Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([CH:14]=O)[CH:7]=[CH:6][C:5]1=2)=[N+:2]=[N-:3].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(OC)(OC)OC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[N:1]([C@@H:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([CH2:14][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:7]=[CH:6][C:5]1=2)=[N+:2]=[N-:3]
Reactant: C1CCNCC1
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 100 mL flame dry round bottom flask was added (R)-5-azido-5,6,7,8-tetrahydro-naphthalene-2-carbaldehyde (200 mg, 0.99 mmol), piperidine (0.5 mL, 5 mmol), dry DCM (10 mL), HOAc (1 drop), and CH(OMe)3. The resulting mixture was stirred under N2 for 3 h at RT. Then, NaBH(OAc)3 (632 mg, 2.98 mmol) was added and stirred for 20 h. The reaction mixture was quenched with 5% NaHCO3 and concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 (95% DCM:5% MeOH) to afford the title compound. MS (m/z): 271.2 (M+H) (Calc'd. for C16H22N4:270.37).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH2:8]([Li])CCC.[CH3:13][O:14][C:15](=[O:42])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH:36]([CH3:38])[CH3:37])=[C:27]([CH:39]=O)[C:26]=2[CH3:41])=[CH:19][CH:18]=1>O1CCCC1>[CH3:13][O:14][C:15](=[O:42])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]([CH3:32])([CH3:34])[CH3:33])[C:28]([O:35][CH:36]([CH3:38])[CH3:37])=[C:27]([C:39]#[CH:8])[C:26]=2[CH3:41])=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1
Reactant: [Li]CCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: C#Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 11.6 %

Procedure:
Anhydrous tetrahydrofuran (3 mL) was added to a 2M solution of trimethylsilyl diazomethane in hexanes (0.37 mL, 0.74 mmol) and the resulting reaction mixture was cooled to −78° C. A solution of 1.6M n-butyl lithium in hexanes (0.5 mL, 0.8 mmol) was added followed, after 30 minutes, by a solution of [4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 144, 0.2 g, 0.49 mmol) in anhydrous tetrahydrofuran and the resulting reaction mixture was stirred at −78° C. for 1 h and at 0° C. for 40 minutes. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 2.5–4% ethyl acetate in hexane as the eluent followed by preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase to afford the title product as a colorless oil (0.023 g, 11.6%).
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[C:11]1([CH2:17][O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])=[CH:24][C:20]=2[C:21]([OH:23])=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=C(N)C=1.C(Cl)CCl>CN(C)C=O.O>[C:11]1([CH2:17][O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:29])=[CH:24][C:20]=2[C:21]([NH:7][C:5]2[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=2)=[O:23])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: Nc1cccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Neat HOBT (94 mg, 0.62 mmol) was added in one charge to a stirred solution of 2-[(phenylmethyl)oxy]-5-(1-pyrrolidinylcarbonyl)benzoic acid (may be prepared as described in Description 55; 200 mg, 0.62 mmol), 3-pyridinamine (57.9 mg, 0.62 mmol) and EDC (118 mg, 0.62 mmol) in N,N-dimethylformamide (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water (50 ml). The precipitate was collected by filtration, washed with ether (5 ml), and dried to yield the title compound as a white solid. 88 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:9]=2[N:10]=[CH:11][N:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[CH2:16][CH2:15][NH:14][CH2:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2-c2ccccn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ncnc3c2CCNC3)nc1
Reaction time: 3 h
Yield: 83 %

Procedure:
To the product of Example 11, step a (157 mg, 0.50 mmol) in DCM (3 mL) was added TFA (1.00 mL). After stirring 3 h the mixture was concentrated in vacuo and loaded directly on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afford the desired product as a tan solid (89 mg, 83%). MS (ESI) mass calcd. C12H12N4, 212.11. m/z found 213.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.05 (s, 1H), 8.71 (s, 1H), 8.06-7.94 (m, 1H), 7.93-7.81 (m, 1H), 7.45-7.32 (m, 1H), 4.17 (s, 2H), 3.16 (s, 4H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([SH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(N(C)C)=O.C[O-].[Na+]>CO>[CH2:10]([S:24][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CCCCCCCCCCCCCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCCCCCCCCCCCCCSc1ccc(C(=O)O)s1

Procedure:
A mixture of 18.6 g (0.090 mole) of 5-bromo-2-thiophenecarboxylic acid, 25.0 g (0.109 mole) of 1-tetradecanethiol and 500 ml of dried dimethyl acetamide is stirred at room temperature after which 10.8 g (0.200 mole) of sodium methoxide is added. The mixture is heated and the methanol formed is allowed to distill off. The mixture is refluxed for 24 hours after which the mixture is cooled and poured into a water-ice mixture, acidified with 10% aqueous hydrochloric acid, filtered, and the precipitate washed with water and dried. The solid obtained is crystallized from the methanol then recrystallized from hexane to give 5-(tetradecylthio)-2 -thiophene carboxylic acid, M.P. 106°-108° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]([C:17]([OH:19])=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C[O:23][C:24]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Br>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([C:17]([NH:30][C:28]3[CH:27]=[CH:26][NH:25][C:24](=[O:23])[CH:29]=3)=[O:19])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:21]=1
Reactant: COc1cc(N)ccn1
Reactant: O=C(O)c1nc2ccccc2nc1Oc1ccc(F)cc1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(Nc1cc[nH]c(=O)c1)c1nc2ccccc2nc1Oc1ccc(F)cc1
Temperature: 100 °C
Yield: 8.9 %

Procedure:
A solution of 3-(4-fluorophenoxy)quinoxaline-2-carboxylic acid (42.6 mg, 0.15 mmol), 2-methoxypyridin-4-amine (22.3 mg, 0.18 mmol), HATU (62.7 mg, 0.16 mmol) and N-methylmorpholine (32.98 μL, 0.30 mmol) in NMP (0.5 mL) was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with water, brine, dried with Na2SO4, filtered through a short plug of silica and evaporated to dryness. The residue was taken up in HBr (0.5 mL of 33% w/v in acetic acid, 2.04 mmol) and heated at 100° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, evaporated and purified by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) and HCl as a modifier to give 3-(4-fluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)quinoxaline-2-carboxamide (35) (5.0 mg, 9%) as a pale yellow solid. ESI-MS m/z calc. 376.10, found 377.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[C:11]([C:15]1[N:19]([CH3:20])[N:18]([CH2:21][CH2:22][CH3:23])/[C:17](=[N:24]/[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2F)/[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([C:15]1[N:19]([CH3:20])[N:18]([CH2:21][CH2:22][CH3:23])/[C:17](=[N:24]/[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:27]=2[O:3][CH2:4][C@@H:5]2[CH2:6][CH2:7][C:8](=[O:10])[NH:9]2)/[CH:16]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Reactant: O=C1CC[C@@H](CO)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H]2CCC(=O)N2)cc(C(C)(C)C)n1C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
Sodium hydride (50 mg, 60% dispersion in mineral oil, 1.25 mmol) was added to a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (72 mg, 0.62 mmol) in dimethylformamide (0.5 mL). After 10 minutes a solution of Example 125A (0.12 g, 0.31 mmol) in dimethylformamide (1.0 mL) was added and the mixture stirred for 3 hours. The reaction mixture was partitioned between EtOAc (15 mL) and saturated NaHCO3 (1 mL). The organic extract was washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (hexanes:EtOAc:MeOH:Et3N (4:4:1:0.2) to afford the title compound (50 mg, 0.10 mmol, 33% yield). 1H NMR (500 MHz, Pyridine-d5) δ ppm 0.76 (t, J=7.5 Hz, 3H), 1.16 (s, 9H), 1.57-1.64 (m, 2H), 1.64-1.69 (m, 1H), 1.95-2.03 (m, 1H), 2.27 (ddd, J=16.9, 9.7, 7.3 Hz, 1H), 2.37-2.45 (m, 1H), 3.71 (s, 3H), 3.88 (t, J=9.3 Hz, 1H), 4.05-4.12 (m, 1H), 4.31 (t, J=7.3 Hz, 2H), 4.38 (dd, J=9.6, 3.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.64 (dd, J=8.5, 2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 9.25 (s, 1H); MS (ESI+) m/z 481.2 [M+H]+. Anal. calculated for C24H31F3N4O3: C, 59.99; H, 6.50; N, 11.66. Found: C, 59.81; H, 6.45; N, 11.52.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>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>[NH2:6][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[CH3:9]
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1N
Temperature: 100 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
[step 2] Under a nitrogen atmosphere, 4-bromo-6-methyl-2-nitroaniline (2.80 g, 12.1 mmol) obtained in step 1 was dissolved in DMF (60 mL), phenylboronic acid (4.40 g, 36.3 mmol), cesium carbonate (7.90 g, 24.2 mmol) and tetrakis(triphenylphosphine)palladium (1.40 g, 2.42 mmol) were added, and the mixture was stirred at 100° C. for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1) to give 4-amino-3-methyl-5-nitrobiphenyl (2.25 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH:15]=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]2[N:9]=[C:15]([C:14]3[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:12]([OH:11])[CH:13]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: Cc1c(Cl)cnc(N)c1N
Solvent: CN(C)C=O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc([N+](=O)[O-])c(O)c3)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
5-Chloro-4-methylpyridine-2,3-diamine (prepared by a method similar to Example 206a) (2.0 g, 12.7 mmol) was dissolved in DMF (40 ml) and heated to 100° C. 3-Hydroxy-4-nitrobenzaldehyde (2.10 g, 12.7 mmol) dissolved in DMF (10 ml) was added slowly (10 min). Air was bubbled through the reaction mixture. After 16 h, the DMF was evaporated off and the residue was purified by column chromatography (EtOAc/methanol, 10:1) giving the title compound (0.7 g, 18%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:32](=[O:34])=[O:33]>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[N:7]=[C:2]([CH2:1][C:32]([OH:34])=[O:33])[CH:3]=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: O=C=O
Reactant: Cc1cccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide (0.5 g, product of example 5) under an argon atmosphere in THF (5 mL) was cooled to −20° C. and treated dropwise at −20° C. with 1.54 mL of a 2 M solution of lithium diisopropylamide in THF/heptane/ethylbenzene (Fluka). The solution was stirred 1 h at −20° C., cooled to −70° C. and then treated with an access of dry ice. The mixture was allowed to warm to RT (1 h), partitioned between diluted aqueous HCl and AcOEt. The layers were separated, the aqueous layer extracted twice with AcOEt, the combined organic layers dried over Na2SO4, filtered and evaporated to give [6-(biphenyl-4-sulfonylamino)-pyridin-2-yl]-acetic acid as light yellow gum (0.779 g) that was used without further purification in the next step.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[CH:17][N:18]=2)[CH:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].O>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([I:1])=[CH:17][N:18]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1ccc2nccn2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2ncc(I)n2c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
10.7 g N-iodosuccinimide was added in divided portions to 100 mL solution of 9 g 6-bromoimidazo[1,2-a]pyridine in N,N-dimethylformamide, and the mixture was stirred for 2 hours. An aqueous sodium thiosulfate solution was added thereto and stirred for 1 hour, water was added thereto, and the formed crystals were collected by filtration. The product was recrystallized from tetrahydrofuran/ethanol to give 13.5 g of the title compound (colorless crystals).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[C:19]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[C:19]=4[N:27]4[N:31]=[CH:30][CH:29]=[N:28]4)=[O:22])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-n4nccn4)CC3C2)n1
Yield: 56.2 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (437.3 mg, 2.0 mmol), 3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (415 mg, 2.0 mmol), HATU (1.14 g, 3.0 mmol) and DIPEA (777 mg, 6.0 mmol) was stirred into DMF (20 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (2×500 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (basic system) to yield pure title compound (458.0 mg, 56%). MS (ESI) mass calcd. for C21H22FN7O, 407.45; m/z found 408.2 [M+H]+. 1H NMR (CDCl3): 7.79 (s, 2H), 7.52-7.45 (m, 1H), 7.36-7.28 (m, 1H), 7.25-7.22 (m, 1H), 6.30 (s, 1H), 3.82 (dd, J=11.6, 7.5, 1H), 3.75-3.66 (m, 2H), 3.58-3.41 (m, 4H), 3.13 (dd, J=10.9, 5.2, 1H), 3.02-2.87 (m, 2H), 2.36-2.24 (m, 6H).
Reaction SMILES: [C:1](/[C:3](=[C:9](\[C:18]1[C:19]([CH:24]([F:26])[F:25])=[N:20][N:21]([CH3:23])[CH:22]=1)/[NH:10][CH:11]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[CH3:12])/[C:4]([O:6]CC)=O)#[N:2].[CH2:27]([NH2:29])[CH3:28].[CH3:30][Al](C)C>C1(C)C=CC=CC=1>[C:1](/[C:3](=[C:9](\[C:18]1[C:19]([CH:24]([F:26])[F:25])=[N:20][N:21]([CH3:23])[CH:22]=1)/[NH:10][CH:11]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[CH3:12])/[C:4]([NH:29][CH:27]1[CH2:30][CH2:28]1)=[O:6])#[N:2]
Reactant: C[Al](C)C
Reactant: CCOC(=O)/C(C#N)=C(\NC(C)c1nccs1)c1cn(C)nc1C(F)F
Reactant: CCN
Solvent: Cc1ccccc1
Product: CC(N/C(=C(/C#N)C(=O)NC1CC1)c1cn(C)nc1C(F)F)c1nccs1
Yield: 54.2 %

Procedure:
A solution of ethyl (2Z)-2-cyano-3-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylate (0.122 g, 0.32 mmol, 1 eq.) in 3 ml of toluene was treated with ethylamine (1 M solution in tetrahydrofurane, 0.96 ml, 0.96 mmol, 3 eq.) and AlMe3 (1 M solution in toluene, 0.96 ml, 0.96 mmol, 3 eq.). The reaction was microwaved at 110° C. for 1800s (fixed hold, high absorption). The reaction was quenched with aqueous saturated NH4Cl and extracted with ethylacetate. The organic layers were combined and dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel to give (2Z)-2-cyano-N-cyclopropyl-3-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylamide (0.068 g, 51% yield) as a mixture of atropoisomers.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][NH:9][C:8](=[O:12])[CH:7]=1.CN(C)C=O.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.[I-].[K+]>C(N(CC)CC)C>[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:3][CH2:4][NH:5][C:6]4[CH:11]=[N:10][NH:9][C:8](=[O:12])[CH:7]=4)[CH2:30][CH2:31]3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=c1cc(NCCCl)cn[nH]1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1cc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)cn[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
2.72 g (12.9 millimoles) of 5-(2-chloroethylamino)-2H-pyridazine-3-one-hydrochloride, 11 ml of anhydrous dimethyl formamide, 5.0 g (22.7 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 6.3 ml of triethyl amine and 0.21 g of potassium iodide are admixed. The reaction mixture is heated to boiling under stirring for 8 hours, cooled to room temperature and filtered. To the mother lye a solution of 2.6 g of sodium hydrogen carbonate and 40 ml of water is added dropwise. The precipitate is filtered, suspended in 100 ml of dichloro methane, stirred for 30 minutes and filtered. The crude product is recrystallized from a 4:1 mixture of water and acetonitrile. The crystals are filtered off. Thus 2.98 g of the desired compound are obtained. Yield 64.6%. M.p.: 97–99° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]1(C)C[CH2:26][CH2:25][NH:24]1>>[CH2:23]([N:24]([CH2:25][CH3:26])[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:22]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CC1(C)CCCN1
Product: CCN(CC)c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 100 °C
Yield: 50 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 82 mg, 0.290 mmol) and 2,2-dimethylpyrrolidine (57.6 mg, 0.581 mmol; ChemBridge, San Diego, Calif.) and heating at 100° C. for 16 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided 2-(3-(diethylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (50% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (s, 6H) 1.96-2.06 (m, 4H) 2.87 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.85, 2.35 Hz, 2H) 3.78 (t, J=6.16 Hz, 2H) 6.95 (br. s., 1H) 7.07 (d, J=2.15 Hz, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.66 (dd, J=8.02, 1.17 Hz, 1H) 7.89-7.94 (m, 1H) 8.62 (s, 1H) 11.99 (br. s., 1H). MS (ESI, pos. ion) m/z: 362.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:35][CH3:36])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:33]=[O:34])[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[K+]>C1COCC1.O>[CH2:35]([C:6]1([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[CH:14][C:15]([C:18]3[CH:19]=[C:20]([CH:33]=[O:34])[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:16][N:17]=2)[CH2:8][CH2:7]1)[CH3:36]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(C=O)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(C=O)c2s1
Yield: 63.4 %

Procedure:
Ethyl-4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-formyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (1.75 g, 3.43 mmol) was dissolved in THF (60 mL) and MeOH (125 mL) and an aqueous solution of KOH (125 mL; 1 mol/L) was introduced and refluxed overnight. After this period the mixture was diluted with water (150 mL), washed with Et2O/EtOAc (1:1, 100 mL) and the residual aqueous acidified to pH 1 (3M HCl) and back extracted with EtOAc (3×100 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo affording 1.05 g (64% yield) of the product as a light yellow solid after flash column chromatography on silica gel (0-10% DCM/MeOH). 1HNMR (CDCl3): δ 10.16 (s, 1H), 8.56 (d, J=20.7 Hz, 2H), 7.95 (d, J=1.5 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 4.51 (d, J=13.9 Hz, 2H), 3.39-3.32 (m, 2H), 3.26-3.15 (m, 2H), 2.20 (d, J=13.4 Hz, 2H), 1.59 (q, J=7.5 Hz, 2H), 1.48-1.34 (m, 2H), 1.21 (t, J=7.2 Hz, 3H), 0.87 (t, J=7.5 Hz, 3H). MS: 483.1 [M+H]+.