Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:36][S:37]([CH:40]=[CH2:41])(=[O:39])=[O:38]>C1COCC1>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][N:31]([CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNC4)cn3)cc2)no1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCN(CCS(C)(=O)=O)C4)cn3)cc2)no1
Temperature: 60 °C
Yield: 79.4 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride (150 mg, 0.30 mmol) was suspended in 3 mL of THF at rt. Methylsulfonylethene (29 μL, 0.33 mmol) and TEA (126 μL, 0.90 mmol) were added sequentially. The resulting mixture was heated at 60° C. for 1 h, then heated at 52° C. for 60 h. LC-MS indicated the reaction was complete. The organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC to give N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yloxy)picolinamide (136 mg, 79%). LC-MS (ESI) m/z 571 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:17][CH2:18][CH3:19].[F:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1>O1CCCC1>[CH2:18]([CH:17]([C:29]([C:28]1[CH:38]=[CH:39][C:25]([F:24])=[CH:26][CH:27]=1)([C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[OH:30])[C:16]([O:21][CH2:22][CH3:23])=[O:20])[CH3:19]
Reactant: CCCC(=O)OCC
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Butyl lithium (65.7 mL of 2.1M solution, 138 mmol) was added to a solution of N-isopropylcyclohexylamine in 100 mL tetrahydrofuran at -20° C. After stirring for 1 hour and cooling to -40° C., ethyl butyrate (16.0 g, 138 mmol) was added. After stiring for an additional hour and further cooling to -70° C., 4,4'-difluorobenzophenone (15 g, 68.8 mmol) was added. The solution was stirred for 3 hours at -70° C., allowed to warm to 20° C. during the next 5 hours and stirred at 20° C. for 8 hours. The reaction was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was crystallized from hexane to give 11.7 g of the title compound; m.p. =99°-101° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH3:30])[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.C(COC)OC>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH3:30])[C:26]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 5 h

Procedure:
A solution of 2.1395 g of L-proline (18.6 mmol) and 1.56 g of NaHCO3 (18.6 mmol) in water (20 ml) is treated with a solution of 4.138 g of the succinimide ester of N-benzyloxycarbonyl-2(S)-aminobutyric acid (12.4 mmol) prepared as in Example 3 b), in dimethoxyethane (25 ml). After 5 hours, 12.4 ml of water are added, the resulting mixture is acidified to pH=2 with concentrated HCl and is extracted with ethyl acetate. The extracts are dried and are evaporated, which leads to a syrup.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([CH2:11][CH3:12])=[CH:10][C:3]=12.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCc1cc2c(Cl)nc[nH]c-2n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)ncnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
A solution of 2.35 g (12.9 mmol) of 4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine in 60 mL of tetrahydrofuran (THF) was added to a 0° C. slurry of 2.20 g (12.9 mmol) of benzylbromide and 0.31 g (12.9 mmol) of sodium hydride in 20 mL of THF. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched by the addition of 20 mL of 2 M sodium hydrogen sulfate and then extracted with 70 mL of ethyl acetate. The organic phase was dried with sodium sulfate and concentrated to 4.0 g of off-white solid. The solid was purified by flash chromatography using (100 g of silica gel, methylene chloride) to provide 1.53 g (43%) of 4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.32 (t, J=7.4 Hz, 3H), 2.67 (q, J=7.4 Hz, 2H), 5.49 (s, 2H), 6.40 (s, 1H), 7.04 (d, J=7.0 Hz, 2H), 7.28 (m, 3H), 8.60 (s, 1H)
Reaction SMILES: [I-:1].Cl[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.CN1CCCC1=O>C(OCC)(=O)C>[I-:1].[N:24]1([C:3]2[CH:12]=[CH:11][C:10]3[N+:9]4[CH:13]=[C:14]5[CH:23]=[CH:22][C:21]6[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=6[N:15]5[C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Clc1ccc2c(ccc3n4c(ccc5ccccc54)c[n+]23)c1
Reactant: C1CCNC1
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)ccc1c[n+]3c4ccc(N5CCCC5)cc4ccc3n12

Procedure:
A mixture of 1.0 g. of 3-chloroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 1.0 ml. of pyrrolidine and 5 ml. of N-methyl-2-pyrrolidinone is stirred and heated at reflux for 17 hours, cooled and diluted with 100 ml. of ethyl acetate. The precipitate of 3-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, stirred with 50 ml. of 1% aqueous triethylamine hydroiodide and recollected; m.p. 312°-320° C. after crystallization from methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:34]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:35]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].CCN(C(C)C)C(C)C>ClCCl.CN(C)C=O>[CH2:39]([O:38][C:36]([CH:35]1[CH2:41][CH2:42][CH2:43][CH2:44][N:34]1[C:15](=[O:16])[C:14]1[CH:18]=[C:19]([Cl:21])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)C1CCCCN1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCCCN1C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.12 g) in dichloromethane (4 ml) was added dimethylformamide (0.05 ml) followed by 2M oxalyl chloride solution in dichloromethane (0.183 ml). The resultant solution was stirred at room temperature for 1 h, and then ethyl pipecolinate (0.096 g) followed by DIPEA (0.160 ml) were added. After 18 h, the reaction mixture was concentrated under reduced pressure and the residue was subjected to preparative hplc. The title compound (0.165 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17](=[O:35])[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=2)[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:21]=1)#[N:9].[OH-].[Na+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17](=[O:35])[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][S:39]([CH3:38])(=[O:41])=[O:40])[CH:29]=2)[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:21]=1)#[N:9]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(N)c2)c1=O
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Reaction time: 0.17 h

Procedure:
Triethylamine (0.2 ml) was added to a solution of 31 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-aminophenyl)-1,2-dihydropyridin-2-one in 2 ml of tetrahydrofuran, 0.1 ml of methanesulfonic acid chloride was dropped thereinto with ice cooling and the mixture was stirred for 10 minutes. To this were added 2 ml of 2N sodium hydroxide, the mixture was stirred at room temperature for 5 minutes and partitioned to ethyl acetate-water, the organic layer was washed with water, dried and concentrated and the residue was purified by a silica gel column chromatography (ethyl acetate-hexane system) to give 38 mg of the title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15](/[CH:16]=[C:17]3/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CN(C=O)C.Cl.[NH2:33][OH:34]>C1COCC1>[OH:34][N:33]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15](/[CH:16]=[C:17]2/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/2)=[CH:14][CH:13]=1
Reactant: NO
Reactant: COc1cccc(C(=O)COc2ccc(/C=C3\SC(=O)NC3=O)cc2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(C(COc2ccc(/C=C3\SC(=O)NC3=O)cc2)=NO)c1
Reaction time: 8 h

Procedure:
A stirring suspension of (5Z)-5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (1.42 g, 3.84 mmol; Supplier=Kalexsyn; Lot=1003-TTP-149) in THF (15 ml) was heated with a heat gun—no solution. Added DMF (5 ml) and heated—no solution. Added another 5 ml DMF and heated until all solids dissolved. The hydroxylamine hydrochloride was added portionwise. Added HONH2.HCl (100 mg) and allowed to sit at RT overnight. HPLC showed a ratio of ca. 2:1 SM:pdt. Added 100 mg HONH2.HCl. After 4 hours there was little change in HPLC. Added 100 mg HONH2.HCl and left to stir over the weekend. The reaction was complete. The reaction mixture was partitioned between EtOAc (30 ml) and 1M KHSO4 (30 ml). The aqueous phase was extracted with EtOAc (30 ml). The combined organic phases were washed with saturated NaHCO3 (30 ml), brine (30 ml), dried (Na2SO4), filtered and evaporated in vacuo to give 1.34 g yellow solid. 1H-NMR (DMSO-d6): δ 12.53(brs, 1H), 12.02(brs, 1H), 7.73(s, 1H), 7.54(d, J=8.9 Hz, 2H), 7.30(t, J=7.9 Hz, 1H), 7.20(m, 2H), 7.10(d, J=8.9 Hz, 2H), 6.95(dd, J=8.1, 2.5 Hz, 1H), 5.31(s, 2H), 3.74(s, 3H). HPLC: 3.690 min., 10 area %, and 3.788 min., 89 area % @ 210 nm; 3.690 min., 6 area %, and 3.789 min., 94 area % @ 254 nm. MS (ESI−) for C19H16N2O5S m/z 383.3 (M−H)−.
Reaction SMILES: [F-].[Cs+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH:14]1[C:23]2[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:21][N:20]([CH3:30])[C:19]=2[CH2:18][C:17](=[O:31])[CH2:16][CH2:15]1)[C:7]([O:9][CH3:10])=[O:8].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>COCCOC>[OH:31][C@:17]1([C:33]([F:35])([F:34])[F:32])[CH2:18][C:19]2[N:20]([CH3:30])[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:23]=2[C@@H:14]([C:13]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[CH3:3])[CH2:15][CH2:16]1
Reactant: COC(=O)c1ccc(C2CCC(=O)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: COCCOC
Product: COC(=O)c1ccc([C@H]2CC[C@@](O)(C(F)(F)F)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
Cesium fluoride (0.037 g, 0.244 mmol) was added to a solution of rac-methyl 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoate (0.190 g, 0.488 mmol) in DME (50 mL). The mixture was stirred at rt for about 20 min then it was cooled in an ice bath and (trifluoromethyl)trimethylsilane (1.44 mL, 9.76 mmol) was added in a dropwise manner. After about 30 min, (trifluoromethyl)trimethylsilane (1.44 mL, 9.76 mmol) was added. After about 45 min, the mixture was partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl solution (100 mL). The organic layer was washed with brine (100 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and 1 M tetrabutylammonium fluoride in THF (0.54 mL, 0.54 mmol) was added. The mixture was stirred at rt for about 1 h then it was washed with saturated NH4Cl (2×50 mL) and brine (50 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 25-50% EtOAc/heptane) to give rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.018 g, 8%): LC-MS (Table 1, Method g) Rt=2.28 min, m/z 460 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.31-8.27 (m, 1H), 7.75-7.72 (m, 1H), 7.69-7.67 (m, 1H), 7.65-7.60 (m, 1H), 7.53-7.49 (m, 1H), 7.10-7.05 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.30 (s, 1H), 5.22-5.14 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.34-3.32 (m, 2H), 2.62 (s, 3H), 2.20-2.08 (m, 1H), 1.98-1.90 (m, 1H), 1.86-1.74 (m, 2H). and rac-methyl 4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.034 g, 15%): LC-MS (Table 1, Method g) Rt=2.28 min, m/z 460 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.35-8.38 (m, 1H), 7.77-7.74 (m, 1H), 7.71-7.69 (m, 1H), 7.68-7.63 (m, 1H), 7.57-7.52 (m, 1H), 7.14-7.10 (m, 1H), 6.96-6.93 (m, 1H), 6.18 (s, 1H), 5.51-5.45 (m, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.36-3.17 (m, 2H), 2.56 (s, 3H), 2.29-2.20 (m, 1H), 1.90-1.79 (m, 1H), 1.76-1.65 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.I[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[N:6]([CH2:16][CH2:17][OH:18])[CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([O:8][CH2:16][CH2:17][OH:18])=[N:6][CH:7]=1
Reactant: OCCI
Reactant: O=c1[nH]cc(Br)cc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1c(N2CCOCC2)cc(Br)cn1CCO
Product: OCCOc1ncc(Br)cc1N1CCOCC1

Procedure:
Method 1 was followed using 5-bromo-3-morpholinopyridin-2(1H)-one (1.0 equiv.), 2-iodoethanol (1.0 equiv.) and potassium carbonate (2.0 equiv.) at room temperature to give 5-bromo-1-(2-hydroxyethyl)-3-morpholinopyridin-2(1H)-one and 2-((5-bromo-3-morpholinopyridin-2-yl)oxy)ethanol as a mixture of two isomers (˜5:1 ratio). LCMS (m/z) (M+H)=303/305, Rt=0.47 min and 0.62 min.
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:19])[CH:9]=2)[N:4]=[CH:3]1.[Cl:20][CH2:21]C(O)=O.[CH:25]1C=CC=CC=1>>[Br:19][C:8]1[CH:7]=[CH:6][C:5]([N:4]2[CH:25]=[N:1][N:2]=[C:3]2[CH2:21][Cl:20])=[C:10]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:18])[CH:9]=1
Reactant: NN1C=Nc2ccc(Br)cc2C1(O)c1ccccn1
Reactant: c1ccccc1
Reactant: O=C(O)CCl
Product: O=C(c1ccccn1)c1cc(Br)ccc1-n1cnnc1CCl

Procedure:
A mixture of a solution of 0.94 g of the thus obtained di-(chloroacetyl) derivative of 3-amino-6-bromo-4-hydroxy-4-(2-pyridyl)-3,4-dihydroquinazoline in 19 ml. of benzene and 0.4 g of monochloroacetic acid is refluxed for 30 minutes. Then, the resulting benzene layer is washed with water and separated from the mixture. After evaporation of benzene under reduced pressure, the residue is washed with a mixture of methanol and isopropyl ether to give 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-chloromethyl-4H-1,2,4-triazole as crystals. Recrystallization from ethyl acetate gives colorless crystals, melting at 146° to 147° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH:10]1[CH2:15][CH2:14][NH:13]CC1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:23]1COC[CH2:24]1>>[NH2:13][CH2:14][CH:15]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23]1
Reactant: O=C(NCc1ccccc1)C1CCNCC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of N-benzylisonipecotamide (7.34 g, 34 mmol) in 60 mL of anhydrous THF, was added, LiAlH4 (1.9 g, 51 mmol) and the mixture was stirred at room temperature for 10 minutes followed by heating to reflux for 3 h. The reaction was quenched by addition of 100 mL sat'd. sodium potassium tartrate, and was extracted with EtOAc (3×50 mL). The combined extracts were washed with 20 mL water and 20 mL brine then dried over MgSO4, filtered and concentrated to give the desired product. 1H-NMR (400 MHz, CDCl3) δ 7-13 (m, 5H), 3.42 (s, 2H), 2.91 (m, 2H), 2.59 (m, 2H), 1.97 (m, 2H), 1.62 (m, 2H), 2.21 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10](C3C=CC(OC)=CC=3)[C:11](=[S:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][OH:26].C(Cl)Cl>[OH-].[Na+]>[OH:26][CH2:25][CH2:24][S:14][C:11]1[S:12][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1
Reactant: COc1ccc(-c2csc(=S)n2-c2ccc(OC)cc2)cc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1

Procedure:
100 g of 4,3-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 320 ml of 2 N sodium hydroxide solution while stirring. 45 ml of 2-bromoethanol are then added, the mixture is stirred at room temperature for 15 minutes, 500 ml of methylene chloride are added, the mixture is filtered through diatomaceous earth, the organic layer is removed and extracted by washing with 200 ml of 2 N sodium hydroxide solution. The combined aqueous phases are subsequently extracted twice with methylene chloride. The organic phases are combined, dried over magnesium sulphate and concentrated by evaporation under reduced pressure. The remaining oil is dissolved in 700 ml of hot diethyl ether, stirred for 1 hour and caused to crystallise at 10°. The crystals are filtered with suction, then washed twice with 150 ml of ice-cold diethyl ether each time and dried under reduced pressure. 2-(2-Hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 82°-83° is obtained.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[O:9][C:10]32[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:6][CH:5]=1)[CH3:3].[C:19]1([C:25]2[N:26]=[CH:27][C:28]([NH:31][C:32](=O)[O:33]C3C=CC=CC=3)=[N:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>CS(C)=O>[CH2:2]([C:4]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[O:9][C:10]32[CH2:11][CH2:12][N:13]([C:32]([NH:31][C:28]2[CH:27]=[N:26][C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:30][N:29]=2)=[O:33])[CH2:14][CH2:15]3)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCc1ccc2c(c1)C1(CCNCC1)OC2=O
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCc1ccc2c(c1)C1(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC1)OC2=O
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a suspension of 6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (53 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) in dimethyl sulfoxide (1 mL) was added 10 M sodium hydroxide aqueous solution (0.02 mL). The mixture was vigorously stirred for 5 minutes followed by partition between water and ethyl acetate. The organic layer was separated and then washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the organic solvent left a residue, which was subjected to the crystallization from ethyl acetate to give the subject compound (46 mg) as crystals (melting point 176-178° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([O:9][CH2:10][CH3:11])[CH2:7][CH3:8].[Mg].Cl[CH:14]1[CH2:18][CH2:17][CH:16]=[CH:15]1>O1CCCC1>[CH2:10]([O:9][CH:6]([CH2:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2][CH:18]1[CH2:17][CH2:16][CH:15]=[CH:14]1)[CH3:11]
Reactant: ClC1C=CCC1
Reactant: CCOC(CC)CCCCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(CC)CCCCC1C=CCC1

Procedure:
The procedure followed is the same as that described in Example 8 with the following substitutions made: the starting material prepared in Example 38, 1-chloro-5-ethoxyheptane (162 g, 1.13 moles) dissolved in tetrahydrofuran (162 ml), granular magnesium (50 g, 2.1 moles) in tetrahydrofuran (500 ml), Li2CuCl4 (29.1 mmoles), and 3-chlorocyclopentene (89 g, 0.86 moles) diluted in 100 ml tetrahydrofuran was used. The crude product is distilled under reduced pressure leaving a clear, colorless oil (121 g, 0.575 moles), BP 76° C./0.34 mm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13])[CH:6]=[CH:5]2.[CH3:21][C:22]([CH3:32])([CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:23]O>>[CH3:23][C:22]([CH3:32])([CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH2:19]1)=[O:13])[CH:6]=[CH:5]2
Reactant: CC1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1
Reactant: CC(C)(CO)CN1CCCCC1
Product: CC1CCN(C(=O)c2ccc3cc(OCC(C)(C)CN4CCCCC4)ccc3c2)CC1

Procedure:
The title compound was synthesised from (6-hydroxy-naphthalen-2-yl)-(4-methyl-piperidin-1-yl)-methanone (intermediate B) and 2,2-dimethyl-3-piperidin-1-yl-propan-1-ol (commercially available) according to the procedure described for the synthesis of Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])C=C[C:3]=1OC.[Cl-:13].[NH+]1C=CC=CC=1.CCO[C:23]([CH3:25])=[O:24]>Cl>[Cl:13][C:3]1[CH:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:25][C:23]=1[OH:24]
Reactant: COc1ccc([N+](=O)[O-])cc1Cl
Reactant: CCOC(C)=O
Reactant: [Cl-]
Agent: Cl
Agent: c1cc[nH+]cc1
Product: O=[N+]([O-])c1ccc(Cl)c(O)c1
Temperature: 200 °C

Procedure:
A mixture of 2-chloro-4-nitroanisole (10 g, 53.3 mmol) and pyridinium chloride (50 g, 426 mmol) was heated at 200° C. for 3 h. After cooling to RT, the mixture was dissolved in 150 mL of aqueous 2N HCl and 150 mL of EtOAc. The organic phase was separated and was washed with aqueous 2N HCl (2×100 mL). The resulting organic phase was dried over MgSO4 and concentrated in vacuo. The title compound was obtained via chromatography (silica gel, 10:1 hexane/EtOAc) as a yellow solid.