Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:34][C:35]#[N:36]>CN(C)C=O>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:34][C:35]#[N:36])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3CC#N)CC1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), sodium hydride and bromoacetonitrile in N,N-dimethylformamide, to give the desired product as a brown gum (11%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[N:7][CH:6]=[N:5]1)[CH3:3].C([Li])CCC.[C:14](=[O:16])=[O:15]>C1COCC1.CCCCCC>[CH3:1][CH:2]([N:4]1[C:8]([C:14]([OH:16])=[O:15])=[N:7][CH:6]=[N:5]1)[CH3:3]
Reactant: O=C=O
Reactant: CC(C)n1cncn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)n1ncnc1C(=O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
1-(1-Methylethyl)-1H-1,2,4-triazole (1 g) was dissolved in THF (15 ml) and cooled to −78° C. under nitrogen. A 1.6 M solution of butyllithium in hexane (5.9 ml) was added dropwise. The solution was stirred for 1.5 h at −78° C., then the solution was treated with solid carbon dioxide (2 g). After 30 min at −78° C. the solution was allowed to warm to RT and stirred overnight. The reaction was quenched with water (1 ml), concentrated in vacuo and dried in a vacuum oven for 1 day at 50° C. to give the title compound (1.29 g) as a white solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[O:10]1[CH2:25][CH:11]1[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[CH:23]C=CC=1)[CH2:14][CH:15]1[O:17][CH2:16]1>O>[CH2:18]([N:13]1[CH2:14][CH:15]([CH2:16][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:17][CH:11]([CH2:25][OH:10])[CH2:12]1)[CH2:19][CH2:24][CH3:23]
Reactant: OCc1ccccc1
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Agent: [Na]
Solvent: O
Product: CCCCN1CC(CO)OC(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
An amount of 125 g of benzyl alcohol is stirred and 0.3 g of finely cut sodium metal (0.013 mole) is added and the mixture then stirred under nitrogen for 2.5 hours. Then with stirring, 27.79 g of N,N-bis(2,3-epoxypropyl)benzylamine (0.15 mole) is added to the reaction mixture and stirring at room temperature continued for 0.5 hour, followed by heating the mixture at reflux for 16 hours. The mixture is then cooled to room temperature and poured into 400 ml of water. The aqueous mixture is extracted with 2×250 ml portions of chloroform, and the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the colorless oil vacuum distilled through a 10 cm vigreux distilling column. The fraction distilling at b.p. 196°-199° @0.4 mm is collected yielding 28.6 g (65%) of the title compound.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH:16]1[CH:21]=[N:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1([C:36]([N:38]2[CH2:42][CH2:41][C:40](=O)[CH2:39]2)=[O:37])[CH2:35][CH2:34]1.Cl>CCCCCC.C1COCC1>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1([C:36]([N:38]2[CH2:39][CH2:40][C:41]3([C:17]4[CH:16]=[CH:21][N:20]=[CH:19][C:18]=4[C:22](=[O:24])[O:23]3)[CH2:42]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3Cl)CC2)C1
Reactant: O=C(O)c1cccnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(Cl)cc4Cl)CC3)C2)c2ccncc21
Temperature: -55 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethyl-piperidine, (1.18 mL, 0.00700 mol) in tetrahydrofuran (30 mL, 0.4 mol) at −78° C. was added n-butyllithium in hexane (2.5 M, 3.7 mL). After stirring for 15 min, a suspension of niacin (0.287 g, 0.00233 mol) in THF was added and the mixture was stirred at −78° C. for 10 min. The reaction mixture was then warmed to −55° C. for 60 min. A solution of 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (580 mg, 0.0019 mol) in THF (2 mL) was added to the above mixture and stirring was continued at −55 degrees celsius for 20 min. The reaction mixture was then allowed to warm to rt for 1 h and then acidified (pH ˜1) using 6M HCl aq. solution. The reaction mixture was stirred at rt overnight and then neutralized (pH ˜7). The product from the mixture was extracted with AcOEt. The organic extract was washed with brine, dried with MgSO4, and concentrated in-vane. The crude product was purified by Combiflash followed by separation of the enantiomers using a chrial column. LCMS: m/z 402.0 & 404.0 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O.C(OCC)(=O)C.C1COCC1>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: COc1ccccc1C[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 474 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(2-methoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 18 ml of dimethoxyethane and 9.07 ml of water is treated dropwise, at RT, with 4.45 ml of a 1M lithium hydroxide solution. After that, the reaction mixture is stirred at RT for 3 h and diluted with ethyl acetate and THF, and the whole is washed in a separating funnel until neutral with a mixture consisting of 54.78 ml of sat. ammonium chloride solution and 4.58 ml of 10% citric acid solution, followed by saline and water. The title compound, which is subjected to further processing without any further purification, is obtained after drying over sodium sulfate and removing the solvent. TLC Rf (hexane/ethyl acetate 2.5:1)=0.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[ClH:16].[CH:17]1([NH:23][CH:24](O)[CH3:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[ClH:16].[CH3:25][CH2:24][N:23]([C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(O)NC1CCCCC1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: CCN(c1c(C(=O)O)cc(OC)c(OC)c1OC)C1CCCCC1

Procedure:
2.0 g of 3,4,5-trimethoxy-benzoic acid, 1.8 g. of cyclohexylamino-ethanol-hydrochloride and 4.0 g. of p-toluene-sulphonic acid are refluxed in 40 ml. of benzene for 12 hours. After cooling the reaction mixture is extracted with a 15% sodium carbonate solution and 10% hydrochloric acid. White crystals precipitate from the hydrochloric acid solution. Thus N-2-ethyl-cyclohexylamino-3,4,5-trimethoxy-benzoate-hydrochloride is obtained. Mp.: 207°-208° C.
Reaction SMILES: C[O-].[Na+].[C:4](=O)([S:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)C.CI.C(=O)([O-])O.[Na+]>CO>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[CH2:7][S:6][CH3:4])=[O:21])=[CH:15][CH:16]=1
Reactant: CC(=O)SC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
Sodium methoxide (0.22 ml, 0.876 mmol) (28% in methanol) was added to a solution of 100 mg (0.292 mmol) of the title compound produced in step (iv) of Reference Example 8 in methanol (1 ml), and the mixture was stirred at room temperature for 15 min. Thereafter, 0.11 ml (1.75 mmol) of methyl iodide was added thereto, and the mixture was stirred at room temperature for 20 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:4) to give 55 mg (yield 60%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].F[C:25]1[C:30]([C:31]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]([NH2:38])[CH:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1>C1COCC1>[NH2:38][C:33]1[N:34]=[C:35]([CH3:37])[N:36]=[C:31]([C:30]2[C:25]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:32]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(N)cc(-c2cccnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(N)cc(-c2cccnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a solution of N-(5-amino-2-chloro-3-pyridinyl)methanesulfonamide (Example 330, Step 2) (0.085 g, 0.384 mmol) in THF (5.0 mL) at 0° C. was added NaHMDS (2 M solution in THF) (0.959 mL, 1.918 mmol). After the addition, the reaction mixture continued to stir at 0° C. under N2 for 30 minutes. 6-(2-fluoro-3-pyridinyl)-2-methyl-4-pyrimidinamine (0.094 g, 0.460 mmol) was added into the reaction mixture and the reaction mixture continued to stir at 0° C. for 10 minutes and was then slowly warmed up at RT. After 1 hour at RT, more NaHMDS (2 M solution in THF) (0.50 mL, 1.0 mmol) was added. After 1 more hour, the reaction mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by HPLC to afford N-(5-((3-(6-amino-2-methyl-4-pyrimidinyl)-2-pyridinyl)amino)-2-chloro-3-pyridinyl)methanesulfonamide (0.0190 g, 0.047 mmol, 12.20% yield). m/z (ESI, +ve) 406.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.68 (s, 1H); 9.66 (s, 1H); 8.61 (d, J=2.74 Hz, 1H); 8.41 (d, J=2.54 Hz, 1H); 8.32 (dd, J=4.89, 1.76 Hz, 1H); 8.10-8.14 (m, 1H); 7.09 (s, 2H); 7.02 (dd, J=7.82, 4.69 Hz, 1H); 6.78 (s, 1H); 3.13 (s, 3H); 2.52 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23])[C:11](=[O:28])[C@:10]([CH2:30][CH:31]([OH:34])[CH2:32][OH:33])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[C:36]1(C)[CH:41]=CC(S(O)(=O)=O)=C[CH:37]=1.COC(OC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23])[C:11](=[O:28])[C@:10]([CH2:30][CH:31]3[CH2:32][O:33][C:36]([CH3:41])([CH3:37])[O:34]3)([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C(=O)OC)N1C(=O)[C@@](C)(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: CC[C@@H](C(=O)OC)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)butanoate prepared above in Step A (749 mg, 1.47 mmol) in DCM (8.2 mL) was added p-toluenesulfonic acid monohydrate (14.0 mg, 0.074 mmol) and 2,2-dimethoxypropane (8.15 mL, 66.3 mmol). After being stirred at rt for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved (EtOAc and sat. aq. NaHCO3) and extracted (3×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Purification by chromatography on silica gel (SiO2, 40 g, 27% and 37% EtOAc/Hexanes) provided the title compound as a colorless film.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17]OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[Na+].O>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][C:23]#[N:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1-Benzyloxycarbonyl-3-mesyloxymethylpiperidine (WO 0100207; 8.4 g) was dissolved in DMSO (100 ml) and sodium cyanide (1.6 g) was added. The mixture was heated to 100° C. and stirred continuously under an argon atmosphere for 6 hours. The mixture was cooled and poured into water (200 ml). The product was extracted with EtOAc, washed with ferrous sulphate solution (10% w/w), dried and evaporated in vacuo. TLC (40% EtOAc/petroleum ether (60/80) Rf. 0.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH3:22])[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[CH3:1][O:2][C:3]1[C:7]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]#[C:15][CH2:14][N:13]([CH3:12])[CH3:22])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: CN(C)CC#CCCCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: COC1=NS(=O)(=O)N=C1NCCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide (1.07 g) and 7-(dimetylamino)hept-5-ynylamine (0.92 g) were reacted to give a solution of 3-methoxy-4-[7-dimethylaminohept-5-ynylamino]-1,2,5-thiadiazole-1,1-dioxide. Reaction with ammonia gas and purification as in Example 1 gave the title compound (1.08 g), m.p. 172°-4° C. (recrystallisation from acetonitrile).
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([CH3:12])[CH2:5]1)[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH2:2]([C:4]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([CH3:12])[CH2:5]1)[CH3:3]
Reactant: CCC1(c2cccc(OC)c2)CN(C)CC(C)(C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: Cc1ccccc1
Product: CCC1(c2cccc(O)c2)CN(C)CC(C)(C)O1
Yield: 89.2 %

Procedure:
2-Ethyl-2-(3-methoxyphenyl)-4,6,6-trimethylmorpholine hydrochloride (1 g) was heated under N2 and under reflux with stirring with a solution of diisobutyl aluminium hydride (15 ml of a 25% w/w solution in toluene) for 24 h. The reaction mixture was cooled, and decomposed by the cautious addition of a saturated solution of potassium sodium tartrate. The toluene layer was separated and the aqueous phase reextracted with toluene. After the combined organic extracts were washed with saturated sodium chloride solution they were dried (MgSO4) and evaporated to an oil which gave 742 mg of crystalline title compound hydrochloride salt mp 185°-188° C. from isopropyl alcohol and a solution of hydrogen chloride in dry ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=[C:14]([F:24])[C:12]=3[N:13]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1.CO.Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[C:14]([F:24])[C:12]=3[N:13]=2)[CH:7]=1
Reactant: CCOC(=O)Cc1cc(F)c2nc(Nc3cc(F)ccc3C)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1Nc1nc2c(F)cc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Ethyl (2-(5-fluoro-2-methylphenylamino)-4-fluoro-6-benzoxazolyl)acetate (215 mg, 0.62 mmol) was dissolved in THF/methanol (1/1, 20 ml). To the resulting solution was added 0.25N NaOH (12.4 ml, 3.10 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured in 1N HCl to acidify the mixture, followed by extraction with chloroform/methanol (10/1). The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give (2-(5-fluoro-2-methylphenylamino)-4-fluoro-6-benzoxazolyl)acetic acid (165 mg, 83%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].N1C=CC=[CH:14][CH:13]=1>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:13]([CH3:14])=[N:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: c1ccncc1
Product: Cc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dye of the invention is prepared by dissolving about 369 parts of 2-amino-4-nitrophenol in about 600 ml of warm pyridine in a 2 liter three-necked flask equipped with a mechanical stirrer, a Dean & Stark adapter or glass trap to collect distilled off solvent, and a condenser. About 600 parts of triethyl orthoacetate are added to the flask while refluxing using an oil bath maintained at 120°-140° C. The ethanol formed is distilled off followed by the pyridine until about 500 ml of total solvent are removed. The reaction mixture is stirred overnight at room temperature after which about 1500 ml of ethanol are added to precipitate the product. Filtering provided 5-nitro-2-methylbenzoxazole (1) as a tannish-brown solid which is washed with ethanol, ethyl acetate, and then ligroin, and dried under vacuum.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]2[N:12]=[CH:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][C:8]1=2.[H-].[Na+].CI.[C:30](OCC)(=O)C>CN(C)C=O.O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[CH2:6][N:7]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]2[N:12]=[CH:11][C:10]([N:18]([CH3:30])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:9][C:8]1=2
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cnc2ccc(=O)n(CC3OCCO3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.15 g of tert-butyl (5-(1,3-dioxolan-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)carbamate in 2 mL of N,N-dimethylformamide, 21 mg of 60% sodium hydride and 32 μL of methyl iodide were added, and the mixture was stirred at room temperature for 2 hours 20 minutes. Thereto were further added 9 mg of 60% sodium hydride and 13 μL of methyl iodide, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=1:1 to 3:7 to obtain 0.13 g of tert-butyl (5-(1,3-dioxolan-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)(methyl)carbamate as a brown oily substance.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:37][CH2:38][CH3:39].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH2:37][CH2:38][CH3:39])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCI
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccc(OC(C)C)cc2)c1C
Reaction time: 8 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (50 mg) and cesium carbonate (0.20 g) in N,N-dimethylformamide (1 mL) was added iodopropane (0.036 mL) at 50%, and the mixture was stirred overnight. Water was added to the reaction mixture, and the resulting mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The resulting semi-purified material was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1-propylpyrazole (28 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8](=[CH:11][CH:12]([CH3:18])[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:9]=[O:10].O.[OH-].[Na+]>C1COCC1>[CH3:7][C:8](=[CH:11][CH:12]([CH3:18])[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:9][OH:10]
Reactant: CC(C)=CCC(C)C=C(C)C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCC(C)C=C(C)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension of LiAlH4 (4.8 g, 126 mmol) in THF (100 ml) was added dropwise a solution of 2,4,7-trimethylocta-2,6-dienal (20 g, 114 mmol) in THF (60 ml) at 5° C. over 1 h. The mixture was stirred at room temperature for 1 h. 5 ml of water, 5 ml of 15% aq. NaOH and 15 ml of water were carefully added subsequently. The mixture was stirred for 1 h. Precipitates were filtered and the filtrate was concentrated in vacuo. The residue was Kugelrohr-distilled to give 2,4,7-trimethylocta-2,6-dien-1-ol (98%). bp: 82-83° C./1 mbar.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][C:8]=1[Cl:22])(=O)=O.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CO.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:17][C:15]([NH:14][C:10]1[CH:11]=[C:12]([Cl:13])[C:7]([C:15]([O:17][CH3:18])=[O:16])=[C:8]([Cl:22])[CH:9]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cc(NC(=O)OC(C)(C)C)cc1Cl
Yield: 119.4 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino)-2,6-dichlorophenyl trifluoromethanesulfonate (14 g, 34 mmol), dppp (1.4 g, 3.4 mmol), Pd(OAc)2 (0.84 g, 3.4 mol) and Et3N (19.6 mL) in MeOH (112 mL) and DMF (224 mL) was refluxed under an atmosphere of carbon monoxide (10 atm) overnight. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc 80:1) to give methyl 4-(tert-butoxy carbonylamino)-2,6-dichlorobenzoate (6.5 g, yield: 60%). 1H NMR (CDCl3, 400 MHz) δ 7.40 (s, 2H), 6.56 (brs, 1H), 3.94 (s, 3H), 1.51 (s, 9H).