Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].[Na].Cl[CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].[SiH4]>CN(C)C=O>[SH:1][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9]
Reactant: S
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [Na]
Agent: [SiH4]
Solvent: CN(C)C=O
Product: CO[Si](CCCS)(OC)OC
Temperature: 110 °C
Yield: 84 %

Procedure:
566 g (10.1 mols) of sodium hydrogen sulfide together with 2,400 g of dimethylformamide were introduced into the apparatus described in Example 1. While stirring, 2,000 g (10.1 mols) of 3-chloropropyltrimethoxysilane were added to the contents of the flask over a period of 60 minutes, whereby the temperature of the contents of the flask rose to about 100° C. By application of additional heat the temperature was increased to 110° C. and maintained at this level. Samples of the reaction mixture were taken at intervals of 15 minutes and gas-chromatographically analyzed. After the elapse of 75 minutes of reaction time only traces of the provided silane compound could be detected in the reaction mixture. The distillative work-up of the raw reaction mixture gave a yield of 84% of 3-mercaptopropyltrimethoxysilane.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[O:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[O:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)co1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)co1
Temperature: 160 °C

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide (160 mg, 0.472 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (378 mg, 1.89 mmol) in n-BuOH (3 mL) was stirred at 160° C. in a sealed tube. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purified by C-18 reverse phase flash chromatography (Biotage Flash 25 M+) on SP4 unit eluting with 10-85% CH3CN/water gradient (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-methyloxazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate as a solid. This material was treated with neat TFA (3 mL), and after 30 minutes the mixture was concentrated in vacuo. The residue obtained was dissolved in few drops of CH2Cl2 and treated with 2M HCl in ether (3 mL). The solid formed was filtered, washed with additional Et2O and dried under high vacuum to provide (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide hydrochloride (23 mg, 12% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.85 (s, 1H), 10.41 (s, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 8.27 (br s, 3H), 8.02 (s, 1H), 4.01-3.99 (m, 1H), 3.69-3.63 (m, 1H), 3.60-3.52 (m, 1H), 3.36-3.29 (m, 1H), 3.06-2.99 (m, 1H), 2.58 (s, 3H), 2.34-2.25 (m, 2H), 1.89-1.82 (m, 1H), 1.59-1.51 (m, 1H); LCMS (APCI+) m/z 419, 421 (M+H)+, Retention time=2.44 minutes (Method 2).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:15]1[C:14]2[CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[CH2:11][O:12][C:13]=2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16]=1[NH2:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(N)cc2c(c1C)OCC2c1ccc(C(C)C)cc1
Solvent: CC#N
Product: Cc1c(C)c2c(c(Br)c1N)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine synthesized in Reference Example 31 (5.62 g, 21.1 mmol) in acetonitrile (60 mL), was added N-bromosuccinimide (3.76 g, 21.1 mmol) at −20° C., and the mixture was stirred at the same temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 0.90 g (yield 34%) of the title compound. Melting point: 191-193° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3]\[CH2:4][S:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1.[CH3:21][C:22]1[C:23]([CH2:31]Cl)=[N:24][CH:25]=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29]>CN(C)C=O.C(Cl)Cl>[CH3:21][C:22]1[C:23]([CH2:31][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]2[S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[N:24][CH:25]=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29]
Reactant: CC(C)=CCC/C(C)=C/CSc1nc2ccccc2[nH]1
Reactant: COc1c(C)cnc(CCl)c1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2c(SC/C=C(\C)CCC=C(C)C)nc3ccccc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 126.3 %

Procedure:
To a solution of 2-[(3,7-dimethyl-2,6(E)-octadienyl)thio]-1H-1,3-benzimidazole from Example 1 (1.5 g, 5.2 mmol) and 3,5-dimethyl-4-methoxy-2-pyridylmethyl chloride (0.465 g, 5 2 mmol) in dimethylformamide (7 mL) at 0° C. under nitrogen was added dropwise triton-B (5 mL of a 40% solution). The solution was stirred at ambient temperature for 72 hours, then at 50° C. for 48 hours. Evaporation of the solvent gave a residue which was dissolved in CH2Cl2, washed with water and dried over Na2SO4. Evaporation of the solvent and flash chromatography of the resultant oil (10% Et2O/CH2Cl2, Merck Kieselgel) gave 1.1 g of 1-(3,5-dimethyl-4-methoxy-2-pyridylmethyl)-2-[(3,7-dimethyl-2,6(E)-octadienyl)thio]-1H-1,3-benzimidazole (free base) which was converted to its oxalate salt (1.36 g). m.p. 76°-80° C. NMR (DMSO-d6) δ7.93(s,1H), 7.5(m,1H), 7.1(m,3H), 5.4(s,2H), 5.37(m,1H), 5.07(m,1H), 3.93(m,2H), 3.70(s,3H), 2,27(s,3H), 2.15(s,3H), 2.0(m,4H), 1.6(s,3H), 1.53(s,3H), 1.07(s,3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11](O)=O)[CH:4]=1.[NH2:14][C:15]1[C:20]([NH2:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:14][C:15]3=[N:16][CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]3[N:21]=2)[CH:4]=1
Reactant: COc1ccnc(CCC(=O)O)c1
Reactant: Cc1cnc(N)c(N)c1
Product: COc1ccnc(CCc2nc3cc(C)cnc3[nH]2)c1

Procedure:
Similarly to Example 1, 0.428 g of 3-(4methoxypyridin-2-yl)propionic acid (starting material A1), 0.26 g of 2,3-diamino-5-methylpyridine (Lappin et al., J. Amer. Chem Soc. 72, 2806 (1950) and 8 g of PPA (4 hours at 140° C.) give 0.25 g of the title compound of m.p. 150–152° C. (crystallized from ethyl acetate). The mass spectrum shows the molecular peaks MH+ and 2MNa+ at 269.3 and 559.1 Da.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][O:13][C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)=[O:15]>N1C=CC=CC=1>[CH3:12][O:13][C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)=[O:21])=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)CC(=O)N3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A mixture of 82.0 mg 5-amino-2-oxindole and 131.0 mg 4-methoxycarbonylbenzoyl chloride in pyridine was stirred at room temperature for 3 hr and poured into ice water. The precipitate was filtered, washed with water and dried in a vacuum oven to give 138.0 mg of 5-(4-methoxycarbonylbenzamido)-2-oxindole (81% yield).
Reaction SMILES: F[C:2]1C=C(SC2N(CC3C=CC=CN=3)C(CCC(OC)=O)=NC=2C(C)C)C=C(F)C=1.[Cl:31][C:32]1[CH:33]=[C:34]([S:38][C:39]2[NH:43][C:42]([CH2:44][O:45]CC3C=CC(OC)=CC=3)=[N:41][C:40]=2[CH:55]([CH3:57])[CH3:56])[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[CH:33]=[C:34]([S:38][C:39]2[N:43]([CH3:2])[C:42]([CH2:44][OH:45])=[N:41][C:40]=2[CH:55]([CH3:56])[CH3:57])[CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cccc(Cl)c3)[nH]2)cc1
Reactant: COC(=O)CCc1nc(C(C)C)c(Sc2cc(F)cc(F)c2)n1Cc1ccccn1
Product: CC(C)c1nc(CO)n(C)c1Sc1cccc(Cl)c1

Procedure:
By the same procedures as in Reference Example 2 (1) through (4), 5-(3-chlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16c) was obtained.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:2]2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(CC2CCCO2)CC1
Agent: Cl
Product: O=C(CN1CCN(CC2CCCO2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 48.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 110, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)acetamido)propanamide (23.1 mg, 48.9%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.92 (d, 1H), 7.60 (d, 2H), 7.29 (m, 5H), 7.21 (t, 2H), 7.03-6.97 (m, 4H), 4.69 (m, 1H), 4.52 (s, 2H), 3.89 (m, 1H), 3.79-3.68 (m, 3H), 3.59 (m, 1H), 2.96 (s, 2H), 2.45 (m, 5H), 2.34 (m, 5H), 1.89 (m, 1H), 1.76 (m, 2H), 1.44 (m, 1H). MS (EI) for C33H39FN4O5. found 591.7 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[CH:19]([C:21]1[O:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+].CCO>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.O>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:24]3[O:25][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.0 g, 0.00303 mol; prepared as described in Scheme 7A) and 5-formyl-2-furanylboronic acid (0.38 g, 0.00273 mol), sodium carbonate (0.64 g, 0.00606 mol) toluene (5 mL), EtOH (5 mL) and water (5 mL) were added. The reaction vessel was degassed with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.106 g, 0.0001515 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled and diluted with chloroform. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, chloroform) to yield the desired product as a yellow solid [0.48 g, 46%]. 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.40 (d, J=3.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 4.50 (brs, 4H), 3.91-3.88 (m, 4H); LC-MS (ESI): Calculated mass: 344.1; Observed mass: 345.0 (RT: 1.39 min).
Reaction SMILES: C([Zn]CC)C.[C:6](O)([C:8](F)(F)F)=[O:7].IC.[CH3:15][C:16]([CH3:35])([CH3:34])[CH2:17][N:18]1[C:26]2[C:21](=[N:22][C:23](/[CH:27]=[CH:28]/[CH2:29]CO)=[CH:24][CH:25]=2)[N:20]([CH3:32])[C:19]1=[O:33]>C(Cl)Cl>[CH3:35][C:16]([CH3:15])([CH3:34])[CH2:17][N:18]1[C:26]2[C:21](=[N:22][C:23]([C@@H:27]3[CH2:28][C@H:29]3[CH2:8][CH2:6][OH:7])=[CH:24][CH:25]=2)[N:20]([CH3:32])[C:19]1=[O:33]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(/C=C/CCO)nc21
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: CI
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCO)nc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diethyl zinc (0.53 mL, 0.53 mmol, 2.0 equiv, 1M in hexanes) was added to anhydrous DCM (0.53 mL) and cooled to 0° C. To this solution was added TFA (41 μL, 0.53 mmol, 2.0 equiv) in anhydrous DCM (0.27 mL), and the resulting mixture was stirred at 0° C. for 15 min. Following this duration, iodomethane (43 μL, 0.53 mmol, 2.0 equiv) in anhydrous DCM (0.27 mL) as added and the resulting reaction mixture was stirred for and additional 20 min. 1-(2,2-Dimethylpropyl)-5-[(1E)-4-hydroxybut-1-en-1-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-3, 77 mg, 0.27 mmol, 1.0 equiv) in anhydrous DCM (0.27) as then added. After 1 h, the reaction vessel was removed from the 0° C. bath and allowed to gradually warm to RT. After 2.5 h, LCMS showed consumption of 32-3. The reaction was quenched with saturated NH4Cl (5 mL) and extracted with ethyl acetate (3×5 ml). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give 32-4 as a white solid. Since the material was determined to be of >95% purity by 1H NMR, further purification was deemed unnecessary. MS m/z (M+H): calculated=303.4; observed=304.1.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[S:4]([C:7]1[C:15]2[O:14]C(C(C)(C)C)=[N:12][C:11]=2[CH:10]=[CH:9][C:8]=1[Cl:20])(=[O:6])=[O:5].S(=O)(=O)(O)O>O1CCOCC1.O>[NH2:12][C:11]1[C:15]([OH:14])=[C:7]([S:4]([N:3]([O:2][CH3:1])[CH3:21])(=[O:6])=[O:5])[C:8]([Cl:20])=[CH:9][CH:10]=1
Reactant: CON(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CON(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 25 °C

Procedure:
2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acid methoxy-methyl-amide (4.8 g, 14.42 mmol) in dioxane (55 ml) and water (20 ml) was treated with concentrated sulphuric acid (20 ml) added dropwise over 30 minutes maintaining the temperature <30° C. The reaction mixture was heated at reflux for 2.5 h and then allowed to cool to RT. Dioxane was removed in vacuo and the resulting aqueous residue was basified with sat. NaHCO3 solution (250 ml) to pH12. The reaction mixture was extracted with EtOAc (3×200 ml) and the combined organic extracts were washed with water (3×100 ml) sat. brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid; [M+H]+ 266.
Reaction SMILES: [OH-].[K+].[N:3]([C@@H:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:7]([OH:20])[CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:4]=[N-:5]>C(O)C>[N:3]([C@H:6]([C@H:7]1[CH2:8][O:20]1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:4]=[N-:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](Cc2ccccc2)N=[N+]=[N-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A solution of 280 mg (5 mmol) of potassium hydroxide in 10 ml of ethanol were added to a solution of 1.37 g (3.8 mmol) of 3(S)-azido-4-phenyl-1-(p-toluene -sulphonyloxy)-2(S)-butanol in 50 ml of ethanol and the mixture was stirred at room temperature for 1 hour. The mixture was then evaporated to dryness and the residue was partitioned between water and dichloromethane. The aqueous phase was back-extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulphate and evaporated to give an oil which was purified by flash chromatography on silica gel using n-hexane/ethyl acetate (4:1) for the elution. There was obtained 0.47 g of 2(S)-[1(S)-azido-2-phenylethyl]oxirane: MS: m/e 189 [M]+.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]2[C@H:5]1[C@@H:6]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]2)(=[O:3])[CH3:2].[CH3:24][CH2:25][CH:26]([OH:29])[CH2:27][CH3:28]>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[C:1]([NH:4][C@@H:5]1[C@@H:6]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C@H:10]1[O:29][CH:26]([CH2:27][CH3:28])[CH2:25][CH3:24])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1=C[C@H]2[C@@H]([C@@H](NC(=O)OC(C)(C)C)C1)N2C(C)=O
Reactant: CCC(O)CC
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 60 %

Procedure:
To a solution of aziridine 13 (16 mg; 0.05 mmol) in 3-pentanol (1 mL) was added Cu(OTf)2 (3 mg; 0.008 mmol). After 16 h the reaction mixture was quenched by addition of saturated solution of NaHCO3 (0.1 ml) and concentrated. Chromatography of residue [hexane-ethyl acetate (3:1)→(2:1), 4.5 ml silica] afforded 12 mg (60%) of compound 15 as white solid: m.p.=144-145° C. (CHCl3); RF=0.3 (ethyl acetate-hexane 1:2); [α]20D=−21.54 (c=0.5, CHCl3); IR (KBr, cm−1) ν 3324, 2976, 3966, 2933, 2877, 2855, 1720, 1687, 1658, 1587, 1536, 1459, 1384, 1297, 1250, 1176, 1146, 1130, 1086, 1054, 1019, 948; 1H NMR (CDCl3, 600 Mhz) δ 6.81 (s, 1H), 5.80 (d, J=9.6 Hz, 1H), 5.11 (d, J=9.0 Hz, 1H), 4.22 (m, 2H), 4.08 (ddd, J=2 x≈4.8, 9.3 Hz, 1H), 3.97 (m, 1H), 3.81 (ddd, J=5.1, 2×9.6 Hz, 1H), 3.37 (qui, J=5.7 Hz, 1H), 2.76 (dd, J=4.8, 17.7 Hz, 1H), 2.31 (m, 1H), 2.00 (s, 3H), 1.51 (m, 4H), 1.44 (s, 9H), 1.30 (t, J=7.2 Hz, 3H), 0.90 (m, 6H); 13C NMR (CDCl3, 150 Mhz) δ 170.85, 165.98, 156.35, 137.65, 129.34, 82.21, 79.73, 76.00, 61.00, 54.47, 49.00, 31.01, 28.33, 26.12, 25.69, 23.41, 14.20, 9.54, 9.21.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=12.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH3:16][N:17]([CH3:19])[CH:18]=[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)[C:11](=[O:13])[CH3:12]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1ccc2nccn2c1
Solvent: CN(C)C=O
Product: CC(=O)C(=CN(C)C)c1ccc2nccn2c1
Yield: 74.4 %

Procedure:
In 200 ml of N,N-dimethylformamide, 33.17 g of 1-(imidazo[1,2-a]pyridin-6-yl)-2-propanone was stirred at 80° C. for 1 hour, together with 45.4 g of N,N-dimethylformamide dimethyl acetal. After cooling, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography (eluted with chloroform-methanol=97:3) to obtain 32.46 g (74.5%) of 4-dimethylamino-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].[CH2:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[CH:24][C:23]=1I)[CH3:21].C(N(CC)CC)C>CN(C)C=O.[Cu]I.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]>[CH2:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[CH:24][C:23]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)[CH3:21]
Reactant: CCc1c(I)cnn1-c1ccccc1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1c(C#Cc2cnn3cc(-c4cnn(C)c4)cc(OC)c23)cnn1-c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20 mg, 0.080 mmol), 5-ethyl-4-iodo-1-phenyl-1H-pyrazole (24 mg, 0.08 mmol), copper (I) iodide (4.5 mg, 0.024 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.2 mg, 0.0079 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.022 ml, 0.16 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 3-[(5-ethyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 4 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 551.1 [M+H]+; tR=3.50 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[O:7]1.CCN(CC)CC>C1(C)C=CC=CC=1>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[C:6](=[O:7])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCO
Yield: 67 %

Procedure:
To a solution of 3-aminopropan-1-ol (1.0 g, 13.1 mmol) and isobenzofuran-1,3-dione (2.0 g, 13.1 mmol) in toluene (25 mL, 3 mL/mmol) was added Et3N (2 mL, 13.1 mmol) and the reaction was heated at reflux for 24 h. Then reaction was quenched with water and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)isoindoline-1,3-dione (1.8 g, 87%). Observed mass (M+1): 206.1. This material was taken to the next step without further purification.
Reaction SMILES: CC1O[C:4]2([N:25]3[CH2:30][CH2:29]OCC3)[CH:9]([CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[C:11]=1[N+:12]([O-:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]2.N.Cl>C(O)C.O>[CH3:29][C:30]1[NH:25][C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:23])([F:22])[F:24])[C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)C2CCCCC2(N2CCOCC2)O1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)C2=C(CCCC2)N1

Procedure:
2 g (4.7 mmol) of 2-methyl-8a-morpholino-3-nitro-4-(2-trifluoromethylphenyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene are suspended in 15 ml of ethanol and dissolved with about 3 ml of concentrated aqueous ammonia solution at 30° to 45° C. The pH is then brought to 3 with concentrated hydrochloric acid and the solution is diluted with 5 ml of water and extracted twice with 10 ml of chloroform each time. After the chloroform has been evaporated off, the residue crystallizes in yellow crystals from a little ethanol.