Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C:21]3([NH:25][C@@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH:22]3I)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C>CO.[Pd]>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)[C@H]1CC(I)C2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reaction time: 8 h

Procedure:
To a solution of methyl (2R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-4-iodo-1,8-diazaspiro[4.5]decane-2-carboxylate (860 mg, 1.179 mmol) in methanol (20 ml), triethylamine (0.822 ml, 5.89 mmol) was added followed by palladium on carbon 10% (172 mg, 0.162 mmol). Resulting mixture was hydrogenated at atmospheric pressure of H2 at room temperature overnight.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Br-:1].[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([OH:14])=[O:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCCCCCCCBr
Solvent: CC#N
Product: O=C(O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution of 81.4 g. 11-bromoundecanoic acid and 85.0 g. triphenylphosphine in 600 ml. acetonitrile is refluxed for 64 hours, then concentrated in vacuo. The resultant oil is dissolved in 200 ml. ether, whereupon crystals of the title compound form.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])=[CH2:2].[F:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH2:25][CH2:26][CH3:27])[C:21](I)=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:4]=[C:3]([CH:9]=[CH:8][CH:7]=1)/[CH:1]=[CH:2]/[C:21]1[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[N:23][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)=[N:19][CH:20]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Reactant: C=Cc1cccc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1/C=C/c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-vinylaniline (19 μL), N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 51 mg) and palladium(II) acetate (3 mg) in acetonitrile (1.5 mL), triethylamine (68 μL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour, and then stirred at 80° C. for 14 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 50% hexane in ethyl acetate) to obtain (E)-5-(3-aminostyryl)-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (F11, 14 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:8]=1)[CH3:2].[CH2:23]([I:25])[CH3:24].[CH2:26](O)[CH3:27]>>[I-:25].[I-:25].[CH2:19]([N+:16]([CH2:23][CH3:24])([CH2:17][CH3:18])[CH2:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH2:26][CH3:27])([CH2:1][CH3:2])[CH2:21][CH3:22])=[CH:12][CH:11]=1)[CH3:20]
Reactant: CCO
Reactant: CCI
Reactant: CCN(CC)CCCc1ccc(CCCN(CC)CC)cc1
Product: CC[N+](CC)(CC)CCCc1ccc(CCC[N+](CC)(CC)CC)cc1
Product: [I-]

Procedure:
304 mg of 1,4-bis(3-diethylaminopropyl)benzene was dissolved in 2.5 ml of absolute ethanol, and after dropwise addition of 1.56 g of ethyl iodide, the mixture was refluxed for 1.5 hours in dark. After cooling, ethanol was partially removed under reduced pressure, the resulting crystal was filtered, quickly washed with ethanol and dried in vacuo to obtain 461 mg of the title compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:20])(=[O:19])[NH2:18].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:19])(=[O:20])[NH2:18].[C:21]([O-:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([O-:26])=[O:25]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C
Solvent: CCO
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
1.5 g of 4-(4-chloro-3-sulfamoylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol were stirred in 10 ml of ethanol with 0.7 of maleic acid for 1 hour at room temperature, the salt desired was precipitated with 50 ml of diisopropyl ether and crystallized under fresh diisopropyl ether/ethyl acetate to yield colorless crystals which melted at 167° C (decomposition).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[N:23]=[N:24][N:25]([C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=3)[CH:26]=2)=[N:20][C:19]([N:34]2[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([N:25]2[CH:26]=[C:22]([C:21]3[C:16]([NH2:8])=[N:17][CH:18]=[C:19]([N:34]4[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]4)[N:20]=3)[N:23]=[N:24]2)=[CH:32][CH:31]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cn(-c4ccc(N)cc4)nn3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cn(-c4ccc(N)cc4)nn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Tert-butyl N-tert-butoxycarbonyl-3-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)-5-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-ylcarbamate (64 mg, 0.1016 mmol) was dissolved in DCM (5 mL) and treated with TFA (500 μL, 6.490 mmol). The reaction was allowed to stir at ambient temperature overnight and then the solvent removed in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (24.3 mg, 30% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (t, J=7.4 Hz, 3H), 3.11 (q, J=7.4 Hz, 2H), 3.30-3.33 (m, 4H), 3.50-3.52 (m, 4H), 6.77 (d, J=8.6 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.88 (s, 1H) and 9.09 (s, 1H) ppm; MS (ES+) 430.0
Reaction SMILES: Cl.[N:2]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([OH:17])[C:13]=3[CH:18]=2)[CH3:8])[CH:6]=[CH:5][N:4]=[CH:3]1.I[CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:20]([O:17][N:14]1[C:13]2[CH:18]=[C:9]([CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[CH:3]3)[CH3:8])[CH:10]=[CH:11][C:12]=2[N:16]=[N:15]1)[CH3:21]
Reactant: CCI
Reactant: CC(c1ccc2nnn(O)c2c1)n1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOn1nnc2ccc(C(C)n3ccnc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
A mixture of 4.5 parts of 6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazol-1-ol monohydrochloride, 3.12 parts of iodoethane, 3.7 parts of sodium carbonate and 63 parts of N,N-dimethylformamide was stirred for 4 hours at room temperature. The reaction mixtur was evaporated and the residue was taken up in water. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 27 parts of ethyl acetate and 21 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.26 parts (51.6%) of 1-ethoxy-6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazole; mp. 81.1° C. (compound 215).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[N:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.C(N(CC)CC)C>[CH3:15][S:16]([O:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[N:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cnn(CCO)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(CCOS(C)(=O)=O)c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-hydroxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (200 g) in a mixture of methylene chloride (2 l) and triethylamine (210 ml) was added dropwise methanesulfonyl chloride (85.5 ml) under ice-cooling. The mixture was stirred for 1 hour at 3°-5° C. The reaction mixture was poured into ice-water (700 ml). The separated organic layer was washed with 1N hydrochloric acid and water, and dried over magnesium sulfate. The solvent was evaporated to give 1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (270.8 g) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cccnc12
Reaction time: 8 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate (10 g, 0.03 mol), ethyl acetate (800 mL) and platinum on carbon catalyst were combined in a Parr bottle and then the mixture was hydrogenated overnight. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide 9.1 g of 1,1-dimethylethyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate as a yellow syrup. Analysis: Calculated for C15H21N5O2+0.1 CH3CO2C2H5: %C, 59.25 %H, 7.04; %N, 22.43; Found: %C, 58.96; %H, 6.87; %N, 22.46.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([F:32])[N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=[O:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH2:1]([S:3]([CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([F:32])[N:11]([C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)(=[O:41])=[O:4])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCS(=O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Product: CCS(=O)(=O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Using the same technique as for the starting material of Example 50, but using two equivalents of 3-chloroperbenzoic acid, there was obtained 4-(3-ethanesulphonylpropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.35 (t, 3H); 2.09 (quintet, 2H); 2.58 (t, 2H); 2.84 (q, 4H); 6.29 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N+:42]=5[O-:48])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N+:42]=5[O-:48])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(Cl)c[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(Cl)c[n+]4[O-])cc2)CCN3)cc1
Reaction time: 2.5 h
Yield: 30.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.20 g) in ethanol (30 ml), sodium borohydride (50 mg) was added at room temperature and the mixture was stirred for 2.5 hours. To the reaction solution was added sodium borohydride (50 mg), and the mixture was stirred for 2.5 hours. Sodium borohydride (50 mg) was further added to the mixture and the mixture was stirred for 1 hour. Sodium borohydride (50 mg) was further added to the mixture, and the mixture was stirred for 13 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 4:1→ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 109) (53 mg) as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24]>>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Product: C=COCCONC(=O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventional workup.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:8][C:9](=[O:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3]1.Br[CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:8][C:9](=[O:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3]1
Reactant: OCCBr
Reactant: O=c1[nH]c(C2CCNC2)cc2ccccc12
Agent: Cl
Product: O=c1[nH]c(C2CCN(CCO)C2)cc2ccccc12

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one hydrochloride (201 mg) and 2-bromoethanol (285 μl), 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinolin-1-one (58 mg) was obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:20]1[CH2:23][C:22](=O)[CH2:21]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O.C(O)(=O)C>[O:20]1[CH2:23][CH:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]3)[CH2:15][CH2:16]2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C3COC3)CC2)CC1
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
In a 100 ml round-bottom flask 2 g (7.42 mmol) of 1-boc-4-(piperidin-4-yl)-piperazine and 1.07 g (14.85 mmol) of 3-oxetanone were dissolved in 30 ml of dichloromethane. 3.16 g (22.27 mmol) of sodium sulfate were added and the reaction was stirred for 10 min. Subsequently, 2.203 g (10.39 mmol) of sodium triacetoxyborohydride were added and the reaction was stirred for 5 min. pH was adjusted to 5-6 with acetic acid and the reaction was stirred over night. Then, 50 ml of water were added and the resulting two phases were separated. The organic phase was washed twice with water dried over MgSO4, filtered and evaporated. The resulting solid was digested in methyl-tert-butyl ether, filtered off, washed with 10 ml of methyl-tert-butyl ether and dried. Flash chromatography (silica gel/gradient from 0 to 20% methanol in dichloromethane) yielded 650 mg of the title compound as a yellowish solid.
Reaction SMILES: Cl.[NH2:2]O.[NH2:4][C:5]1[S:6][C:7]([CH:10]=O)=[CH:8][N:9]=1.[CH:12]([O-:14])=O.[Na+].C(O)=O>CO.C(Cl)(Cl)Cl>[C:10]([C:7]1[S:6][C:5]([NH:4][CH:12]=[O:14])=[N:9][CH:8]=1)#[N:2]
Reactant: NO
Reactant: O=C[O-]
Reactant: Nc1ncc(C=O)s1
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1cnc(NC=O)s1
Yield: 60.4 %

Procedure:
Hydroxylamine hydrochloride (24.0 g, 0.30 m+15% molar excess), crude 2-amino-5-formylthiazole (38.4 g, 0.30 m), and sodium formate (37.5 g, 0.55 m) are combined in 450 ml of 97% (commercial) formic acid. The mixture is heated on a steam bath until TLC (10% CH3OH/CHCl3) shows only a single product spot (about 7-8 hr.). The reaction mixture is filtered hot and the filtrate condensed under reduced pressure. The residue is triturated in ice water, the solid collected by filtration, washed with water, and air-dried to yield 27.7 g (0.18 m, 60.5%) of 5-cyano-2-formamidothiazole as a reddish-brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[CH:4][C:3]=1[F:16].[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20]C)[CH3:18].ClC(OC1C=CC=CC=1)=[O:26].N1CCCC1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:20]([N:19]3[CH2:22][CH2:23][CH2:18][CH2:17]3)=[O:26])[CH:8]=2)=[CH:4][C:3]=1[F:16]
Reactant: CCN(CC)CC
Reactant: Nc1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1F
Yield: 13 %

Procedure:
To a solution of 4-(4-amino-3-fluorophenoxy)pyridin-2-ylamine (500 mg) in tetrahydrofuran (10 ml) was added triethylamine (0.223 ml), and then phenyl chloroformate (0.200 ml) was added thereto while stirring in an ice bath, followed by stirring under a nitrogen atmosphere for 2 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (10 ml) and pyrrolidine (0.667 ml) were then added, followed by stirring at room temperature for 21 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated to provide the titled compound (94 mg, 13%) as a purple oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:16][CH2:17][S:18][C:19]#[N:20]>O1CCCC1>[Cl-:16].[CH3:1][N+:2]([CH3:15])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:17][S:18][C:19]#[N:20]
Reactant: N#CSCCl
Reactant: CCCCCCCCCCCCN(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCC[N+](C)(C)CSC#N
Product: [Cl-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.4 %

Procedure:
A 2 liter flask was charged with 1 liter of tetrahydrofuran, 277 g of dimethyldodecylamine and then 153.7 g of chloromethylthiocyanate. The reaction mixture was stirred at ambient temperature for 17 hours. A considerable amount of solids was formed. The reaction was then stirred for 7 more hours at 35° C. The solid was filtered off with suction and the solid washed with diethyl ether. The filtrate now formed more solid which was filtered off, washed with ether and then combined with the other solid. The combined solids were now allowed to air dry to constant weight, 331.0 g, for a 79.4% yield. Analysis (nmr) showed a purity of better than 98%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:47])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39]S(C)(=O)=O)[C:22]=1[CH2:44][CH2:45][CH3:46])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:47])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:44][CH2:45][CH3:46])[CH3:16]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 69.4 %

Procedure:
A mixture of 1.16 g (0.006 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.93 g (0.006 mole) of [4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester and 1.65 g (0.012 mole) of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 21 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 40% ethyl acetate-hexane to give 2.45 g (70% yield) of [4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1>[Pd].C(O)C>[NH3:3].[N:3]1[CH:2]=[CH:7][CH:6]=[C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: Clc1ccc(N2CCCNCC2)nn1
Agent: [Pd]
Solvent: CCO
Product: N
Product: c1cnnc(N2CCCNCC2)c1
Reaction time: 8 h

Procedure:
A mixture of 1-(3-Chloro-6-pyridazinyl)-homopiperazine (5.56 g, 26.1 mmol), palladium on carbon (2.1 g, 10%) and ethanol (150 ml) was stirred under hydrogen overnight. The crude product was filtered through celite and evaporated. Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as free base. Yield 2.78 g, 60%, 185.0-186.9° C.