[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=4[O:21][CH3:22])[C:6]=3[CH:23]=2)=[O:34])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Reactant: O=C(Cl)OC1CCCC1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1ccc(Cn2cnc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A solution of methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g.) and 2,6-lutidine (0.36 ml.) in dichloromethane (10 ml.) was treated with cyclopentyl chloroformate (0.33 g.). After stirring for 24 hours the solution was diluted with dichloromethane. The mixture was washed successively with 20% w/v sodium hydroxide, water, and brine, then dried (MgSO4) and evaporated. The resultant residue was purified by flash chromatography on a 6×20 cm. silica gel column using 1:3 v/v hexane:ethyl acetate as the eluent to give the title compound (0.57 g., 93%); NMR: 1.7[m,8H, (CH2)4 ], 3.8(s,3H, OCH3), 3.9(s,3H, OCH3) 5.2(m,1H, CHO), 6.17-7.0(br m,3H), 7.5-7.8(br m,4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.CC(O[C:18]([CH3:20])=[O:19])=O.CN(C)C=O.[CH:26](OC)(OC)[O:27][CH3:28]>CCOCC>[O:12]=[C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:18](=[O:19])[CH3:20])=[CH:11][CH:10]=2)/[C:5](=[CH:26]\[O:27][CH3:28])/[C:6](=[O:13])[NH:7]1
Reactant: COC(OC)OC
Reactant: Nc1ccc2c(c1)CC(=O)NC2=O
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(NC(C)=O)cc21
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 90 mg (0.50 mmol) of 6-aminoisoquinoline-1,3(2H,4H) -dione, 0.80 ml (8.5 mmol) of Ac2O, and 0.20 ml of N,N-dimethylformamide is added 0.11 ml 1.0 mmol) of trimethyl orthoformate. The mixture is heated to 125° and maintained for 30 m, cooled, diluted with ether, and stirred for 10 minutes. The resulting amber solid is filtered, washed with ether, and dried to give 96 mg (74%); MS (ES+) m/z 261.1 (M+H)+1.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:49][CH2:48][CH2:47][C@H:2]1[C:3]([NH:5][C@H:6]([C:16]([N:18]1[CH2:46][CH2:45][CH2:44][C@H:19]1[C:20]([NH:22][C@H:23]([C:34]([O:36]CC1C=CC=CC=1)=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:33])[NH:29][N+]([O-])=O)=[O:21])=[O:17])[CH2:7][O:8]CC1C=CC=CC=1)=[O:4]>[C].[Pd]>[NH:1]1[CH2:49][CH2:48][CH2:47][C@H:2]1[C:3]([NH:5][C@H:6]([C:16]([N:18]1[CH2:46][CH2:45][CH2:44][C@H:19]1[C:20]([NH:22][C@H:23]([C:34]([OH:36])=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:33])=[O:21])=[O:17])[CH2:7][OH:8])=[O:4].[CH3:23][C:34]([OH:36])=[O:35]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]
Agent: [Pd]
Product: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1)C(=O)O

Procedure:
150 mg of Z-Pro-Ser(Bzl)-Pro-Arg(NO2)-OBzl was reduced in the presence of palladium-carbon in the same manner as in Example 26-(5). The resulting product was purified by high-performance liquid chromatography at 12 ml/min. (flow rate), 0 to 10% (B) 20 min. linear gradient (A) (mobile phase), subjected to Dowex 1×2 (acetate type) treatment and freeze-dried to obtain the desired compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CS(C)=O.[C:29]([C:33]1[O:34][C:35]2[C:36](=[C:38]([C:50]#[N:51])[C:39]([CH3:49])=[C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:41]=2F)[N:37]=1)([CH3:32])([CH3:31])[CH3:30]>C(OCC)(=O)C>[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:41]2[C:40]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[C:39]([CH3:49])[C:38]([C:50]#[N:51])=[C:36]3[C:35]=2[O:34][C:33]([C:29]([CH3:32])([CH3:30])[CH3:31])=[N:37]3)[CH2:20]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)C)nc2c1C#N
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CCC[C@H](NC(=O)OCc3ccccc3)C2)c2oc(C(C)(C)C)nc2c1C#N
Temperature: 90 °C
Reaction time: 11 h
Yield: 75.3 %

Procedure:
Triethylamine (83 μl, 598 μmol) and (3S)-3-benzyloxycarbonylaminopiperidine (70 mg, 298 μmol) were added to a dimethyl sulfoxide (3.8 ml) solution of 2-tert-butyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-72) (77 mg, 249 μmol), followed by stirring at 90° C. for 11 hours. After cooling, the reaction liquid was diluted with ethyl acetate, this was washed with saturated brine and 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1→4:1, v/v) to obtain the entitled compound (98 mg, 75%) as a colorless oil.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[I-].[K+]>O.CN(C)C=O>[OH:10][CH2:9][C:2]1[O:3][CH:4]=[C:5]([O:8][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[C:6](=[O:7])[CH:1]=1
Reactant: O=c1cc(CO)occ1O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 56.8 g (0.4 mole) kojic acid, 55,3 g (0.4 mole) potassium carbonate, 133.3 g (0.4 mole) 1-octadecyl bromide, 1 g potassium iodide and 450 mL anhydrous dimethylformamide is stirred for 10 hours at 90° C.. After cooling, the mixture is mixed with 1.5 L of water, the precipitate formed is filtered off, well stirred up once with ethyl acetate, filtered off and recrystallized from propan-2-ol with the addition of active charcoal. There is obtained a colorless product: m.p. 71°-73° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][O:6][CH2:5]1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=[O:26])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:10][C:4]1([CH3:3])[CH2:9][CH2:8][CH2:7][O:6][CH2:5]1.[C:18](=[O:26])([O-:17])[O:19][C:20]1[C:25]([C:4]2([CH3:3])[CH2:9][CH2:8][CH2:7][O:6][CH2:5]2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CC1(O)CCCOC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(OC(=O)Oc2ccccn2)CCCOC1
Product: CC1(c2cccnc2OC(=O)[O-])CCCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (207 mg, 5.17 mmol) in THF (20 mL) was added 3-methyltetrahydro-2H-pyran-3-ol (500 mg, 4.30 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (931 mg, 4.30 mmol) in THF (20 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude material. the crude material was purified via biotage (40 g column, 5-40% EtOAc:Hex) to give the expected product 3-methyltetrahydro-2H-pyran-3-ylpyridin-2-yl carbonate (173 mg, 17.94% yield) as a clear thick oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.50-8.30 (m, 1H), 7.89-7.74 (m, 1H), 7.27-7.22 (m, 1H), 7.14 (d, J=8.3 Hz, 1H), 4.22-4.05 (m, 1H), 3.88-3.74 (m, 1H), 3.60-3.49 (m, 1H), 3.44 (d, J=12.0 Hz, 1H), 2.38-2.20 (m, 1H), 2.03-1.88 (m, 1H), 1.84-1.72 (m, 1H), 1.63-1.57 (m, 1H), 1.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].O.[Br:11][CH:12]([CH3:16])[C:13](Br)=[O:14]>C(Cl)(Cl)Cl>[Br:11][CH:12]([CH3:16])[C:13]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(Br)C(=O)Br
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)NC(C)(C)C(=O)O
Temperature: -12 °C
Yield: 70.9 %

Procedure:
A stirring mixture of 2-aminoisobutyric acid (52.08 g; 0.51 mol), sodium hydroxide (20.20 g; 0.51 mol), water (200 ml) and chloroform (50 ml) was cooled to −12° C. 2-Bromopropionyl bromide (100 g; 0.46 mol) in chloroform (150 ml) was added to the mixture over 15 minutes. The reaction mixture was then allowed to warm to room temperature after which time the mixture was filtered to isolate the solid that had precipitated. The solid was combined with hot toluene (700 ml) and this mixture was then allowed to cool. The while solid was isolated by filtration and was dried under vacuum to afford 77.60 g (70% yield) of 2-(2-bromopropionylamino)-2-methylpropionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-:13].[K+].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([C:23](=O)[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=1.Cl>C(O)C.O.CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:18]=1)[C:24]([CH3:25])=[C:5]2[C:6]([OH:11])=[O:13]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc2c1C(=O)O
Temperature: 20 °C
Yield: 87.2 %

Procedure:
5-Bromoisatin (198 g, 788 mmol) was dissolved in ethanol (1.2 L) in a 6 L conical jacketed lab reactor equipped with a mechanical stirrer and an internal temperature probe. A solution of KOH (265 g, 4730 mmol) in water (0.480 L) was added slowly via addition funnel over ca. 1 hour, such that the vessel temperature was maintained at 20° C. 1-[3-(Trifluoromethyl)phenyl]-1-propanone (159 g, 788 mmol) was added in one portion and the reactor was heated to reflux for 1 h. The reaction mixture was cooled to 20° C. and acidified to pH˜2 by addition of 450 mL of concentrated HCl. An additional 1.5 L of 50% EtOH/H2O was added to facilitate filtration. The slurry was filtered and the filter cake was rinsed twice with 1 L portions of 50% EtOH/water. The solid was dried in vacuo to give 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (281.7 g, 87% yield) as a fine off-white solid. MS (m/z) 412.7 (M+H+).