Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C=C)[C:11]([C:16](F)(F)F)=[CH:10][C:9]=1[NH:20][C:21](=[O:38])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.[C:40](O)([C:42]([F:45])([F:44])[F:43])=O>C(Cl)Cl>[CH3:37][C:33]1[CH:32]=[C:31]([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:38])[NH:20][C:9]4[CH:10]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:12]([CH:11]=[CH2:16])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH:36]=[CH:35][N:34]=1
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example M224) (300 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (133 mg, 56%).
Reaction SMILES: [BrH:1].[CH2:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)[CH3:3].O>CC(O)=O>[CH2:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:1])=[CH:6][CH:5]=1)[CH3:3]
Reactant: Br
Reactant: CCc1ccc(CO)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
35 ml of a 33% solution of HBr in AcOH are cooled to 0° C., 5 g of 4-ethylbenzyl alcohol are added dropwise and the reaction mixture is stirred for 30 minutes at 0° C. and then overnight at RT. It is poured into 200 ml of iced water, the mixture is extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO3 solution and with saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated off under vacuum to give 5.6 g of the expected product.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.CN([CH:16]=[O:17])C>CCOC(C)=O>[C:1]([C:5]1[O:9][N:8]([CH2:2][C@H:1]2[CH2:5][CH2:6][CH2:16][O:17]2)[C:7](=[NH:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1cc(=N)n(C[C@H]2CCCO2)o1
Temperature: 85 °C
Reaction time: 70 h
Yield: 17 %

Procedure:
A mixture of 5-tert-butylisoxazol-3-amine (1 g, 7.1 mmol) and a solution of Example 39A (1.7 g, 6.8 mmol) in 1.5 mL DMF was warmed to 85° C. and was allowed to stir for 70 hours at 85° C. The mixture was cooled to ambient temperature, concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50% hexanes in EtOAc then 10% CH3OH in EtOAc) to afford the title compound (0.48 g, 1.2 mmol, 17% yield). MS (DCI/NH3) m/z 225 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]O)[CH2:25][CH2:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([O:14][CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: OCCN1CCOCC1
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (55 mg, 0.18 mmol), 2-morpholinoethanol (47 mg, 0.36 mmol), and polymer-bound PPh3 (3.0 mmol/g, 167 mg, 0.50 mmol) in 1 mL of THF at room temperature was added DIAD (72 mg, 0.36 mmol). The mixture was stirred for 1 h and HPLC analysis indicated most of the starting material disappeared. The polymer was filtered off through Celite® and the filtrate was concentrated and purified by preparative HPLC to afford the title compound (50 mg, 67%). MS(ESI+) m/z 418.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O.C(OCC)(=O)C>[Si:16]([O:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: C=C(C(=O)OCC)C(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C(=O)OCC)C(C)O[Si](C)(C)C(C)(C)C
Reaction time: 10 h
Yield: 95.5 %

Procedure:
To a suspension of ethyl 2-(1-hydroxyethyl)acrylate (40 g) and imidazole (28.3 g) in N,N-dimethylformamide (200 ml)was added portionwise t-butyldimethylsilyl chloride (46 g) at 0° C. After the mixture was stirred for 10 hours, the reaction mixture was poured into a mixture of water and ethyl acetate. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with water, 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The evaporation of the solution gave ethyl 2-[1-(t-butyl-dimethylsilyloxy)ethyl]acrylate (68.5 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH:3]=[CH2:4].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.[BH4-].[Na+]>CO>[CH2:1]([C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH2:7][NH:17][CH:14]1[CH2:16][CH2:15]1)[CH2:2][CH:3]=[CH2:4]
Reactant: NC1CC1
Reactant: C=CCCc1cc(F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCc1cc(F)ccc1CNC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
A mixture of 2-(but-3-en-1-yl)-4-fluorobenzaldehyde (50 mg, 0.281 mmol) and cyclopropanamine (16.02 mg, 0.281 mmol) in MeOH (2 mL) was stirred at rt for 30 min. Sodium borohydride (5.31 mg, 0.140 mmol) was added and stirred at rt for 1 h. It was then quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 25% EtOAc/hexane to isolate N-(2-(but-3-en-1-yl)-4-fluorobenzyl)cyclopropanamine (20 mg, 0.091 mmol, 32.5% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J=8.3, 6.1 Hz, 1H), 6.93-6.82 (m, 2H), 5.95-5.84 (m, 1H), 5.13-5.00 (m, 2H), 3.83 (s, 2H), 2.81-2.75 (m, 2H), 2.41-2.33 (m, 2H), 2.18 (tt, J=6.6, 3.5 Hz, 1H), 0.51-0.44 (m, 2H), 0.43-0.35 (m, 2H).
Reaction SMILES: [CH2:1]1[C@@H:3]([NH2:4])[C@@H:2]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.Br[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.O1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[N+:27]([C:26]1[C:21]([NH:4][CH2:3][C:2]2([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:1][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:22][CH:23]=[CH:24][CH:25]=1)([O-:29])=[O:28]
Reactant: C1CCOC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Br
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccnc1NCC1(c2ccccc2)CCCCC1
Temperature: 60 °C

Procedure:
A solution of compound 1 (1.21 g; 6.39 mmol) in anhydrous tetrahydrofuran (30 mL) was treated with N,N-diisopropylethylamine (1 mL; 5.73 mmol) and 2-bromo-3-nitro-pyridine (1.18 g; 5.81 mmol). The reaction mixture was heated at 60° C. for 21 h. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate and 10% aqueous hydrochloric acid. The organic layer was separated, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The product was purified by recrystallization from a minimum amount of ethyl acetate to provide 1.3 g of (3-nitro-pyridin-2-yl)-(1-phenyl-cyclohexylmethyl)-amine as light tan solid. Mass Spec [M+H]+=312.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](Cl)=[C:11]2[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:11]2[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2c1c(Nc1ccccc1)nn2Cc1ccccc1
Solvent: CCO
Product: c1ccc(Cn2nc(Nc3ccccc3)c3c(Nc4ccccc4)ncnc32)cc1

Procedure:
1 g of 1-benzyl-4-chloro-3-phenylamino-pyrazolo[3,4-d]pyrimidine is suspended in 8 ml of ethanol; 27 ml of aniline are added thereto and, under nitrogen, the reaction mixture is heated under reflux for 2.5 hours until, according to thin-layer chromatography, all the starting material has disappeared. The reaction mixture is concentrated to dryness by evaporation, the residue is suspended in water and the pH is adjusted to pH 8.5-9 with 0.1N NaOH. Extraction is then carried out with ethyl acetate and the ethyl acetate phase is then dried and concentrated by evaporation. The crude product is chromatographed on silica gel, mixtures of toluene/ethyl acetate being used as eluant. Product-containing column fractions are stirred with cyclohexane/hexane, yielding colorless crystals of 1-benzyl-3,4-diphenylamino-pyrazolo[3,4-d]pyrimidine; FAB-MS: (M+H)+ =393 (C24H20N6).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCNC1
Yield: 9.9 %

Procedure:
A mixture of 101.5 g (0.37 mole) of 1,1-dimethylethyl [1-(phenylmethyl)-3-pyrrolidinyl]carbamate, 5.0 g of 20% Palladium on carbon and 1 liter of tetrahydrofuran was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtering through Celite, and the filtrate was concentrated in vacuo to give 6.8 g of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate which solidified upon standing and was of sufficient purity to be used as is for the ensuing steps.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[O:14]=[C:15]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:33](=[O:34])[CH2:32][N:16]3[CH2:17][CH2:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:15]3=[O:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)nc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(c2ccc(Cl)cn2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(5-chloropyridin-2-yl)piperazine (0.037 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (2 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 8.12 (dd, J=2.6, 0.7 Hz, 1H), 7.45 (dd, J=9.0, 2.7 Hz, 1H), 7.18-7.38 (m, 10H), 6.54 (dd, J=9.1, 0.7 Hz, 1H), 4.24 (s, 2H), 3.67-3.72 (m, 2H), 3.54 (t, J=6.6 Hz, 2H), 3.51-3.56 (m, 2H), 3.44-3.50 (m, 2H), 3.36-3.42 (m, 2H), 2.82 (t, J=6.6 Hz, 2H); MS (ESI+) m/z 475 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][O:4]1.N1C=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)(Cl)Cl>[O:9]=[C:7]1[CH2:6][CH2:5][O:4][CH:3]([CH2:2][O:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH2:8]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCOC(CO)C1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CCOC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of 2-hydroxymethyl-tetrahydro-pyran-4-one (625 mg, 4.81 mmol) in a mixture of pyridine (778 μl, 9.62 mmol) and chloroform (6.0 ml) at 0° C. under nitrogen was slowly added 4-nitrobenzenesulfonyl chloride (1.60 g, 7.22 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h. Chloroform (30 ml) was added and the solution washed with 2.0 N hydrochloric acid (3×10 ml), 5% NaHCO3 (3×10 ml) and water (3×10 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated in vacuo. The solid residue was purified by column chromatography on silica gel using a gradient of dichloromethane:hexane:ethyl acetate (1:1:0 to 8:0:2) as eluent. Pure fractions were collected and the volatiles were evaporated in vacuo affording 0.98 g (65%) of 4-nitro-benzenesulfonic acid 4oxo-tetrahydro-pyran-2-ylmethyl ester as a solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@:13]([C:16]#[CH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][C:28](OC(C)=O)=[O:29]>N1C=CC=CC=1>[C:28]([O:15][CH2:14][C@@:13]1([C:16]#[CH:17])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10][C@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])(=[O:29])[CH3:27]
Reactant: C#C[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 11 h
Yield: 94.9 %

Procedure:
To a pyridine (4 mL) solution of 10a (161 mg, 0.423 mmol) was added Ac2O (120 mL, 1.269 mmol) at 0° C., and the mixture was stirred at room temperature for 11 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (60 mL×3/20 mL). Silica gel column chromatography (hexane/EtOAc=3/1) of the organic layer gave 11 (169.7 mg, 95%) as a foam: UV (MeOH):λmax 266 nm (ε9200),λmin 234 nm (E2000); 1H NMR(CDCl3)δ0.10 and 0.14 (6H, each as s, SiMe), 0.90 (9H, s, SiBu-t), 1.90-1.94 (4H, m, H-2′a and Me), 2.14 (3H, s, Ac), 2.58 (1H, s, ethynyl), 3.01 (1H, ddd, Jgem=14.8 Hz, J1′,2′b=8.3 Hz and J2′b,3′=5.0 Hz, H-2′b), 4.37 (1H, d, Jgem=11.1 Hz, H-5′a), 4.45 (1H, d, J2′b,3!=5.0 Hz, H-3′), 4.53 (1H, d, Jgem=11.1 Hz, H-5′b), 6.40 (1H, dd, J1′,2′a=2.8 Hz and J1′,2′b=8.3 Hz, H-1′), 7.53 (1H, d, J6,Me=1.3 Hz, H-6), 8.04 (1H, br, NH); FAB-MS m/z 461 (M++K). Anal. Calcd for C20H30N2O6Si: C, 56.85; H, 7.16; N, 6.63. Found: C, 56.84; H, 7.35; N, 6.26.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][CH:22]([F:24])I>CN(C=O)C>[F:21][CH:22]([F:24])[O:13][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: FC(F)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC(F)F)c1
Temperature: 25 °C

Procedure:
To a cooled solution of 1 g of methyl-3-hydroxy-4-nitrobenzoate, 3.31 g of cesium carbonate in 20 mL of DMF, was carefully added 1.5 equivalents of difluoroiodomethane. The reaction was allowed to warm to room temperature and followed by TLC. Upon completion of the reaction, the mixture was concentrated and purified by silica get chromatography to give 1.2 g of methyl 3-(difluoromethoxy)-4-nitrobenzoate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:31]=[C:30]([C:32]([NH:34][NH2:35])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:35][NH:34][C:32]([C:30]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([Cl:21])[CH:31]=3)=[O:33])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1Cl
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1Cl
Temperature: 0 °C
Yield: 85.2 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.568 mmol, 154.8 mg) synthesized in Synthetic Example 3, methyl 2-chloro-4-hydrazinocarbonylbenzoate (0.568 mmol, 130.0 mg) synthesized in Reference Synthetic Example 41 and p-tosylic acid monohydride (30 mol %, 29.4 mg) were dissolved in isopropyl alcohol (15 mL) and stirred under heating with reflux for 8 hours, and the reactor was cooled to 0° C. The reaction solution was filtered and dried by means of a vacuum pump to give the desired product as a white solid (233.7 mg, yield 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1.[CH3:28]C1N=C(CO)C=CC=1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Reactant: Cc1cccc(CO)n1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cccc(C)n4)nn23)on1

Procedure:
The title-compound was prepared from the product of Example 120, step a, and 6-methyl-2-pyridylcarbinol using the procedure given for Example 1, 1H NMR (360 MHz, CDCl3) δ 2.48 (3H, s, CH3), 2.64 (3H, s, CH3), 5.74 (2H, s, CH2), 7.07 (1H, s, Ar—H), 7.18 (1H, d, J=7.7 Hz, Ar—H), 7.44 (1H, d, J=7.6 Hz, Ar—H), 7.69 (1H, t, J=7.7 Hz, Ar—H), 7.85 (1H, m, Ar—H), 7.99 (1H, m, Ar—H), 8.35 (1H, d, J=8.6 Hz, Ar—H), 8.71 (1H, d, Ar—H); MS (ES+) m/e 373 [MH]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52]1>CN(C=O)C>[CH3:50][N:51]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cnn(C)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 69.7 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 71% yield: LCMS (ESI) m/z 376 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.Br.[NH2:14][C@@:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:14]([C@@:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:10]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: C[C@]1(N)CCC(=O)NC1=O
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@]1(N2C(=O)c3ccc(Br)cc3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
A mixture of 4-bromophthalic anhydride (7.53 g, 33.2 mmol), (3S)-3-amino-3-methyl-piperidine-2,6-dione hydrobromide (8.00 g, 44.1 mmol) and sodium acetate (2.72 g, 33.2 mmol) in acetic acid (150 mL) was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was stirred in water (170 mL) for 3 hours, and the resulting solid was filtered, washed with additional water (80 mL), and dried, to afford 6.3 g of 5-bromo-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione, in 54% yield; 1H NMR (DMSO-d6) δ 1.89 (s, 3H), 2.01-2.09 (m, 1H), 2.53-2.73 (m, 3H), 7.79 (dd, J=5.7 Hz, J=2.7 Hz, 1H), 8.06 (m, 2H), 11.04 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.5, 29.0, 58.9, 124.9, 125.9, 128.3, 130.0, 133.0, 137.4, 166.6, 167.2, 172.0, 172.1.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.[CH3:16][C:17]([NH2:25])([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:18].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.C(Cl)Cl>[CH3:15][C:3]1[C:2]([NH:25][C:17]([CH3:18])([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:16])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12](=[O:14])[CH3:13])[N:4]=1
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Reactant: CC(C)(N)CCS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(=O)c1cccc2nc(C)c(NC(C)(C)CCS(C)(=O)=O)nc12
Yield: 100.1 %

Procedure:
A solution of 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g, 300 mg, 1.469 mmol), 2-methyl-4-(methylsulfonyl)butan-2-amine (338b, 486 mg, 2.94 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.02 mL, 5.88 mmol) in NMP (2.94 mL) was stirred at 120° C. for 16 h when product and a small amount of hydrolysis were observed via lcms. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (3×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 2% 2 M NH3 in MeOH/DCM to give 1-(2-methyl-3-((2-methyl-4-(methylsulfonyl)butan-2-yl)amino)quinoxalin-5-yl)ethanone (338c, 513 mg, 1.47 mmol, 100% yield) as a red oil contaminated with NMP. 1H NMR (400 MHz, CDCl3) δ ppm 1.56 (s, 6H) 2.56 (s, 3H) 2.62-2.68 (m, 2H) 2.78 (s, 3H) 2.83 (s, 3H) 2.94-3.01 (m, 2H) 4.82 (s, 1H) 7.40 (dd, J=8.12, 7.34 Hz, 1H) 7.70 (dd, J=7.34, 1.47 Hz, 1H) 7.92 (dd, J=8.12, 1.47 Hz, 1H). MS (ESI, pos. ion) m/z: 350.2 (M+1).