Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:18][CH2:19][C@H:20]3[NH:26][C:24](=[O:25])[CH:23]=[CH:22][C@:21]3([CH3:27])[C@H:5]1[CH2:4][CH2:3]2.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.C1N(CCCS(O)(=O)=O)CCOC1.C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>>[CH3:1][C@@:2]12[C@@H:10]([C:11]([NH:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:18][CH2:19][C@H:20]3[NH:26][C:24](=[O:25])[CH2:23][CH2:22][C@:21]3([CH3:27])[C@H:5]1[CH2:4][CH2:3]2
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=S(=O)(O)CCCN1CCOCC1
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To obtain sufficient transformed inhibitor for mass spectral analysis, a preparation of baculovirus-expressed enzyme was employed that consisted of all protein sedimenting between 1,000 to 100,000×g. The enzyme-[3H]finasteride complex was formed in a solution containing 1.39 μM enzyme (41,000 units, 141 mg protein), 1.14 μM unlabeled finasteride (15.0 nmol), 0.0113 uM tracer [3H]finasteride (1.56 μCi), and 573 μM NADPH, in a buffer composed of 0.1M MOPS, 1M sucrose, and 10 mM EDTA at pH 7.20 in a total volume of 13.1 mL. The enzyme was dispersed in the solution with a dounce and stirred for 45 min as it warmed to room temperature, which produced 73% inhibition. The solution was then dialyzed overnight at 4° C. in 14,000 Da cutoff dialysis tubing (SPECTRAPOR 2) against 2 changes of 4L water containing 1 mM MOPS and 1 mM EDTA at pH 7.20. This resulted in 88% retention of the radioactivity. (Analysis of the radioactivity lost to dialysis indicated 62% chromatographed as [3H]dihydrofinasteride, and the remainder as [3H]finasteride. This corresponds to loss of 8% of the total starting radioactivity as [3H]dihydrofinasteride, implying a partition ratio of 1.08 in this instance.)
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([O:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>ClCCl>[C:1]([O:4][C:5]1[C:13]([O:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:19])=[O:8])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Oc1cccc(C(=O)O)c1OC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C(=O)Cl)c1OC(C)=O

Procedure:
24 g of 2,3-bis(acetyloxy)benzoic acid was suspended in 100 ml of dichloromethane and, at -10° C., 23 g of phosphorous pentachloride was added. The hydrogen chloride gas that formed was removed The resulting clear solution was then evaporated in an oil-pump vacuum yielding a brown honey. This was dissolved in 300 ml of petroleum ether and filtered over active carbon. After distilling off the solvent, the title compound was obtained in the form of white crystals (25.1 g); melting point 97°-99° C. (dec.)
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8]CN2CCN(C3C(OC)=CC=CN=3)CC2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:40][O:41][C:42]1[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[N:44][CH:45]=[CH:46][CH:47]=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][N:51]2[CH2:52][CH2:53][N:48]([C:43]3[C:42]([O:41][CH3:40])=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:49][CH2:50]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cccnc1N1CCNCC1
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cccnc1N1CCN(CCc2csc3ccccc23)CC1

Procedure:
The title compound was prepared (0.63 g, 56%, mp 208°-215° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thieneethanol tosylate (Example 47) with 1-(3-methoxy-2-pyridinyl)piperazine.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([CH3:35])[CH:17]2[C:20]2([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH2:23][CH2:22][CH2:21]2)=[CH:12][C:11]=1[O:36][CH3:37])C1C=CC=CC=1.Cl.[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([CH3:35])[CH:17]2[C:20]2([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=3)[CH2:23][CH2:22][CH2:21]2)=[CH:12][C:11]=1[O:36][CH3:37]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccc(OC(F)(F)F)cc3)CCC1)N(C)CC2
Agent: Cl
Agent: O=C(O)C(=O)O
Product: COc1cc2c(cc1O)C(C1(c3ccc(OC(F)(F)F)cc3)CCC1)N(C)CC2

Procedure:
A mixture of 7-benzyloxy-6-methoxy-2-methyl-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.94 g), industrial methylated spirits (65 ml) and concentrated hydrochloric acid (65 ml) was heated under reflux for 45 minutes. The mixture was concentrated, and dried by azeotropic distillation with propan-2-ol. The residue was dissolved in ether and treated with one equivalent of oxalic acid to yield 7-hydroxy-6-methoxy-2-methyl-1-[1-(4-trifluoromethoxyphenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline oxalate which was crystallised from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:8]2[CH2:35][C:36]([CH2:43][CH3:44])([CH2:41][CH3:42])[C:37]([O:39]C)=[O:38])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28](=[O:34])[CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[C:8]2[CH2:35][C:36]([CH2:41][CH3:42])([CH2:43][CH3:44])[C:37]([OH:39])=[O:38])=[CH:45][CH:46]=1
Reactant: CCC(CC)(Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Temperature: 70 °C

Procedure:
The compound from Step E was hydrolysed using THF (2.5 mL), MeOH (0.6 mL) and NaOH (1N, 1.5 mL). The solution was heated at 70° C. for 2 weeks. The reaction was neutralized by addition of Na4OAc buffer (20 mL of 25% w/v) and extracted with EtOAc (3×30 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (eluant:EtOAc-hexane-HOAc (250:750:1)) to give the title compound. Anal. C, H, N for sodium salt·11/2 H2O; Calc. C, 67.70; H, 6.43; N, 4.15 Found C, 67.67; H, 6.31; N, 4.06.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH:17]=1
Reactant: Nc1cccnc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)Nc3cccnc3)ccc2N1
Yield: 37.4 %

Procedure:
A solution of 5-chlorosufonyl-2-oxindole (3 g) and 3-aminopyridine (1.46 g) in pyridine (15 mL) was stirred at room temperature overnight at which time a brown solid was present. The solid was filtered, washed with ethanol and dried under vacuum to yield 1.4 g (38%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32]I.[H-].[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:21][Si:22]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:28])[CH3:27])[CH:29]([CH3:31])[CH3:30])=[CH:18][CH:19]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 18 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E203) in THF under N2 and cooled to 0° C. was added CH3I followed by NaH and the solution was warmed and allowed to stir for 18 h. The mixture was taken up in EtOAc and extracted with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-10% MeOH/CH2Cl2 gradient) gave pure 3-(tert-butoxycarbonyl(methyl)amino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E204).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.C(N(CC)CC)C.[P:32](Cl)([O:36][CH3:37])([O:34][CH3:35])=[O:33]>C(Cl)Cl.CCOC(C)=O>[CH3:35][O:34][P:32]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1)([O:36][CH3:37])=[O:33]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: COP(=O)(Cl)OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COP(=O)(OC)N1CCCC(C(C)Nc2nccc(-n3cnc4ccccc43)n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 18) (44 mg, 0.136 mmol) in CH2Cl2 (1.5 mL) was added triethylamine (29 μL, 0.204 mmol) followed by dimethyl chlorophosphate (22 μL, 0.204 mmol) at 0° C. After stirring 30 min at 0° C., the reaction mixture was diluted with EtOAc (10 mL) and was washed with saturated aqueous NaHCO3 followed by brine. The organic layer was dried over Na2SO4. After removal of the solvent, the crude product was purified by preparative thin layer chromatography (3:1 acetone:hexane) to obtain 40.6 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.36 (br s, 1H); 8.14 (d, J=7.3 Hz, 1H); 7.83 (d, J=7.3 Hz, 1H); 7.38 (m, 2H); 6.78 (d, J=5.4 Hz, 1H); 4.15 (m, 1H); 3.67 (s, 3H); 3.65 (s, 3H); 1.28 (d, J=6.5 Hz, 3H). Mass spectrum 431.3 (ESI, M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.Cl.ClC[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:6][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: c1cncc(CN2CCNCC2)c1
Yield: 86.7 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (930 mg), 3-chloromethyl-pyridine hydrochloride (902 mg) and cesium carbonate (3.6 g) were reacted in DMF (5 ml), followed by further treatment with TFA, to obtain 1-pyridin-3-ylmethyl-piperazine (767 mg, 87%) as a pale brown oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=2)=[C:11]([CH3:25])[CH:10]=1.C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH3:25])[C:12]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][CH:21]=2)=[C:13]([CH3:15])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-c2c(C)cc(OCCO)cc2C)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCOc1cc(C)c(-c2ccc(C(C)=O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Acetyl chloride (0.226 mL) was added to a mixture of 1-[4′-(2-hydroxyethoxy)-2′,6′-dimethylbiphenyl-4-yl]ethan-1-one (0.75 g) and triethylamine (0.556 mL) in methylene chloride (2 mL), and the mixture was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3-1/2) to afford 1-[4′-(2-acetoxyethoxy)-2′,6′-dimethylbiphenyl-4-yl]ethan-1-one (0.672 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([C:13]([Cl:16])([Cl:15])[Cl:14])[C:10](F)=[S:11].[CH3:17][N:18]1[CH:22]=[C:21]([OH:23])[CH:20]=[N:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH:22]=[C:21]([O:23][C:10](=[S:11])[N:9]([CH3:8])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH:20]=[N:19]1
Reactant: Cn1cc(O)cn1
Reactant: CN(C(F)=S)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C(=S)Oc1cnn(C)c1)C(Cl)(Cl)Cl
Reaction time: 4 h
Yield: 86.6 %

Procedure:
5.1 g (0.05 mol) of triethylamine were added dropwise to a mixture of 11.3 g (0.05 mol) of N-methyl-N-trichloromethylthio-carbamoyl fluoride, 4.9 g (0.05 mol) of 1-methyl-4-hydroxypyrazole and 150 ml of toluene. After 4 hours, the mixture was extracted twice with 25 ml of water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was subjected to incipient distillation under a high vacuum. 12.5 g (82% of theory) of N-methyl-N-trichloromethylthiocarbamic acid O-(1-methyl-pyrazol-4-yl) ester were thus obtained in the form of a yellow oil with a refractive index nD23 of 1.5492.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[N:18]1.CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2.C([O-])(=O)C.[K+]>CC(O)(CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][N:17]1[C:21]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][NH:8][C:9]3=[O:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=2)=[C:20]([CH3:22])[N:19]=[N:18]1
Reactant: O=c1[nH]ccc2c([N+](=O)[O-])cc(Br)cc12
Reactant: Cc1cn(C)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CCC(C)(C)O
Product: Cc1nnn(C)c1-c1cc([N+](=O)[O-])c2cc[nH]c(=O)c2c1
Temperature: 120 °C
Yield: 60 %

Procedure:
A mixture of 7-bromo-5-nitroisoquinolin-1(2H)-one (293b, 4.00 g, 14.9 mmol), 1,4-dimethyl-1H-1,2,3-triazole (2.17 g, 22.3 mmol), palladium acetate (334 mg, 1.49 mmol), CatacXiumA (butyl di-1-adamantylphosphine) (1.10 g, 2.97 mmol), and potassium acetate (7.30 g, 74.3 mmol) in 2-methyl-2-butanol (100 mL) was degassed with nitrogen, and heated at 120° C. in a sealed tube overnight. After cooling down room temperature, the reaction mixture was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was separated, washed with brine (1×300 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0%-10% methanol in ethyl acetate), affording 7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-nitroisoquinolin-1(2H)-one (293c, 2.55 g, 60% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 11.95 (br. s., 1H), 8.57 (s, 2H), 7.55 (d, J=5.38 Hz, 1H), 6.98 (d, J=7.34 Hz, 1H), 4.00 (s, 3H), 2.29 (s, 3H). MS: 284 [M−1].
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][N:6]=[C:5]2[S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[O:21].N1C[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)CCC>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:5]2[N:4]3[CH:3]=[CH:2][N:1]=[C:9]3[CH:8]=[CH:7][N:6]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: O=C1CSC(=O)N1CCCCSc1nccc2nccn12
Reactant: C1CCNCC1
Solvent: CCO
Solvent: CCCC=O
Product: CCCC=C1SC(=O)N(CCCCSc2nccc3nccn23)C1=O
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1.612 g (5 mmol) of 3-[4-(imidazo[1,2-c]pyrimidin-5-ylthio)butyl]thiazolidine-2,4-dione and 20 ml of ethanol were placed in a reaction flask, followed by stirring at 60° C. for 20 minutes, to dissolve the starting materials. After this mixture was kept standing to 50° C., an ethanol solution of 0.05 ml (0.5 mmol) of piperidine was added. Next, an ethanol solution of 0.45 ml (5 mmol) of n-butyraldehyde was added, followed by refluxing for 100 minutes. After the reaction mixture was cooled, the solvent was distilled off, followed by extraction with dichloromethane and water. After the organic layer was dried with sodium sulfate, the solvent was distilled off. The residue was eluted by column chromatography (eluent, hexane/ethyl acetate=1/4) to yield 1.052 g (55.9%, white crystal) of the desired product.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N+](C1C=CC(S(O[CH2:34][C:35]([C@@H:38]2[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]2)([CH3:37])[CH3:36])(=O)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:37][C:35]([C@@H:38]4[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]4)([CH3:34])[CH3:36])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: CC1(C)OC[C@@H](C(C)(C)COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC1(C)OC[C@@H](C(C)(C)COc2cccc3ccc(-c4nnc5ccccn45)nc23)O1
Temperature: 85 °C
Yield: 7.5 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (0.25 g, 0.95 mmol), (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl 4-nitrobenzenesulfonate (0.41 g, 1.1 mmol) and cesium carbonate (0.62 g, 1.9 mmol) were added to minimal amount of N,N-dimethylacetamide and heated to 85° C. The reaction was cooled, ethyl acetate was added and the mixture was sonicated. Solids were filtered off and the filtrate was dried over MgSO4, filtered and evaporated. The crude material was purified on silica gel using isopropyl alcohol containing 2% NH4OH and DCM to yield 30 mg of the desired product (90% pure. The crude material was used without further purification in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH:12]=[O:13])[CH2:3][CH2:4][CH2:5][C:6]([O:9][CH3:10])([CH3:8])[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(OCC)C>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([CH3:8])([O:9][CH3:10])[CH3:7])[CH2:11][CH2:12][OH:13]
Reactant: COC(C)(C)CCCC(C)CC=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: COC(C)(C)CCCC(C)CCO
Reaction time: 0.5 h

Procedure:
93.2 g. of 7-methoxycitronellal dissolved in 200 ml. of absolute diethyl ether are added dropwise with ice cooling to a suspension of 7.6 g. of lithium aluminum hydride in 500 ml. of absolute diethyl ether. Subsequently, the mixture is stirred for 30 minutes and decomposed in the cold by the addition of 100 ml. of aqueous ammonium chloride solution. The resulting mass is filtered through diatomaceous earth, the filtrate washed once with saturated aqueous ammonium chloride solution and once with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is distilled at 0.1 mmHg. There is obtained pure 3,7-dimethyl-7-methoxy-1-octanol of boiling point 87° C./0.1 mmHg; nD20 = 1.4456.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][C:28]([C:30]1[C:35]([NH2:36])=[CH:34][C:33]2[O:37][CH2:38][O:39][C:32]=2[CH:31]=1)=[O:29]>O1CCCC1>[C:28]([C:30]1[C:35]([NH:36][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:34][C:33]2[O:37][CH2:38][O:39][C:32]=2[CH:31]=1)(=[O:29])[CH3:27]
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Reactant: COc1cc(OCc2ccccc2)cc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OCc2ccccc2)cc(C(=O)Nc2cc3c(cc2C(C)=O)OCO3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into solutions of 163 (2.77 g, 0.01 mmol) in 200 mL of dry tetrahydrofuran were added triethylamine (10 mL) and 2-amino-4,5-methylenedioxy acetophenone (148) (1.79 g, 0.01 mmol). The mixtures were stirred at room temperature for 24 h and then evaporated. The residue was purified by column chromatography (SiO2, CH2Cl2/EtOAc=3/1) to give 164.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([OH:12])(=[O:11])=[O:10].[OH-].[Ca+2:14].[OH-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O-:12])(=[O:11])=[O:10].[Ca+2:14].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)O
Agent: [Ca+2]
Agent: [OH-]
Product: COc1ccccc1S(=O)(=O)[O-]

Procedure:
To 1000 g of 10% methoxybenzene sulfonic acid aqueous solution stirred at room temperature, 30 g of calcium hydroxide was added. The stirring was continued while measuring the pH value. At the time when the pH value reached 6, approximately, filtration was done by using a 0.4 μm glass filter to remove the insoluble components, so as to obtain a calcium methoxybenzenesulfonate aqueous solution.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:15])OC(C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:17]([O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)C>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([N:29]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[NH:8][C:9]2=[O:15])=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (12.5 g), 4-benzyloxyaniline hydrochloride (19.3 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.53 g), Pd2(dba)3 (2.0 g) and sodium tert-butoxide (12.6 g) in toluene (160 mL)—2-propanol (40.0 mL) was stirred at 100° C. under Ar overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 g) as a light brown solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][C:13]3[N:17]4[N:18]=[C:19]([C:22]([O:24]CC)=O)[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:27][CH3:28]>C1COCC1>[CH3:28][NH:27][C:22]([C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=4[CH:11]=3)=[CH:14][N:15]=2)[N:18]=1)=[O:24]
Reactant: CN
Reactant: CCOC(=O)c1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1

Procedure:
Ethyl 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxylate (115 mg, 0.3 mmol) was heated with 2 mL of 2.0 M NH2Me in THF at 85° C. in a sealed tube for 1 h, at 100° C. for 1 h, then at 110° C. overnight. LCMS analysis showed that the reaction was complete. Solvent was evaporated under reduced pressure, and the residue was dried in a vacuum oven to give N-methyl-3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxamide, which was used directly for the next step. LCMS (ESI) m/z 370 (M+H)+.