Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[S:15][C:16]([S:19][CH2:20][C:21]2[O:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][N:25]=2)=[CH:17][N:18]=1.[CH3:30][CH:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)[CH3:32].CN(C)C=O>CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[CH3:27][C:26]([C:23]1[O:22][C:21]([CH2:20][S:19][C:16]2[S:15][C:14]([NH:13][C:39]([CH:36]3[CH2:37][CH2:38][N:33]([CH:31]([CH3:32])[CH3:30])[CH2:34][CH2:35]3)=[O:40])=[N:18][CH:17]=2)=[N:25][CH:24]=1)([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cnc(CSc2cnc(N)s2)o1
Reactant: CC(C)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N1CCC(C(=O)Nc2ncc(SCc3ncc(C(C)(C)C)o3)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]thiazole (0.7 g, 2.6 mmol, 1 eq), 1-(1-methylethyl)-4-piperidine carboxylic acid (0.78 g, 3.9 mmol, 1.5 eq), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol, 0.5 eq), N,N-dimethylformamide (2.6 mL) and CH2Cl2 (7.8 mL). The reaction mixture was stirred at rt for 1 h, diluted with 30 mL of water and extracted with ethyl acetate (2×70 mL). The organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with a gradient of 5-10% triethylamine in ethyl acetate. The material was recrystallized from ethanol and water to provide 0.93 g (85%) of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]- 1-(1-methylethyl)-4-piperidinecarboxamide as a yellowish solid. MS: 423 [M+H]+; HPLC: 100% at 3.15 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.[N+:26]([C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[O:32][CH2:33][C:34](O)=[O:35])([O-:28])=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][CH:39]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: O=C(O)COc1cccc([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(C(=O)COc3cccc([N+](=O)[O-])c3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) and 3-nitrophenoxyacetic acid (0.23 mmol) in DMF (2 ml) was added TBTU (0.21 mmol) followed by diisopropylethylamine (0.21 mmol, 35 μL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 0.5% CH3OH in CH2Cl2), yielding the pure title compound (41 mg) which was characterized by its mass spectrum: MS m/z (%): 538 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6]([N:8]([CH3:10])[CH3:9])=O)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1([F:11])[CH2:5][CH:4]([CH2:6][N:8]([CH3:10])[CH3:9])[CH2:3]1
Reactant: CN(C)C(=O)C1CC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CC1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A solution of 3,3-difluoro-N,N-dimethylcyclobutanecarboxamide (24 g, 147 mmol) prepared in Part A in THF (500 mL) was added to a stirred suspension of lithium aluminum hydride (7.5 g, 198 mmol) in 500 in THF at 0° C. The mixture was allowed to come to RT. After stirring the reaction mixture at RT for 18 h, it was quenched by slowly adding 10 mL 6 N NaOH and 5 mL water at 5° C. with stirring. The mixture was stirred at RT for 0.5 h, dried over Na2SO4 and filtered. The filtrate was concentrated to ca. 30 mL by a careful distillation of most of the THF using a vigreux column. The remaining material was distilled under slightly reduced pressure (ca. 100-200 mm Hg); the fraction (20 mL, bp 70-90° C.) contained the title compound contaminated with THF. The residual THF was carefully purged with a gentle stream of nitrogen to yield 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine (12 g, 80 mmol, 54.7% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.46-2.94 (2 H, m), 2.38 (2 H, d, J=6.55 Hz), 2.16-2.28 (9 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])OC(C)(C)C)=[CH:4][C:3]=1[CH3:16].C([Li])(C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=O)C(OCC)=O.[NH4+].[Cl-:38]>CCOCC.CCCCC.C1COCC1>[Cl:38][C:30]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH3:22])[C:6]2[C:5](=[CH:4][C:3]([CH3:16])=[C:2]([Cl:1])[CH:7]=2)[NH:8][C:9]1=[O:15]
Reactant: [Cl-]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1Cl
Reactant: CCOC(=O)C(=O)c1ccccc1OC
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(Cl)C(=O)Nc2cc(C)c(Cl)cc21
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 5 g of tert-butyl 4-chloro-3-methylphenylcarbamate in 45 ml of ether is cooled to −70° C. under an argon atmosphere, 30 ml of a 1.5M solution of tert-butyllithium in pentane are added dropwise, the mixture is left stirring for 1 hour while allowing the temperature to rise to −10° C., and is left stirring for 1 hour 45 minutes at −10° C. The reaction mixture is cooled to −70° C., a solution of 5 g of the compound obtained in step A in 25 ml of THF is added dropwise and the mixture is left stirring for 1 hour while allowing the temperature to rise to −30° C., and is then stirred overnight while allowing the temperature to rise to RT. Saturated NH4Cl solution is added to the reaction mixture, the THF is evaporated off, the resulting aqueous phase is extracted three times with EtOAc, the organic phase is washed with water, with saturated NaCl solution and dried over Na2SO4, the solvent is partially evaporated off and the crystalline product is spin-filtered off. 2.6 g of the expected product are obtained; m.p.=254-256° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH3:19][O:20][C:21](=[O:46])[N:22]=[C:23]([S:44][CH3:45])[C:24](=[N:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=1)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([OH:33])[C:26]=1[F:34].O>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:46])[N:22]=[C:23]([S:44][CH3:45])[C:24]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:26]=1[F:34])=[N:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(O)c1F
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCCO[Si](C)(C)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
After adding 0.489 g of cesium carbonate and 0.348 ml of (3-bromopropoxy)-t-butyldimethylsilane to a solution of 0.401 g of [2-(4-cyanophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 10 ml of DMF, the mixture was stirred at room temperature for 24 hours. Next, 50 ml of water was added to the reaction mixture and extraction was performed with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 0.517 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:19][O:14][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 15 (0.100 g, 0.390 mmol) in DMF (3 mL), was added K2CO3 (0.080 g, 0.58 mmol) and stirred at 25° C. for 10 minutes. To the reaction mixture methyl iodide (0.083 g, 0.58 mmol) was added slowly and stirred at 25° C. for 1 hour. DMF was removed under vacuum and reaction mass quenched with water, extracted with ethyl acetate (3×10 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 8% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: F[C:2](F)([C:8]([F:11])([F:10])[F:9])[CH:3]=[C:4](I)[CH2:5][OH:6].[OH2:13].Cl.[NH2:15]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:9][C:8]([F:11])([F:10])[C:2]1[O:13][N:15]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: NO
Reactant: O
Reactant: OCC(I)=CC(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCc1cc(C(F)(F)F)on1

Procedure:
2.72 g of 4,4,5,5,5-pentafluoro-2-iodo-2-pentene-1-ol was dissolved in 7 ml of ethanol, and 3 ml of water, 0.69 g of hydroxylamine hydrochloride and 1.38 g of potassium carbonate were then added. The mixture was stirred and heated under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.57 g of (5-trifluoromethyl-isoxazol-3-yl)methanol.
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@@H:12]3[CH3:24])[C:5]=2[C@H:4]([CH3:25])[CH2:3]1.[ClH:26]>C(Cl)Cl>[ClH:26].[ClH:26].[CH3:25][C@H:4]1[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]3[CH3:24])=[N:9][CH:8]=[N:7][C:6]=2[C@H:2]([OH:1])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNC[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
T a solution of the (S)-tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.106 g, 0.304 mmol) in DCM (20 mL) was added HCl (4M in dioxane, 4 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford (5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.098 g, 99%). MS (APCI+) [M+H] +249.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1N=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1)#[N:31].C(#[N:42])C>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:31]([CH2:30][C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:42])=[CH:34][CH:33]=2)[CH:7]=[N:8][CH:9]=1
Reactant: CC#N
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1
Product: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Step B (8.00 g, 20.9 mmol) in acetonitrile (70 mL) was added 4-cyanobenzyl bromide (4.10 g, 20.92 mmol) and heated at 55° C. for 3 hours. The reaction was cooled to room temperature and the resulting imidazolium salt was collected by filtration. The filtrate was heated at 55° C. for 18 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 mL) and the resulting precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 mL) and heated to reflux for 30 minutes. After this time, the solvent was removed in vacuo. The resulting residue was suspended in EtOAc (75 mL) and the solid isolated by filtration and washed with EtOAc. The solid was treated with sat. aq. NaHCO3 solution (300 mL) and CH2Cl2 (300 mL) and stirred at room temperature for 2 hours. The organic layer was separated, dried, (MgSO4) and evaporated in vacuo to afford the title compound as a white solid
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([O:14]C(C)C)=[O:13])#[N:10].N1CCCCC1>C(O)(=O)C>[C:9]([C:11](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: CC(C)OC(=O)CC#N
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccccc1)C(=O)O

Procedure:
A mixture of 95 g of benzaldehyde, 114.3 g of 7A, 1 g of piperidine and 200 ml of acetic acid was heated on a steam bath for 1 hour. The acetic acid and unreacted benzaldehyde were distilled off, to 100° C./0.2 Torr. The residue was extracted with hot hexane; no residue was left. The solution was chilled, and the solid that formed was recrystallized from methanol to give the 1-methylethyl ester of 2-cyano-3-phenyl-2-propenoic acid (7B), mp: 72°-73° C.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[N:32]1[C:41]2[C:36](=[CH:37][C:38]([CH:42]=O)=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.CC(O)=O>CN(C=O)C>[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][N:28]([CH2:42][C:38]6[CH:37]=[C:36]7[C:41](=[CH:40][CH:39]=6)[N:32]=[CH:33][CH:34]=[CH:35]7)[CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5]
Reactant: O=Cc1ccc2ncccc2c1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc5ncccc5c3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) in DMF (1 mL), was added quinoline-6-carbaldehyde (31 mg, 198 μmol), DIPEA (34 mg, 46 μL, 264 μmol) and AcOH (11.8 mg, 11 μL, 198 μmol). The reaction mixture was stirred at room temperature for 1 hour. STAB (42 mg, 198 μmol) was added and stirring was continued for 18 hours. The reaction mixture was partitioned between EtOAc (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 ml). The organic layer was washed with further saturated aqueous sodium hydrogen carbonate solution (2×10 mL), dried over magnesium sulfate and concentrated in vacuo to furnish a brown oil. The crude material was purified by HPLC Method A to afford 20.6 mg of the title compound.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][C@@H:18]([NH2:23])[CH2:17]2.CCN(CC)CC.[CH2:31]([NH:33][C:34]1[CH:39]=[C:38]([O:40][C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)[N:37]=[CH:36][N:35]=1)[CH3:32]>C(Cl)Cl>[CH2:31]([NH:33][C:34]1[CH:39]=[C:38]([O:40][C:41]2[CH:47]=[CH:46][C:44]([NH:45][C:2]([NH:23][C@H:18]3[CH2:17][C:16]4[C:20](=[CH:21][CH:22]=[C:14]([Br:13])[CH:15]=4)[CH2:19]3)=[O:4])=[CH:43][CH:42]=2)[N:37]=[CH:36][N:35]=1)[CH3:32]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1cc(Oc2ccc(N)cc2)ncn1
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNc1cc(Oc2ccc(NC(=O)N[C@@H]3Cc4ccc(Br)cc4C3)cc2)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of triphosgene (117 mg, 0.393 mmol) in CH2Cl2 (12 ml) under N2-atmosphere is cooled by an ice bath. A solution of [(R)-5-bromo-indan-2-yl-amine (250 mg, 1.178 mmol; preparation see Adv. Synth. Catal. 2001, 343, 461) and NEt3 (164 μl; 1.177 mmol) in CH2Cl2 (10 ml) is added dropwise, the dropping funnel rinsed with CH2Cl2 (2 ml) and the resulting suspension stirred for 60 min at rt. Then a solution of 4-(4-ethylaminopyrimidin-6-yl-oxy)-aniline (258 mg, 1.12 mmol) and NEt3 (164 μl; 1.177 mmol) in CH2Cl2 (10 ml) is added dropwise and the dropping funnel rinsed with CH2Cl2 (2 ml). A brown solution is formed, which is stirred for 16 h at rt. SiO2 is then added to the resulting mixture. After concentration in vacuo, the powder is put on top of a MPLC column (SiO2). Eluation with SiO2/AcOEt 4:1→AcOEt, partial concentration and filtration of the crystallized material yields the title compound: m.p.: 247° C.; 1H-NMR (DMSO-d6): 8.33 (s, 1H), 8.06 (s, 1H), 7.43 (s, 1H), 7.36 (d, 2H), 7.30 (m, 1H), 7.26 (t, 1H), 7.19 (d, 1H), 6.96 (d, 2H), 6.43 (d, 1H), 5.63 (s, 1H), 4.40 (m, 1H), 3.2 (m, 4H), 2.75 (AB×d, 2H), 1.07 (t, 3H); Anal.: CHNBr.
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1C(C)(C(OCCCCCCCCCCCC)=O)[CH:21]=[C:20]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:19]1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:4]([CH3:5])([C:3]2[CH:2]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:21]=[C:20]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:19]1
Reactant: C=Cc1ccccc1C
Reactant: CCCCCCCCCCCCOC(=O)C1(C)C=C(C(=O)OCC)NN1c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C1=CC(C)(c2ccccc2)N(c2ccc(Cl)cc2Cl)N1
Yield: 63.5 %

Procedure:
23.7 g of 2-methylstyrene and 14.8 g of compound (IIa) (see Example 1) together with 50 ml saturated aqueous sodium carbonate solution are heated for 4 hours at 80° C. The aqueous phase is subsequently separated off, and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (eluent n-heptane/ethyl acetate 1:1) over silica gel gives 6.9 g of the above-described pyrazoline as a colorless solid of melting point 87°-89° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH-].[Na+].[O-:27]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>CO.O.OO>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:27])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
2 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.76 g of 45% NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.77 g H2O2 (50% aqueous solution), and further diluted with 10 ml of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Lansoprazole with a yield of about 90.8% (LC purity>95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[Cl:19][C:20]1[C:29]([CH:30]=O)=[C:28]([Cl:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>CO>[Cl:19][C:20]1[C:29]([C:30]2[NH:1][C:2]3[CH:3]=[C:4]([N:10]4[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]4)[CH:5]=[C:6]([CH3:9])[C:7]=3[N:8]=2)=[C:28]([Cl:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: CC(=O)N1CCN(c2cc(C)c(N)c(N)c2)CC1
Reactant: O=Cc1c(Cl)nc2ccccc2c1Cl
Solvent: CO
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)nc5ccccc5c4Cl)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A 3.6 mmol of 1-[4-(3,4-Diamino-5-methyl-phenyl)-piperazin-1-yl]-ethanone was taken in 40 mL of methanol, to which was added 0.921 gm (3.6 mmol) of the 2,4-Dichloro-quinoline-3-carboxaldehyde, and the mixture was stirred for 10 hrs at room temperature, solvent was evaporated to dryness, and the residue was chromatographed to provide the product. LRMS [M+H]+454; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H, J=7.6 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.85 (dd, 1H, J=7.6, 8.4 Hz), 7.78 (dd, 1H, J=7.6, 8.4 Hz), 6.86 (brs, 1H), 6.83(brs, 1H), 3.76 (br, 2H), 3.62 (br, 2H), 3.15 (br, 2H), 3.01 (br, 2H), 2.66 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:17])[CH3:16]>>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]([CH2:11][NH:17][CH2:15][CH3:16])([OH:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Product: CCNCC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.2 g (53.9 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane are added dropwise to 60 ml of aqueous ethylamine solution (50%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:30][CH3:31])[C:13]([NH:15][C:16]([CH3:29])([CH3:28])[C:17]#[C:18][CH:19]([O:24][SiH](C)C)C(C)(C)C)=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.C(OCC)(=O)C>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([CH2:30][CH3:31])[C:13]([NH:15][C:16]([CH3:28])([CH3:29])[C:17]#[C:18][CH2:19][OH:24])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(Oc1ccc2ncccc2c1)C(=O)NC(C)(C)C#CC(O[SiH](C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc2ncccc2c1)C(=O)NC(C)(C)C#CCO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.8 %

Procedure:
2-(6-Quinolinyloxy)-N-(1-tert.butyldimethylsilyloxy-4-methylpent-2-yn-4-yl)butyramide (0.58 g) in tetrahydrofuran (10 ml) was stirred at 3–5° C. and a solution of tetra n-butylammonium fluoride (2.64 ml of 1M solution in tetrahydrofuran) was added dropwise over 5 minutes. On completion of addition, the mixture was stirred for 0.5 hour at 0° C., 0.75 hour at ambient temperature then stored for 18 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and aqueous ammonium chloride. The organic phase was separated, washed with aqueous ammonium chloride, brine, dried over magnesium sulphate and evaporated under reduced pressure to give a gum that was fractionated by chromatography (silica; hexane/ethyl acetate, 1:2 by volume) to give the required product as a colourless glass (0.30 g).