Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH:11](O)=O>O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:9]=[CH:11][NH:8][C:6]=2[CH:7]=1
Reactant: O=CO
Reactant: Cc1cc(Br)cc(N)c1N
Solvent: O
Product: Cc1cc(Br)cc2[nH]cnc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
To a solution of 5-bromo-3-methylbenzene-1,2-diamine (2.02 g, 10 mmol) was added water (10 mL) followed by formic acid (1.16 mL, 30 mmol). The mixture was stirred at 100° C. for 6 hours before cooling to room temperature. A solid precipitated from the solution and was allowed to sit at room temperature for 2 days. To this mixture was then added 1 N KOH (35 mL) and the solids were isolated by vacuum filtration. The solids were air dried and recrystallized from CHCl3 (70 mL) to provide 6-bromo-4-methyl-1H-benzimidazole (0.82 mg, 39%). Additional batches of product were obtained from the CHCl3 mother liquors (1.01 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C.C([O-])(O)=O.[Na+]>[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][N:20]1[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C:15]2[C:14]([F:24])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:8]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:9]=3)[N:16]=2)[CH2:19]1
Reactant: O=Cc1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(Cc5ncc[nH]5)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.16 g, 0.32 mmol) in 1,2-dichloroethane (2 mL) was added 1H-imidazole-2-carbaldehyde (0.03 g, 0.36 mmol) followed by 2 drops of acetic acid and Na(OAc)3BH (0.10 g, 0.49 mmol). The reaction mixture was heated at 60° C. for 18 h. The mixture was cooled to room temperature and diluted with aqueous saturated NaHCO3 solution. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-20% MeOH/CH2Cl2) to afford the product, 4a.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:10][CH2:11][C:12]([NH:14][NH2:15])=[N:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:25][CH2:26][C:27](Cl)=O.C([O-])(=O)C.[Na+]>>[Cl:25][CH2:26][C:27]1[N:13]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[C:8]=3[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:10][CH2:11][C:12]2=[N:14][N:15]=1
Reactant: NNC1=Nc2cccc(C(F)(F)F)c2C(c2ccccc2F)=NC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Fc1ccccc1C1=NCc2nnc(CCl)n2-c2cccc(C(F)(F)F)c21

Procedure:
In the manner given in Preparation 10, 6-(trifluoromethyl)-5-(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine is reacted with chloroacetyl chloride and after 1.5 hours with sodium acetate, then refluxed to give 1-(chloromethyl)-7-(trifluoromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([OH:33])=O)[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.O[N:40]1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]2[C:31]([NH2:40])=[O:33])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A 3 L round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC*HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCO3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, ˜100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=375.3; [M±H]+=475.4; [M-tBu+H]+=419.3. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9-2.05 (m, 2H), 1.65-1.9 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][C:20]=1[CH3:30])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[CH:21][C:20]=3[CH3:30])[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: Cc1cc(C(C)(C)C#N)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C#N)ccc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21
Yield: 43.1 %

Procedure:
To a solution of (7-cyano-1H-benzimidazol-1-yl)acetic acid (250 mg, 1.24 mmol) prepared according to scheme 3, 2-[4-(1-aminoethyl)-3-methylphenyl]-2-methylpropanenitrile (251 mg 1.24 mmol) prepared according to scheme 15 and DMAP (150 mg, 1.24 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (473 mg, 1.24 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4 N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product 2-(7-cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}acetamide (206 mg, 43%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.45 (d, J=6.84 Hz, 3H) 1.66 (s, 6H) 2.37 (s, 3H) 5.20 (q, J=6.84 Hz, 1H) 5.30 (s, 2H) 7.25 (d, J=1.95 Hz, 1H) 7.32 (dd, J=8.20, 2.15 Hz, 1H) 7.38 (dd, J=8.11, 7.71 Hz, 1H) 7.44 (d, J=8.20 Hz, 1H) 7.67 (dd, J=7.42, 0.78 Hz, 1H) 7.96 (dd, J=8.20, 0.98 Hz, 1H) 8.24 (s, 1H), MS [M+H], calcd: 386.2. found: 386.2.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([NH:37][CH2:38][CH2:39][OH:40])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:48].C1(OC)C=CC=CC=1>CCOC(C)=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([NH:37][CH2:38][CH2:39][OH:40])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:48]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCO
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCO

Procedure:
Boc-Tyr-DAla-Phe-Met-NHCH2CH2OH (2.0 g) was treated with HCl, anisole, EtOAc as in Step B to give H-Tyr-DAla-Phe-Met-NHCH2CH2OH.HCl which was chromatographed on Amberlite XAD-2 as in Step E to give 1.23 g (64%) of H-Tyr-DAla-Phe-Met-NHCH2CH2OH.HOAc, m.p. 200°-203° C., [α]D26 =10.21° (c, 1.01 in methanol).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[CH3:2][N:3]([CH3:8])[C:4](=[O:7])[CH2:5][NH:6][C:17]1[CH2:21][S:20][C:19](=[O:22])[N:18]=1
Reactant: CN(C)C(=O)CN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To a solution of N,N-dimethylglycinamide hydrochloride (5 g) and triethylamine (5.03 mL) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (4.81 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/THF) to give the title compound (4.68 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([N:17]([CH2:39][CH2:40][CH3:41])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: CC(C)[C@H]1C[C@@H](NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)N1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN([C@@H]1C[C@H](C(C)C)N(OCc2ccccc2)C1=O)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
N-[(3R,5R)-1-(Benzyloxy)-5-isopropyl-2-oxopyrrolidinyl]-4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonamide (0.030 g, 0.056 mmoles, Example 27b), 1-iodopropane (0.033 mL, 0.34 mmoles), cesium carbonate (0.028 g, 0.085 mmoles) and anhydrous N,N-dimethylformamide (0.40 mL) was stirred at 55° C. (oil temperature) over night, concentrated by rotary evaporation, taken up diethylether and washed with water once. The aqueous phase was washed with a second portion of diethylether, the combined organic phases were washed with brine, dried with potassium carbonate, filtered and concentrated by rotary evaporation. Flash chromatography of the crude product on silica using dichloromethane-methanol (99:1) as eluent gave the title compound as a colourless oil. LC-MS (APCI) m/z 575 (M+1). 1H NMR (CDCl3) δ 8.10 (d, J=9 Hz, 2H), 7.73 (d, J=9 Hz, 2H), 7.72 (app s, 5H), 7.43–7.34 (m, 4H), 5.09 (d, J=10 Hz, 1H), 4.92 (d, J=10 Hz, 1H), 4.54 (t, J=10 Hz, 1H), 3.34 (ddd, J1=4 Hz, J2=6 Hz, J3=10 Hz, 1H), 3.12 (t, J=8 Hz, 2H), 2.30 (ddd, J1=7 Hz, J2=10 Hz, J3=13 Hz, 1H), 2.24–2.14 (m, 1H), 1.88–1.58 (m's, 3H), 0.90 (d, J=7 Hz, 3H), 0.89 (d, J=7 Hz, 3H) and 0.84 (t, J=7 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:10][C@@H:11]([CH3:12])[C:5]2=[N:4][N:3]=1.Br[C:37]1[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24]([C:37]4[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=4)=[CH:23][C:8]=3[N:9]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH2:10][C@@H:11]([CH3:12])[C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Reactant: Nc1cnc(Br)cn1
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: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3cnc(N)cn3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 24.9 %

Procedure:
To a solution of (R)-1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (0.34 mmol) in 1,4-dioxane and H2O (10:1, 5 mL) was added 5-bromopyrazin-2-amine (63.2 mg, 0.36 mmol), Cs2CO3 (197.3 mg, 0.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (21.9 mg, 0.03 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyrazin-2-amine (39 mg, 28%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[Br:47][C:48]1[CH:56]=[CH:55][C:51]([CH2:52][NH:53][NH2:54])=[CH:50][CH:49]=1>CCOC(C)=O>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:16]([NH:54][NH:53][CH2:52][C:51]1[CH:55]=[CH:56][C:48]([Br:47])=[CH:49][CH:50]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NNCc1ccc(Br)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Cbz-(L)-Valine (1.04 g, 4.14 mmol) was dissolved in EtOAc (50 mL) and EDAC (0.870 g, 4.54 mmol), HOBT (0.610 g, 4.51 mmol), and NMM (0.500 mL, 4.55 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and then 4-bromo-benzylhydrazine (1.00 g, 4.97 mmol) in EtOAc (5 mL) was added and the stirring was continued for 2 h. After evaporation of the solvent, CHCl3 was added and the solution was washed with saturated NaHCO3 (aq.) and brine followed by drying (Na2SO4), filtration and evaporation of the organic solvent. The crude product was purified by column chromatography (silica, CHCl3/MeOH, 100:0-95:5) yielding the title compound (1.42 g, 79%) as a white solid.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N+](C1C=CC(S(O[CH2:34][C:35]([C@@H:38]2[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]2)([CH3:37])[CH3:36])(=O)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:37][C:35]([C@@H:38]4[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]4)([CH3:34])[CH3:36])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC[C@@H](C(C)(C)COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reactant: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](C(C)(C)COc2cccc3ccc(-c4nnc5ccccn45)nc23)O1
Temperature: 85 °C
Yield: 7.5 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (0.25 g, 0.95 mmol), (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl 4-nitrobenzenesulfonate (0.41 g, 1.1 mmol) and cesium carbonate (0.62 g, 1.9 mmol) were added to minimal amount of N,N-dimethylacetamide and heated to 85° C. The reaction was cooled, ethyl acetate was added and the mixture was sonicated. Solids were filtered off and the filtrate was dried over MgSO4, filtered and evaporated. The crude material was purified on silica gel using isopropyl alcohol containing 2% NH4OH and DCM to yield 30 mg of the desired product (90% pure. The crude material was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([C:29]1[N:30]=[CH:31][C:26]([C:2]2[C:3]([F:17])=[CH:4][C:5]3[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=3[CH:16]=2)=[CH:27][CH:28]=1)#[N:33]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3ccc(C#N)nc3)c(F)cc2s1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
A solution of 1-(5-bromo-6-fluoro-benzothiazol-2-yl)-3-ethyl-urea (0.10 g, 0.31 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.144 g, 0.63 mmol) and K3PO4 (0.133 g, 0.63 mmol) in DMF-H2O (5.0 mL, 4:1) was degassed by flushing with nitrogen for 15 min. Dichlorobis(triphenylphosphine)-palladium(II) (0.022 g, 0.03 mmol) was then added to the reaction mixture followed by degassing with nitrogen for another 15 min. The resulting reaction mixture was then heated to 100° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature and poured onto ice-cold water followed by extraction with EtOAc (2×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was then purified over silica gel (100-200 M, 2.50% MeOH-DCM) to obtain the desired product (0.075 g, 71%). 1H-NMR (400 MHz, DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 3.20 (m, 2H), 6.71 (br s, 1H), 7.90 (d, J=6.80 Hz, 1H), 8.03 (d, J=10.80 Hz, 1H), 8.15 (m, 1H), 8.31 (m, 1H), 9.0 (s, 1H) and 10.90 (br s, 1H). MS: 340.06 (M−H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:9]([NH:11][C:12]3[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=3)([N:10]=1)[N:8]=[CH:7][N:6]=2.[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[CH:4][C:5]3[C:9]([NH:11][C:12]4[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=4)([N:10]=2)[N:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: CC1CCNCC1
Reactant: Cc1cc(NC23N=CN=C2C=NC(Cl)=N3)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(NC23N=CN=C2C=NC(N2CCC(C)CC2)=N3)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4-methylpiperidine (4 mL, 8.01 mmol) and the reaction mixture heated at reflux overnight. The solvent was evaporated and the residue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (×2) and rinsed with Et2O (×2) to afford IV-33 as a white solid (225 mg, 90%): mp >300° C.; H NMR (DMSO) δ 0.91 (3H, d), 1.10 (2H, m), 1.65 (3H, m), 2.24 (3H, s), 2.84 (2H, m), 4.60 (2H, m), 6.40 (1H, s) 7.87 (1H, m), 9.37-9.59 (1H, m), 12.03-12.39 (2H, m); IR (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14](Br)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1>CN(C=O)C.[Cu]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([O:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[N:15]=1
Reactant: Oc1cccnc1
Reactant: Nc1ncc(Br)nc1-c1nc2ccccc2[nH]1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncc(Oc2cccnc2)nc1-c1nc2ccccc2[nH]1
Yield: 11.4 %

Procedure:
3-(1H-Benzimidazol-2-yl)-5-bromo-pyrazin-2-amine (100 mg, 0.3447 mmol), dicesium carbonate (366 mg, 1.034 mmol), copper (2.2 mg, 0.034447 mmol) and pyridin-3-ol (327.8 mg, 3.447 mmol) in DMF (2 mL) were heated at 130° C. under microwave conditions for 1 hour. The reaction mixture was filtered through a pad of silica eluting with 90 to 100% EtOAc/Petroleum Ether and the relevant fractions concentrated in vacuo. The resiude was redissolved in EtOAc and washed with saturated aqueous NaHCO3 (×2) and brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (12 mg, 11% Yield). 1H NMR (400.0 MHz, CDCl3) δ 7.33-7.38 (2H, m), 7.77-7.8 (2H, m), 7.82-7.88 (1H, m), 8.05-8.1 (1H, m), 8.15 (1H, s), 8.8-8.55 (1H, m) and 10.2 (1H, s) ppm; MS (ES+) 305.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C)C=O.O>[CH:20]1([CH2:19][O:9][C:5]2[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][CH:6]=2)[CH2:22][CH2:21]1
Reactant: ClCC1CC1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NCc1cccc(OCC2CC2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
3-Cyanophenol (12.4 g) was dissolved in N,N-dimethylformamide (hereinafter, referred to as DMF; 100 mL). To the solution, potassium carbonate (30.5 g), potassium iodide (1.74 g), and (chloromethyl)cyclopropane (10.2 mL) were added, and the mixture was stirred at 90° C. for 4 hours. To the reaction mixture, water (130 mL) was added, and the resultant mixture was then extracted with toluene (130 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (hereinafter, referred to as THF; 60 mL). To the solution, a solution of lithium aluminum hydride (hereinafter, referred to as LAH) in THF (2.4 M, 68 mL) was gradually added dropwise at 0° C., and the reaction mixture was then stirred at 45° C. for 4 hours. To the reaction mixture, water (10 mL), an aqueous sodium hydroxide solution (1.0 M, 10 mL), and water (5.0 mL) were gradually added at 0° C. The resultant precipitate was removed by filtration and washed with 10% methanol/THF (400 mL). Then, the combined filtrate was concentrated under reduced pressure. To the residue, water (50 mL) was added, and the resultant mixture was then extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (18.1 g) as a crude product.