Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH3:30])=[CH:28][CH:27]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CN(C)CCc1ccc(N)cc1
Product: CN(C)CCc1ccc(NC(=O)/C=C/c2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 172 starting from (E)-3-(4′-chloro-biphenyl-4-yl)-acrylic acid and 4-(2-dimethylamino-ethyl)-phenylamine.
Reaction SMILES: [CH:1]1([C:4]2[C:5](OS(C(F)(F)F)(=O)=O)=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC.CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:1]1([C:4]2[C:5]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)c(C2CC2)cc1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccccn2)c(C2CC2)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A mixture of methyl 5-cyclopropyl-2-ethoxy-4-(((trifluoromethyl)sulfonyl)oxy)benzoate (2.5 g), 2-(tributylstannyl)pyridine (3.75 g), tetrakis(triphenylphosphine)palladium (0.784 g), and DMF (20 mL) was stirred overnight at 100° C. The reaction mixture was poured to water, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (480 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:24])[CH2:26][CH2:27]2)[C@@H:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a solution of (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, mmol) and N-benzyloxycarbonyl-4-piperidone (1.2 g, 5 mmol) in methanol (8 mL) was added acetic acid (0.28 mL) and the solution was stirred at RT for 1 h. Sodium cyanoborohydride (310 mg, 5 mmol) was added and the reaction mixture was stirred at 45° C. overnight and then 1 N NaOH (5 mL) was added. The aqueous phase was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, concentrated under vacuum, and purified by silica gel chromatography (0-5% MeOH/DCM). Pure fractions were combined and concentrated under vacuum to provide the title intermediate (0.71 g, 30% yield) as a clear oil. (m/z): [M+H]+ calcd for C23H35N3O4 418.26 found 418.1.
Reaction SMILES: C([C:3]1[C:11]([N+:12]([O-])=O)=[C:10]([CH:15]=[CH:16][C:17]([O:19]C)=O)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])C.[C:21](O)(=O)[CH3:22]>[Pd]>[O:19]=[C:17]1[CH2:16][CH2:15][C:10]2[C:11](=[CH:3][C:4]([C:5]([O:7][CH2:21][CH3:22])=[O:6])=[CH:8][CH:9]=2)[NH:12]1
Reactant: CC(=O)O
Reactant: CCc1c(C(=O)O)ccc(C=CC(=O)OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: CCOC(=O)c1ccc2c(c1)NC(=O)CC2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The solution of 2.80 g of ethyl 4-(2-methoxycarbonylvinyl)-3-nitrobenzoic acid in 20 ml of glacial acetic acid is hydrogenated in the presence of 0.288 g of 10% Pd/C at room temperature over 16 hours. The reaction mixture is stirred at 70° C. over 1 hour and subsequently concentrated by evaporation to dryness. The residue is admixed with 250 ml of 1M sodium hydrogencarbonate and extracted with ethyl acetate (2×250 ml). The organic phases are washed with water (250 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of crystallization (ethyl acetate-hexane). Rf=0.24 (1:1 EtOAc-heptane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[N:22]=[CH:23][CH:24]=[N:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1c[nH]nn1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1nccn1

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.15 g, 0.57 mmol) and 1,2,3-triazole (0.037 mL, 0.63 mmol) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:5](OC)=[O:6].O.[NH2:39][NH2:40]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:39][NH2:40])=[O:6])[CH:9]=[CH:10][C:11]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)C(C)(C)C)CC(C)(C)O3)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=O)NN)cc3Cl)nc2O1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (22 mmol) and 2.0 mL of hydrazine hydrate in 10 mL of CH3OH was refluxed for 10 h. After cooling to rt, the reaction mixture was concentrated to give the product, which was taken into the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:19]([NH:22][C:23]([NH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1)=[O:24])[CH2:20][CH3:21]
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1N
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCNC(=O)Nc1nn(Cc2ccccc2)cc1C(=O)OCC
Yield: 48 %

Procedure:
Sodium (1.9 g) was dissolved in anhydrous ethanol (100 ml) to prepare a solution of sodium ethoxide. To this, were added 3-amino-4-ethoxycarbonylpyrazole (12.4 g) and benzyl chloride (10 g), and the resulted mixture was refluxed for 1 h. After filtration of the hot mixture, the filtrate was concentrated to quarter volume, and cooled to crystallize. The crude product was recrystallized from an ether-water mixture to give 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (10.7 g, yield 44%). To a solution of 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (0.2 g) in dried toluene (30 ml), were added propyl isocyanate (0.307 ml) and triethylamine (0.11 ml), and the mixture was refluxed in a sealed tube for 8 h. The reaction mixture was evaporated under reduced pressure followed by silica-gel column chromatography (toluene : ethyl acetate=20:1) to give the title compound (0.129 g, yield 48%). 1H-NMR (CDCl3) δ ppm: 0.92 (3H, t, J=7Hz, CH2CH2CH3 ), 1.32 (3H, t, J=7Hz, COOCH2CH3 ), 1.57 (2H, 6th, CH2CH2CH3), 4.28 (2H, q, J=7Hz, COOCH2CH3), 5.14 (2H, s, CH2 --Ph), 7.25 (5H, m, CH2 --Ph), 7.91 (2H, brs, NH), 8.00 (1H, s, C5-H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccnc(Br)c1

Procedure:
A mixture of 2-bromo-4-methylpyridine (12.2 g), N-bromosuccinimide (30 g) and 2,2′-azobis(2-methylpropionitrile) (100 mg) in carbon tetrachloride (200 ml) was heated at reflux for 2.5 hours. The mixture was allowed to cool and the insoluble material removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by filtration through a silica pad eluting with ethyl acetate/hexane (10/1) to give 2-bromo-4-bromomethylpyridine.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][C@H:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH2:24][CH3:25].O>CN(C=O)C>[CH2:23]([NH:1][C@@H:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][C@H:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:24][CH3:25]
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@H]1N)OCCO2
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Temperature: 50 °C
Yield: 96.4 %

Procedure:
Ethyl 8-amino-trans-1,4-dioxaspiro[4.5]decane-7-carboxylate (118.0 g, 0.52 mole) was dissolved in DMF (1 l) and potassium carbonate (107 g, 0.77 mole) and propyl bromide (158.4 g, 1.3 mole) were added. The mixture was heated to 50° C. for three hours, then poured into water, and the hydrogen ion concentration was adjusted to pH 10. The product was extracted with methylene chloride, dried and evaporated to give 136 g of a dark orange oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH3:29])[C:6]([C:9]3[CH:10]=[C:11]([CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=4)[CH:21]=3)[C:12]([O:14]C(C)(C)C)=[O:13])=[N:7][N:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.Cl>CO>[CH:1]1([C:4]2[N:5]([CH3:29])[C:6]([C:9]3[CH:10]=[C:11]([CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=4)[CH:21]=3)[C:12]([OH:14])=[O:13])=[N:7][N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(-c3nnc(C4CC4)n3C)c2)nc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3nnc(C4CC4)n3C)c2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-(5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)-5-(5-methylpyridin-2-yl)benzoate (0.38 g, 0.97 mmol) in methyl alcohol (10 mL) was added trifluoroacetic acid (5.0 mL, 67.3 mmol) and hydrogen chloride (4.0 M in dioxane; 5.0 mL, 20.0 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated and dried under reduced pressure gave the hydrochloride salt of the title compound. MS 335.1 (M+1).
Reaction SMILES: [C:1]([CH:3]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[N:2].[O-]CC.[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:3]1([C:1]#[N:2])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:27]
Reactant: N#CC1c2ccccc2Cc2ccccc21
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1(C#N)c2ccccc2Cc2ccccc21
Yield: 70.2 %

Procedure:
9-Cyano-9,10-dihydroanthracene [2] (1.25 g, 6.09 mmol) was added to sodium ethoxide prepared from Na (0.196 g, 8.53 mmol) and EtOH (10 mL) and heated at reflux (1 hr). The solution was then cooled in an ice bath and ethyl bromoacetate (1.42 g, 8.53 mmol) was added drop wise via a syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 1.245 g (70%) of the product as a colorless oil, which crystallized on prolonged standing: mp 69-70° C. (EtOAc-pet. ether). 1H NMR (CDCl3)d: 1.10-1.15 (t, J=7.5 Hz, CH3), 2.85 (s, 2H, CH2), 3.97-4.14 (m, 4H, CH2), 7.33-7.89 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 14.53, 35.27, 46.05, 46.28, 61.63, 121.89, 127.58, 127.70, 128.93, 134.21, 135.10, 167.96
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:10][CH2:11][C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:7][CH2:8][O:9][C:12](=[O:13])[CH2:11][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CS)OCCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser, hot plate (with magnetic stirring apparatus included within) and spin bar are placed 12.2 grams of phenylethyl alcohol; 23.0 grams mercaptoacetic acid; and 0.5 grams of para-toluene sulphonic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:42][CH2:41][C:39]1[N:40]=[C:36]([C:32]2[CH:31]=[C:30]([C:29]3[CH2:28][C:27](=[O:50])[NH:20][C:9]4[CH:10]=[C:11]([CH3:19])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[O:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-methyl-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.21 g) (Example J24) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K11) (0.31 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.16 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[OH:15]O>C(O)(=O)C>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:15])[CH:3]=1
Reactant: Cc1cncc2cc([N+](=O)[O-])ccc12
Reactant: OO
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])cc2cc([N+](=O)[O-])ccc12

Procedure:
A solution of 4-methyl-7-nitroisoquinoline (400 mg), and 30% hydrogen peroxide (0.65 ml) in acetic acid (2 ml) was refluxed for 3.5 hours. After removal of the solvent, the residue in ether (50 ml) was stirred to give yellow powder. The powder was collected and washed with ether and dried to give 4-methyl-7-nitroisoquinoline N-oxide (360 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Br)cc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Br)cc3)cc21

Procedure:
Prepared analogously to Example 2, from 6-[4-(4-bromo-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-methyl-4-nitrobenzoic acid suspended in CH2Cl2 under Ar was added DMF then oxalyl chloride. The reaction was stirred at room temperature 1.5 hours then the solvent was evaporated. The residue was dissolved in THF and ammonia gas was bubbled through the reaction for 15 minutes. The solvent was evaporated and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 2-methyl-4-nitrobenzamide (E111).
Reaction SMILES: [ClH:1].C(OC(=O)[N:8]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)[CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:21]=2[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1)(=[O:14])=[O:13])(C)(C)C>CO.ClCCl>[ClH:1].[ClH:1].[N+:40]([C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][CH2:31][NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]2[C:16]3[CH:17]=[CH:18][N:19]=[CH:20][C:21]=3[CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:24]=2)(=[O:14])=[O:13])=[CH:35][CH:36]=1)([O-:42])=[O:41]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCCNCCNS(=O)(=O)c2cc(-c3ccccc3)cc3cnccc23)cc1

Procedure:
Bubble gaseous HCl through a solution of [3-(4-Nitro-phenyl)-propyl]-[2-(7-phenyl-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (1.9 g, 2.9 mmol) in methanol/dichloromethane (1:1) with cooling for 15 minutes. Remove the solvent under reduced pressure to afford the title compound as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH:12][CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(CC)CC)C.[Br:26][C:27]1[C:28](Cl)=[N:29][C:30]([Cl:33])=[N:31][CH:32]=1>C(Cl)Cl>[Br:26][C:27]1[C:28]([N:12]([CH2:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])=[N:29][C:30]([Cl:33])=[N:31][CH:32]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)CCNCc1cc(OC)cc(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)CCN(Cc1cc(OC)cc(OC)c1)c1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
3-[(3,5-dimethoxyphenyl)methylamino]-N-methyl-propanamide (Intermediate 98; 1 g, 3.96 mmol) was dissolved in DCM (10 mL) and triethylamine (0.68 mL, 4.36 mmol). 5-bromo-2,4-dichloropyrimidine (Aldrich; 993 mg, 4.36 mmol) was added and the mixture stirred at room temperature for 18 hours. The mixture was diluted with DCM and washed with water, brine, dried (MgSO4), filtered and evaporated to give a yellow gum which was purified on a 40 g ISCO companion eluting with 50-70% ethyl acetate in iso-hexane to give the title compound as a white solid (461 mg, 26%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[N:17]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[CH2:28][CH:24]2[CH:23]=[CH:22]3)[C:18]1=[O:19].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][N:17]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[CH2:28][CH:24]2[CH:23]=[CH:22]3)[C:18]1=[O:19])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1C2C3C=CC(C3)C2C(=O)N1OS(=O)(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of trifluoromethanesulfonic anhydride (6.5 g, 23 mmole) in methylene chloride (20 ml), a solution of N-hydroxy-bicyclo[2,2,1]-hept-5-ene-2,3-dicarboximide (3.6 g, 20 mmole) and pyridine (1.6 g) in methylene chloride (10 ml) was added dropwise at 0°-5° C. and continued to stir for 15 minutes at the same temperature. The reaction mixture was washed with H2O (20 ml×3), dried over anhydrous MgSO4 and evaporated. The residue was recrystallized from ethanol to give 6.1 g of N-trifluoromethanesulfonyloxy-bicyclo-[2,2,1]-hept-5-ene-2,3-dicarboximide as white needles. m.p. 89°-90° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](O)=[O:34])[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:34])[NH:45][CH2:44][C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)cc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a mixture of 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (21 mg, 0.042 mmol) and (4-fluorophenyl)methanamine (10.52 mg, 0.084 mmol) in DMF (1 mL) was added DIEA (0.037 mL, 0.210 mmol), HATU (32.0 mg, 0.084 mmol) and DMAP (1.027 mg, 8.41 μmol) and the resulting mixture was stirred at rt for 16 h. At this point LCMS indicated completion of reaction. The reaction mixture was then filtered and purified by prep HPLC to afford (2S)-ethyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-((4-fluorobenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (12 mg, 0.020 mmol, 47.1% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 7.34-7.30 (m, 2H), 7.23 (t, J=6.4 Hz, 1H), 7.20 (s, 1H), 7.06-6.99 (m, 2H), 6.85 (d, J=10.7 Hz, 1H), 4.96 (s, 1H), 4.67-4.53 (m, 2H), 4.35 (t, J=5.3 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 2.79 (s, 3H), 2.76 (t, J=6.6 Hz, 2H), 2.24-2.14 (m, 2H), 1.82 (s, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.17 (s, 9H). LCMS (M+H)=607.4.