Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:29][CH2:30][CH2:31][CH3:32])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([O:21][Si](C(C)(C)C)(C)C)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:29]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([OH:21])[CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
In 75 ml of tetrahydrofuran was dissolved 4.02 g (8.52 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldimethylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde, and 25.5 ml of tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran) was added dropwise thereto with stirring at room temperature. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.74 g of a blackish brown crystal (yield: 89.9%).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH3:15])[CH2:10][C:11]([O:13]C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+]>CO>[Si:1]([O:8][CH:9]([CH3:15])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CC(C)O[Si](C)(C)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(CC(=O)O)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
There was dissolved 3.58 g (15.4 mmol) of methyl (-)-3-t-butyldimethylsilyloxybutyrate in 30 ml of methanol, to which 30 ml of 1 N potassium hydroxide was added and the mixture was stirred for 15 minutes. After distilling away most methanol from the mixture, the solution was acidified with 1 N hydrochloric acid and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate, which was concentrated under reduced pressue to give 3.18 g of (-)-3-t-butyldimethylsilyloxybutyric acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH3:13])[C:7]=1[CH2:14]Br)=[O:5])[CH3:2].[CH2:16]([O:18][C:19](=[O:29])[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH3:13])[C:7]=1[CH2:14][N:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(Br)c(Br)n(C)c1CBr
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1C)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4,5-dibromo-2-bromomethyl-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 549 (M+Na+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].Br[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:13][CH2:12][CH2:11][N:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COCCN1CCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
Add NaH (0.47 g, 11.8 mmol) to a solution of morpholin-3-one (Vieles, P.; Seguin, J., Bulletin de la Societe Chimique de France, 1953, 287-9) (1.0 g, 9.9 mmol) in DMF (10 ml) at room temperature. Stir for 30 min, add (2-bromo-ethoxymethyl)-benzene (2.2 g, 10.2 mmol), and stir at room temperature for 18 h. Dilute with water and extract with EtOAc (2×). Combine the organics, dry, and concentrate. Purify by flash chromatography using 0-5% MeOH in CH2Cl2, to give the product as an oil. (1.7 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.28 (m, 5H), 4.48 (s, 2H), 4.13 (s, 2H), 3.80 (t, 2H, J=5.1 Hz), 3.65 (m, 2H), 3.59 (dd, 2H, J=7.5, 2.6 Hz), 3.48 (t, 2H, J=5.1 Hz).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>BrC1C=CC(CC)=CC=1.O1CCCC1>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1)[OH:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1OCc1ccccc1
Reactant: CCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
1-Bromo-4-ethylbenzene (6.69 g, 0.036 mol) was added to a suspension of magnesium (17.2 g) and tetrahydrofuran (50 mL) and heated to reflux. Subsequently, a tetrahydrofuran (300 mL) solution of 1-bromo-4-ethylbenzene (97.9 g, 0.529 mol) was added for two hours at room temperature. After stirred at room temperature for 1.5 hours, the reaction mixture was cooled to 4° C. and a tetrahydrofuran (100 mL) solution of 2-benzyloxybenzaldehyde (100 g, 0.471 mol) was added for one hour. After stirred for two hours, the reaction mixture was poured into a saturated ammonium chloride aqueous solution. After the mixture was extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain (2-benzyloxyphenyl)(4-ethylphenyl)methanol (152 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][CH:17]=2)=O)=[CH:7][CH:6]=1)=[O:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].O>O1CCCC1>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[S:30][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCOc1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 146.4 %

Procedure:
A suspension of 1-(4-methoxycarbonylphenyl)-4-(4-n-pentyloxyphenyl) butane-1,4-dione (765 mg) and phosphorus pentasulfide (533 mg) in tetrahydrofuran (10 ml) was stirred for 6 hours at room temperature, poured into water and stirred for 1 hour. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give methyl 4-[5-(4-n-pentyloxyphenyl)thiophen-2-yl]benzoate (668 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Cl[CH2:10][CH2:11][C:12]([N:14]([C:16]1[C:17]([Cl:27])=[N:18][N:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=1)[CH3:15])=[O:13]>CN(C=O)C.[NH4+].[Cl-].CCOC(C)=O.[Na+].[Cl-]>[Cl:27][C:17]1[C:16]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][CH2:10][N:3]2[CH2:4][CH2:5][O:1][C:2]2=[O:6])=[CH:20][N:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:18]=1
Reactant: O=C1NCCO1
Reactant: CN(C(=O)CCCl)c1cn(-c2cccnc2)nc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)CCN1CCOC1=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxazolidin-2-one (0.038 g, 0.44 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 0.011 g, 0.44 mmol). The mixture was stirred at a temperature of about 0° C. for 10 minutes, and 3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H- pyrazol-4-yl)-N-methyl propanamide (0.12 g, 0.40 mmol) was added. The resulting brown-yellow mixture was stirred at room temperature for two hours and diluted with saturated aqueous NH4Cl. The mixture was diluted with EtOAc and saturated aqueous NaCl solution. The organic phase was separated, and the aqueous phase extracted with EtOAc (2×50 mL). The combined EtOAc extracts was dried over MgSO4, filtered, and concentrated under reduced pressure to give light brown gum. The gum was purified on silica gel eluting with MeOH/CH2Cl2 to give the title compound F31 as a colorless oil (0.13 g, 94%).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].C[Si](C)(C)[O-].[K+].Cl>C1COCC1.CCOC(C)=O>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1cccc(Oc2ccccc2)c1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Temperature: 45 °C

Procedure:
To a solution of methyl 2-methyl-2-(3-phenoxy-phenyl)-propionate (712 mg, 2.63 mmol) in THF (8 mL) was added potassium trimethylsilanolate (90% technical grade; 563 mg; 1.5 eq) and the solution heated to 45° C. for 5 hrs. The solution was allowed to cool, diluted with EtOAc (15 mL) and acidified with 2M HCl to ˜pH 3. The organic layer was separated and the aqueous phase extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and evaporated to dryness to afford the desired acid, 2-methyl-2-(3-phenoxy-phenyl)-propionic acid, as a colorless powder. 1H NMR (500 MHz, CDCl3) δ 7.25-7.35 (3H, m), 7.08-7.16 (3H, m), 7.01 (2H, dd, J=7.7, 0.6 Hz), 6.86 (1H, dd, J=8.1, 2.3 Hz), 1.58 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]([CH3:30])[C:25]([O:27]CC)=[O:26])[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[K+]>CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]([CH3:30])[C:25]([OH:27])=[O:26])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)C(C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
A mixture of ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate (201 mg), aqueous potassium hydroxide solution (4 ml of 2M solution) and methanol (20 ml) was boiled under reflux for 1 hour. The mixture was concentrated under reduced pressure to around 5 ml and then diluted with water (30 ml). The mixture was hot filtered and filtrate was cooled and then acidified with dilute acetic acid until no further precipitation occurred. The mixture was heated on a hot plate until the gel which had been obtained became a finely divided solid. The solid was collected by filtration to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionic acid, m.p. 239.5-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[N+:13](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.Cl>[Na+].[Cl-].CCOCC.O1CCOCC1.CN(C=O)C>[ClH:1].[NH2:13][N:4]1[CH:5]=[CH:6][C:2]([Cl:1])=[C:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1[nH]ccc1Cl
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccn1N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of methyl 3-chloro-1H-pyrrole-2-carboxylate (2.50 g, 15.7 mmol) and DMF (10 mL) at 0° C. was added 60% sodium hydride (0.816 g, 20.4 mmol). After 15 min, O-(2,4-dinitrophenyl)hydroxylamine (3.74 g, 18.8 mmol) was added and the mixture was stirred at 0° C. for 1 hr before warming to RT. After 18 hrs, the mixture was diluted with 10% NaCl and extracted with EtOAc. The organic fractions were dried with sodium sulfate and purified by silica gel chromatography using 10-30% Hexanes:EtOAc to afford a crude, brown oil. The oil was taken up in Et2O and treated with 4 N HCl in dioxane. The resulting off-white precipitate was collected by filtration to afford methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate hydrochloride.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cccc(Br)n1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.40 g (26.7 mmol) of 6-bromo-2-pyridinecarboxylic acid were initially charged in 150 ml of tetrahydrofuran, 6.51 g (40.0 mmol) of carbonyldiimidazole were added and the mixture was boiled at reflux for 1 h. After cooling to room temperature, 3.81 g (40.0 mmol) of methanesulphonamide were added, the mixture was stirred for 10 min, then 6.10 g (40 mmol) of diazabicycloundecene (DBU) were added and the mixture was stirred at room temperature for 16 h.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.S(=O)(=O)(O)O.[C-:17]#[N:18].[Na+].CCOCC>CO>[C:17]([C:2]1([OH:11])[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)#[N:18]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: N#CC1(O)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a well stirred solution of 2-adamantanone (45.0 grams, 0.3 mol) in 200 ml methanol were added 50 ml concentrated sulfuric acid at a rate that caused the solution to reflux. Then a saturated aqueous solution of sodium cyanide (88.2 grams, 0.6 mol) was added, and the mixture was first refluxed for 1 hour and then stirred at room temperature for 3 additional hours. Ether was added, and the organic solution was decanted from the precipitated salts. The ether solution was washed with an aqueous solution of sodium chloride and water and then dried and evaporated to leave 43.0 grams (81%) of compound 4 as a beige crystalline solid, melting point >240° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH3:20])=[CH:5][CH:4]=1.C([O-])(O)=[O:22].[Na+].[BH4-].[Na+].[Cl-].[NH4+]>ClC1C=CC=CC=1.CO>[OH:22][CH2:20][C:10]1[S:11][C:12]2[C:17]([C:18](=[O:19])[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2c(C)sc3ccccc3c2=O)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Clc1ccccc1
Solvent: CO
Product: COc1ccc(-c2c(CO)sc3ccccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
The compound (1.0 mmol, 282 mg) obtained in (1) above and SeO2 (1.2 mmol, 133 mg) were dissolved in 5 mL of chlorobenzene, and the solution was refluxed for 12 hours under a nitrogen atmosphere. After the disappearance of the starting materials was confirmed by NMR, the temperature of the solution was returned to room temperature, and saturated NaHCO3 was poured thereinto to terminate the reaction. The organic substances were extracted with methylene chloride, the obtained organic layer was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was passed through a silica-gel column, and directly used in the subsequent reaction. The obtained mixture was dissolved in 2 mL of methanol, to which NaBH4 (1.0 mmol, 38 mg) was added; and under a nitrogen atmosphere, the resulting product was stirred at 0° C. for 2 hours. A saturated ammonium chloride solution was added thereto to terminate the reaction. Then, the organic layer extracted with ethyl acetate was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized with hexane/ethyl acetate. Thereby, the title compound (0.41 mmol, 122 mg) was obtained in a two-step yield of 41%.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>O1CCCC1.[OH-].[Na+]>[C:9]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.6 %

Procedure:
A solution of valine (20 g, 0.17 mole) in tetrahydrofuran (20 ml) and 2N NaOH (111 ml) was cooled down to 10° (ice-water bath) under nitrogen and treated dropwise with benzoyl chloride (23.8 ml, 0.21 mole). The reaction mixture was warmed up to room temperature, stirred for 3.0 hours then cooled back down to 0° (ice-salt bath) and treated with concentrated sulfuric acid (8.0 ml). The mixture was extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml), dried (anhydrous MgSO4), filtered and evaporated to dryness to give title compound as a solid (41.97 g, 100% crude yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH2:16](N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
2-Chloro-4-(trifluoromethyl)-benzeneacetic acid (3 g) [CAS Reg. No. 601513-26-2] was dissolved in DCM (30 mL) and methyl chloroformiate (1.18 g, 0.97 mL) followed by triethylamine (1.4 g, 1.93 mL) were added drop by drop. To the mixture was added DMAP (0.154 g) and the yellow mixture was allowed to stir for 1 hour at 0° C. A clear solution was obtained. The mixture was diluted with DCM (30 mL) and was poured into sat. NH4Cl solution. The layers were separated and the aqueous phase was further extracted with 2 portions of DCM. The organic layers were washed with brine, dried over Na2SO4 and evaporated to give the title compound (3.0 g) that was used without further purification. NMR (□, CDCl3): 7.6-7.4 (m, 3H); 3.84 (s, 2H); 3.74 (s, 3H).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][CH3:11])[CH:5]1[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][CH3:11])[CH:5]1[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC1CCCC(N=[N+]=[N-])C1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CCCC(N)C1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of racemic [1-Azido-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51g, (2.57 g; 6.3 mmol) in 20 mL of ethyl acetate was hydrogenated with Pd—C 10% (5 mole %; Degussa) at 45 PSI in a Parr hydrogenation apparatus for 1 h. The reaction mixture was filtered over a nylon and glass fiber filter and concentrated in vacuo to provide 2.32 g of the desired product 51h as a white solid.
Reaction SMILES: Cl.[C:2]([S:21][CH2:22][CH2:23][NH2:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:25]([S:28]([C:31]1[CH:39]=[CH:38][C:37]([NH:40][S:41]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)(=[O:43])=[O:42])=[C:36]2[C:32]=1[CH:33]=[C:34]([C:49](O)=[O:50])[NH:35]2)(=[O:30])=[O:29])[CH2:26][CH3:27].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH2:25]([S:28]([C:31]1[CH:39]=[CH:38][C:37]([NH:40][S:41]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)(=[O:43])=[O:42])=[C:36]2[C:32]=1[CH:33]=[C:34]([C:49]([NH:24][CH2:23][CH2:22][S:21][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:50])[NH:35]2)(=[O:29])=[O:30])[CH2:26][CH3:27]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCS(=O)(=O)c1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a mixture of 2-(tritylthio)ethylamine hydrochloride (0.42 g), triethylamine (0.17 mL) and N,N-dimethylformamide (15 mL) were added 4-(propylsulfonyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.42 g), 1H-1,2,3-benzotriazol-1-ol (0.20 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.25 g) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (690 mg, yield 97%) as pale-yellow prism crystals. melting point 200-201° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([F:17])[CH:10]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:17][C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH2:16]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnccc2Oc2cc(F)c(N)cc2F)cn1
Temperature: 90 °C
Yield: 64.5 %

Procedure:
In a sealed tube, 4-(3-bromopyridin-4-yloxy)-2,5-difluorobenzenamine (0.42 g, 1.395 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.363 g, 1.744 mmol), potassium carbonate (0.578 g, 4.18 mmol), and tetrakistriphenylphosphine palladium (0) (0.081 g, 0.070 mmol) were suspended in dioxane (8 mL) and water (1.333 mL). The mixture was degassed with Ar and heated at 90° C. overnight. The reaction mixture was cooled and partitioned between EtOAc and saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried, evaporated and purified by silica gel chromatography (hexanes/EtOAc) to yield 2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (272 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H) 8.22-8.20 (m, 2H), 8.00 (s, 1H), 7.24-7.19 (tri, 1H), 6.76-6.71 (m, 1H), 6.62 (d, 1H), 5.50 (br s, 2H), 3.78 (s, 3H); MS (ESI) m/z: 301.0 (M+H+).