Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[O:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[O:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:26]=[CH:25][C:9]=3[N:10]=2)[CH2:16][CH2:17]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Reactant: CN1CCNCC1
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NC2CCOc4ccccc42)=N3)CC1
Yield: 100.1 %

Procedure:
Prepared from the above described rac-2-chloro-N-[2-(chroman-4-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (186 mg, 0.50 mmol; HPLC 1.092 min) and 1-methylpiperazine (1.1 ml, 10 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (218 mg, 100%; HPLC 0.413 min), MS (ISP) m/e=436.1 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:7]([O:8][CH2:9][CH:10]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[O:12][CH2:11]3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: Clc1nccnc1OCC1COc2ccccc2O1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccnc2OCC2COc3ccccc3O2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and N-ethylpiperazine (219 mg, 1.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 128 mg (66%) of the title product. HRMS m/z calcd for C19H24N4O3(M)+356.1848, found 356.1848. Anal. (C19H24N4O3) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: NC1CCCCC1
Product: COc1cc2ncc(NC3CCCCC3)nc2cc1OC
Temperature: 135 °C
Yield: 69 %

Procedure:
To 0.3 g (1.34 mmol) of 2-chloro-6,7-dimethoxyquinoxaline is added approx. 1 mL of cyclohexylamine. The mixture is heated overnight at 105° C. and a further 10 hours at 135° C. The mix is partitioned between CH2Cl2 and saturated NaHCO3. The organic layer is dried (MgSO4) and concentrated. The resulting syrup is chromatographed (1:1 EtOAc : CH2Cl2) to provide 0.265 g of the product as a lt. brown solid in 69% yield (m.p. 188-189.5). Anal. calcd for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.82; H, 7.28; N, 14.45.
Reaction SMILES: [CH:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(O)C.[Pd]>[CH2:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1cc2ccccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc2ccccc2[nH]1

Procedure:
2-Hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure until the hydrogen gas consumption was stopped completely. The reaction mixture was filtered through Celite. The solvent was evaporated to afford the product.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.[CH2:14]([N:21]1[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][C:25]=2C(=O)[O:23][C:22]1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(N(C)C)=O>[CH2:14]([N:21]1[C:26]2[C:25](=[CH:30][CH:29]=[CH:28][N:27]=2)[C:5]([OH:7])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:22]1=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ncccc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a slurry of sodium hydride (60%, 0.118 g, 2.95 mmol) in anhydrous dimethylacetamide (6 mL) at 0° C. under N2 was added diethyl malonate (0.472 g, 2.95 mmol) dropwise over 5 minutes. The mixture was stirred at ambient temperature for 1 hour, reacted with the product of Example 15A (0.50 g, 1.97 mmol), and heated at 120° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and cold water, and adjusted to pH to 5 with 1 M HCl. The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was recrystallized from methanol to give the title compound as a white solid (0.439 g, 68%). MS (ESI+) m/z 325.0 (M+H)+, 347.0 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=7.17 Hz, 3H), 4.32 (q, J=7.23 Hz, 2H), 5.55 (s, 2H), 7.23 (m, 5H), 7.37 (dd, J=7.91, 4.60 Hz, 1H), 8.45 (dd, J=7.91, 2.02 Hz, 1H), 8.71 (dd, J=4.78, 1.84 Hz, 1H), 13.00 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][C:33]([F:43])=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:44])[NH:19][C@:18]2([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:45][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:51]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[ClH:51].[NH2:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][C:33]([F:43])=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:44])[NH:19][C@:18]2([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:45][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2

Procedure:
A solution of (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(3-fluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1c, 1.3 g, 1.9 mmol) in 1 N HCl (4.7 ml, 19 mmol) was stirred at room temperature for 2 h. The reaction mixture was diluted with chloroform and toluene and evaporated to provide the title compound (1.11 g, quantitative yield) as a colorless solid. This material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14]C)=O)=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][NH2:23]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([NH:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[O:14])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: NCc1ccccn1
Reactant: COC(=O)c1ncc2cccnc2c1O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccn1)c1ncc2cccnc2c1O

Procedure:
To a solution of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1, Step 2 (0.05 g, 0.245 mmol) in dry toluene (3 mL) was added 1-pyridin-2-ylmethanamine (0.029 g, 0.270 mmol) and the mixture was heated to reflux for 16 hours. The solution was reduced to a smaller volume and refluxed for 4 additional hours. The solvent was removed under reduced pressure and the residue redissolved in DMF and filtered and the solution was purified by preparative HPLC (Gilson semipreparative HPLC system and a YMC Combiprep Column (50×20 mm I.D., C18, S-5 uM, 120 A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:18][CH3:19].[H-].[Na+].[H][H].CI.Cl[C:27]1(OC)C(Cl)=CC2C(=O)C(C3CCCC3)(C)CC=2C1>COCCOC>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)([CH3:27])[C:8]2=[O:12])=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Reactant: COC1(Cl)CC2=C(C=C1Cl)C(=O)C(C)(C1CCCC1)C2
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2

Procedure:
6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-methoxy-1H-inden-1-one (7.5 g., 0.025 mole) is dissolved in dry 1,2-dimethoxyethane (200 ml.) under nitrogen. Sodium hydride (57% in mineral oil; 1.16 g., 0.0275 mole) is then added and the mixture is stirred at 80° until evolution of hydrogen ceases (2 hours). The solution is cooled and methyl iodide (7.5 ml.) is added, the mixture is again brought to reflux and then cooled. Most of the 1,2-dimethoxyethane is evaporated and water is added to the residue which soon solidifies and is crystallized from methylcyclohexane and from ethanol-water (4:1) to obtain 3.4 g. of 5,6-dichloro-2-cyclopentyl-2,3-dihydro-5-methoxy-2-methyl-1H-inden-1-one, m.p. 109°-111.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[N:7]=1.Cl[C:22]1[S:23][CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(OC)n1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: COc1nc(-c2sccc2[N+](=O)[O-])cs1

Procedure:
2-Methoxy-4-(3-nitrothiophen-2-yl)thiazole was prepared from 2-methoxy-4-(tributylstannyl)thiazole (1.0 g, 2.47 mmol) and 2-chloro-3-nitrothiophene (0.404 g, 2.47 mmol) according to protocol E. Retention time (min)=2.516, method [1], MS(ESI) 242.9 (M+H).
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCOCC.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1>[CH:22]1([C:25]([O:16][CH2:15][CH2:14][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:26])[CH2:24][CH2:23]1
Reactant: CCCCCCCCCCCCSCCO
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCCCSCCOC(=O)C1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 2.0 g. 2-hydroxyethyl dodecyl sulfide, 60 ml. anhydrous ether and 1.27 g. cyclopropyl carboxylic acid chloride at 0° is added 1.3 ml. pyridine. The mixture is allowed to warm to room temperature and is stirred for three days. The product is isolated using the procedure of Example 3 to yield 3-thiapentadecyl cyclopropanecarboxylate, boiling point 131° -137°137° (0.03 mm.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:5].[CH3:17][O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)=[O:20].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:25]([C:24]1[CH:28]=[CH:29][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:22][CH:23]=1)=[O:26]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cccc(CCNC(=O)CCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCCC(=O)NCCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-N-(3-methoxyphenethyl)propanamide (60 mg, 0.27 mmol) was added 4-(methoxycarbonyl)benzoic acid (49 mg, 0.27 mmol), hydroxybenzotriazole (3.7 mg, 0.027 mmol), triethylamine (42 μL, 0.30 mmol) and dimethyformamide (2.7 mL). Lastly, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (57 mg, 0.30 mmol) was added and the solution was allowed to stir overnight at room temperature in a capped vial. Upon completion of the reaction an aqueous workup is performed to give the crude product which was purified using flash chromatography.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].IC.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:19]3[N:20]([CH2:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]4)[C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[C:28]#[CH:29])=[N:22][C:18]=3[CH:17]=[C:16]([C:38]3[NH:42][C:41](=[O:43])[O:40][N:39]=3)[N:15]=2)[CH:11]=[N:12][CH:13]=1.[CH3:44]CN(C(C)C)C(C)C>[Cu]I.CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:19]3[N:20]([CH2:30][C@H:31]4[CH2:32][CH2:33][C@H:34]([CH3:37])[CH2:35][CH2:36]4)[C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[C:28]4[N:1]=[N:2][N:3]([CH3:44])[CH:29]=4)=[N:22][C:18]=3[CH:17]=[C:16]([C:38]3[NH:42][C:41](=[O:43])[O:40][N:39]=3)[N:15]=2)[CH:11]=[N:12][CH:13]=1
Reactant: C#CC1CCCN1c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(C(C)C)C(C)C
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cc(C2CCCN2c2nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)nn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a reaction vessel were added DMSO (0.4 mL), sodium azide (0.005 g, 0.080 mmol) and iodomethane (0.006 mL, 0.085 mmol). The reaction vessel was sealed and stirred at 50° C. for 12 hours. To the reaction was then added 3-(4-(5-chloropyridin-3-yl)-2-(2-ethynylpyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (0.020 g, 0.039 mmol), CuI (0.004 g, 0.019 mmol), and DIEA (0.015 mL, 0.086 mmol). The reaction vessel was sealed and further stirred at 50° C. for 6 hours. To the reaction was added DMSO (0.6 mL), and the solution was passed through a syringe filter. The filtrate was purified by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v TFA modifier) to afford 3-(4-(5-chloropyridin-3-yl)-2-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (TFA salt). MS ESI calc'd. for C28H31ClN10O2 [M+H]+ 575. found 575. 1H NMR (500 MHz, DMSO-d6): δ 12.81 (s, 1H); 8.85 (s, 1H); 8.77 (d, J=2.3 Hz, 1H); 8.41 (s, 1H); 7.94 (s, 1H); 7.79 (s, 1H); 5.50 (t, J=7.1 Hz, 1H); 3.94 (s, 3H); 3.80-3.86 (m, 3H); 3.43-3.46 (m, 1H); 2.37-2.39 (m, 1H); 2.12-2.18 (m, 2H); 1.95-2.00 (m, 1H); 1.28-1.30 (m, 2H); 0.96-1.03 (m, 2H); 0.66 (d, J=6.5 Hz, 4H); 0.41-0.44 (m, 3H); 0.30-0.36 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([OH:6])=[O:5].[CH2:10]([C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)=[N:22][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>ClCCl>[CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([O:6][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:20]=[CH:19][C:18]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][N:22]=2)=[CH:29][CH:28]=1)=[O:5]
Reactant: CC[C@H](C)[C@H](Cl)C(=O)O
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(OC(=O)[C@@H](Cl)[C@@H](C)CC)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8 g of (S,S)-3-methyl-2-chloropentanoic acid, 16 g of p-(5-n-octylpyrimidin-2-yl)phenol, 11.6 g of N,N-dicyclohexylcarbodiimide, 0.6 g of 4-N,N-dimethylamino-pyridine and 300 ml of dichloromethane is stirred overnight at room temperature. After filtering off the precipitated urea derivative, the filtrate is washed with dilute hydrochloric acid and water, and the organic phase is worked up in the usual manner. p-(5-n-Octylpyrimidin-2-yl)-phenyl (S,S)-3-methyl-2-chloropentanoate is obtained.
Reaction SMILES: C[OH:2].NC1C=CN=CC=1.[CH2:10]([O:17][CH2:18][C@@H:19]1[O:21][CH2:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C]=O.C1[CH2:28][O:27][CH2:26]C1>>[CH3:26][O:27][C:28](=[O:2])[CH2:20][C@@H:19]([OH:21])[CH2:18][O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CO
Reactant: C1CCOC1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: Nc1ccncc1
Agent: [C]=O
Product: COC(=O)C[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
In a 50 mL-volumetric autoclave were added deaerated methanol (15 mL) and THF (10 mL), and thereto were added 4-aminopyridine (47 mg, 0.5 mmol) and (R)-benzylglycidyl ether (3.3 g, 20 mmol, >99% ee). Then to the mixture was added crystalline dicobaltoctacarbonyl complex (171 mg, 0.5 mmol). After covering the autoclave with a cap, carbon monoxide (1 MPa) was introduced therein and the mixture was reacted at 35° C. for 24 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to Kugelrohr distillation to give (R)-4-benzyloxy-3-hydroxybutanoic acid methyl ester (4.0 g, 89%, >99% ee) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)=[O:1]
Reactant: OCc1ccc(-c2cccc3cncn23)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(-c2cccc3cncn23)cc1

Procedure:
A solution of 5-(p-hydroxymethylphenyl)imidazo[1,5-a]-pyridine (0.52 g) in 10 ml of methylene chloride is refluxed with 5.2 g of activated manganese dioxide for 24 h. An additional 5.2 g of manganese dioxide is added and the reaction mixture is refluxed an additional 6 h, filtered, and the solvent is evaporated to yield 5-(p-formylphenyl)-imidazo[1,5-a]pyridine, m.p. 144°-146°.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:45])[NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[C:29]6=[O:41])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)[CH2:3][CH2:2]1.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C@H:30]1[CH2:31][CH2:32][N:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:19]3[S:20][C:13]4[C:14](=[N:15][CH:16]=[CH:17][C:12]=4[O:11][C:10]4[CH:42]=[CH:43][C:7]([NH:6][C:5]([NH:4][CH:1]5[CH2:3][CH2:2]5)=[O:45])=[CH:8][C:9]=4[F:44])[CH:18]=3)=[N:26][CH:25]=2)[C:29]1=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1=O
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To a solution of 107 (120 mg, 0.19 mmol) in DCM (20 mL) was added water (0.5 mL) and TFA (4 mL, 51.9 mmol). The reaction mixture was stirred at RT for 6 h, concentrated, diluted with ethyl acetate, and washed with 1N NaOH. The organic phase was collected and the aqueous phase was re-extracted with ethyl acetate. The combined organic layers (a lot of unsoluble material stayed on the walls of the separatory funnel which was dissolved in MeOH and combined with the organic layers) were concentrated. A 1N NaOH solution was added; the suspension was stirred for 30 min and the solid was collected by filtration. The crude product was purified by Biotage (SNAP 50 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 40/60 over 20 CV), to afford the title compound 108 (77 mg, 0.14 mmol, 76% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 8.55-8.51 (m, 2H), 8.36 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.81 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.2 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.65 (d, J=5.6 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.52 (d, J=15.2 Hz, 1H), 4.45 (d, J=15.2 Hz, 1H), 4.15-3.65 (m, 214), 3.58 (t, J=8.8 Hz, 1H), 3.30-3.14 (m, 2H), 2.59-2.52 (m, 1H), 2.34-2.23 (m, 1H), 1.77-1.65 (m, 1H), 0.68-0.62 (m, 2H), 0.45-0.37 (m, 2H). MS (m/z): 533.6 (M+H).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[C:6](Cl)(=O)[C:7]([CH3:10])([CH3:9])[CH3:8].Cl.[NH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1)[NH2:15]>>[C:7]([C:6]1[CH:1]=[C:2]([CH3:3])[N:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][OH:24])=[CH:20][CH:21]=2)[N:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC#C[Mg]Br
Reactant: CC(C)(C)C(=O)Cl
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: Cc1cc(C(C)(C)C)nn1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 63 from propynylmagnesium bromide, pivaloyl chloride and 2-(4-hydrazinophenyl)ethanol hydrochloride: MS (EI) m/z 334 [M]+, 1H-NMR (CDCl3) δ 7.39-7.29 (4H, m), 6.05 (1H, s), 3.85 (2H, m), 2.90 (2H, m), 2.30 (3H, s), 1.60 (1H, br.s), 1.33 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[CH:22]=[N:23][O:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[O:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)[CH:26]=[CH:25][C:21]=2[CH:22]=[N:23]1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4cnoc4c3)n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5cnoc5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-benzo[d]isoxazol-6-yl-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(benzo[d]isoxazol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}4-tert-butyl-benzamide.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:1][C:2]2[C:11]3[C:6](=[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:18])[C:3]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: O=c1oc2c(-c3ccccc3)cccc2c(O)c1-c1ccccc1
Reactant: ClCCN1CCOCC1
Product: O=c1oc2c(-c3ccccc3)cccc2c(OCCN2CCOCC2)c1-c1ccccc1
Yield: 75 %

Procedure:
15.7 g. (0.05 mol) of 4-hydroxy-3,8-diphenyl-coumarin are treated, as in Example 8, with 9.7 g. (0.065 mol) of 1-chloro-2-morpholinoethane. After recrystallisation from isopropanol, 16 g. are obtained. M.P. 106°-108° C. Yield 75% (theoretical yield 21.3 g.).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N:16]#[C:17]Br>C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:17]#[N:16])[CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Solvent: ClCCl
Product: N#CN1CCN(Cc2ccc(F)cc2)C(=O)C1

Procedure:
To 1-(4-Fluorobenzyl)piperazin-2-one (0.50 g, 2.40 mmol, Example 1, Step 4) dissolved in methylene chloride (75 mL) was added diisopropylethylaime (0.84 mL, 4.80 mmol) and cyanogen bromide (0.28 g, 2.64 mmol) and the resultant solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel using a 0-5% MeOH/CHCl3 gradient. The pure fractions were concentrated to yield the title compound as a white solid. 1H NMR (400 MHz, d6 DMSO) δ 7.31 (m, 2H), 7.18 (m, 2H), 4.54 (s, 2H), 3.98 (s, 2H), 3.49 (m, 2H), and 3.33 (m, 2H); ES MS (M+1)=234.3.