Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH:10]=[C:11]2[CH2:14][O:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH:15]([N:28]1[CH2:33][CH2:32][N:31]([C:11]2([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH2:14][O:13][CH2:12]2)[CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(C=C1COC1)c1ccccc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CO
Product: O=S(=O)(CC1(N2CCN(C(c3ccccc3)c3ccccc3)CC2)COC1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
A clear solution of 3-((phenylsulfonyl)methylene)oxetane (450 mg, 1.284 mmol) in methanol (10 mL) was treated with 1-benzhydrylpiperazine (389 mg, 1.541 mmol) and stirred at 50° C. overnight, more 3-((phenylsulfonyl)methylene)oxetane (100 mg) was added, stirred at 50° C. overnight and, concentrated. The crude was purified by ISCO (40 g), eluted with ethyl acetate: hexane=0-50%, the desired fractions were concentrated to yield 1-benzhydryl-4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperazine (670 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([CH3:11])[CH2:8][C:7]=2[CH:12]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([CH3:11])[CH2:8][C:7]=2[CH:12]=1)=[O:1]
Reactant: CC1Cc2cc(CO)ccc2O1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC1Cc2cc(C=O)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of 680 mg (4.14 mmole) 5-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran in 100 ml methylene dichloride was added 5.44 g manganese dioxide in one portion and the mixture stirred at room temperature overnight or until the reaction was complete as evidenced by thin-layer chromatography. The mixture was then filtered and the solvent evaporated to provide the title compound in quantitative yield. 1H-NMR(CDCl3)ppm(delta): 1.6 (d, 3H), 2.7-3.6 (m, 1H), 5.1 (m, 2H), 6.8 (d, 1H), 7.6 (m, 2H), 9.8 (s, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[CH3:19])[C:8](=[O:9])[C:7]2[C:6](=[CH:23][CH:22]=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=2)[N:5]=1
Reactant: COc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c(C)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(-n2c(CF)nc3ccc([N+](=O)[O-])cc3c2=O)c(C)c1
Yield: 86.8 %

Procedure:
4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-methoxyaniline, 3.5 g of boron trifluoride etherate and 30 ml of acetic acid are treated in the same manner as described in Example 1-(2)l, whereby 3.3 g of 2-fluoromethyl-3-(2-methyl-4-methoxyphenyl)-6-nitro-4(3H)-quinazolinone are obtained as yellow prisms.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:39][C:40](=[O:53])[C@@H:41]([O:50][CH2:51][CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[CH3:38].N(C(OCC)=O)=NC(OCC)=O>>[CH2:37]([O:39][C:40](=[O:53])[C@@H:41]([O:50][CH2:51][CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:11][CH2:10]/[CH:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)\[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:45][CH:44]=1)[CH3:38]
Reactant: OC/C=C(\c1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(F)cc2)cc1)OCC
Yield: 84.9 %

Procedure:
Reaction of (E)-3-(4-fluorophenyl)-3-phenyl-prop-2-en-1-ol (200 mg, 0.88 mmol), triphenylphosphine (242 mg, 0.92 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (200 mg, 0.84 mmol) and diethyl azodicarboxylate (160 mg, 0.92 mmol) in an identical manner to example 1 gave the title compound (320 mg, 85%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+]=[N-].[Na+].O.[OH-].[Na+]>CS(O)(=O)=O>[CH2:1]([N:8]1[CH2:9][C:10]2[CH:11]=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[NH:21][C:16](=[O:18])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CN(Cc1ccccc1)CC2=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CN(Cc1ccccc1)CC(=O)N2
Temperature: 65 °C
Yield: 73 %

Procedure:
To a solution of 2-benzyl-7-methoxy-2,3-dihydro-1H-isoquinolin-4-one (7.0 g, 26.2 mmol) in methanesulfonic acid (50 mL) was added sodium azide (3.4 g, 52.4 mmol) portionwise with stirring (Caution: mild exotherm, gas evolution). The mixture was heated to 65° C. for two hours before being cooled to ambient temperature. Water (100 mL) was added, the mixture was cooled in an ice-water bath, and the pH was adjusted to 7-8 (10N NaOH). The gummy precipitate was extracted (DCM), the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Further purification by flash chromatography over silica gel (DCM/MeOH) gave 4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (5.4 g, 73%) as a tan solid; 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.33 (m, 5H), 6.97 (d, J=8 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 6.82 (s, 1H), 3.73 (s, 3H), 3.67 (s, 4H), 3.09 (s, 2H); MS (m/e) 283 (M+1); mp 134° C.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:25][C:24]=2[OH:35])[CH:13]=1)[CH3:4]>C(O)C>[CH2:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-:18])=[O:17])=[C:14]([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:25][C:24]=2[OH:35])[CH:13]=1)[CH3:4].[Na+:2]
Reactant: CCNc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cc(-c3cccnc3)ccc2O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNc1ccccc1-c1ccc(C(=O)[O-])c(NC(=O)c2cc(-c3cccnc3)ccc2O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethanol (2.0 mL) and a 1 mol/L aqueous solution of sodium hydroxide (0.067 mL) were added to the obtained 4-(2-(ethylamino)phenyl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoic acid (0.032 g), followed by stirring at room temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. The solid substance was collected by filtration to obtain 0.024 g of sodium 4-(2-(ethylamino)phenyl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[N:6]=[CH:7][C:2]=1[N:1]([S:21]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23])[S:21]([C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)(=[O:23])=[O:22])(=[O:11])[CH3:10]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1cc(Cl)ncc1N
Solvent: c1ccncc1
Product: CC(=O)c1cc(Cl)ncc1N(S(=O)(=O)c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of 1-(5-amino-2-chloropyridin-4-yl)ethanone (1.0 equiv.) in pyridine (0.26 M) was added 4-nitrophenylsulfonylchloride (3.0 equiv.). The resulting amber solution was stirred at rt for 18 hours, at which time it was poured onto ice. The resulting solid was filtered, rinsed with H2O and pumped on yielding N-(4-acetyl-6-chloropyridin-3-yl)-4-nitro-N-(4-nitrophenylsulfonyl)benzenesulfonamide (88%). LC Rt=4.77 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[C:10]([O-])(O)=O.[Na+].[Na+].[Cl-]>CO>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:10])=[O:7]
Reactant: O=C([O-])O
Reactant: NCCCCC(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-aminovaleric acid (5 g, 42.68 mmol) in MeOH (100 mL) at room temperature was added HCl conc. (37%, 16 mL). The solution was stirred for 48 h at room temperature and monitored by HPLC-MS. The resulting solution was treated with a saturated aqueous solution of NaHCO3 then the solvents were evaporated under reduced pressure. The aqueous layer was washed several times with CH2Cl2 and AcOEt. The aqueous phase was concentrated to produce a solid containing the desired product, NaCl, and NaHCO3. The solid was washed with MeOH, and the organic filtrate was concentrated to afford the title compound (36) as a white solid (7.88 g, 100%): 1H NMR: (300 MHz, CD3OD) δ 3.34 (s, 3H), 2.61 (br. s, 2H), 2.10-2.06 (m, 2H), 1.39-1.34 (m, 4H); MS (ES) m/z 132.2 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.CN(C)C=O>[Pd].C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ncc[nH]3)c2n2ccnc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ncc[nH]1)c1ccccc1-2
Yield: 30.1 %

Procedure:
The procedure is performed as in Example 21, but starting with 1.65 g of 10-(2-imidazolylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 300 ml of dimethylformamide, 5 ml of acetic acid and 0.17 g of 10% palladium on charcoal. 0.5 g of 10-(2-imidazolylmethyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is obtained, in the form of a pale yellow solid melting above 260° C. (Analysis % calculated C: 67.32, H: 4.32, N: 23.09, O: 5.27, % found C: 67.2, H: 4.3, N: 23.0).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][NH:6][C:7](=[O:37])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])(F)F)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[OH-].[Na+].[CH3:41]O>>[F:36][CH:33]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:38])=[O:37])=[CH:9][CH:10]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)[CH3:41]
Reactant: CO
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CC(Sc1ccc(-c2ccc(OC(C)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 5 h

Procedure:
To a mixture of 3-{4-[3-Methyl-1-(4′-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]-benzoylamino}-propionic acid methyl ester (20 mg) in methanol (2 mL) is added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h. The reaction mixture is concentrated and acidified by 5 N HCl (0.5 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (18 mg). MS (ES): 531.2 [M−H]−.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C.[BrH:31]>C1(C)C=CC=CC=1>[BrH:31].[BrH:31].[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCc3ccccc3C2)CC1
Agent: Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCN(C1CCNCC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(3,4-Dihydro-1H-isoquinolin-2-yl)piperidine-1-carboxylic acid benzyl ester (290 mg, 0.83 mmol) was mixed with 25% hydrobromic acid acetic acid solution (3 ml) and stirred at room temperature for 2 hours. The reaction solution was mixed with toluene, the solvent was removed by evaporation under a reduced pressure, and the thus precipitated crystals were washed with a small amount of cold toluene and collected by filtration to obtain 150 mg (0.40 mmol, 48% in yield) of the title compound. MW 378.15 (C14H22Br2N2); Mass spectrum EI-Ms m/z 216 (M−2HBr)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[CH3:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(OCCCl)cc1
Reactant: Cc1nc2ccccc2s1
Product: ClCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Yield: 90 %

Procedure:
The named compound was prepared as described in Example 17 starting with 4-chloroethoxybenzaldehyde (4.0 g, 22 mmol) and using 2-methylbenzothiazole in place of 2-methylbenzoxazole to give (E)-2-[2-(4-chloroethoxyphenyl)ethenyl]benzothiazole (G) (7.6 g, 90% yield) as a yellow solid, mp 92°-94° C. 1H NMR (CDCl3): δ 8.09-6.85 (m, 10H), 4.23 (t, J=5.2 Hz, 2H), 3.81 (t, J=5.2 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:49]=[CH:48][C:25]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:28][C:24]=3[CH:23]=2)[CH:17]=1)[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O1CCOCC1.Cl>[NH:26]1[C:25]2[CH:48]=[CH:49][C:22]([C:18]3[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=3)[CH2:15][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:23][C:24]=2[N:28]=[N:27]1
Reactant: CN(C)CCCN(Cc1ccccc1)Cc1cccc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)CCCN(Cc1ccccc1)Cc1cccc(-c2ccc3[nH]nnc3c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
N-Benzyl-N′,N′-dimethyl-N-[3-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-propane-1,3-diamine (60 mg, 0.093 mmol) was dissolved in a mixture of 5 mL of ethanol, 5 mL of dioxane and 8 mL of 2M aqueous hydrochloric acid solution, and the resulting mixture was stirred at room temperature for 6 h. The volatiles were removed in vacuo and the residue partitioned between diethyl ether and 1M HCl solution. The aqueous phase was washed with diethyl ether and the combined organic phases were concentrated in vacuo to obtain the crude product, which was dissolved in small amount of 1M HCl solution and freeze dried. Purification by HPLC (elution with 30% acetonitrile/70% water (containing 0.1% trifluoroacetic acid)) afforded 30 mg of the title compound. LC/MS (short method): Retention time 1.19 min; (M+H)=400.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]3[N:11]=2)=[CH:8][C:7]([S:24](Cl)(=[O:26])=[O:25])=[C:6]([O:28][CH3:29])[CH:5]=1)[CH3:2].CN(C1C=CC=CN=1)C.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:28][CH3:29])[C:7]([S:24]([N:43]2[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]2)(=[O:26])=[O:25])=[CH:8][C:9]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)c(OC)cc3OCC)nn12
Reactant: CN1CCNCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)c(OC)cc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
20 mg (0.045mmol) of 4-ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 0.5 ml of dichloromethane and admixed with a spatula tip of dimethylaminopyridine and 14 mg (0.136 mmol) of N-methylpiperazine, and the reaction mixture is stirred at room temperature overnight. Purification over silica gel gives 12.8 mg (55%) of 2-[2-ethoxy4-methoxy-5-(4-methylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:50])[CH3:49]>C(Cl)Cl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:25]2[CH2:26][CH2:27][CH2:28][C@@H:23]([NH:22][C:18]3[N:17]=[C:16]([C:15]4[N:14]5[C:10]([S:11][CH:12]=[CH:13]5)=[N:9][C:8]=4[C:4]4[CH:3]=[C:2]([NH:1][C:48](=[O:50])[CH3:49])[CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:20][N:19]=3)[CH2:24]2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
The 4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine (0.1 g, 0.177 mmol) was dissolved in DCM (5 ml) and treated sequentially with Hunig's base (46 uL, 0.265 mmol) and acetyl chloride (15 uL, 0.212 mmol). The mixture was kept at room temperature for two hours then was diluted with DCM (10 ml). The organic phase was washed with water (2×10 ml) and with an aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow foam. The product was triturated in ether and filtered off, giving the title compound as a yellow solid (97 mg). M.p.=169-174° C. 400 MHz 1H NMR (DMSO-d6) δ: 9.89 (s, 1H), 8.72 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.82 (s, 1H), 7.80-7.75 (m, 2H), 7.70-7.64 (m, 3H), 7.41 (d, J=4.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.4 Hz, 1H), 6.42 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.74 (d, J=8.6 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.54-2.43 (m, 1H), 2.34 (t, J=10.2 Hz, 1H), 2.05 (s, 3H), 1.94-1.81 (m, 2H), 1.65-1.53 (m, 1H), 1.44-1.34 (m, 1H). LCMS: 608 [M+H]. Calc. for C28H26N7O3S2Cl.0.38 water.0.41 dioxane: C, 54.68; H, 4.65; N, 15.06. Found C, 54.68; H, 4.32; N, 15.05.
Reaction SMILES: [Na+].[Br:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:5][CH:4]=1.[CH3:16]I.O>CN(C)C=O>[CH3:16][O:13][C:12](=[O:14])[C:11](=[O:15])[CH:10]=[CH:9][C:6]1[CH:7]=[N:8][C:3]([Br:2])=[CH:4][CH:5]=1
Reactant: CI
Reactant: O=C([O-])C(=O)C=Cc1ccc(Br)nc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)C=Cc1ccc(Br)nc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A mixture of the 4-(6-bromo-pyridin-3-yl)-2-oxo-3-butenoic acid sodium salt (900.0 mg, 3.2 mmol) in the form of a pale yellow solid, methyl iodide (400.0 mL, 6.47 mmol) in N,N-dimethylformamide (20.0 mL) was stirred at 75° C. for 3 hours. Distilled water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 615.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([C:31]([CH:33]4[CH2:35][CH2:34]4)=O)[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([CH2:31][CH:33]4[CH2:35][CH2:34]4)[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(C1CC1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(Oc2ccc3c(c2)[C@@]24CCCC[C@H]2[C@@H](C3)N(CC2CC2)CC4)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
To a suspension of 0.4 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran was added dropwise, 4.6 g (0.011 mol) of (-)-3-phenoxy-N-cyclopropylcarbonylmorphinan in 30 ml of anhydrous tetrahydrofuran over a period of 15 minutes. After the mixture had been refluxed under nitrogen for 16 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated. The residue was partitioned between ether and 4 N hydrochloric acid. The acidic phase was made basic with concentrated ammonium hydroxide and the aqueous suspension was extracted with ether. The ether solution was washed with water and dried. Removal of the ether under reduced pressure afforded 2.6 g (59%) of the product (-)-3-phenoxy-N-cyclopropylmethylmorphinan. For analysis, a sample of this compound was distilled, bp 190°200°/0.1mmHg, [α]25D -89.07° (c 0.99, MeOH).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[N:23]=[C:24]([CH2:27]O)[S:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[S:25][CH:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[N:23]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: OCc1nc(C(F)(F)F)cs1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (65 mg), [4-(trifluoromethyl)-1,3-thiazol-2-yl]methanol (73 mg) and triphenylphosphine (156 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (140 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from 2-propanol-diisopropyl ether to give the title compound (42 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])[N:21]([CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>C(#N)C>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])[N:21]([CH2:22][CH2:23][NH2:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Temperature: 25 °C
Yield: 81.7 %

Procedure:
Trifluoroacetic acid (100 mL) was added with stirring to a solution of 1,1 -dimethylethyl N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (30.0 g, 78.2 mmol) in acetonitrile (100 mL). The reaction mixture was maintained at ambient temperature for 24 hours and then it was concentrated under vacuum. The residue was dissolved in a minimal amount of water and the pH of the solution was adjusted to pH 13 using 10% sodium hydroxide. The resulting precipitate was isolated by filtration and dried under high vacuum to provide 18.1 g of 2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine as an off-white solid, m.p. 196-199° C.