Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:3](=[O:4])[CH2:2][Br:1])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Temperature: 0 °C
Yield: 41.2 %

Procedure:
Bromo acetyl bromide (4.86 ml, 21.47 mmol, 1 eq) was added dropwise to a stirred ice cold mixture of the Piperazine-1-carboxylic acid tert butyl ester (4.0 g, 21.47 mmol, 1 eq) and diisopropyl ethyl amine (12.05 g, 92.5 mmol, 4.3 eq) in dichloromethane (108 ml). The resulting mixture was washed with water (2×50 mL) and saturated sodium chloride solution (100 mL), and dried over MgSO4. After filtration, the solvent was evaporated and the residue was purified with chromatography with (ethyl acetate/n-hexane 1/1) to give the product (2.72 g, 41%) as a orange oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35]>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[C:30](=[O:35])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: CN1CCNCC1=O
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.45 mmol) and 1-methylpiperazine-2-one hydrochloride (65 mg, 0.435 mmol) were suspended in NMP (0.483 mL). The RM was stirred at 180° C. for 5 h. The mixture was filtered and the obtained filtrate was purified by reverse phase chromatography (water+0.1% TFA/acetonitrile+0.1% TFA). The collected fractions were concentrated and the residue was dissolved in MeOH, passed through an SPE cartridge of PL-HCO3 MP. The filtrate was concentrated to afford the title compound as a brownish oil (tR 3.19 min (conditions 1), MH+=423).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[C:30]1(=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:30]1([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]2[CH:28]=[CH:29][C:16]([CH2:15][N:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)[CH2:8][C:9]3[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=3)=[CH:17][CH:18]=2)[CH3:27])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CN(CCCCN)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCCNC1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
The compound (110.0 mg) obtained in Example 103-7 was dissolved in anhydrous methanol (4.4 ml). Then, the solution was added with cyclohexanone (0.058 ml) and sodium cyanoborohydride (52.8 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16.5 hours. After the reaction, the solvent was distilled off. Subsequently, the residue was added with a 1 mol/l sodium hydroxide aqueous solution (3.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (96.7 mg) of the subject compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][C:15]([O:17]CC)=O)([O-])=O.[H][H]>CO.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([CH2:13][CH2:14][C:15](=[O:17])[NH:1]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)CC2
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 100 mL 3-necked round bottom flask was placed a solution of ethyl 3-(2,4-dinitrophenyl)propanoate (1.5 g, 5.60 mmol) in methanol (20 mL). To the mixture was added Pd/C (0.5 g). Hydrogen gas was passed through. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 30° C. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 0.5 g (55%) of 7-amino-3,4-dihydroquinolin-2(1H)-one as a green-yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N+:13]([CH3:16])([O-:15])=[O:14]>>[N+:13]([CH:16]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C[N+](=O)[O-]
Product: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)cc1
Yield: 98 %

Procedure:
In close analogy to the procedure described above, 4-Trifluoromethyl-benzaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH:11]([C:8]1[S:9][CH:10]=[C:6]([CH:4]=[O:3])[N:7]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(C)c1nc(C=O)cs1
Reaction time: 0.75 h

Procedure:
A solution of 2.7 g (13 mmol) of 2-isopropyl-thiazole-4-carboxylic acid ethyl ester (J. Med. Chem., 1998:602-617) in CH2Cl2 (50 mL) was cooled to −78° C. under nitrogen and treated dropwise with DIBAL (15 mL of 1.0 M in CH2Cl2; 15 mmol). The mixture was stirred at low temperature for 45 minutes and then treated with another 15 mL of DIBAL. The solution was stirred for 1 hour at −78° C. Five percent citric acid was added, and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated. Chromatography of the residue over silica gel, eluting with 3:1 hexane:EtOAc, gave the title compound.
Reaction SMILES: C([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(O)=O.S(Cl)(Cl)=O.C[N:24](C)C=O>C1(C)C=CC=CC=1>[NH2:24][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-carboxy-4-methoxy-3-nitrobenzoate (3.43 g, Reference Example 10) was dissolved in toluene (20 ml) was treated with thionyl chloride (1.5 ml) then with dimethylformamide (0.015 ml). The resulting solution was stirred at reflux for 1 hour then cooled to room temperature and then evaporated. The residue was dissolved in acetone (20 ml) and added to a solution of sodium azide (1.3 g) in water (20 ml cooled in an ice bath. The mixture was stirred for 1 hour then diluted with water. The resulting precipitate was collected by filtration. This solid was dissolved in a mixture of t-butanol and water (20 ml, 9:1) and gradually warmed to reflux and held at this temperature for 1 hour. The solution was cooled to room temperature and then evaporated. The residue was subjected to flash chromatography on silica to give the title compound (1.8 g). M+H 227. NMR ((CD3)2SO): δ 3.82(s, 3H), 3.90(s, 3H), 6.53(d, J=8 Hz, 1H), 7.1(bs, 2H), 7.96(d, J=8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)C.[CH:13](N(C(C)C)CC)(C)C.S(OC)(OC)(=O)=O.O>C(OCC)(=O)C>[CH3:1][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
68.15 g (0.412 mol) of 4-aminobenzoic acid ethyl ester was suspended in 86 mL (0.5 mol) diisopropyl ethyl amine and 60.0 g (45 mL, 0.474 mol) dimethyl sulfate was added drop wise. During the addition, the temperature rose to 95° C. The reaction is allowed to continue for 1 hour at 120° C. The reaction mixture was allowed to cool down to room temperature and 300 mL of water was added. The mixture was allowed to stand over night. The precipitated residue was isolated and treated with 250 mL of ethyl acetate. The solution in ethyl acetate was extracted twice with 100 mL of water, dried over MgSO4 and evaporated under reduced pressure. 4-methylaminobenzoic acid ethyl ester was purified by preparative column chromatography on Kieselgel 60 (Aldrich), using cyclohexane/ethyl acetate 4/1 as eluent. 36.3 g 4-methylaminobenzoic acid methyl ester was isolated (m.p. 66-67° C.).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].N1CC[CH2:13][CH2:12][CH2:11]1.C(C=C)=O>C(O)(C)C>[CH3:9][C:2]1[N:1]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: C1CCNCC1
Agent: C=CC=O
Solvent: CC(C)O
Product: CCOC(=O)c1cccnc1C
Temperature: 100 °C

Procedure:
To a mixture of 800 ml. of ethyl 3-aminocrotonate, 30 ml. of piperidine and 1.4 l. of isopropanol, stirred at 25°-30° C., 540 ml. of acrolein were added slowly over a 2 hour period with stirring. Upon completion of the addition of the acrolein, the reaction mixture was heated to reflux and refluxed for 31/2 hours. Then the reaction mixture was evaporated at reduced pressure to dryness. The residue was heated to 100° C. and 610 g. of sulfur were added thereto portionwise. The reaction mixture was then heated at 100° C. for 2 hours and at 125° C. for 11/2 hours. The reaction mixture was allowed to cool to about room temperature and 1 l. of chloroform was added thereto. The reaction mixture was filtered through Celite and the filter cake was washed with additional chloroform. The combined chloroform filtrate and washings were extracted three times with 1 l. portions of 2 N. hydrochloric acid. The aqueous acidic layers were combined and, with cooling, were made basic with 2 N. sodium hydroxide solution. The obtained aqueous basic solution was extracted three times with 1 l. portions of chloroform. The chloroform extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain an oily residue which was distilled under high vacuum to obtain the pure product (350 g.), b.p. 73°-77° C./0.5 mm. Hg.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[F:8][CH:9]([F:42])[N:10]1[C:14]2[C:15]([O:33][C@@H:34]([C@H:36]3[CH2:40][NH:39][C:38](=[O:41])[CH2:37]3)[CH3:35])=[N:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[CH:18][C:13]=2[N:12]=[CH:11]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl.CCOC(C)=O.O.[Cl-].[Na+].O>[C:1]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([C:17]3[N:16]=[C:15]([O:33][C@@H:34]([C@H:36]4[CH2:40][NH:39][C:38](=[O:41])[CH2:37]4)[CH3:35])[C:14]4[N:10]([CH:9]([F:8])[F:42])[CH:11]=[N:12][C:13]=4[CH:18]=3)=[CH:20][C:21]=2[O:31][CH3:32])[CH2:26][CH2:27]1)(=[O:2])[CH3:3]
Reactant: COc1cc(-c2cc3ncn(C(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Reactant: O=C(O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(-c2cc3ncn(C(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(C)=O)CC1
Reaction time: 1.5 h

Procedure:
The crude TFA salt of (R)-4-((R)-1-((3-(difluoromethyl)-6-(3-methoxy-4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: 3.67 (0.064 mmol) was dissolved in DCM (1 mL) and triethylamine (70 μL, 0.5 mmol) was added followed by acetic anhydride (7.5 μL, 0.079 mmol). The reaction mixture was stirred for 1.5 h and was diluted with EtOAc, water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-15% MeOH in DCM) to provide (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (3.69).
Reaction SMILES: [F:1][CH:2]([C:4]1[CH:9]=[CH:8][N:7]=[C:6](I)[CH:5]=1)[CH3:3].[Br:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1.CC([O-])(C)C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=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].C1(C)C=CC=CC=1>[Br:11][C:12]1[N:17]=[C:16]([NH:18][C:6]2[CH:5]=[C:4]([CH:2]([F:1])[CH3:3])[CH:9]=[CH:8][N:7]=2)[CH:15]=[C:14]([CH3:19])[CH:13]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: CC(F)c1ccnc(I)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(Br)nc(Nc2cc(C(C)F)ccn2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
4-(1-Fluoroethyl)-2-iodopyridine (90 g, 359 mmol, 1.05 equiv), 6-bromo-4-methylpyridin-2-amine (63.7 g, 341 mmol, 1.00 equiv), toluene (900 mL), t-BuOK (57.6 g, 1.50 equiv), BINAP (10.8 g, 17.3 mmol, 0.05 equiv) and Pd2(dba)3 (15.7 g, 17.1 mmol, 0.05 equiv) were combined into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred overnight at 90° C. in an oil bath and then cooled to r.t, diluted with DCM (500 mL). The solid was filtered out, washed with DCM and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel column (1:15 ethyl acetate/petroleum ether) to afford 6-bromo-N-[4-(1-fluoroethyl)pyridin-2-yl]-4-methylpyridin-2-amine as a light yellow solid. ESI calc'd for C13H14BrFN3 [M+H]+ 309. found 309. 1H NMR (CD3OD, 400 MHz, ppm): δ 8.23-8.22 (m, 1H), 7.66 (s, 1H), 7.45 (s, 1H), 6.934-6.91 (m, 2H), 5.72-5.51 (m, 1H), 2.32 (s, 3H), 1.68-1.61 (m, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH3:2].[C:13](Cl)([Cl:15])=[O:14]>>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)[C:13]([Cl:15])=[O:14])[CH3:2]
Reactant: CCNc1ccc2c(c1)OCO2
Reactant: O=C(Cl)Cl
Product: CCN(C(=O)Cl)c1ccc2c(c1)OCO2

Procedure:
By following the procedure described in example 1A, N-ethyl-3,4-methylenedioxyaniline (1.65 g, 10 mmol) was reacted with phosgene to give 1.5 g N-ethyl-N-(3,4-methylenedioxyphenyl)carbamoylchloride. M.p. 68°-69° C.
Reaction SMILES: [C:1]1(=[O:11])[C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[C:3](=[O:10])[NH:2]1>CO.[Pd]>[C:1]1(=[O:11])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3](=[O:10])[NH:2]1
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)C2CCCCC12
Yield: 85.4 %

Procedure:
A solution of (3aR,7aS)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (3.0 g, 19.9 mmol) and 10% Pd/C (300 mg) in MeOH (100 mL) was shaken in an H2 atmosphere (300 psi) in a Parr apparatus for 24 h. The reaction mixture was filtrated and the liquids concentrated to dryness, affording the title compound (2.6 g, 16.99 mmol), that was sued without any further purification, as a white powder.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:35]=[C:33]1[C:32]2[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30](=[O:40])[N:34]1[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Diisopropyl azodicarboxylate (1.17 mL, 6.04 mmol) was added to a THF (15 mL) solution of tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (1 g, 4.64 mmol), phthalimide (888 mg, 6.04 mmol), and triphenylphosphine (1.58 g, 6.04 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography to obtain the target (1.45 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:17]=[C:18]([C:20](O)=[O:21])[N:19]=4)[N:16]=3)[C:6]=2[CH:23]=1.C(N(C(C)C)C(C)C)C.[N-:33]=[N+:34]=[N-:35].[Na+].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:17]=[C:18]([C:20]([N:33]=[N+:34]=[N-:35])=[O:21])[N:19]=4)[N:16]=3)[C:6]=2[CH:23]=1
Reactant: O=C(O)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Reactant: [N-]=[N+]=[N-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC(=O)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylic acid 13B (3.6 g, 9.65 mmol), N-ethyl-N-isopropylpropan-2-amine (7.48 g, 57.9 mmol) and sodium azide (6.27 g, 96 mmol) in anhydrous DMF (60 mL), PyBOP (6.02 g, 11.58 mmol) was added in portions at ambient temperature over 5 min. The reaction was stirred for another 30 min and then poured into a EtOAc/H2O (100/300 mL) mixture and shaken well. The resulting precipitate was filtered, rinsed with H2O followed by EtOAc, and dried in vacuum over P2O5 for 18 hrs to provide the title compound, 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carbonyl azide 13C (2.1 g, 5.28 mmol, 55%). The EtOAc solution washed with 5% citric acid (2×100 mL), NaHCO3, dried with MgSO4, filtered and concentrated to dryness to give additional crude product (1.6 g of 80% pure material). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.28 (s, 2 H) 7.37 (d, J=9.60 Hz, 1 H) 7.59 (dd, J=8.84, 1.77 Hz, 1 H) 8.09 (d, J=8.84 Hz, 1 H) 8.26 (d, J=10.10 Hz, 1 H) 8.32 (d, J=1.26 Hz, 1 H) 8.92 (s, 1H). MS:m/z 398.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:54][C:55]1[S:56][S:57][C:58](=[S:60])[N:59]=1.O.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[C:15]([NH:54][C:55]3[S:56][S:57][C:58](=[S:60])[N:59]=3)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccc(OCc2ccc(F)cc2)cc1)c1ccc(OCc2ccc(F)cc2)cc1
Reactant: Nc1nc(=S)ss1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nc(=S)ss1)C(c1ccc(OCc2ccc(F)cc2)cc1)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
2,2-Bis{4-[(4-fluorobenzyl)oxy]phenyl}acetic acid (1.00 g, 2.17 mmol) was dissolved in tetrahydrofuran (7 ml), and 1,1′-carbonyldiimidazole (0.423 g, 2.61 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at room temperature. Sodium hydride (60% oil suspension 0.087 g, 2.17 mmol) was suspended in tetrahydrofuran (7 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.326 g, 2.17 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 17 hours at room temperature. The reaction mixture, with saturated ammonium chloride water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and saturated brine successively, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 2,2-bis{4-[(4-fluorobenzyl)oxy]phenyl}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 11) (0.256 g, 20%).
Reaction SMILES: [O:1]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4](O)[CH2:3][CH2:2]1.S(Cl)([Cl:14])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:14][CH:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:1][CH2:2][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCOc2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClC1CCOc2ncccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol (21 mmol) in 80 mL DCM was added 2.3 mL thionyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then at reflux for 30 min. After cooling to RT, sat. aq. NaHCO3 solution was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to obtain the desired product as orange oil.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1.[C:12]([O-:15])(=[O:14])[CH3:13].[K+]>CN(C)C=O>[C:12]([O:15][CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1)(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: ClC[C@@H]1CN2CCC[C@H]2CO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Yield: 96.9 %

Procedure:
(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (2.30 g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred in dimethylformamide (25 mL) at 140° C. for 20 h. The mixture was partitioned between ethyl acetate and water. The organic portion was washed twice with water, then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate as a brown oil (2.53 g, 12.7 mmol, 97% yield). 1H NMR (400 MHz, CDCl3): 4.14-4.02 (m, 3H), 3.81-3.72 (m, 1H), 3.37-3.31 (m, 1H), 3.09 (dt, 1H), 3.00 (dd, 1H), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H), 1.39-1.24 (m, 1H); MS (EI) for C00H17NO3: 200 (MH+).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:20]([Cl:21])=[CH:19][C:18]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:17][C:16]=3[Cl:30])[CH:11]=[CH:10][C:9]=2[O:31]C)(=[O:7])=[O:6])[CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:16]([Cl:30])=[CH:17][C:18]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:19][C:20]=3[Cl:21])[CH:11]=[CH:10][C:9]=2[OH:31])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)NC1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2cc(Cl)c(Oc3ccc(O)c(S(=O)(=O)NC4CC4)c3)c(Cl)c2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of the title compound of Step F (16 mg, 0.032 mmol) in dichloromethane (0.5 ml) at 0° C. was added boron tribromide (1M in dichloromethane, 0.06 ml, 0.06 mmol). The reaction mixture was stirred at room temperature for one hour, then quenched by addition of 1N HCl (5 ml). The resulting solution was extracted with dichloromethane (3×5 ml). The combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (7% methanol in dichloromethane) to afford the title compound (11 mg, 68% yield) as a white solid. MS (APCl−) Calc: 502.0, Found: 501.2 (M−1).