Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[N:6][CH:7]=1.[B:9]1(B2OC(C)(C)C(C)(C)O2)[O:13]C(C)(C)C(C)(C)[O:10]1.C([O-])(=O)C.[K+].C(Cl)Cl>O>[NH2:8][C:3]1[C:2]([B:9]([OH:13])[OH:10])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Nc1ncncc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Nc1ncncc1B(O)O
Temperature: 105 °C
Reaction time: 18 h

Procedure:
To a vial was added 5-bromopyrimidin-4-amine (0.200 g, 1.149 mmol), bis(pinacolato)diboron (0.438 g, 1.724 mmol), and potassium acetate (0.338 g, 3.45 mmol). The vial was capped with a rubber septum and then evacuated and backfilled with N2. Dioxane (0.120 ml) was added via syringe through the septum. The reaction mixture was sparged with N2, then PdCl2(dppf).CH2Cl2 (0.042 g, 0.057 mmol) was added. The septum was then replaced with a Teflon screw valve and the vial was sealed. The reaction mixture was heated at 105° C. in a metal pie block. After 18 h, reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with EtOAc. The filtrate was concentrated to afford a brown solid. MS (ESI): m/z=140.0 [M+H]+ HPLC Peak ret. T=0.24 minutes was product (HPLC conditions: Column:Luna C18 4.6×30 mm 3 u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:23]I>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the ester from step (a) above (4.3 g, 15.5 mol) in DMF (30 mL) was added NaH (60% in mineral oil, 0.93 g, 23.2 mmol) and the mixture was stirred at 0° C. for 1 h. MeI (1.16 mL, 18.6 mmol, Aldrich) was added drop-wise with stirring at 0° C., and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (50 mL), washed with saturated solution of NH4Cl (25 mL) and brine (25 mL), dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 10% EtOAc/hexane, to give the title compound as a light-yellow oil, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 292 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=O)[CH2:15]Br)=[CH:12][CH:11]=1>CC(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[C:14]([C:13]3[CH:18]=[CH:19][C:10]([Br:9])=[CH:11][CH:12]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Cc1ccc(N)nc1
Solvent: CC(C)=O
Product: Cc1ccc2nc(-c3ccc(Br)cc3)cn2c1

Procedure:
A mixture of 18.8 g of 2-amino-5-methylpyridine and 27.8 g of p-bromophenacyl-bromide in 200 ml of acetone was refluxed for 8 hrs. The precipitate was collected and dissolved in hot methanol and 2 ml of concentrated HBr was added. The methanol solution was then basified with ammonium hydroxide. The precipitated product was collected and recrystallized from ethanol; yield 18.5 g (68%); mp 215°-216° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:5]([N:13]=O)[C:4]([CH3:15])=[N:3]1>[Pd].CCOC(C)=O>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:15])[C:5]=1[NH2:13]
Reactant: Cc1nn(C)c(NCC(C)(C)C)c1N=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(NCC(C)(C)C)c1N
Temperature: 23 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
(2,5-Dimethyl-4-nitroso-2H-pyrazol-3-yl)-(2,2-dimethyl-propyl)-amine (3.44 g, 16.36 mmol), 400 mg of 10% Pd/C and 60 mL EtOAc were placed under a balloon of H2 and stirred at 23° C. After 4 h, the reaction mixture was filtered through Celite and evaporated to an orange oil. Flash chromatography on silica gel, eluting with CHCl3/MeOH (20/1), gave a yellow solid. Recrystallization from hot hexanes/EtOAc gave 2.86 g (14.57 mmol, an 89% yield) of the title compound as an off-white crystalline solid. mp: 65-69° C.; 1H NMR (300 MHz, CDCl3): δ1.00 (s, 9H), 1.65 (brs, 2H), 2.13 (s, 3H), 2.77 (brs, 2H), 2.89 (brs, 1H), 3.62 (s, 3H); IR (KBr, cm−1): 3347-3204brs, 2952s, 2903w, 1599m, 1528m, 1495m, 1477m, 1378m, 1316m; MS (ES) m/z (relative intensity): 197 (M++H, 100).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.O=S(Cl)Cl.[CH3:19]O>>[CH3:19][O:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:12]([I:14])=[CH:13][C:5]=1[NH2:4]
Reactant: CO
Reactant: CC(=O)Nc1cc(I)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)cc1N
Temperature: 65 °C

Procedure:
To 2-acetylamino-4-iodo-benzoic acid (13.8 g, 45.3 mmol) in 200 mL of dry methanol was added SOCl2 (32.7 mL, 453 mmol) dropwise at 0° C. The reaction mixture was then heated at 65° C. for 2 h. The reaction was then cooled to 0° C., an additional portion of SOCl2 (10 mL, 137 mmol) was added, and the reaction was heated at 65° C. for 2 h. The reaction was then cooled to 0° C., a final portion of SOCl2 (10 mL, 137 mmol) was added, and the reaction was heated at 65° C. for 48 h. The reaction was then cooled to 22° C. and concentrated in vacuo The resulting residue was diluted with H2O and extracted with 3×150 mL CH2Cl2. The combined organic fractions were washed with brine and dried over Na2SO4 to give i-b (11.7 g, 93%): MS m/z═278 (M+H).
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH3:9].[N+:11]([O-])([OH:13])=[O:12].C(Cl)(Cl)Cl>OS(O)(=O)=O>[CH3:9][C:2]1[C:3]([CH3:8])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([CH3:7])=[CH:6][N+:1]=1[O-:10]
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
A suspension of 2,3,5-collidine-N-oxide (3.77 g, 28 mmol) in conc. H2SO4 (8 mL) was cooled to 0° C. and fuming HNO3 (5 mL, 100 mmol) was added dropwise. The resulting transparent solution was stirred at 100° C. for 24 h, cooled to r.t., poured onto ice, and the pH was adjusted to 10. Work-up (CHCl3), drying (MgSO4), and evaporation gave the title compound, (97% yield, 97% purity). Rf (MeOH/EtOAc 1:9): 0.7. HPLC Rt: 4.756 min. 1H-NMR (CDCl3): δ 8.08 (s, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). m/z (%) 183.1 (M+1, 100%).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[NH2:8].[N-:18]=[N+:19]=[N-].[Na+]>S(=O)(=O)(O)O.C(O)(=O)C>[N:8]([C:7]1[C:6]([Cl:5])=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][C:9]=1[Cl:17])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (3.2 g) in concentrated sulphuric acid (22 ml) was added dropwise with cooling to a solution of 2,6-dichloro-4-trifluoromethylaniline (9.3 g) in glacial acetic acid (48 ml). The mixture was stirred at room temperature for half an hour and then cooled to 0°-5°. A solution of sodium azide (2.6 g) in the and the mixture stirred at 0°-5° for 1 hour and then at room temperature overnight. The mixture was poured into ice/water, extracted with dichloromethane and the extract worked up in conventional manner to give 1-azido-2,6-dichloro-4-trifluoromethylbenzene, as a red oil. A solution of this oil (25.6 g) and 2-propyn-1-ol (40 ml}in xylene (80 ml) were stirred under nitrogen and heated under reflux overnight. The mixture was cooled and the solvent was evaporated under reduced pressure. Trituration of the residue with light petroleum (bp 30°-40°) gave a crude material which was purified by filtration through silica to give [1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl]methanol, m.p.123°-125°.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C=O.[CH:14](O)=O.Cl>>[CH3:14][N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: O=CO
Reactant: CCOC(=O)C1CCNCC1
Agent: C=O
Agent: Cl
Product: CCOC(=O)C1CCN(C)CC1
Temperature: 25 °C

Procedure:
To ethyl isonipecotate (10 g, 64 mmol) was slowly added a 37% aqueous solution of formaldehyde (10 mL, 128 mmol) followed by formic acid (10 mL, 233 mmol) and the mixture was heated to reflux for about 3 days. The mixture was allowed to cool to room temperature, the pH was adjusted to 2 by addition of concentrated hydrochloric acid and the mixture was extracted with ethyl acetate. The pH of the aqueous layer was then adjusted to 11 by addition of 2N aqueous sodium hydroxide, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts of the second extraction were dried (MgSO4), filtered, and concentrated under vacuum to provide the desired product. 1H NMR (500 MHz, CDCl3-d): δ 1.25 (t, J=6 Hz, 3H), 1.40 (m, 1H), 1.59 (m, 1H), 1.62 (m, 1H), 1.95 (m, 2H), 2.06 (m, 1H), 2.26 (s, 3H), 2.71 (m, 1H), 2.94 (m, 1H), 4.13 (dd, J=6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([N:21](C=O)[CH3:22])[CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.Cl.[OH-].[Ca+2].[OH-]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([NH:21][CH3:22])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOC(=O)c1cn(N(C)C=O)c2nc3cc(Cl)c(F)cc3cc2c1=O
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reaction time: 4 h
Yield: 97.7 %

Procedure:
A suspension of 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 164 cm3 of acetic acid and 164 cm3 of an aqueous 17.5% hydrochloric acid solution is heated at a temperature close to 100° C., with stirring, for 4 hours. After cooling to a temperature close to 10° C., 165 cm3 of 30% slaked lime is added at between 10° and 20° C. The product is drained and washed with 3 times 150 cm3 of water, 3 times 150 cm3 of ethanol and 3 times 150 cm3 of diethyl ether. 13.64 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 354°-356° C.
Reaction SMILES: [F:1][C:2]([C:17]([F:20])([F:19])[F:18])([O:6][C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3](F)=[O:4].C[Si](C)(C)[O-:23].[Na+:26]>ClC1C=CC=CC=1Cl>[F:1][C:2]([C:17]([F:18])([F:19])[F:20])([O:6][C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:10])[F:11])[C:3]([O-:4])=[O:23].[Na+:26]
Reactant: C[Si](C)(C)[O-]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 77.3 %

Procedure:
The procedure of Example 1 was followed using perfluoro-2-methyl-3-oxahexanoyl fluoride (16.6 g, 50 mmol), sodium trimethylsilanolate (5.6 g, 50 mmol), dry o-dichlorobenzene (200 mL), and 1 h at room temperature followed by rapid heating to 150°. Sodium perfluoro-2-methyl-3-oxahexanoate (13.6 g, 77% yield) was isolated as a white solid: The 19F NMR data were the same as reported in Example 15.
Reaction SMILES: Cl.O1CCOCC1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:20]=3[N:19]=2)[N:9]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][CH:55]([CH:65]1[CH2:67][CH2:66]1)[CH2:56][C:57]([NH:59][C:60]1[NH:61][CH:62]=[CH:63][N:64]=1)=[O:58]>C(Cl)Cl>[CH:65]1([CH:55]([NH:54][C:27]([C:25]2[CH:24]=[CH:23][C:21]3[NH:22][C:18]([C:10]4[N:9]=[CH:8][C:17]5[C:12]([CH:11]=4)=[CH:13][CH:14]=[CH:15][CH:16]=5)=[N:19][C:20]=3[CH:26]=2)=[O:28])[CH2:56][C:57](=[O:58])[NH:59][C:60]2[NH:61][CH:62]=[CH:63][N:64]=2)[CH2:67][CH2:66]1
Reactant: NC(CC(=O)Nc1ncc[nH]1)C1CC1
Reactant: O=C(O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CC(NC(=O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1)C1CC1)Nc1ncc[nH]1
Yield: 4.3 %

Procedure:
203 mg (1.0 mmol) of 3-tert-butoxycarbonylamino-3-cyclopropyl-propionic acid (0.23 g, 1 mmol) was reacted with 380 mg (1.0 mmol) of HBTU and 130 mg (1.0 mmol) of 2-aminoimidazole sulfate as described in general procedure A. The desired amide product was isolated by column chromatography (EtOAc/silica) and carried on directly to the next step. The BOC compound in DCM (3 mL) was treated with 4.0 M HCl/dioxane (15 mL) for approximately 1 h. The solid 3-Amino-3-cyclopropyl-N-(1H-imidazol-2-yl)-propionamide (180 mg, 100%) was collected by filtration and used directly in the next step 289 mg (1 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid (289 mg, 1 mmol) was reacted with 380 mg (1 mmol) of HBTU and 3-amino-3-cyclopropyl-N-(1H-imidazol-2-yl)-propionamide (230 mg, 1 mmol) as described in general procedure A. A solid precipitated from the solution and was collected by filtration, washed with 1H2O and Et2O, to give 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-cyclopropyl-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide (20 mg, 4%). LCMS: 466 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 9.20 (s, 1H), 8.56 (s, 1H), 8.09-7.34 (m, 9H), 6.39 (s, 2H), 3.71 (t, 1H), 2.44 (m, 2H), 0.81 (m, 1H), 0.10 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(C(=O)O)cc1Cl
Temperature: 135 °C

Procedure:
A solution was prepared from 100 g of the commercially available hemihydrate of 3-chloro-4-hydroxybenzoic acid in 300 mL of acetic anhydride. After adding 7 drops of concentrated sulfuric acid, the mixture was refluxed at 135° C. for 2 hrs. The product crystallized out on cooling. About 500 mL of cold water was added with stirring, which continued while cooling in an ice/water bath for 1 hr. After filtration and drying, the product was recrystallized from 350 mL of ethyl alcohol to yield 40 g of 3-chloro-4-acetoxybenzoic acid melting at 152-159° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(O)(=O)C>O>[C:10]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1N
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To 25 ml of 2,6-xylidine (0.20 mole) was added slowly a mixture of 25 ml of acetic anhydride (0.26 mole) and 25 ml of acetic acid (0.44 mole) under stirring at room temperature. The mixture was stirred for 30 minutes at room temperature and, then, diluted with water. The crystalline precipitate was collected by filtration to give 30.1 g (91%) of the title compound (m.p. 182°-184° C.; colorless needles).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=O)([O-:3])=[O:2].C1(S([NH2:25])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]#[N:25])([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A mixture of 21.2 grams (0.1 mole) of 2,4-dinitrobenzoic acid and 32.0 grams (0.21 mole) of benzenesulfonamide is stirred and heated in an oil bath at 205°-210° for 1 hour and then at 225° for 1 hour and allowed to cool to room temperature under a nitrogen atmosphere. The residue is shaken with methylene chloride and dilute NaOH solution and the methylene chloride layer separated and washed with water. The solvent is removed by distillation. There is obtained 6.05 grams (31%) of material melting at 88°-92°. Recrystallization from ethanol raises the melting point to 100°-2°. The infrared spectrum shows a weak nitrile band at 2200 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24](OS(C)(=O)=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1

Procedure:
A solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.375 g, 1.93 mmol), (R)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (0.513 g, 1.93 mmol), and Cs2CO3 (0.943 g, 2.90 mmol) in anhydrous DMF (5.1 mL) was heated to 100° C. for 6 h. The reaction mixture was partitioned between EtOAc and H2O and separated. The aqueous layer was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (3×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a brown oil. This material crude was purified by chromatography on silica gel [eluting with 12% EtOAc in CHCl3] resulting in the title compound as a viscous oil. 1H NMR (400 MHz, CDCl3): δ=1.32 (s, 12H), 1.47 (s, 9H), 2.36 (q, J=7.0 Hz, 2H), 3.46-3.79 (m, 3H), 3.81-3.92 (m, 1H), 4.90 (quint, J=6.1 Hz, 1H), 7.73 (s, 1H), 7.81 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15][N:16](C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19]N>CCO>[NH:19]1[C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=2[CH:15]=[N:16]1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1

Procedure:
To a solution of tert-butyl-3-[(dimethylamino)methylene]-4-oxopiperidine-1-carboxylate (63.6 g, 250 mmol) in EtOH (200 mL) is added hydrazine (9.6 mL, 305 mmol) and the mixture is heated at reflux for 2 hr. Solvent is evaporated in vacuo and residue is purified by flash column with 5% MeOH in DCM to give the title compound as a white solid. MS (M+1): 224.1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].O>ClCCl>[C:13]([Si:17]([CH3:20])([CH3:19])[O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 881.2 %

Procedure:
A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (10 g, 96 mmol) and imidazole (9.8 g, 140 mmol) in dichloromethane (200 mL) was added tert-butyldimethylchlorosilane (15.9 g, 10.6 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated to give 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol as a colorless oil (20.4 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C@H:12]([OH:15])[CH2:13][OH:14].N1C=CC=CC=1.[C:22](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:22]([O:14][CH2:13][C@H:12]([C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[OH:15])(=[O:23])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
To a suspension of (S)-1-(2-Bromo-6-methyl-4-nitrophenyl)ethane-1,2-diol (17.0 g, 61.6 mmol) in DCM (435 mL) at 0° C. was added pyridine (18.6 g, 235.4 mmol) and PivCl (13.4 g, 110.8 mmol) slowly. After stirring at 0° C. for 5 min, the system was raised to room temperature and stirred at this temperature for 5 h. TLC showed the reaction was complete. The reaction mixture was treated with saturated aqueous NaHCO3 (500 mL), and the resulting system was extracted with DCM (2×200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated in vacuum, and purified by silica gel column (Petroleum Ether:EtOAc (30:1)) to afford (S)-2-(2-Bromo-6-methyl-4-nitrophenyl)-2-hydroxyethyl pivalate (17 g, 77%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.28 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 5.70-5.66 (m, 1H), 4.58-4.53 (m, 1H), 4.31-4.26 (m, 1H), 2.84 (d, J=5.6 Hz), 2.68 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1>CO>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CO
Product: COC(=O)C1CCC(O)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
A Parr bottle was charged with 150 ml of methanol and 25 g of methyl 4-hydroxybenzoate was added, then the bottle was flushed with nitrogen, 2.5 g of 5% rhodium on alumina was added and the reaction mixture was pressurized under hydrogen at 3.74 atmospheres for 18 hours with constant shaking. The reaction was then flushed with nitrogen and filtered through diatomaceous earth to remove the catalyst. The diatomaceous earth was rinsed with methanol, being careful not to filter the catalyst to dryness. The filtrates were combined and the methanol was removed under reduced pressure with very gentle heat (ca. 40° C.). The residue of product and alumina was taken up in 200 ml of ether to which 3 g of anhydrous potassium carbonate was added. The precipitated alumina and potassium carbonate were removed by filtration through diatomaceous earth. This was rinsed with ether, the filtrates were combined and the solvent was removed under reduced pressure to yield the crude product. This was bulb-to-bulb distilled on Kugelrohr apparatus at 80°-100° C./ca. 1 mm to yield 25.0 g (98%) of methyl 4-hydroxycyclohexanecarboxylate. 1H NMR (CDCl3, 60 MHz) δ 3.85 (s, 1 H); 3.65 (s, 3 H); 2.50-1.20 (m, 10 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(C(C)C)C(C)C)C.[CH3:19][O:20][CH2:21]Cl>ClCCl>[CH3:19][O:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C=O)c1
Reaction time: 1 h

Procedure:
A solution of 100 g of 3-hydroxybenzaldehyde and 214 ml of N-ethyldiisopropylamine in 800 ml of dichloromethane was ice-cooled and a solution of 68.4 ml of chloromethyl methyl ether in 200 ml of dichloromethane was added dropwise. After stirring for one hour, an ice bath was removed and the mixture was continuously stirred at room temperature overnight. The reaction solution was washed in turn with an aqueous 10% sodium hydroxide solution and 10% citric acid and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was distilled off under reduced pressure to obtain 81.3 g of the desired compound as a colorless oily substance. Boiling point: 125 to 127° C./10 mmHg