Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35](O)=[O:36])[N:30]=[CH:29]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:35](=[O:36])[CH2:34][CH2:33][C:31]4[N:30]=[CH:29][NH:28][CH:32]=4)[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(C(=O)CCc2c[nH]cn2)C1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.10 g, 0.00028 mol), 3-(1H-4-imidazolyl)propanoic acid (0.050 g, 0.00035 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0068 g, 0.00035 mol), N,N-diisopropylethylamine (0.068 g, 0.00053 mol) and 1-hydroxy-7-azabenzotriazole (0.038 g, 0.00028 mol) in anhydrous N,N-dimethylfornamide (13 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(1H-4-imidazolyl)-1-propanone (0.040 g, 0.00008 mol).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>>[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])(=[O:37])=[O:36]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1Br
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccccc1Br)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 61 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2-bromobenzenesulfonyl chloride under the conditions used in example 2 giving 61% of the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>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>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][OH:7]
Reactant: Brc1nccs1
Reactant: OCc1ccccc1B(O)O
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: C1COCCO1
Solvent: O
Product: OCc1ccccc1-c1nccs1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a stirred solution of 2-bromothiazole (1.0 g, 6.1 mmol) in dioxane/water (20/5 mL) was added (2-(hydroxymethyl)phenyl)boronic acid (1.4 g, 9.1 mmol), sodium carbonate (1.29 g, 12.2 mmol), and Pd(PPh3)4 under nitrogen. The mixture was heated at reflux for 18 h. After cooling to rt, water (50 mL) was added and aqueous was extracted with DCM (3×50 mL). The combined organic layer was dried and evaporated. The residue was purified by column chromatography to yield (2-(thiazol-2-yl)phenyl)methanol (0.95 g, 5.1 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:13]=1)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC.[CH3:33][C:34](OC(C)=O)=[O:35].CO>CCOC(C)=O>[CH:21]1([O:20][C:14]2[CH:13]=[C:12]([CH:3]([C:4]#[C:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:2][NH:1][C:34](=[O:35])[CH3:33])[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C(C#Cc2ccccc2)CN)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(C#Cc2ccccc2)CNC(C)=O)cc1OC1CCCC1
Reaction time: 0.08 h

Procedure:
A solution of (+/-)-4-amino-3-(3 cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne (50 mg, 0.15 mmol) and Et3N (0.2 ml) in EtOAc (30 ml) at 5° was treated with Ac2O (0.2 ml). After 5 minutes, the reaction was treated with MeOH, to decompose excess Ac2O. The reaction was washed with H2O and 0.05 N HCl, dried, and the solvent was evaporated. The residue was purified by flash chromatography (alumina, neutral, activity 1, 5% MeOH/CHCl3), and then by recrystallization from a mixture of cyclohexane and Et2O, and gave the titled compound, 37 mg (65%). mp 114-117°. 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.32 (m, 3 H), 6.92 (m, 2 H), 6.84 (d, 1 H), 5.78 (broad s, 1 H), 4.76 (m, lH), 4.02 (t, 1 H), 3.82 (s, 3 H), 3.64 (m, 1 H), 3.50 (m, 1 H), 2.06 (s, 3 H), 1.78-2.00 (m, 6 H), 1.62 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1I.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:25]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[Cl:23])=[CH:16][CH:15]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 25.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 2-chloro-1-iodo-4-(trifluoromethyl)benzene (0.147 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.51 (d, J=8.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.67-7.87 (m, 3H), 7.84 (t, J=8.4 Hz, 2H), 8.05 (d, J=8.4 Hz, 2H), 8.11 (s, 1H), 12.75 (br s, 1H). MS (m/z): 492.22 (M+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[N+:12]([O-])=O>O1CCCC1.[Pd]>[CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:12]
Reactant: CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a suspension of N-methyl-2,6-dinitroaniline (407 mg, 2.06 mmol) in tetrahydrofuran (6.5 mL) was added palladium on carbon (45 mg), and the mixture was purged with hydrogen and stirred under balloon pressure hydrogen for 5 hr at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (280 mg, 2.04 mmol, 99%) as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12](Cl)=[O:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.O.[NH2:16][NH2:17]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([NH:16][NH2:17])=[O:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=C(Cl)C1(c2cccs2)CCOCC1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)C1(c2cccs2)CCOCC1

Procedure:
4-(2-Thienyl)tetrahydropyran-4-carboxylic acid was reacted with thionyl chloride and a catalytic amount of DMF in methylene chloride under heating to obtain 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride. A THF solution of 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride was added dropwise to a THF solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 4-(2-thienyl)tetrahydropyran-4-carbohydrazide.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[N:9]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>O1CCOCC1>[CH2:26]([NH:28][C:29](=[O:30])[NH:23][C:22]1[CH:24]=[CH:25][C:19]([C:10]2[N:9]=[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=2)=[CH:20][CH:21]=1)[CH3:27]
Reactant: CCN=C=O
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 70 °C
Yield: 93.1 %

Procedure:
4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]aniline (100 mg, 0.28 mmol) was dissolved in dioxane (4 mL). Ethylisocyanate (0.109 mL, 1.38 mmol) was added and the reaction heated at 70° C. for 4 hours. Reaction was complete and was evaporated to dryness. The resultant oil was purified by chromatography, eluting with 10-50% ethyl acetate in isohexane, to give 3-ethyl-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea as a pale yellow oil (113 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:8]=2)[S:3]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2S1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloridel. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 100 degrees C. for 24 h, allowed to cool to room temperature and then treated with a further 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was then degassed, placed under argon and then heated in the sealed tube at 100 degrees C. for 96 h. The mixture was cooled to room temperature and extracted with 3×10 ml of ether. The organic extracts were combined, washed successively with 25 ml of water and 25 ml of saturated sodium chloride solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes followed by 3% ethyl acetate in hexanes) to give the title compound as a yellow, crystalline solid. PMR (CDCl3): & 0.23 (9H, s) , 1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 (1H, dd, J-8.2 Hz, 1.8 Hz), 7.25 (1H, d, J-1.8 Hz), 7.30 (1H, d, J-8.2 Hz). MS exact mass, m/l 302.1519 (calcd. for C18H26S Si, 382.1524).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:7]([C:11]([NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:12]([C:14]3[S:15][C:16]([C:19]#[C:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:18]=3)[N:13]=2)[CH:8]=[CH:9][N:10]=1)=[O:4].[OH-].[Na+].C(O)(=O)C.C(Cl)Cl.CCCCCC>CO.CC#N>[C:28]([NH:27][C:11]1[N:7]2[CH:8]=[CH:9][N:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2=[N:13][C:12]=1[C:14]1[S:15][C:16]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:18]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1nccn2c(NC(C)(C)C)c(-c3ccc(C#Cc4ccccc4)s3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2c(C(=O)O)nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A solution of 200 mg (0.47 mmol) of 3-(tert-butylamino)-2-(5-(phenylethynyl)-thiophen-2-yl)imidazo[1,2-a]pyrazine-8-carboxylic acid methyl ester (Example 106) in a mixture of MeOH (5 ml) and MeCN (5.5 ml) was combined with 5 ml (0.51 mmol) of a 0.1M aq. NaOH solution and stirred at RT for 1 h. The reaction mixture was then combined with 26 μl of a 5 N aq. acetic acid solution. The solvents were then largely removed by distillation under a vacuum. The residual aq. phase was repeatedly extracted with EA. The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 87 mg (0.21 mmol, 44%) of 3-(tert-butylamino)-2-(5-(phenylethynyl)thiophen-2-yl)imidazo[1,2-a]pyrazine-8-carboxylic acid were obtained by crystallisation of the group from DCM/hexane (1:2).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].CCN(CC)CC>O1CCOCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:11]3[N:10]=[N:9][C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCN[C@H](C)C2)c1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Yield: 75.3 %

Procedure:
A mixture of compound 47 (6.0 g, 20.27 mmol), 5-chloropyrazine-2-carboxylic acid methyl ester (5.3 g, 30.30 mmol), Et3N (6.2 g, 60.60 mmol) and dioxane (100 mL) is heated to reflux overnight. Solvent is removed. Saturated NH4Cl solution is added and extracted with EtOAc. The organic layer is concentrated to afford the crude product that is purified by chromatography on silica gel (EtOAc/heptane: 50%˜100%) to give the title compound (6.6 g, 76%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([C:37]1[S:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:41][C:37]([C:35]#[N:36])=[CH:38][CH:39]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)s1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2ccc(C#N)s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (30 mg, 0.060 mmol), 5-cyanothiophen-2-ylboronic acid (27.5 mg, 0.180 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.29 mg, 3.59 mol) and 2-(dicyclohexylphosphino)biphenyl (1.259 mg, 3.59 mol) in dioxane (2 mL) and DMF (0.500 mL) was heated to 160° C. via microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(5-cyanothiophen-2-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (10 mL). The mixture was stirred at room temperature for 60 minutes and then concentrated. The resulting crude material was reconstituted in MeOH and DCM (10.0 mL) and was purified via preparative HPLC, eluting with a gradient of 20-25% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the solvent was stripped to dryness via rotary evaporation to yield a TFA salt of the title compound (3.3 mg, 15%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.78 (d, J=14.16 Hz, 1H), 2.04-2.21 (m, 1H), 3.57-3.67 (m, 1H), 3.73-3.88 (m, 2H), 4.01 (d, J=10.74 Hz, 2H), 4.36 (d, J=11.23 Hz, 1H), 4.48 (br s, 2H), 7.47 (br s, 1H), 7.91-8.02 (m, 3H), 8.73 (br s, 1H), 9.13 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H16FN5O2S, 374. found, 374.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:27]([O:29][CH3:30])=[O:28])=[C:9]([NH:11][CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:13])[CH3:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.O1CCOCC1.C[O-].[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH:12]([N:11]2[C:4]3[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=3)[C:8]([C:27]([O:29][CH3:30])=[O:28])=[C:9]2[CH3:10])[CH3:13])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)C(=C(C)NC(C)C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1Br
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A 250 mL round bottom flask was charged with a magnetic stir bar, (R or S,Z)-tert-butyl 4-(1-(3-(2-bromophenyl)-4-methoxy-4-oxobut-2-en-2-ylamino)ethyl)piperidine-1-carboxylate (3.33 g, 6.92 mmol), RuPhos Pre-catalyst II (Chloro-(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl ether adduct) (0.463 g, 0.553 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.387 g, 0.830 mmol), anhydrous 1,4-dioxane (27.7 ml, 6.92 mmol), and sodium methoxide (0.561 g, 10.38 mmol). The reaction mixture was purged and back-filled with nitrogen and heated to 100° C. with stirring overnight before being allowed to cool to rt. The reaction was diluted with ethyl acetate (˜100 ml) and the mixture was filtered through a bed of diatomaceous earth. The filtrate was pre-absorbed onto silica gel (˜30 g) and purified via silica gel chromatography (120 g) using ethyl acetate/hexanes (1:1) as eluent to afford the title compound (2.01 g, 4.77 mmol, 68.9% yield).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH:32]1[C:36]([CH2:37][C:38](O)=[O:39])=[N:35][N:34]=[N:33]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[NH:32]1[C:36]([CH2:37][C:38]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]4[N:18]=[C:19]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:20][C:21]=4[C:22]([F:23])([F:25])[F:24])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)=[O:39])=[N:35][N:34]=[N:33]1
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCN(C(=O)Cc3nnn[nH]3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide, hydrochloride (53 mg, 0.117 mmol), (1H-tetrazol-5-yl)-acetic acid (15 mg, 0.117 mmol), and triethylamine (49 uL, 0.351 mmol) were dissolved in 1.5 mL of DMF and chilled in an ice bath. To this solution was added BOP (52 mg, 0.122 mmol) in one portion. The mixture was stirred at room temperature for 30 minutes and then diluted with 30 ml CH2Cl2. The organic phase was washed with 1N citric acid (1×8 mL), water (3×8 mL) and saturated sodium chloride (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness under vacuum. The residue was crystallized from acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-1H-tetrazol-5-yl-acetyl)-piperazin-1-yl]-phenyl}-amide as light yellow crystals (26 mg, 42%). ES-MS calcd for C24H21F3N8O3 (m/e) 526.48, obsd 527 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O>CCO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[C:15]([F:16])([F:17])[F:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)c1ccc(C(F)(F)F)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-nitro-4-(trifluoromethyl)benzoate (11.58 g, 44 mmol) was taken up in EtOH (150 ml) and vacuum purged. Then, under a nitrogen atmosphere, Pd/C (1.15 g) was added. The mixture was stirred at RT overnight under a hydrogen atmosphere using a balloon. The reaction was filtered through a pad of celite and the filtrate reduced under reduced pressure to give ethyl 3-amino-4-(trifluoromethyl)benzoate a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH2:11][O:12][CH3:13])[CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[CH3:13][O:12][CH2:11][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][C:7]=1[NH2:10]
Reactant: [H][H]
Reactant: COCc1cc([N+](=O)[O-])ccc1N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCc1cc(N)ccc1N
Reaction time: 1 h

Procedure:
5 g (27.5 mmol) of 4-Nitro-2-methoxymethyl-aminobenzene and 0.250 g of palladium (10% on carbon) are placed in a 250 ml Parr bottle and 50 g of ethyl acetate is added. Hydrogenation is carried out using a Parr apparatus under 50-60 psig (64.7-74.7 psi or 446-515 kPa) of hydrogen pressure. In the course of the reaction the yellowish grey suspension turns to a darker grey suspension. The reaction is also carefully monitored for rapid hydrogen uptake and additional hydrogen is introduced to keep pressure above 50 psig (64.7 psi or 446 kPa). After 1 hour the suspension clears, leaving a yellow solution. The reaction is continued for 2.5 hours to ensure complete conversion. The catalyst is removed by filtration through glass microfiber filter paper. The filtrate is concentrated to ca. 25 ml, and 25 ml of toluene are added to precipitate the product. The product is collected on filter paper with suction and dried at 60° C. under vacuum. The product yield is 4.5 g.