Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCCCN
Solvent: CCN(CC)CC
Product: CCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(butylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-butylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:10][C:11](=O)[C:12]([OH:14])=[O:13]>C1COCC1>[CH2:6]([O:5][C:3]([C:2]1[S:8][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[N:1]=1)=[O:4])[CH3:7]
Reactant: O=C(O)C(=O)CBr
Reactant: CCOC(=O)C(N)=S
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C(=O)O)cs1
Temperature: 50 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of ethyl 2-amino-2-thioxoacetate (10.1 g), 3-bromo-2-oxopropanoic acid (12.7 g) and THF (200 ml) was stirred at 50° C. overnight. The mixture was concentrated in vacuo, and the resulting solid was suspended in EtOAc. The precipitate was collected by filtration to give the title compound (7.4 g) as a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]1C=CC=C[CH:3]=1.ICCC.[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[CH2:28][CH2:27][N:26]([CH2:1][CH2:2][CH3:3])[C:25]2=[O:29])[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Solvent: CCCI
Product: CCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Yield: 60 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 1-iodopropane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 60% yield: 1H NMR (300 MHZ, CDCl3) δ 4.18 (q, J=7.2 Hz, 2H), 4.07-3.94 (m, 2H), 3.53-3.48 (m, 2H), 3.20 (t, J=7.2 Hz, 2H), 2.52 (s, 3H), 1.58-1.46 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H); MS (ES+) m/z 298.3 (M+1).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[F:17])(=O)C.O.ClCCl>O1CCOCC1>[F:17][C:9]1[C:10]([CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][OH:6]
Reactant: CC(=O)OCc1cccc(C(C)C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1cccc(CO)c1F
Reaction time: 5 h
Yield: 97.7 %

Procedure:
44 g of 8% strength sodium hydroxide solution are added to a solution of 15.3 g (73 millimoles) of 2-fluoro-3-isopropylbenzyl acetate in 100 ml of dioxane. After 5 hours at 50° C., the mixture is poured into 100 ml of water. 12 g (98%) of 2-fluoro-3-isopropylbenzyl alcohol are obtained by extraction with dichloromethane.
Reaction SMILES: [CH:1]1[C:6](Cl)=[CH:5][CH:4]=[C:3]([Cl:8])[CH:2]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CC[O-].[Na+]>C(O)C.O1CCOCC1>[Cl:8][C:3]1[CH:2]=[CH:1][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(Cl)cc1
Reactant: C1CCNCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1ccc(N2CCCCC2)cc1
Yield: 59 %

Procedure:
15 mmol of p-dichlorobenzene (2.2 g), 15.5 mmol of piperidine (1.3 g), 15.5 mmol of NaOEt solution in ethanol (10% by weight) and 50 mg of trans-di-μ-chlorobis[2-[bis(1,1-dimethylethyl)phosphino]-2-methylpropyl-C,P]dipallium(II) are suspended in 75 ml of dioxane and refluxed for 15 hours. After aqueous work-up, extraction with petroleum ether and drying over sodium sulfate, the solvents are removed under reduced pressure. This gives crude N-(4-chlorophenyl)piperidine as a light brown liquid which can be purified by distillation (boiling point: 50° C./0.08 torr); melting point: 69° C.; yield: 59%.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2]>CO>[O:40]1[CH2:41][CH2:42][N:37]([CH2:36][C:33]2[CH:34]=[CH:35][N:31]([C:13]3[C:14]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)=[CH:15][C:10]([NH:9][C:6]4[N:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=4)=[N:11][CH:12]=3)[CH:32]=2)[CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(CN3CCOCC3)c2)C1
Solvent: CO
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(-n3ccc(CN4CCOCC4)c3)cn2)cn1
Reaction time: 2 h
Yield: 6.6 %

Procedure:
Crude tert-butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-(morpholinomethyl)-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (90 mg) was dissolved in methanol (1 mL) and absorbed onto a TsOH solid phase extraction cartridge and allowed to stand for 2 h. The cartridge was eluted with 7M ammonia in methanol. The basic fractions were evaporated to dryness. The crude product was purified by HPLC to give 5-(5-(3-(morpholinomethyl)-1H-pyrrol-1-yl)-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (4.93 mg, 7% over 3 steps).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.C([C:24]1[S:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=1)(O)=O>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:24]1[S:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: OB(O)c1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of thien-2-ylboronic acid (0.939 g, 7.34 mmol) and Na2CO3 (2.40 g, 22.6 mmol) in water (75 mL) is added p-dioxane (75 mL). This mixture is treated sequentially with 5-carboxy-2-thiophenecarboxaldehyde (1.43 g, 7.48 mmol) and palladium (II) acetate (151 mg, 0.673 mmol) and allowed to stir at ambient temperature for 16 hours. The solvent is evaporated in vacuo. To the residue is added EtOAc (400 mL) and water (300 mL). The aqueous layer is acidified to pH 1 with 1.0N aq. HCl. The aqueous layer is extracted with EtOAc (2×200 mL). The organic extracts are combined, washing with brine (200 mL), 5% aq. Na2S2O3 (200 mL), sat. aq. NaCl (200 mL), drying (Na2SO4), and the solvent evaporation in vacuo affords the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-:10].[Na+].[C:12]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)(=O)[CH3:13]>C(#N)C>[I-:10].[C:4]1([CH2:3][CH2:2][NH+:17]2[CH:18]=[CH:19][N:15]([CH2:12][CH2:13][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:16]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: CC(=O)n1ccnc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C1=C[NH+](CCc2ccccc2)CN1CCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of (2-bromoethyl)benzene (27.3 ml), sodium iodide (60.0 g), 1-acetylimidazole (22.2 g), and acetonitrile (220 ml) was refluxed 6.5 hrs. under nitrogen. The solution was cooled to 25° C. and the acetonitrile was evaporated. Water and potassium carbonate were added to the oily residue, which was extracted with dichloromethane. Combined extracts were washed with water, dried, filtered, and concentrated to give 1,3-bis(2-phenylethyl)-1H-imidazolium iodide (J, 35.4 g), m.p. 145.5°-147° C. from ethyl acetate.
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:13](=[O:14])[O:12][CH:11]3[CH:18]=[CH:19][CH3:20])C(C)=CC=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:3][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:13](=[O:14])[O:12][CH:11]2[CH:18]=[CH:19][CH3:20]
Reactant: CC=CC1OC(=O)c2ccc(-n3c(C)ccc3C)cc21
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC=CC1OC(=O)c2ccc(N)cc21
Yield: 82.2 %

Procedure:
1.1 g of 5-(2,5-dimethylpyrrol-1-yl)-3-(1-propenyl)-phthalide, 8.56 g of hydroxylamine-hydrochloride and 4.58 g of potassium hydroxide in 75 ml of ethanol/water (16:6,8, vv) are heated for 24 hours at 120° C. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na2SO4) and concentrated by evaporation and chromatographed on silica gel. 640 mg of 5-amino-3-(1-propenyl)-phthalide, melting point 125-130° C., is obtained with dichloromethane/methanol (99:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=1[N+:12]([O-:14])=[O:13])=[O:9]
Reactant: Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1cc(Cl)ccc1O
Yield: 8.1 %

Procedure:
Using 5-chlorosalicylic acid and 2-nitro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1.C([N-]C(C)C)(C)C.[Li+].[C:19](=[O:21])=[O:20].[OH-].[Na+]>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C(OCC)C.O.O1CCCC1>[CH3:1][N:2]1[C:6]([C:19]([OH:21])=[O:20])=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1
Reactant: O=C=O
Reactant: Cn1ccc(C(F)(F)F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: Cn1nc(C(F)(F)F)cc1C(=O)O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a mixture of 8.71 g of 1-methyl-3-trifluoromethyl-1H-pyrazole and 130 ml of tetrahydrofuran was added dropwise 32 ml of a 2.0 mol/L lithium diisopropylamide solution in heptane/tetrahydrofuran/ethylbenzene at −78° C. The mixture of stirred at −78° C. for 2 hours and then poured into a mixture was dry ice and 50 ml of tetrahydrofuran. The mixture was stirred for 2 hours while allowing it to rise to around room temperature. Water and diethyl ether were poured into the reaction mixture. The aqueous layer was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then layers were separated. The resulting aqueous layer was washed with diethyl ether two times, adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 8.19 g of 1-methyl-3-trifluoromethyl-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[C:36]([C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CCCCCC.CS(C)=O>[C:37]1(/[C:36](/[C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[CH:16]/[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(c1ccccc1)c1cccnc1
Reactant: O=C(O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCCCCCCCC/C=C(/c1ccccc1)c1cccnc1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.7 g, 68 mmoles) was washed with hexane and, after removal of the hexane under reduced pressure, dimethyl sulfoxide (40 ml) was added and the mixture was stirred with heating at 85° C. for an hour. After cooling, a dimethyl sulfoxide solution (20 ml) containing 10-carboxydecyltriphenylphosphonium bromide (18.0 g, 34 mmoles) was added dropwise to the mixture. After 10 minutes, a solution of 3-benzoylpyridine (6.2 g, 33.8 mmoles) in dimethyl sulfoxide (10 ml) was added. The reaction was allowed to proceed for an hour and, following addition of water (200 ml), the reaction product was washed with toluene. The aqueous layer was acidified with 2N hydrochloric acid to pH 5.2, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and distilled under reduced pressure to remove the solvent. The residue was then subjected to silica gel column chromatography using ethyl acetate as the developing solvent to give (Z)-12-phenyl-12 -(3-pyridyl)-11-dodecenoic acid (Compound Id-8, 3.2 g), after fractional recrystallization from isopropylether.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:3]=1[C:4]#[N:5].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[F:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1c([N+](=O)[O-])cc(C#N)c(F)c1O
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1cc([N+](=O)[O-])c(O)c(O)c1F
Reaction time: 1.5 h

Procedure:
550 mg of 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile are dissolved in 30 ml of methylene chloride, whereupon the solution is treated with 0.44 ml of boron tribromide. After stirring at 23° for 6 hours an additional 0.1 ml of boron tribromide are added thereto, whereupon the mixture is stirred at 23° for an additional 1.5 hours. Thereupon, 3 ml of ethanol are added thereto at -15°. The reaction mixture is evaporated and the residue is dried in a high vacuum at 23°. By recrystallization from ether/hexane there is obtained 2-fluoro-3,4-dihydroxy-5-nitrobenzonitrile of m.p. 154°.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]([CH3:30])([CH3:29])[CH2:15][N:16]([C:25](=[O:28])[CH2:26]Br)[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH3:24])([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+]>O1CCCC1.O>[C:7]([O:11][C:12]([N:13]1[CH2:26][C:25](=[O:28])[N:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[CH3:24])[CH2:15][C:14]1([CH3:30])[CH3:29])=[O:31])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc(F)cc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A solution of 2.87 g of potassium t-butoxide (25.6 mmol) in tetrahydrofuran (170 ml) was added to a solution of 7.13 g of {2-[(2-bromoacetyl)-(5-fluoro-2-methylphenyl)amino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in Example (70b) (17.0 mmol) in tetrahydrofuran (170 ml) under a nitrogen atmosphere and under cooling in a dry ice-acetone bath over 20 minutes, and the mixture was stirred at the same temperature for 10 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture. The mixture was returned to room temperature and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=2/1) to obtain 4.5 g of the title compound (yield: 78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([CH2:35][O:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)=[CH:3][CH:2]=1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[N:19]1([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:32]=[C:33]([CH2:35][O:36][C:37]5[CH:46]=[CH:45][C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[N:38]=5)[N:34]=[C:8]4[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2nc(OCc3cn4c(-c5ccc(N6CCNCC6)nc5)cnc(-c5ccncc5)c4n3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of compound 87e (60.0 mg, 0.0976 mmol) in 3 mL of DCM at rt was added TFA (0.50 mL). The resulting mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the residue was triturated with Et2O. The solid was collected by filtration and washed with Et2O. After drying under reduced pressure, the title compound 120 was obtained as an orange solid. 1H-NMR (CD3OD; 400 MHz) 9.36 (d, J=6.1 Hz, 2H), 8.92 (d, J=6.1 Hz, 2H), 8.62 (s, 1H), 8.30 (s, 1H), 8.05-8.20 (m, 3H), 7.82 (t, J=7.3 Hz, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.82 (s, 2H), 3.96-4.04 (m, 4H), 3.34-3.41 (m, 4H). Mass spectrum (LCMS, ESI pos.): Calcd. for C30H26N8O, 515.2 (M+H). found 515.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[C:11]([O-:14])(=[O:13])[CH3:12].[Na+].C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])/[CH:5]=[CH:12]/[C:11]([OH:14])=[O:13]
Reactant: Cc1ccc(C=O)cc1C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(/C=C/C(=O)O)cc1C
Yield: 69.8 %

Procedure:
A 1 L single-neck round bottom flask equipped with a condenser, magnetic stir bar, and a nitrogen inlet was charged with 3,4-dimethylbenzaldehyde (Lancaster 97%, 70.0 g, 0.52 mol), sodium acetate (anhydrous, 47.1 g, 0.57 mol), and acetic anhydride (300 mL, 3.2 mol). The mixture was stirred and heated to reflux. After 48 hours heating was discontinued and the reaction mixture was quenched, while still hot, by the cautious addition of water (300 mL). Ice-water was added to double the volume and the mixture was extracted with diethyl ether (700 mL); the organic phase was separated, washed with water (4×1 L), dried over anhydrous magnesium sulfate, and evaporated to dryness. Recrystallization of the crude product from methanol gave trans-3,4-dimethylcinnamic acid (64.0 g, 97% purity by GC) as yellow crystals. 1HNMR (CD2Cl2, 500 MHz) δ7.74 (d, JAB=16 Hz, 1H); 7.36 (br s, 1H); 7.32 (d, JAB=8 Hz, 1H); 7.18 (d, JAB=8 Hz, 1H); 6.41 (d, JAB=16 Hz, 1H); 2.29 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][CH2:13][C:14]([OH:16])=[O:15]>CCO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1cccc(C=CCC(=O)O)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(CCCC(=O)O)c1OC
Reaction time: 2 h
Yield: 100 %

Procedure:
Acid 5 (3.7 g, 0.017 mol) was dissolved in 25 mL absolute EtOH and added to a Parr hydrogenation bottle containing 0.6 g of 10% Pd/C. The bottle was then pressurized to 25 psi H2 and shaken for 2 h. The contents were then filtered through Celite, the solvents were evaporated, and the resulting oil dried under high vacuum to yield a grey solid (3.7 g, 0.017 mol, quant. yield). The solid was recrystallized from EtOAc/hexanes to produce fine white needles; mp 58-59° C. (lit.27 mp 58.5-60° C.). 1H NMR: (300 MHz, CDCl3): δ 6.97 (t, 1H, J=8 Hz, ArH); 6.76 (d, 1H, J=8 Hz, ArH); 6.75 (d, 1H, J=8 Hz, ArH); 3.84 (s, 3H, ArOCH3); 3.80 (s, 3H, ArOCH3); 2.67 (t, 2H, J=7 Hz, HO2CCH2CH2); 2.37 (t, 2H, J=7 Hz, ArCH2); 1.92 (p, 2H, J=7 Hz, HO2CCH2CH2). ESIMS (M+Na+)=247.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[C@@H:9]([O:10][CH3:11])[C@H:8]([CH3:12])[O:7][C@@H:6]([O:13][N:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)[C@@H:5]1[O:41][CH3:42])[CH3:2].C(O)C.Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:1]([O:3][C@@H:4]1[C@@H:9]([O:10][CH3:11])[C@H:8]([CH3:12])[O:7][C@@H:6]([O:13][NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:40])([F:39])[C:35]([F:37])([F:38])[F:36])=[CH:29][CH:28]=4)[N:23]=3)=[CH:20][CH:21]=2)[C@@H:5]1[O:41][CH3:42])[CH3:2]
Reactant: CCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON=Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ONCc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.4 %

Procedure:
To a solution of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde O-((2S,3R,4R,5S,6S)-4-ethoxy-3,5-dimethoxy-6-methyl-tetrahydropyran-2-yl)-oxime (P-1; 257 milligrams (mg), 0.429 millimoles (mmol)) in 190 proof ethyl alcohol (EtOH; 10 milliliters (mL)) at room temperature was added pyridine borane complex (200 microliters (μL), 1.99 mmol) in one portion. 3 N Hydrochloric acid (HCl; 1.4 mL) was then added dropwise. When the addition was complete, the mixture stirred at room temperature for 23 hours (h). The mixture was then diluted with EtOH/water (H2O) and treated with saturated sodium bicarbonate (NaHCO3). The resulting aqueous mixture was extracted with ethyl acetate (EtOAc; 2×). The organic extracts were combined, dried, washed with brine and dried with anhydrous sodium sulfate (Na2SO4). The solvent was evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 50% EtOAc in Hexane). The title product (164 mg, 63%) was isolated as a white sticky solid: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.22-8.16 (m, 2H), 7.87-7.80 (m, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.46-7.38 (m, 2H), 6.04 (s, 1H), 5.01 (d, J=1.4 Hz, 1H), 4.18 (s, 2H), 3.84-3.28 (m, 12H), 3.11 (dd, J=12.0, 6.5 Hz, 1H), 1.30 (ddd, J=20.9, 10.3, 4.6 Hz, 6H); ESIMS m/z 603 (M+H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][OH:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[CH3:34][S:35]([O:18][CH2:17][C@@H:16]([NH:19][C:20]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:15][CH:12]1[CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:14][CH2:13]1)(=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-hydroxypropan-2-ylcarbamate (101.6 g, 0.263 mol) and Et3N (66.3 g, 0.656 mol) in CH2Cl2 (500 mL) was added MsCl (66.1 g, 0.577 mol) at −20° C., which was allowed stir for 1 h at rt. The reaction mixture was treated with water (300 mL) and extracted with CH2Cl2 (3×100 mL). The organic layers dried over Na2SO4 and evaporated give (S)-2-(tert-butoxycarbonylamino)-3-(4-(tert-butyldimethylsilyloxy)cyclohexyl)propyl methanesulfonate (121 g, 99%).