Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@H:11]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:38][N:39]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([NH2:48])[S:47][C:41]=2[CH2:40]1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@H:11]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:48][C:46]3[S:47][C:41]4[CH2:40][N:39]([CH3:38])[CH2:44][CH2:43][C:42]=4[N:45]=3)=[O:20])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CC[C@H](Oc3cccc(C(=O)O)c3)C2)cc1
Reactant: CN1CCc2nc(N)sc2C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCc2nc(NC(=O)c3cccc(O[C@H]4CCN(c5ccc(C#N)cc5)C4)c3)sc2C1
Reaction time: 1 h

Procedure:
Dissolve 3-[(S)-1-(4-cyano-phenyl)-pyrrolidin-3-yloxy]-benzoic acid (80.2 mg, 0.26 mmol), EDC (99.2 mg, 0.52 mmol) and HOBT (79.6 mg, 0.52 mmol) into 2 mL of DMF. The mixture is stirred for 1 h. Add 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (46.5 mg, 0.28 mmol) to the mixture and place in a 60° C. bath with an Ar stream blowing over it. Stir mixture for 14 h resulting in a concentrated residue. LC-MS analysis indicates the desired product. Dissolve into 5 mL of DMF and purify via the Gilson Prep HPLC system (5%-80% CH3CN/H2O) to give 59.4 mg of the title compound, MS, electrospray 560.58 (M+H), rt 6.01 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=2)=[N:13][CH:14]=1)[CH3:19]
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Reactant: CCc1ccc(Nc2cc(Cl)nn3ccnc23)nc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(Nc2cc(-c3ccccc3)nn3ccnc23)nc1
Temperature: 110 °C
Yield: 22 %

Procedure:
A mixture of 6-chloro-N-(5-ethylpyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (329 mg, 1.21 mmol), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (221 mg, 1.81 mmol), Pd2(dba)3 (70 mg, 0.121 mmol), X-Phos (231 mg, 0.484 mmol) and K2CO3 (499 mg, 3.62 mmol) in dioxane (40 mL) and H2O (10 mL) was heated to 110° C. for 20 h under N2. The mixture was cooled and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:5) to afford N-(5-ethylpyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (84 mg, 22%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.69 (s, 1H), 8.37 (d, 1H, J=1.8 Hz), 8.24 (s, 1H), 8.09-8.01 (m, 3H), 7.68-7.55 (m, 5H), 7.02 (d, 1H, J=8.4 Hz), 2.75 (q, 2H, J=7.8 Hz), 1.37 (t, 3H, J=7.8 Hz). LC-MS: 316, [M+H]+, tR=1.827 min, HPLC: 99.73% at 214 nm, 99.88% at 254 nm, tR=3.262 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][NH:67][C:68]([CH3:71])([CH3:70])[CH3:69])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][NH:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-tert-butylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Fluoro-4-nitrophenol (10 g, 63.65 mmol) was dissolved in N,N-dimethylformamide (120ml), and then sodium hydride (2.68 g, 67.00 mmol, 60% in oil) was added and the mixture was stirred for 15 minutes at room temperature under a nitrogen atmosphere. After adding benzyl bromide (7.6 ml, 63.65 mmol), the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water was added to the reaction solution, and the precipitated crystals were filtered out, washed with water and dried by aspiration to obtain the title compound (16.06 q, quant.) as crude light yellow crystals. These were used without further purification for the following reaction.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[N:8][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:6][C:5]=2[N:4]([CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]2)[CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOC(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.O>[CH2:12]([NH:11][C:7]1[N:8]=[CH:9][C:10]2[C:2]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[CH:3][N:4]([CH2:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]3)[C:5]=2[N:6]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ncc2c(Br)cn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Reactant: OB(O)c1ccc(F)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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCNc1ncc2c(-c3ccc(F)cc3)cn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 120 °C

Procedure:
A 10 mL microwave tube was charged with tert-butyl trans-4-((5-bromo-2-(butylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)cyclohexylcarbamate (0.096 g, 0.20 mmol), 4-fluorophenylboronic acid (0.042 g, 0.30 mmol), potassium carbonate (0.055 g, 0.40 mmol), tetrakis(triphenylphosphine)palladium (0.024 g, 0.020 mmol), dioxane (2 mL) and water (0.50 mL). The reaction was heat at 120° C. for 10 min in microwave. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), concentrated, and purified by Isco to provide tert-butyl trans-4-((2-(butylamino)-5-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)cyclohexylcarbamate. This intermediate was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (0.6 mL) was added at ambient temperature. After stirring for 2 h, the solvent was evaporated. The residue was purified by preparative HPLC to provide 7-((trans-4-aminocyclohexyl)methyl)-N-butyl-5-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (UNC1537A) as a yellow solid (TFA salt) (UNC1537A) (0.032 g, 41%). 1H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 7.67 (s, 1H), 7.67-7.61 (m, 2H), 7.21 (t, J=8.5 Hz, 2H), 4.10 (d, J=7.0 Hz, 2H), 3.54 (t, J=7.1 Hz, 2H), 3.16-3.01 (m, 1H), 2.07 (d, J=10.3 Hz, 2H), 2.04-1.92 (m, 1H), 1.85 (d, J=12.2 Hz, 2H), 1.76-1.65 (m, 2H), 1.54-1.44 (m, 2H), 1.44-1.34 (m, 2H), 1.34-1.20 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); MS m/z 396.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12](O)([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(C(=O)O)c1ccc(F)cc1
Solvent: CCOCC
Product: CC(C)=C(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 734 %

Procedure:
90 g of polyphosphoric acid were placed in a 350 ml sulphonation flask. Then, it was treated dropwise with a solution of 10.0 g (47 mmol) of 2-(p-fluorophenyl)-3-hydroxy-3-methylbutyric acid in 70 ml of CH2CL2 at 20-25°. The viscous, yellow colored mixture was stirred for 2 hours, with the temperature rising to 35°. After hydrolysis with ice-water the mixture was left to stand overnight and then treated with ether. The organic phase was separated, washed 3 times with water, dried over MgSO4, filtered and the filtrate was concentrated. The residue was dissolved in CH2CL2 and the solution was treated with hexane and concentrated on a rotary evaporator until crystallization occurred. After standing at RT for 1 hour the crystals were filtered off under suction and washed with cold hexane. There were obtained 67 g (73%) of 2-(p-fluorophenyl)-3-methylcrotonic acid as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:18][C:19]=1[NH:20][CH:21]([CH3:23])[CH3:22])=[O:14]>ClCCCl>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:18][C:19]=1[N:20]([CH:21]([CH3:23])[CH3:22])[C:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)=[O:9])=[O:14]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)cc1NC(C)C
Agent: CC1=CCC(C(=O)Cl)CC1
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccc(F)cc2)cc1N(C(=O)C1CC=C(C)CC1)C(C)C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
4-Methyl-cyclohex-3-enecarbonyl chloride was prepared according to the procedure reported in Journal of Organic Chemistry (1986) 51(23), PP4485-8. This 4-Methyl-cyclohex-3-enecarbonyl chloride (0.121 g, 0.77 mmol) was dissolved along with 5-(4-Fluoro-phenyl)-3-isopropylamino-thiophene-2-carboxylic acid methyl ester (0.150 g, 0.51 mmol) in anhydrous 1,2-dichloroethane (2 mL). The reaction mixture was stirred for 16 h at reflux. Then, the solvents were removed and the residue was purified by flash chromatography (8:2 Hexane/EtOAc) to obtain 140 mg (66%) of 5-(4-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester. 1H NMR (CDCl3, 400 MHz): δ 7.60 (m, 2H), 7.15 (m, 2H), 7.02 (d, 1H), 5.42-5.20 (m, 1H), 4.99 (m, 1H), 3.83 (d, 3H), 2.41-1.50 (m, 10H), 1.20 (m, 3H), 0.98 (d, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH:30]=2)[C:9]=1Br>O1CCOCC1.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][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH:30]=2)[C:9]=1/[CH:32]=[CH:35]\[O:37][CH2:38][CH3:39]
Reactant: CCOC(=O)C1(C)CC=C(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCO/C=C\c1c(C2=CCC(C)(C(=O)OCC)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (Int-18g, 48 mg, 0.061 mmol), (Z)-1-ethoxy-2-(tributylstannyl)ethane (72 mg), Pd(PPh3)4 (11 mg, 0.01 mmol) in dioxane (3 ml) was stirred at 100° C. under Ar for 8 h. After cooling to rt, the reaction mixture was passed through a short SiO2/KF (9:1) plug to removed majority of the Sn species. The filtrate was concentrated to give (Z)-ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(2-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (Int-18h) which was used in the next step directly without further purification. HPLC-MS tR=3.02 min (UV254 nm); mass calculated for formula C43H61N5O5Si2 783.4, observed LCMS m/z 784.2 (M+H).
Reaction SMILES: F[C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:23]=[C:24]([C:26]1[CH:27]=[CH:28][C:29]([CH3:44])=[C:30]([NH:32][C:33]([C:35]2[N:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]3=[N:37][CH:36]=2)=[O:34])[CH:31]=1)[NH2:25]>CN1C(=O)CCC1>[F:9][CH:2]1[CH2:3][CH:4]([C:6]2[O:8][N:23]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH3:44])=[C:30]([NH:32][C:33]([C:35]4[N:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]5=[N:37][CH:36]=4)=[O:34])[CH:31]=3)[N:25]=2)[CH2:5]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 3,3-difluorocyclobutanecarboxylic acid (264 mg, 1.94 mmol) in anhydrous NMP (6 mL) was added 1,1′-carbonyldiimidazole (315 mg, 1.94 mmol). The reaction was stirred for 5 minutes. 5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (500 mg, 1.62 mmol) was added and the reaction was stirred for 25 minutes, then heated in the microwave at 120° C. for 12 minutes. The crude product was purified by silica chromatography to give N-(5-(5-(3-fluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F13). 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 9.53-9.50 (m, 1H), 8.70 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.90-7.87 (m, 1H), 7.83 (d, J=1.6, 8.0 Hz, 1H), 7.70-7.65 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.33-7.29 (m, 1H), 3.93-3.84 (m, 1H), 3.25-3.02 (m, 4H), 2.37 (s, 3H). MS m/z 410.3 (M+1)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[NH:42][C:41]2[C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][C:48](=[NH:51])[NH:49]O)[C:38](=[O:52])[N:37]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]=2[N:35]=1>CS(C)=O>[Cl:33][C:34]1[NH:42][C:41]2[C:40](=[O:43])[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][C:48]3[N:49]=[C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][N:51]=3)[C:38](=[O:52])[N:37]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]=2[N:35]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCn1c(=O)n(CCCCC(=N)NO)c(=O)c2[nH]c(Cl)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CS(C)=O
Product: CCCCCn1c(=O)n(CCCCc2noc(-c3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 40 °C
Reaction time: 5 h
Yield: 25.1 %

Procedure:
Benzoic acid (18 mg, 0.15 mmol) was treated with a solution of 1H-1,2,3-benzotriazol-1-ol hydrate (25 mg, 0.19 mmol) in DMSO (0.3 ml). To this was added a solution/suspension of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) in DMSO (0.3 ml) followed by a solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (55 mg, 0.15 mmol) in DMSO (0.3 ml). The mixture was heated at 40° C. for 1 h, then at 80° C. for 5 h and then cooled. The mixture was subjected to purification by MDAP. Product-containing fractions were blown to dryness by a stream of nitrogen to yield the title compound as a white solid (17.2 mg, 25%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8](O)=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:11])[CH2:14][CH2:13]1
Reactant: Cc1ccccc1CC(=O)O
Reactant: NC1CC1
Product: Cc1ccccc1CCNC1CC1

Procedure:
Synthesized according to typical procedures C and D from o-tolylacetic acid and cyclopropylamine.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1[CH:25]=[CH:24][C:23]2[CH2:26][CH2:27][CH2:28][N:21]3[C:22]=2[C:14]=1[C:15]1[C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]=13.[CH3:30][C:31]1[N:35](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=[N:33][C:32]=1[CH:55]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(O)(=O)C>[CH3:30][C:31]1[NH:35][CH:34]=[N:33][C:32]=1/[CH:55]=[C:17]1\[CH2:18][CH2:19][C:20]2[N:21]3[CH2:28][CH2:27][CH2:26][C:23]4[CH:24]=[CH:25][CH:13]=[C:14]([C:15]=2[C:16]\1=[O:29])[C:22]3=4
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCc2c1c1cccc3c1n2CCC3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: Cc1[nH]cnc1/C=C1\CCc2c(c3cccc4c3n2CCC4)C1=O
Reaction time: 0.5 h
Yield: 220.1 %

Procedure:
n-Butyllithium (1.73M in hexane; 4.14 ml) was added dropwise to a cold (-70°) stirred solution of diisopropylamine (1 ml) in dry THF (10 ml) under nitrogen. The resulting solution was stirred at 0° for 30 min, cooled to -70° and added dropwise to a cold (-70°) stirred suspension of 5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (645 mg) in dry THF (20 ml) under nitrogen. The solution was allowed to reach 0° over 1 h, cooled to -70° and a solution of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (1.01 g) in dry THF (10 ml) was added dropwise. The stirred mixture was allowed to reach room temperature over 2 h, and then stirred for a further 3 h. The solution was cooled to -70° and treated with acetic acid (8 ml) and p-toluenesulphonic acid (5.44 g) and heated at reflux for 16 h. The solvent was removed in vacuo, the residue was treated with 8% sodium bicarbonate solution (150 ml) and extracted with dichloromethane (4×50 ml). The combined, dried organic extracts were evaporated to give a gum (ca. 2 g) which was purified by FCC eluting with System A to give the title compound (145 mg) as a solid, m.p. 260°-264°.
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:18]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:12]1([C:10]2[S:11][C:7]3[C:8]([N:9]=2)=[C:18]2[C:4](=[CH:5][CH:6]=3)[NH:21][C:20](=[O:22])[CH2:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1c([N+](=O)[O-])ccc2sc(-c3ccccc3)nc12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(ccc3sc(-c4ccccc4)nc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (5-nitro-2-phenyl-benzothiazole-4-yl)-acetonitrile (204.2 mg 0.692 mmol) (Starting Material 6) was suspended in concentrated H2SO4/H2O (1/1, 3 mL)) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (5 mL) heated at reflux was added excess zinc dust (0.45 g, 6.92 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-thiazolo[4,5-e]indol-7-one. (Yield 20 mg, 11%)
Reaction SMILES: O[CH2:2][C:3]1[C:8]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[N:4]=1.CCN(S(F)(F)[F:39])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:39][CH2:2][C:3]1[C:8]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[N:4]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2CO)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2CF)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A solution of 1-methylethyl 4-[({2-(hydroxymethyl)-6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (131 mg, 0.28 mmol) in CH2Cl2 (5 mL) was cooled to −78° C. DAST (0.12 mL, 0.85 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was poured into aqueous NaHCO3 and extracted with EtOAc (50 mL×2). The combined organic extract was washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a purplish-red oil. The crude material was purified by flash chromatography on a silica gel column eluted with 20% EtOAc/CH2Cl2 to give 86 mg (66%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, 2H, J=8.6 Hz), 8.00 (d, 2H, J=8.3 Hz), 7.80-7.75 (m, 1H), 7.31 (d, 1H, J=8.8 Hz), 5.58 (d, 2H, J=47.4 Hz), 4.92 (septet, 1H, J=6.2 Hz), 4.22 (bs, 2H), 3.92 (d, 2H, J=6.1 Hz), 3.07 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 465 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:43])([CH3:42])[C@@H:3]([C:16]([N:18]1[CH2:26][C@H:25]([O:27][C:28]2[C:37]([CH:38]=C)=[N:36][C:35]3[C:30](=[CH:31][C:32]([O:40][CH3:41])=[CH:33][CH:34]=3)[N:29]=2)[CH2:24][C@H:19]1[C:20]([O:22][CH3:23])=[O:21])=[O:17])[NH:4][C:5]([O:7][C@@H:8]1[CH2:10][C@H:9]1[CH2:11][CH2:12][CH2:13][CH:14]=C)=[O:6]>ClCCCl>[C:2]([C@H:3]1[C:16](=[O:17])[N:18]2[CH2:26][C@@H:25]([CH2:24][C@H:19]2[C:20]([O:22][CH3:23])=[O:21])[O:27][C:28]2=[N:29][C:30]3[CH:31]=[C:32]([O:40][CH3:41])[CH:33]=[CH:34][C:35]=3[N:36]=[C:37]2[CH:38]=[CH:14][CH2:13][CH2:12][CH2:11][C@@H:9]2[CH2:10][C@H:8]2[O:7][C:5](=[O:6])[NH:4]1)([CH3:43])([CH3:1])[CH3:42]
Reactant: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(OC)ccc3nc2C=C)C[C@H]1C(=O)OC)C(C)(C)C
Agent: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCC/C=C/c1nc3ccc(OC)cc3nc1O2
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCC=Cc1nc3ccc(OC)cc3nc1O2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution (0.02 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valyl-(4R)-4-[(7-methoxy-3-vinylquinoxalin-2-yl)oxy]-L-prolinate in DCE was heated to 80° C. then treated with Zhan 1 catalyst (0.15 eq). The resulting mixture was stirred at 80° C. for 1 h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (20-50% EtOAc/petroleum ether) to give the title compound (25% for 2 steps) as a foam. MS (ES+) m/z 567 (M+H)+