Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([CH2:45][CH2:46][CH2:47][C:48](Cl)=[O:49])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CO>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:48](=[O:49])[CH2:47][CH2:46][CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Reactant: O=C(Cl)CCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)CCCc1ccccc1)CC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the resulting mixture cooled to 0° C. Added to this was 4-phenylbutanoyl chloride (12.79 mg, 0.070 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air, taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% CF3CO2H, Sunfire 19×100 mm, C18, 5 μm). The product-containing fractions were combined, concentrated to remove the organic solvent and the resulting precipitate isolated by filtration to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(4-phenylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (7.7 mg, 55% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.41-7.57 (1H, m), 7.12-7.40 (7H, m), 7.02-7.12 (1H, m), 4.88 (1H, s), 4.29-4.42 (1H, m), 4.15-4.29 (0.5H, m), 3.80-4.06 (1H, m), 3.44-3.70 (2.5H, m), 2.67 (1H, t, J=7.53 Hz), 2.57 (0.5H, t, J=7.40 Hz), 2.34-2.53 (2H, m), 2.20 (0.5H, t, J=7.53 Hz), 1.74-1.98 (2H, m), 1.23-1.42 (9H, m), 1.16 (3H, dd, J=6.65, 4.39 Hz), 0.88-1.09 (9H, m). 19F NMR (400 MHz, CD3OD) δ ppm −114.74, −115.22. LCMS (M+H) calcd for C35H44FN2O4: 575.32. found: 575.02.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])[C:14](=[O:23])[N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)=[N:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:13]1[C:14](=[O:23])[N:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][N:9]=2)[CH:12]=1)#[N:31]
Reactant: CC(=O)Oc1ccc(-c2cc(-c3ccccc3C#N)c(=O)n(-c3ccccc3)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1cc(-c2ccc(O)cn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
953 mg of 5-(5-acetoxypyridin-2-yl)-3-(2-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-one and 192 mg of potassium carbonate were added to 50 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. The mixture was further incorporated with 50 ml of methanol, and stirred at 40° C. for 15 minutes. The reaction mixture was diluted with ethyl acetate, and filtered by silica gel. The filtrate was concentrated under a vacuum and washed with a diethyl ether/methanol-based solvent, to obtain 786 mg of the subject compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22](C=O)=[CH:23][CH:24]=1.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:27]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][CH3:17])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3OC)nc(=O)c1-2
Yield: 127.2 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9 mmol), anisaldehyde (2.45 g, 18 mmol), xylenes (50 ml) and p-toluenesulfonic acid (0.5 g) was refluxed for 32 hours. The reaction mixture was stripped to dryness, treated with ethanol (100 ml) and then again concentrated to dryness. The residue was treated with CHCl3 (100 ml) and 10% K2CO3 (100 ml), the layers were separated and the aqueous layer was extracted with chloroform (3×100 ml). The combined organic layers were concentrated to approximately 25 ml and then combined with silica gel (30 g). The preloaded silica was placed on a silica gel column and eluted with ether/hexanes (8/10) to ether (100%) to afford 1.25 g (41%) of 1-cyclopentyl-3-ethyl-6-(2-methoxyphenyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 135°-136° C., after recrystallization from cyclohexane.
Reaction SMILES: C([O:5][C:6](=[O:44])[C@H:7]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:8][C:9](=[O:36])[C@H:10]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:11][C:12](=[O:27])[CH:13]([S:17]CC1C=CC(OC)=CC=1)[CH2:14][CH2:15][CH3:16])(C)(C)C.C1(OC)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[SH:17][CH:13]([CH2:14][CH2:15][CH3:16])[C:12]([NH:11][C@H:10]([C:9]([NH:8][C@H:7]([C:6]([OH:44])=[O:5])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]
Reactant: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(S)C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Combine 2-(4-methoxybenzylthio)-pentanoyl-(L)-homophenylalanyl-(L)-phenylalanine t-butyl ester (0.20 g, 0.33 mmol), mercury (II) acetate (0.134 g, 0.42 mmol), and anisole (0.37 mL, 3.4 mmol) in dichloromethane (9 mL). Cool in an ice bath and degas by repeatedly applying vacuum and filling the vessel with nitrogen, Add trifluoroacetic acid (4 mL). After 1 hour, warm to ambient temperature. After 3 hours, purge with hydrogen sulfide (gas) for about 10 minutes. Filter and evaporate in vacuo to give a residue. Repeatedly, combine the residue and carbon tetrachloride and evaporate in vacuo to give a residue. Triturate the residue with hexane to give the title compound as a solid (85 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH:16]1(/[CH:22]=[CH:23]/[C:24](Cl)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[CH:16]1(/[CH:22]=[CH:23]/[C:24]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:5]3[CH:13]=[CH:14][C:2]([CH3:1])=[CH:3][C:4]=3[N:15]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Reactant: Cc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methyl-2-amino-N-(2-pyridyl)aniline and (E)-3-Cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 407.47; mp: 141.0-142.0° C.; 1H-NMR (DMSO) δ: 8.73-8.71 (1H, m), 8.14 (1H, t, J=7.0 Hz), 7.61-7.56 (2H, m), 7.46 (1H, s), 7.26 (1H, d, J=8.1 Hz), 7.05 (1H, d, J=8.1 Hz), 6.92 (1H, dd, J=15.8, 7.0 Hz), 6.38 (1H, d, J=15.8 Hz), 2.42 (3H, s), 2.25-2.10 (1H, m), 1.80-1.55 (5H, m), 1.40-1.05 (5H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:17](=[O:18])[C:16](=[CH:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:15]2[N:11]([C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:13][N:14]=2)[C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]1=2)([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O>[C:1]([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:17](=[O:18])[CH:16]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:15]2[N:11]([C:12]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:13][N:14]=2)[C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 87.5 %

Procedure:
Following the procedure described for Example 1(A), Step B, [4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester (4.84 g, 9.37 mmol) was reduced in EtOH (150 mL) for 3 hours at 80° C. The residue was dissolved in EtOAc and was washed with aqueous NH4Cl (1×) and brine (1×). The organic solution was dried (Na2SO4), filtered and concentrated to provide 4.26 g of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester. 1H NMR (DMSO-d6) δ 7.65 (d, 1H), 7.53-7.38 (m, 7H), 7.27 (m, 1H), 7.18 (m, 2H), 6.98 (m, 1H), 6.89 (m, 2H), 4.75 (d, 1H), 4.43 (d, 1H), 3.82 (t, 1H), 3.59 (m, 2H), 1.22 (s, 9H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([F:34])[CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[C:24]([F:34])[CH:23]=1)[CH3:19]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 90 °C
Yield: 39.9 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-ethyl-3-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (131 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)—N-ethyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (82.3 mg, 0.182 mmol, 39.9% yield) as a yellow-green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.08 (m, 3H) 1.77-1.96 (m, 3H) 2.04-2.18 (m, 1H) 2.35-2.43 (m, 4H) 2.93-3.07 (m, 4H) 3.13-3.23 (m, 2H) 3.28-3.38 (m, 3H) 3.47-3.57 (m, 1H) 3.88-3.95 (m, 1H) 6.92 (d, J=2.02 Hz, 1H) 6.97 (t, J=8.84 Hz, 1H) 7.47-7.57 (m, 3H) 8.28 (t, J=5.56 Hz, 1H) 10.37 (s, 1H). [M+H] calc'd for C24H29FN6O2, 453; found, 453.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2Cl)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[NH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(Cl)cc1)c1cnccc1Cl
Solvent: O
Solvent: CO
Product: Clc1ccc(-c2n[nH]c3ccncc23)cc1
Reaction time: 3 h
Yield: 33 %

Procedure:
(4-Chlorophenyl)-(4-chloropyridin-3-yl)-methanone (3.88 g, 15.4 mmol) was dissolved in MeOH (20 mL) at room temperature and hydrazine hydrate (20 mL) was added. The reaction mixture was stirred for 3 h. The precipitate was filtered and purified by recrystallisation from PhMe/MeOH (˜4:1, ˜150 mL) to give 3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridine (1.16 g, 33.0%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[N:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=1)[C:7]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:6]=1[S:5]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([NH:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[N:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=1)[C:7]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:6]=1[S:5]2)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)sc1nc(N)nc(=Nc3ccccc3)n12
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc2c(c1)sc1nc(NC(C)=O)nc(=Nc3ccccc3)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
2-Amino-8-methoxy-4-phenylimino-4H-1,3,5-triazino[2,1-b]benzothiazole (0.3 g) and acetic anhydride (0.14 g) in dry pyridine (15 mls) were heated at 100° for 24 hours. After cooling to room temperature, methanol (5 mls) was added, the solution was stirred for 1 hour and the solvents were removed in vacuo. The residue was dissolved in chloroform, the solution washed with water, brine, dried (Na2SO4) and evaporated in vacuo to give a yellow solid (0.27 g). Purification by chromatography (silica gel, chloroform) gave the title compound as pale yellow crystals (0.18 g), mp 248°-29°.
Reaction SMILES: [C:1]([N:20]1[C:28]2[CH:27]=[C:26]([NH2:29])[N:25]=[CH:24][C:23]=2[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:35]([N:37]2C=N[CH:39]=[CH:38]2)=[O:36])C=1.CCN(C(C)C)C(C)C.N1C=CN=C1.[F:56][C:57]1[CH:62]=[CH:61][C:60]([C@H](N)C)=[CH:59][CH:58]=1>CCOC(C)=O.O1CCOCC1>[F:56][C:57]1[CH:62]=[CH:61][C:60]([C@H:38]([NH:37][C:35]([NH:29][C:26]2[N:25]=[CH:24][C:23]3[CH:22]=[N:21][N:20]([C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:28]=3[CH:27]=2)=[O:36])[CH3:39])=[CH:59][CH:58]=1
Reactant: Nc1cc2c(cn1)cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 28.6 %

Procedure:
1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (301 mg, 0.8 mmol), CDI (519 mg, 3.2 mmol), DIEA (0.5 ml, 2.87 mmol and 1,4-dioxane (5 mL) were charged in a microwave vial. The mixture was stirred at 50° C. for 4.5 h. Additional CDI (519 mg, 3.2 mmol) and imidazole (218 mg, 3.20 mmol) were added, the mixture was stirred at 50° C. for 16 h and then treated with (R)-1-(4-fluorophenyl)ethanamine (536 mg, 3.85 mmol). The mixture was stirred at 50° C. for 2 h and then diluted with EtOAc washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford a residue, which was purified by chromatography on silica gel (0-40% EtOAc in hexane, 25 CV; 40-100% EtOAc in hexane, 20 CV) to afford (R)-1-(1-(4-fluorophenyl)ethyl)-3-(1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (154 mg, 0.229 mmol, 28%) as a yellow solid. MS ESI calc'd. for C34H29FN5O [M+H]+ 542, found 542.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][CH2:18][CH2:19]Cl)[CH3:16].O>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:17][CH2:18][CH2:19][O:7][C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: Cc1ncccc1O
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCCOc1cccnc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
Potassium carbonate (2.20 g, 15.9 mmol) was added to a stirred solution of 3-hydroxy-2-methylpyridine (1.45 g, 13.3 mmol) and 2-chloroethyl ethyl ether (1.75 mL, 15.9 mmol) in DMF (7 mL) and the mixture was stirred at 70° C. overnight. The reaction was not complete and additional 2-chloroethyl ethyl ether (1 equiv.) and potassium carbonate (1 equiv.) were added and the mixture was stirred at 85° C. for 8 h. Water and ethyl acetate were added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 50% ethyl acetate), obtaining 1.80 g (75%) the title compound.
Reaction SMILES: [C:1]([NH:8][C:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO.O>[CH2:38]([O:11][C:10](=[O:12])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)(Cc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
BOC-2,2-dibenzyl glycine (3.29 g, 9.25 mmol) is dissolved in a solution of methanol(18 ml) and water (2 ml) and the pH adjusted to 8 with 20% cesium carbonate solution (11 ml). The solution is concentrated in vacuo to dryness and the residue dissolved in dimethylformamide (DMF) (25 ml) and re-concentrated twice and dried under high vacuum. The cesium salt is taken up into DMF (25 ml), benzyl bromide (1.74 g, 10.2 mmol) is added and the mixture stirred at room temperature for 16 hours. The mixture is concentrated in vacuo and the residue diluted with ether. The organic phase is washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 10% ethyl acetate in hexane to give BOC-2,2-dibenzyl glycine benzyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[Cl:14].S(Cl)(Cl)=O.O.N.[CH3:21]O>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH3:21])=[O:12])[C:3]=1[Cl:14]
Reactant: CO
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 5 °C

Procedure:
To a solution of 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (i.e. the product of Step D1 or D2 of Example 2) (2.0 g, 8.5 mmol) in methanol (20 mL) was added dropwise thionyl chloride (4 mL, 70 mmol). The mixture was heated at reflux for 24 h. Concentrated sulfuric acid (5 drops) was added, and the reaction mixture was heated at reflux for 16 h. After the mixture was cooled, water (30 mL) was added, and aqueous ammonia (28%, 10 mL) was added dropwise. The mixture was cooled to 5° C., and the solid was isolated by filtration, washed with water and dried in a vacuum oven at 40° C. to afford the title product (2.3 g), a compound of the present invention.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[CH2:25][C@@H:24]4[C:26]([O:28]C)=[O:27])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]4[CH2:25][C@H:24]4[C:26]([OH:28])=[O:27])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H]1C[C@@H]1c1ccc(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc([C@@H]4C[C@H]4C(=O)O)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a suspension of (1S, 2S)-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclopropanecarboxylate (111 mg, 0.269 mmol) in ethanol (5 ml) was added 2 N NaOH (5 ml, 10.00 mmol). The mixture was stirred under nitrogen at room temperature overnight. Reaction mixture was neutralized by addition of acetic acid, and then acidified with a few drops of 1 N aqueous HCl (pH about 2). White solid precipitated and was collected by filtration, washed with 0.1N HCl (3×5 mL), and dried under vacuum to give Trans-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclopropanecarboxylic acid (64 mg, 59%). LCMS (Table 1, Method f) Rt=2.99 min, m/z 399.16 (M+H)+. 1H NMR (400 MHz, DMSO) δ ppm 8.07 (d, 2H), 8.05 (d, 1H), 7.99 (dd, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 4.82 (sept., 1H), 2.54 (m, 1H), 1.97 (m, 1H), 1.53 (td, 1H), 1.46 (ddd, 1H), 1.35 (d, 6H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[C:5]([F:21])[CH:4]=1.CNN(NC)C(Cl)=[O:26].[CH:30]([N:33]([CH2:37]C)[CH:34](C)C)(C)C>ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:10](=[O:20])[NH:11][N:12]=[C:13]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:37]([N:33]([CH3:34])[CH3:30])=[O:26])[CH2:16]2)=[C:5]([F:21])[CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNN(NC)C(=O)Cl
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1F
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 4 mL screwcap vial was placed 4-(4-bromo-2-fluorophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.265 mmol), polystyrene-DIEA (216 mg, 3.68 mmol/g loading, 0.794 mmol) and 2 mL dichloromethane. The contents were lightly swirled. In a separate vial, N,N-dimethylaminocarbamoyl chloride (0.265 mmol) was taken up in 1 mL dichloromethane and added to the starting material dropwise via pipette. The vial was capped and the solution was lightly agitated at room temperature overnight. The reaction had only progressed by 50% via LCMS analysis. Another equivalent of N,N-dimethylaminocarbamoyl chloride (0.265 mmol) was added to the reaction. After 8 h at room temperature, another equivalent of N,N-dimethylaminocarbamoyl chloride (0.265 mmol) was added, as well as N,N-diisopropylethylamine (0.100 mL). After 1 h, the reaction mixture became clear. The solution was filtered to remove the polystyrene-DIEA and then concentrated in vacuo. Reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA) was utilized in purifying the title compound (60 mg, 55%). MS(ES)+ m/e 412.3, 414.1 [M+H]+.
Reaction SMILES: C([NH:4][CH:5]([C:13]1[NH:14][C:15]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.ClCCl.C(O)C>Cl.CO>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([CH:5]([NH2:4])[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:14][C:15]=2[CH:21]=1
Reactant: CC(=O)NC(Cc1ccccc1)c1nc2ccc(Cl)cc2[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: NC(Cc1ccccc1)c1nc2ccc(Cl)cc2[nH]1

Procedure:
1.35 g (4.302 mmol) of rac.-N-acetyl-1-(5-chlorobenzimidazol-2-yl)-2-phenylethylamine is placed in a mixture of 20 mL of 4 molar hydrochloric acid and 15 mL of methanol and the mixture is refluxed for 2 hours. Then all the volatile constituents are removed under reduced pressure. The crude product is further reacted directly. Rf value: 0.50 (silica gel; dichloromethane/ethanol=8:2).