Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23]3)[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]([CH3:34])[C:8](=[O:35])[CH2:7][CH2:6]2.[H-].[Na+].[CH3:38]I.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C@@H:22]3[CH2:26][CH2:25][C:24](=[O:27])[N:23]3[CH3:38])[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]([CH3:34])[C:8](=[O:35])[CH2:7][CH2:6]2
Reactant: CI
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(CC3CCC(=O)N3)[C@H]1c1ccccc1)N(C)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1CN[C@H]1CCCN(C[C@@H]3CCC(=O)N3C)[C@H]1c1ccccc1)N(C)C(=O)CC2
Reaction time: 0.33 h
Yield: 12.5 %

Procedure:
To 6-Methoxy-1-methyl-7-{[1-(5-oxo-pyrrolidin-2-ylmethyl)-(2S,3S)-2-phenyl-piperidin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one (194 mg, 0.408 mmol) in 5 mL of THF at room temperature was added 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil and stirred for 20 minutes. Methyl iodide (0.028 mL, 0.448 mmol) was then added and stirred for 1 hour 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil was added and stirred overnight. A small amount of water was added and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed twice with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (95:5 ethyl acetate/methanol) as the eluent gave 25 mg (13%) of the title compound, a pale yellow oil. Rf=0.07 (9:1 ethyl acetate/methanol). MS (M+H)+=491.2; 1H NMR (400 MHz, CDCl3): δ 1.42–1.60 (m, 3H), 1.84–1.88 (dd, J=13.4 Hz, 4.8 Hz, 1H), 2.01–2.14 (m, 5H), 2.17–2.24 (m, 2H), 2.54–2.57 (t, J=7.3 Hz, 3H), 2.67–2.73 (m, 1H), 2.76–2.78 (t, J=7.3 Hz, 2H), 2.88 (s, 3H), 3.13 (s, 3H), 3.21–3.24 (d, J=10.9 Hz, 1H), 3.32–3.33 (d, J=3.0 Hz, 1H), 3.36–3.40 (d, J=14.3 Hz, 1H), 3.56 (s, 3H), 3.61–3.68 (m, 2H), 6.49 (s, 1H), 6.65 (s, 1H), 7.18–7.34 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 20.4, 23.9, 25.5, 27.5, 29.6, 31.8, 45.4, 54.2, 55.5, 56.3, 58.0, 59.9, 72.7, 109.9, 116.0, 127.1, 128.1, 129.0, 133.6, 140.9, 152.8, 170.0, 175.0. The dihydrochloride salt was prepared by the addition of 2 M HCl In ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(CC)CC>CC(O)C>[I:8][C:7]1[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:3][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: FC(F)(F)c1ccc(I)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: FC(F)(F)c1ccc(I)c(N2CCCCC2)n1
Yield: 58.4 %

Procedure:
A solution of 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (Tet. Lett., 1998, 39(13), 1749-1752) (350 mg, 1.14 mmol), piperidine (135 μl, 1.37 mmol) and Et3N (640 μl, 4.56 mmol) in i-PrOH (2 mL) was heated for 1 h at 140° C. in a microwave reactor. The reaction mixture was concentrated to dryness and the crude was purified through flash chromatography (SiO2, heptane) to afford 237 mg (58%) of the title compound.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[CH:8][CH:7]=1.O>C(#N)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]=2[CH:4]=[CH:3][CH:1]=[O:2])=[CH:8][CH:7]=1
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: C=CC=O
Solvent: O
Solvent: CC#N
Product: CC(C)n1c(C=CC=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Use of the crude acrolein coming from Example 3a. To a suspension of 3-[3-(4-Fluorophenyl)-1-(1-Methylethyl)-1H-Indole (35.8 g) phosphorus oxychloride (31.4 g) in acetonitrile (35 ml) cooled at 5° C. a solution of crude acrolein (32.3 g from Example 3a) in acetonitrile (40 ml) is added dropwise in 30 minutes. The reaction mixture is then warmed to 60° C. and kept under stirring at 60° C. for 4 hours; water (300 ml) is added and after 1 hour at 60° C. the formed solid is filtered on Buchner and washed with 75 ml of water. The wet solid (49.7 g) is dissolved in toluene (250 ml), celite (1 g) and charcoal (0.5 g) are added and the mixture is stirred at room temperature for 30 minutes. After filtration of the solid, the solvent is distilled off at reduced pressure and the residue is dissolved at 75° C. with isopropanol (72 ml). The solution is cooled at 20° C. and stirred at room temperature for 1 hour. The precipitate is filtered on Buchner, washed twice with isopropanol (15 ml) and dried at 60° C. under vacuum. 30.2 g (70% molar yield) of the product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:25][CH3:26])[CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.O.NN>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:25][CH3:26])[CH2:11][CH2:12][CH2:13][NH2:14])=[CH:6][CH:7]=1
Reactant: CCN(CCCN1C(=O)c2ccccc2C1=O)CCc1ccc(Cl)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CCCN)CCc1ccc(Cl)cc1
Yield: 98.7 %

Procedure:
To a solution of N-[3-[[2-(4-chlorophenyl)ethyl](ethyl)amino]propyl]-phthalimide (1.41 g, 3.8 mmol) in EtOH (20 ml) was added a solution of hydrazine monohydrate (1.5 g, 30 mmol) in EtOH (5 ml). The solution was stirred at RT for 4h, and then filtered. The filtrate was concentrated under vacuum to dryness. After adding water, the mixture was extracted with chloroform, washed with brine, dried over sodium sulfate, and filtered. Concentrating under vacuum gave N-[2-(4-chlorophenyl)ethyl]-N-ethyl-1,3-diaminopropane (903 mg, 99%) which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:19][CH:20]=1>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.C1(C)C=CC=CC=1>[CH3:13][O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][N:19]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-bromo-5-methoxybenzoate (0.1 g, 0.4 mmol), 5-methyl-2-(tributylstannyl)pyridine (0.1 mL, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) and toluene (4 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to room temperature and purified via flash chromatography to afford the desired product as a light yellow oil. LC-MS: 257.9 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].[CH:38]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH2:39]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:39][CH2:38][S:40]([CH3:43])(=[O:42])=[O:41])[CH2:30][CH2:31]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: C=CS(C)(=O)=O
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(CCS(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.2 g, 0.397 mmol) in MeOH (2 mL), methyl vinyl sulfone (0.063 g, 0.596 mmol) was added and stirred it at room temperature for 12 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure, finally the residue was washed with diethyl ether to provide the desired compound (41% yield). LCMS: 610.45 (M+1)+; HPLC: 97.26% (@ 254 nm) (Rt; 6.037); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.82 (t, 1H), 8.27 (s, 1H), 7.80 (s, 1H), 6.88 (s, 1H), 5.89 (s, 1H), 5.21-5.17 (m, 1H), 4.37 (d, 2H, J=4.4 Hz), 3.32-3.25 (m, 4H), 3.02 (s, 3H), 2.95 (d, 2H, J=10.40 Hz), 2.73 (d, 2H, J=4 Hz), 2.67 (bs, 4H), 2.32 (m, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.99-1.94 (m, 2H), 1.81-1.79 (m, 2H), 1.49 (d, 6H, J=6.4 Hz), 1.45 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[O:23]=[C:22]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
11.68 g (63 mmol) of 3-amino-2-anilinopyridine was dissolved in ethanol (150 mL), and 12.07 g (69 mmol) of diethyl ketomalonate was added thereto. The mixture was heated to reflux for 4 hours while stirring. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue thus obtained was washed using diisopropyl ether, to obtain 10.74 g (yield: 58%) of ethyl 3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate as pale yellow crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17](Br)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2].[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:27]4[CH:28]=[CH:29][C:24]([S:23][CH3:22])=[CH:25][CH:26]=4)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(=O)O[C@@H](C)c1nnc(-c2ccc3occ(Br)c3c2)o1
Product: CSc1ccc(-c2coc3ccc(-c4nnc([C@H](C)OC(C)=O)o4)cc23)cc1
Yield: 64 %

Procedure:
In the same manner as in Reference Example 19 and using (1S)-1-[5-(3-bromo-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]ethyl acetate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 64%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][Mg]I.[CH3:4][S:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])(=[O:7])=[O:6]>C1COCC1>[CH3:4][S:5]([C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH3:1])[CH:13]=[CH:14][CH:15]=1)(=[O:6])=[O:7]
Reactant: C[Mg]I
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Solvent: C1CCOC1
Product: CC(O)c1cccc(S(C)(=O)=O)c1
Temperature: 0 °C
Yield: 32.5 %

Procedure:
Methylmagnesium iodide (3M in THF, 13.2 mL, 4.4 mmol) was added dropwise via syringe at 0° C. to 3-(methylsulfonyl)benzaldehyde (0.74 g, 4.0 mmol) in THF (15 mL). The resulting reaction mixture was stirred at 0° C. until no more conversion to product occurred (monitored by GC-MS). The reaction was quenched with saturated ammonium chloride, the aqueous phase was extracted with EtOAc and the organic phase was washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (EtOAc:hexane 1:4) to give the title compound (260 mg) that was used in the next step without any further purification (approximate purity 50%).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>C(O)(C)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][N:35]([CH2:20][CH:2]([OH:1])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]3[C:14]4[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=4[O:12][N:11]=3)[CH2:6][CH2:5]1)[CH2:34][CH2:33]2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CC(O)CN1CCC(c3noc4cc(F)ccc34)CC1)CC2
Reaction time: 8 h
Yield: 11 %

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3yl)piperidine (3.2 g, 11.6 mmol), K2CO3 (2 gm, 1.25 eq) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1.25 eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. The mixture was cooled and filtered. The solvent was removed to about 50 ml and the solution was allowed to stand overnight. Crystals (0.6 g) formed and were collected. The mother liquor was concentrated to a white solid. Recrystallization twice from ethanol yielded the product (1.95 g, m.p. 153°-154° C.
Reaction SMILES: [Na].[OH:2][CH:3]([C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[N:21]=[N:22][NH:23][N:24]=2)[CH:17]=[CH:18][CH:19]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[OH:2][CH:3]([C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[N:21]=[N:22][N:23]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:24]=2)[CH:17]=[CH:18][CH:19]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CBr
Reactant: CCCCCC(O)c1cccc(OCc2cccc(-c3nn[nH]n3)c2)c1
Agent: [Na]
Solvent: CCO
Product: CCCCCC(O)c1cccc(OCc2cccc(-c3nnn(CC(=O)OCC)n3)c2)c1
Yield: 85.7 %

Procedure:
To a solution of 0.3 g of sodium in 60 ml of ethanol was added 4.3 g of 5[3-[3-(1-hydroxyhexyl)phenoxymethyl]phenyl]-2H-tetrazole and 2.0 g of ethyl bromoacetate. The mixture was refluxed for 18 hours. The solvent was evaporated and the residue was partitioned between ether and water. The ether layer was dried and evaporated to give 4.5 g of a viscous oil. This was passed through a short silica gel column and eluted with chloroform:methanol (4:1). The product (2.3 g) was obtained as a light amber oil.
Reaction SMILES: [SH:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[ClH:19].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][S:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: Cc1nc2ccccc2nc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc2ccccc2nc1SCc1ccccc1N(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In a mixture of 50 ml of acetone and 5 ml of water were suspended 2.80 g of 2-mercapto-3-methylquinoxaline, 3.28 g of 2-dimethylaminobenzyl chloride hydrochloride, and 8.0 g of potassium carbonate. The resulting mixture was stirred at room temperature for 40 min., and the solvent was removed under reduced pressure. The residue was extracted with chloroform after addition of chloroform and water. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was diluted with 50 ml of ethanol. To the solution under chilling with ice were successively added 1.33 ml of conc. hydrochloric acid and ether to precipitate crystals. The crystals were collected by filtration to give 4.56 of 2-(2-dimethylaminobenzylthio)-3-methylquinoxaline hydrochloride as a dark brown crystalline powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl.CCN(CC)CC>[C:31]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
To a solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml DCM, 0.3 ml NEt3 and 11 mg acetic acid anhydride were added at RT and stirred over night. After removal of the solvent under reduced pressure the residue was directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:19][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:3][CH:2]([C:4]1[S:19][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]4[NH:22][N:21]=[N:20][N:18]=4)=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1cc2c(=O)n3cc(C#N)ccc3nc2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1
Temperature: 124 °C
Yield: 55.8 %

Procedure:
A mixture of 5.1 g (0.01894 mol) of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 16), 6.5 g (0.1 mol) of sodium azide and 5.35 g (0.1 mol) of ammonium chloride in 150 ml of dimethylformamide is stirred and heated at 124° C. for twenty-two hours under nitrogen. The reaction mixture is cooled, filtered and the filtrate evaporated. The residue is treated with 1 l water and acidified with concentrated hydrochloric acid. The resulting precipitate is collected, suspended in hot water, the suspension cooled and filtered to give 3.3 g of 2-(1-methylethyl)-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 288° C. (dec) after recrystallization from pyridine-ethanol.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]1([C:54](Cl)=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1>N1C=CC=CC=1>[N:49]1([C:54]([O:39][C@H:36]2[CH2:37][CH2:38][C@@H:33]([C:30]3[CH:31]=[CH:32][C:27]([C:23]4[N:22]=[C:21]5[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]6[CH2:15][O:14][C@@H:13]7[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]67)=[N:19][C:20]5=[CH:25][C:24]=4[Cl:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: O=C(Cl)N1CCCC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](OC(=O)N5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg) is dissolved in pyridine (1 mL), treated with pyrrolidine-1-carbonyl chloride (80 μL) and stirred for 12 hours at 70° C. Pyrrolidine-1-carbonyl chloride (160 μL) is added and the mixture is stirred for 48 hours at 100° C.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[C:19]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)[C:18]([O:32][CH3:33])=[C:17]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:16]=2)=[CH:13][CH:12]=[C:11]([CH3:38])[N:10]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][C:19]2[CH:20]=[C:15]([C:14]3[C:9](=[O:8])[NH:10][C:11]([CH3:38])=[CH:12][CH:13]=3)[CH:16]=[C:17]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:18]=2[O:32][CH3:33])=[CH:24][CH:25]=1
Reactant: COc1c(C=Cc2ccc([N+](=O)[O-])cc2)cc(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(CCc2ccc(N)cc2)cc(-c2ccc(C)[nH]c2=O)cc1C(C)(C)C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
step 5—A mixture of 68 (180 mg, 0.354 mmol) and Pd(OH)2 (20 wt % on C, 75 mg, 0.107 mmol) in EtOAc (10 mL) and MeOH (10 mL) was stirred under an atmosphere of hydrogen for 2 h before the catalyst was filtered, and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (75 to 100% EtOAc) to afford 68 mg (49%) of 3-{3-[2-(4-amino-phenyl)-ethyl]-5-tert-butyl-4-methoxy-phenyl}-6-methyl-1H-pyridin-2-one (70) as a foam.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[CH:2][CH3:3].[ClH:11]>>[Cl:11][CH:1]([N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3]
Reactant: CC=CN1C(=O)CCC1=O
Reactant: Cl
Product: CCC(Cl)N1C(=O)CCC1=O
Reaction time: 240 h

Procedure:
Anhydrous hydrogen chloride is bubbled through a mixture of 10 g. (0.072 mole) of N-propenylsuccinimide and 1.04 g. of stannic chloride for 6 hours. The solution is allowed to stand at room temperature for 10 days, the solution being saturated again with hydrogen chloride gas after 3 and 4 days. Solvents are removed under reduced pressure at 30°-40° C. to give 1-chloro-1succinimidopropane as a yellow oil.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8]/[C:7]/1=[N:20]\[NH2:21])[CH2:2][CH2:3][CH2:4][CH3:5].[C:22](OCC)(OCC)(OCC)[CH3:23]>>[CH3:22][C:23]1[N:8]2[C:9](=[O:19])[C:10]3[NH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:20][N:21]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Product: CCCCCn1c2nc(C(F)(F)F)[nH]c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone (0.020 g, 0.14 mmol) and triethyl orthoacetate (2 mL, 10 mmol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by preparative LCMS. The product fractions were collected and lyophilized to yield pure product as white powder. LCMS calculated for C13H15F3N6O: (M+H) 329.1. Found: 329.1.