Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[NH2:3][C@@H:4]([CH2:13][CH2:14][CH2:15][N:16]1[C:24]([S:25][C:26]2[C:34]([I:35])=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:36])[C:5]([O:7]C1CCCC1)=[O:6].O>O1CCCC1.O.C(O)(=O)C>[NH2:3][C@@H:4]([CH2:13][CH2:14][CH2:15][N:16]1[C:24]([S:25][C:26]2[C:34]([I:35])=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:36])[C:5]([OH:7])=[O:6]
Reactant: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCO3)n2CCC[C@H](N)C(=O)OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCO3)n2CCC[C@H](N)C(=O)O
Reaction time: 12 h
Yield: 34.1 %

Procedure:
Lithium hydroxide (2.88 mg, 0.12 mmol) was added to a solution of (S)-cyclopentyl 2-amino-5-(6-amino-8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)pentanoate (14.0 mg, 0.02 mmol) in tetrahydrofuran (1 ml) and water (3 drops). After stirring for 12 h, 5 drops of acetic acid and water (0.1 ml) were added to the reaction mixture. The solid was collected by filtration and dried in vacuo to afford the title compound (3.6 mg) as a white solid. m/z 529 [M+H]+, 527 [M−H]−. 1H NMR (400 MHz, DMSO-d6), δ: 8.1 (1H, s), 7.4 (1H, s), 7.3 (2H, bs), 6.8 (1H, s), 6.0 (2H, s), 4.1 (2H, m), 3.1 (1H, m), 1.8-1.4 (5H, m).
Reaction SMILES: F[C:2]1[N:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:7]=1)=[O:5].[OH-].[NH4+:34]>>[NH2:34][C:2]1[N:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:7]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3c(C(=O)c3cccnc3F)n2)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3c(C(=O)c3cccnc3N)n2)CC1
Temperature: 120 °C
Yield: 76 %

Procedure:
A microwave vial was charged with tert-butyl 4-(1-(2-fluoronicotinoyl)isoquinolin-3-yl)piperazine-1-carboxylate (8 mg, 0.018 mmol) and a saturated aqueous solution of ammonium hydroxide (3 ml). The reaction mixture was heated under microwave irradiation at 120° C. for 30 minutes. The mixture was cooled down to room temperature, partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (6 mg, 76% yield).
Reaction SMILES: C1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)C=C1N1CCCC1.[Li][CH2:16][CH2:17][CH2:18][CH3:19].IC.C(O)(C(F)(F)F)=[O:23].[Na+].[Cl-]>CC1CCCO1.C(Cl)Cl>[CH3:19][CH:18]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:16][C:17]1=[O:23]
Reactant: O=C(O)C(F)(F)F
Reactant: C1=C(N2CCCC2)Cc2ccccc21
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: CC1CCCO1
Product: CC1C(=O)Cc2ccccc21
Temperature: -55 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-(1H-inden-2-yl)pyrrolidine (1.00 g, 5.40 mmol) in anhydrous 2-methyltetrahydrofuran (13.3 mL) was cooled to −55° C. and treated with a solution of n-BuLi (1.6 M in hexanes, 4.0 mL, 6.4 mmol) dropwise. The mixture was then stirred at −55° C. for 15 min. Iodomethane (0.4 mL, 6.3 mmol) was added and, after stirring for 5 min, the mixture was quenched by addition of 1 N HCl (6.7 mL). The solvent was removed in vacuo, water (17 mL) was added and the mixture was heated at reflux for 10 min. The mixture was then cooled to ambient temperature and extracted with diethyl ether. The organic layer was washed with brine, and the combined aqueous layers were saturated with NaCl and extracted twice more with diethyl ether. The combined organic extracts were dried (Na2SO4), filtered and concentrated to give an oil, which was treated with TFA (2.5 mL) in CH2Cl2 (2.5 mL) for 5 min. The mixture was concentrated in vacuo and the residue purified by reverse phase preparative HPLC eluting with a gradient of 90:10 to 0:100 A:B where A=0.1% TFA in H2O and B=0.1% TFA in CH3CN). The fractions containing product were combined and concentrated to give an aqueous residue which was saturated with NaCl and extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound. MS: m/z=147.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13]>C(O)CCCC.CCOCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CCCCCO
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Yield: 101 %

Procedure:
2,6-Dichloro-9H-purine (650 mg, 3.44 mmol) and 3-nitroaniline (1.9 g, 13.76 mmol) were stirred in 1-pentanol (5 mL) at 100° C. for 2 h under N2. The mixture was cooled and diluted with Et2O (40 mL). The precipitate was filtered and washed successively on a sinter with Et2O, PriOH, H2O, 10% aq Na2CO3, H2O, PriOH, and Et2O (2×20 mL each). It was then dried in vacuo to afford the title compound as a lemon-yellow powder (1.01 g, quant.). TLC (9:1 CH2Cl2/MeOH): RF=0.35.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[N:8][N:7]2[CH:4]2[CH2:3][CH2:2][N:1]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:6][CH2:5]2)=[CH:11][CH:12]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc2cnn(C3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2cnn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Yield: 42.2 %

Procedure:
1-(Piperidin-4-yl)-1H-indazol-6-amine (3.33 mmol, 0.721 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.33 mmol, 1.124 g) and potassium carbonate (6.67 mmol, 0.921 g) were combined and stirred overnight at room temperature in acetonitrile (15 mL). The reaction mixture was concentrated at reduced pressure and the resulting residue taken up in dichloromethane. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 8% methanol/dichloromethane) to afford the title compound (664 mg). MS (ESI) m/z 473.5 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])O[C:5](=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH3:16][N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:15])[N:18]([N:17]([CH3:16])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5](=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccc(Cl)cc2)=C1Cl
Reactant: CN(N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(c1ccccc1)N1C(=O)C(Cl)=C(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.65 g (15 mmol) of 3-chloro-4-(4-chlorophenyl)furan-2,5-dione were initially charged in 75 ml of chloroform and, at room temperature, admixed dropwise with stirring with 1.83 g (15 mmol) of N-methyl-N-phenylhydrazine dissolved in 15 ml of chloroform, and the mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure and the residue was taken up in 200 ml of methylene chloride, washed three times with in each case 150 ml of water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 4.6 g of a crystalline solid, m.p. 155-157° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:71]=[C:70]([C:72](O)=[O:73])[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)=[CH:58][CH:57]=1>O.CN(C=O)C>[F:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[CH:71]=[C:70]([C:72]([NH:1][C:2]3[O:3][C:4]([C:7]4[O:8][CH:9]=[CH:10][CH:11]=4)=[N:5][N:6]=3)=[O:73])[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)=[CH:60][CH:61]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)nc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cc(-c2ccc(F)cc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
Commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (57 mg, 0.38 mmol), HOAt (51 mg, 0.37 mmol), HATU (143 mg, 0.38 mmol), and N,N-diisopropylethylamine (87 μL, 0.50 mmol) were added to a DMF (2 mL) solution of commercially available 2-(4-fluorophenyl)-4-quinolinecarboxylic acid (67 mg, 0.25 mmol), and the mixture was stirred at room temperature for 3 days. To the reaction solution, water was added, and the deposited solid was collected by filtration, and washed with water and then with methanol and methylene chloride in this order. The obtained solid was dried to obtain the title compound (61 mg, 0.15 mmol).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CC(C)(C)CCN
Product: COc1cc(CNCCC(C)(C)C)ccc1Oc1ccc(C(N)=O)cn1
Yield: 31.2 %

Procedure:
Using a method similar to Example 405, using 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 3,3-dimethylbutylamine (0.0186 g, 0.184 mmol) gives the title compound (0.0205 g, 31.3%): TOF MS ESt 358.2 (M+H)+, HRMS calcd for C20H28N3O3 358.2131 (M+H)+, found 358.2131 time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.8 min, 100% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[C:17]([C@@H:19]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:9])=[N:6][CH:7]=1.[CH3:36][N:37]([CH3:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH3:36][N:37]([CH3:47])[C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][C@@H:14]4[CH2:16][C@H:11]3[CH2:12][N:13]4[C:17]([C@@H:19]([NH:24][C:25]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:9])=[N:6][CH:7]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(Br)cn1
Reactant: CN(C)c1ccc(B(O)O)cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)c1ccc(-c2ccc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)[C@@H](NC(=O)c3cc4ccccc4[nH]3)C(C)(C)C)nc2)cc1
Temperature: 80 °C
Yield: 41.8 %

Procedure:
A mixture of N-[(1S)-1-({(1S,4S)-5-[(5-bromo-2-pyridinyl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1H-indole-2-carboxamide (100 mg, 0.186 mmol), [4-(dimethylamino)phenyl]boronic acid (31 mg, 0.186 mmol), Pd(Ph3P)4 (10 mg, 0.009 mmol), potassium carbonate (26 mg, 0.186 mmol) in toluene (6 mL), ethanol (2 mL), and water (0.5 mL) was heated to 80° C. for 10 h under a nitrogen atmosphere. The solution was concentrated and the resulting residue was purified by reverse phase HPLC. Concentration of the desired fractions containing product afforded the title compound (45 mg) as a pale brown solid. LCMS (m/z): 579.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm: 0.90-1.20 (m, 9H), 1.80-2.20 (m, 2H), 2.90-3.15 (m, 6H), 3.50-4.20 (m, 4H), 4.60-5.60 (m, 4H), 6.90-7.70 (m, 9H), 7.80-8.10 (m, 2H), 8.60-8.85 (m, 1H), 9.15-9.45 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1.C(O)C.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:28][CH:29]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
tert-Butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I5) (0.250 g, 0.420 mmol) was dissolved in EtOAc (8 mL) and absolute ethanol (10 mL) under an atmosphere of nitrogen. 10% Pd/C (0.200 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (7×10 mL). The solvent was removed in vacuo to give the title compound (I6) (0.211 g, 84% yield) as a yellow solid. LCMS Method C: rt 6.78 min; m/z 600.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CS(C)=O.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>[F:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([F:17])[CH:23]=2)[N:7]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1cccc(CNc2cncc(Cl)n2)c1
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1cccc(CNc2cncc(-c3ccnc(F)c3)n2)c1
Temperature: 110 °C
Yield: 41 %

Procedure:
To 6-chloro-N-(3-fluorobenzyl)pyrazin-2-amine (140 mg, 0.589 mmol) was added 2-fluoropyridin-4-ylboronic acid (125 mg, 0.884 mmol), PalladiumTetrakis (82 mg, 0.071 mmol), DME (3.3 ml), and 2M sodium carbonate (1.031 ml, 2.062 mmol). The resulting reaction mixture was stirred at 110° C. until completion as indicated by LCMS, about 3 hours. The reaction mixture was cooled to room temperature, diluted with 20 ml of ethyl acetate, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, filtered and purified by prep LC. After lyphilization, 72 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 299.1 (MH+), retention time=0.89 min.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>C(Cl)Cl>[CH3:1][C@@H:2]1[N:7]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 105.6 %

Procedure:
To a solution of 1,1-dimethylethyl(3S)-3-methyl-1-piperazinecarboxylate (2.05 g, 10.2 mmol) in DCM (50 ml) was added DIPEA (2.68 ml, 15.4 mmol) and the mixture stirred at rt for 10 minutes before addition of 4-(trifluoromethyl)benzenesulfonyl chloride (3.00 g, 12.3 mmol) at 0° C. The resultant mixture stirred under an atmosphere of argon for 16 hours before addition of water (50 ml) and DCM (30 ml). The layers were separated using a hydrophobic frit and the organic layers concentrated to dryness giving the title compound (4.40 g) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[C:23]([O:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=2)[N:16]=1>CN(C=O)C>[CH3:29][O:28][C:23]1[C:22]([NH:21][C:17]2[N:16]=[CH:15][N:20]=[C:19]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=4)[CH:3]=[N:2]3)[N:18]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COc1ncccc1Nc1ncnc(Cl)n1
Reactant: N#Cc1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1Nc1ncnc(-n2ncc3ccc(C#N)cc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1H-indazole-6-carbonitrile (70 mg, 0.49 mmol) in DMF (5 mL) was added NaH (60% oil dispersion, 39.12 mg, 0.98 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes before the addition of 4-chloro-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (139.45 mg, 0.59 mmol). Stirring at RT was continued for 2 hr. The reaction mixture was then quenched with water and EtOAc was added. Precipitate formed was collected by suction filtration, then redissolved in DCM and washed with water. Further trituration (9:1 mixture of heptane/Et2O) gave the title compound: 1H (250 MHz, CDCl3, VT @ 323K) δ 4.10 (3H, s), 7.06 (1H, br. s.), 7.60 (1H, dd, J=8.22, 1.37 Hz), 7.91 (1H, dd, J=8.22, 0.76 Hz), 7.97 (2H, d), 8.42 (1H, d, J=0.76 Hz), 8.74 (1H, dd, J=7.84, 1.60 Hz), 8.86 (1H, s), 9.20 (1H, s); m/z=+345.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:28])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: CN(Cc1ccccc1)c1ccn(CCc2ccc(CO)cc2)c(=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(Cc1ccccc1)c1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 280 mg (0.80 mmol, 74% purity) 4-(benzyl-methyl-amino)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 14c) in 5.0 mL of DCM is added at 0° C. 53 μL (0.56 mmol) phosphorus tribromide. The mixture is stirred overnight at RT and is diluted with aqueous NaHCO3-solution and water. The layers are separated and the organic phase is dried over MgSO4, filtered and the solvent is removed. The residue is used directly without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:12][CH2:11][O:10][B:9]([OH:13])[C:8]=2[CH:14]=1)([O-])=O.CCN(CC)CC.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([C:32]([F:35])([F:34])[F:33])[CH:24]=1>C1COCC1.CCOC(C)=O.[Pd]>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:4]2[CH:5]=[CH:6][C:7]3[CH2:12][CH2:11][O:10][B:9]([OH:13])[C:8]=3[CH:14]=2)=[O:28])=[C:25]([C:32]([F:33])([F:34])[F:35])[CH:24]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)B(O)OCC2
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)B(O)OCC2)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (100 mg, 0.52 mmol) in THF (10 mL) was passed through H-cube equipped with a 10% Pd/C cartridge. The collected light yellow solution was immediately treated with Et3N (144 μL, 2.0 mmol, 2.0 eq.), followed by 4-fluoro-2-trifluoromethyl-benzoyl chloride (94 μL, 0.62 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with EtOAc (20 mL), washed with 1N HCl (10 mL), H2O (10 mL), brine (10 mL) and then dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure and the crude material was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give the title compound as a white solid. LCMS (M/Z): 354 (M+H); 1H NMR (DMSO-d6) δ: 10.43 (s, 1H), 8.40 (s, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.75 (dt, J=5.9, 2.9 Hz, 2H), 7.58-7.67 (m, 2H), 7.15 (d, J=8.2 Hz, 1H), 4.03 (t, J=5.9 Hz, 2H), 2.80 (t, J=5.8 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21](OC(=O)N)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:12]1[CH2:11][CH2:10][N:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:21]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cn2)C1

Procedure:
With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)-1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared by the hydrogenation of (R)-1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[C:4]([N+]([O-])=O)[C:3]=1[C:16]([OH:18])=O.[ClH:19].[NH2:20][C:21]([NH2:23])=[NH:22]>>[Cl:19][C:4]1[C:3]([C:16]([NH:22][C:21]([NH2:23])=[NH:20])=[O:18])=[C:2]([CH3:1])[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]=12
Reactant: Cc1nc2c(c([N+](=O)[O-])c1C(=O)O)CCCCC2
Reactant: N=C(N)N
Reactant: Cl
Product: Cc1nc2c(c(Cl)c1C(=O)NC(=N)N)CCCCC2
Yield: 16 %

Procedure:
When the method of Inventive Example 17 was repeated using 2-methyl-4-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylic acid (750.1 mg, 3.00 mmol) and guanidine hydrochloride (2.77 g, 29.0 mmol), chlorination of the nitro group occurred at the same time and the title compound (134.5 mg, 16.0%) was obtained as white powder.