Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[I:15]N1C(=O)CCC1=O.C(#N)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[I:15][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[N:5][C:6]=1[CH3:8]
Reactant: Cc1cc(C)nc(N2CCOCC2)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nc(N2CCOCC2)nc(C)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(4,6-dimethylpyrimidin-2-yl)morpholine (20.6 g, 107 mmol), N-iodosuccinimide (28.8 g, 128 mmol) and ACN (400 ml) is stirred at RT for 24 h. DCM and an aqueous solution containing 3% sodium thiosulfate is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. This material is used without further purification. Yield: 33.7 g (89%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:17][C:16](=O)[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:16]1[N:15]=[C:14]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)[nH]c(=O)n2)ccc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (3.74 g, 10.6 mmol) and phosphoryl chloride (35 mL) according to the general procedure I. Obtained as a light brown solid. MS (EI) 370.0 [(M)+]; mp 89° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[Br:13]Br>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Br:13])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(Br)c(O)c(C(C)(C)C)c1
Reaction time: 0.33 h

Procedure:
2-t-Butyl-4-methylphenol (10 g, 60.8 mmol) is dissolved in CH2Cl2 (300 mL). Bromine (3.1 mL, 60.8 mmol) is added dropwise to the solution. After 20 minutes, the crude mixture is washed with H2O, dried over MgSO4, filtered and rotovapped to give yellow oil: 12.6 g, 85%. 1H NMR (CDCl3) δ: 1.402 (s, 9H, t-Bu), 2.267 (s, 3H, CH3), 5.640 (s, 1H, OH), 7.017 (s, 1H, Ar), 7.167 (s, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([F:14])[C:3]=1[CH:15]([OH:20])S([O-])(=O)=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([F:14])[C:3]=1[CH:15]=[O:20]
Reactant: COC(=O)/C=C/c1cc(F)c(C(O)S(=O)(=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.4 %

Procedure:
Under an atmosphere of nitrogen, sodium {2,6-difluoro-4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}(hydroxy)methanesulfonate (1.211 kg, 3.52 mol) was to a 100 L vessel followed by potassium carbonate (0.974 kg, 7.05 mol). Water (9.1 L) was added and the agitator was started. Ethyl acetate (9.1 L) was added. The mixture was agitated at 25° C. for 5 hours. The agitator was stopped and the mixture was allowed to stand for 14 hours at 25° C. The lower aqueous phase was removed and discarded. The upper organic phase was concentrated under reduced pressure to afford a pale brown solid. The solid was dried in vacuo to afford (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate as a brown solid (608 g, 76%). 1H NMR (500 MHz, DMSO, 27° C.) δ 3.77 (3H, s), 6.94 (1H, d), 7.66 (1H, d), 7.71 (2H, d), 10.20 (1H, s).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.[Ni]>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([OH:14])[CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Temperature: 0 °C
Reaction time: 5.25 h
Yield: 87.3 %

Procedure:
Dissolve (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (28.85 g, 135 mmol, prepared in example 10) in ethanol (75 mL) and treated with Raney nickel (1.85 g, 32 mmol, previously washed with water (2×50 mL) and ethanol (2×50 mL)). Charge the atmosphere with hydrogen at 50 psi (344.74 kPa) and shake the mixture. After 5.25 hours, filter the reaction. Cool the filtrate to 0° C. and treat with sodium borohydride (0.54 g, 14.3 mmol). After stirring for 2 hours, concentrate the solution under vacuum and distill the resulting oil by Kugelrohr distillation (40°-60° C., 1 mmHg) to provide the title compound (25.5 g, 87%) as a colorless oil, [α]20 =-3.9°, (c=0.99, chloroform); 1H NMR (CDCl3) δ4.4 (m, 1H), 4.3 (m, 1H), 3.03 (d, 1H, J=10.5 Hz), 1.9-1.6 (m, 6H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3) δ74.9, 74.1, 44.4, 34.2, 34.1, 25.8, 17.9, -4.9, -5.0; IR (neat) νmax 3405, 2957, 2932, 2888, 2858, 1256, 1091, 1069, 1038, 1026 cm-1 ; CIMS m/e (% relative intensity) 217 (M+H+ 81), 199 (M+H+ --H2O, 37) 67 (100). This (-)-enantiomer (title compound) could not be separated from the (+)-enantiomer (antipode) using the previously described chiral column.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([C:14]#[C:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:4][N:3]=1>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[N:8]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:6]=2[N:7]=1
Reactant: CCOC(C#Cc1cnc(Cl)nc1NC(CC)CC)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C(CC)CC
Temperature: 70 °C
Yield: 94.2 %

Procedure:
To a solution of [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-(1-ethyl-propyl)-amine (326 mg, 1 mmol) in THF (2 mL) is added IN TBAF in THF (5 mL, 5 mmol) at ambient temperature. The reaction mixture is heated at 70° C. for 2 h. After cooling down, the mixture is concentrated in vacuo and purified by BIOTAGE column (EtOAc/heptane 5:5 to 40:60) to give 307 mg of 2-chloro-6-diethoxymethyl-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow oil.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].[Cl:8][C:9]1[C:10](=O)[O:11][CH:12](O)[C:13]=1[Cl:14].C([O-])(=O)C.[Na+]>O>[Cl:8][C:9]1[C:10](=[O:11])[NH:6][N:7]=[CH:12][C:13]=1[Cl:14]
Reactant: NN
Reactant: O=C1OC(O)C(Cl)=C1Cl
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc(Cl)c1Cl
Yield: 55.7 %

Procedure:
Hydrazine sulfate (305.7 g, 2.35 mol) was added to a solution of 3,4-dichloro-5-hydroxy-5H-furan-2-one (419 g, 2.48 mol) and sodium acetate (212 g, 2.58 mol) in water (600 mL). The mixture was stirred at reflux for 4 h. After filtration and evaporation, the residual solid was recrystallized from ethanol to afford 4,5-dichloropyridazin-3(2H)-one (216 g, 67%) as an off-white solid. LC-MS 165 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CC(O)=O>CN1C(=O)CCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Yield: 81.7 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.574 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (123 mg, 0.574 mmol) and DIEA (0.150 mL, 0.862 mmol) in NMP (3 mL) was stirred at room temperature for 20 h. HOAc (0.3 mL) was added. Then, water was added to induce precipitation. The precipitate was collected, dried on vacuum to give tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (165 mg). A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (80 mg, 0.227 mmol), 3-(2H-1,2,3-triazol-2-yl)aniline (50 mg, 0.312 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (20 mg, 0.032 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated. The aqueous phase was extracted with EtOAc again. The combined organic phases were dried over Na2SO4, concentrated in vacuo to give a crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg). The crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg) was dissolved in TFA (4 mL). After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2S)-2-aminocyclohexylamino)pyrazine-2-carbonitrile (28 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:21])=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.[C:22](Cl)(Cl)=[O:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([N:17]=[C:22]=[O:23])=[CH:15][C:14]=2[Cl:21])=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:7]=1
Reactant: Nc1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1
Temperature: 105 °C

Procedure:
2 g (5.8 mmol) of 4-(3-chloro-5-difluoromethoxy-2-pyridyloxy)-3,5-dichloroaniline were dissolved in 25 ml of anhydrous toluene, 2.9 g (29 mmol) of phosgene gas were introduced at 0° C., and the mixture was slowly warmed to 105° C. Excess phosgene was expelled using inert gas, the solvent was concentrated by evaporation, and the residue was dried in a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH3:13][O:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[I-].[K+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:16][CH2:15][O:14][CH3:13]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc([N+](=O)[O-])ccc1OC
Temperature: 80 °C
Yield: 97.5 %

Procedure:
A mixture of 2-methoxy-5-nitrophenol (6 g, 35 mmol), 2-bromoethyl methyl ether (4 ml, 40 mmol), potassium carbonate (5.8 g, 40 mmol) and potassium iodide (0.5 g) in DMF (50 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool and poured into water (400 ml). The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4-methoxy-3-(2-methoxyethoxy)nitrobenzene (7.75 g, 98%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CC(C)OC(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(O)(=O)C>O>[OH:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[N:1]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1CCO
Temperature: 100 °C
Yield: 39.6 %

Procedure:
A flask containing 2-aminophenethyl alcohol (565 mg, 4.12 mmol), phthalic anhydride (641 mg, 4.32 mmol) and acetic acid (4 mL) was heated at 100° C. for 1 h. The reaction mixture was poured into water (30 mL) and the solid was filtered off and the solids were washed with water. The crude was purified by flash column chromatography to afford the desired product as white solid (435 mg, 1.63 mmol, 40%). 1H NMR: 1.79 (br s, 1H), 2.78 (t, 2H, J=6.4 Hz), 3.81 (t, 2H, J=6.4 Hz), 7.20 (d, 1H, J=8 Hz), 7.36-7.41 (m, 1H), 7.46 (d, 2H, J=4 Hz), 7.79-7.83 (m, 2H), 7.94-7.97 (m, 21-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8](F)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]([O:17]C(=O)C)([CH3:16])[CH3:15].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O.[OH-].[Li+].CCOC(C)=O>CN(C)C1C=CN=CC=1.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]([OH:17])([CH3:15])[CH3:16]
Reactant: C1CCNCC1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(S(=O)(=O)F)cc1Cl
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(O)C(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of N-[2-chloro-4-(fluorosulphonyl)phenyl]-2-acetoxy-2-methylpropanamide (Method B) (340 mg, 1 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and piperidine (0.1 ml, 1 mmol) in acetonitrile (5 ml) was heated under reflux for 18 h. After evaporation to dryness, the residue was dissolved in 1% aqueous ethanol (10 ml) and lithium hydroxide monohydrate (84 mg, 2 mmol) was added. The mixture was stirred for 2 h at ambient temperature, then EtOAc (25 ml) was added. The resulting solution was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography using 50% EtOAc/isohexane to yield the title compound as an oil (226 mg, 0.6 mmol). NMR: 1.4 (s, 6H), 1.5 (m, 6H), 2.9 (m, 4H), 6.2 (d, 1H), 7.7 (d, 1H), 7.8 (m, 1H), 8.6 (d, 1H), 9.8 (s, 1H); MS: 361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:29][CH:26]2[CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NC1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CC2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (500 mg, 1.4 mmol) and cyclopropyl amine (0.5 ml, 7 mmol) in DMF (5 ml), added PyBOP (730 mg, 1.4 mmol) then triethyl amine (0.4 ml, 3 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C18H20BN3O5S): 401.12. MS found (ESI negative): (M−H)−=400.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.84 (s, 1H), 8.14 (d, J=4 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.11 (dd, J=8.4 Hz, 1H), 6.43 (d, J=2 Hz, 1H), 6.36 (dd, J=8.4 Hz, 1H), 4.88 (s, 2H), 3.74 (s, 2H), 2.67 (m, 1H), 0.64 (m, 2H), 0.44 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.[CH3:26][C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>>[OH:31][C:27]([CH3:28])([CH3:26])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1CN1CCC(=O)C1)CCOc1ccc(Br)cc1-2
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CN3CCC(=O)C3)n1CCO2
Yield: 31 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((3-oxopyrrolidin-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a yellow solid (34.0 mg, 31%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:28](Cl)(=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38]>>[O:6]=[C:5]([N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:28](=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])=[CH:24][CH:25]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:27]
Reactant: C=CCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1ccc(C(F)(F)F)cc1
Product: C=CCCCCCCCCC(=O)Nc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Yield: 71 %

Procedure:
The same procedure as employed in the preparation of Example 15, step d using ethyl{(4-aminobenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate and undec-10-enoyl chloride gave the title compound as a colorless oil (71%). HPLC (Condition A), Rt: 6.7 min (HPLC purity: 99%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCOCC1>[O:17]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
This compound was prepared from trans-2-amino-1-cyclohexanecarboxylic acid (1.0 g, 7.0 mmol) by reacting it with sodium carbonate (1.48 g, 14.0 mmol) and 4-phenoxybenzenesulfonyl chloride (2.25 g, 8.38 mmol) in dioxane:water (40:20 mL) in the same manner as described in Example 1. This yielded 1.275 g (48%). The melting point was 192-194° C. Mass spectrometry revealed a molecular ion (MH)+ peak at m/z 376.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2I)=[CH:5][CH:4]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:21])[NH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CCNC(=O)c2ccccc2I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COc1ccc(Cc2c[nH]c(=O)c3ccccc23)cn1
Reaction time: 48 h

Procedure:
Under a N2 atmosphere, 2.04 g (5.17 mmol) of an (E/Z) mixture of 2-iodo-benzoic acid-[3-(6-methoxy-pyridin-3-yl)-allylamide], 1.53 g (5.17 mmol) of tetra-butylammonium chloride and 22 mg (0.1 mmol) of palladium diacetate are dissolved in 80 ml of DMF, then 1.8 ml (12.9 mmol) of trethylamine are added and stirring effected for 2 days at 110° C. Filtration is carried out, and the DMF is partially evaporated on a RE. The residue is dissolved with EtOAc and diluted Na2CO3 solution, the water phase separated and extraction effected twice more with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, methylene chloride/acetone 3:1), concentration by evaporation and stirring in petroleum ether yield 4-[(6-methoxy-pyridin-3-yl)-methyl]-2H-isoquinolin-1-one; m.p. 191° C.; HPLC(gradient20-100) tRef=13.0.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:10])[C:7]#[C:8][CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:10][CH2:6][C:7]#[C:8][CH3:9])(=[O:4])=[O:3]
Reactant: CC#CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
305 ml methanesulfonyl chloride was added dropwise to a solution of 138 g 2-butyn-1-ol and 683 ml triethylamine in 2.7 L methylene chloride under ice-cooling, and the mixture was stirred at 0° C. for 1 hour and 40 minutes. Ice was added to the reaction solution under ice-cooling, and this mixture was extracted with methylene chloride. The organic layer was successively washed with 1M aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine, and the organic layer was dried over magnesium sulfate. This organic layer was filtered and then the solvent was evaporated, to give a dark brown oil (280 g, 96%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:41])([C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[CH:14]([CH3:16])[CH3:15])=[CH:9][C:8]=1[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)(=O)=O.[C:51](=[NH:64])([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(=O)([O-])[O-]>C1(C)C=CC=CC=1>[C:52]1([C:51](=[N:64][C:7]2[C:8]([C:42]3[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=3)=[CH:9][C:10]([C:13]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:21]=3)([OH:41])[CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=2)[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(C)C(O)(c1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C(O)(c1ccc(N=C(c2ccccc2)c2ccccc2)c(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 85 °C
Reaction time: 16.5 h

Procedure:
To a solution of 4′-fluoro-5-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-yl trifluoromethanesulfonate (1.06 g), benzophenone imine (0.035 ml) and cecium carbonate (1.23 g) in toluene (15 ml) were added (RS)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (56.4 mg) and tri(dibenzylideneacetone)dipalladium(0) (27.7 mg), and the mixture was stirred at 80-90° C. for 26 h. (RS)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (112 mg) and tri(dibenzylideneacetone)palladium(0) (55.4 mg) were further added, and the mixture was stirred at 80-90° C. for 16.5 h, and at 105° C. for 3.5 h. The reaction mixture was filtered through Celite, and the filtrate was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent; hexane:ethyl acetate=5:1→1:1) to give the yellow amorphous title compound (115 mg).