Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH2:27][C:28]1[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:27][C:28]1[S:29][C:30]([C:34]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:35])=[C:31]([CH3:33])[N:32]=1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: Cc1nc(N)sc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1sc(N)nc1C)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (100 mg, 0.28 mol) was dissolved in DMF (3 mL), and 2-amino-4-methylthiazole-5-carboxylic acid (44 mg, 0.28 mmol) was added. PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (0.15 mL, 0.83 mmol) were subsequently added, and the mixture was stirred at rt overnight. The mixture was purified by HPLC to give the title compound (6 mg, 4%): LC MS RT=1.06 min, MH+=500.1; 1H NMR (DMSO-d6) δ: 12.59 (1H, s), 7.55 (1H, d), 7.47 (1H, s), 6.98 (1H, d), 4.13 (2H, t), 3.93 (4H, m), 3.86 (3H, s), 3.55 (4H, t), 2.47 (3H, s), 2.45 (2H, t), 2.33 (4H, m), 1.93 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17]>CN(C)C=O.CCOC(C)=O>[CH2:16]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:17]
Reactant: CCI
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (226 mg, 2.0 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (0.33 g, 2.4 mmol) and iodoethane (0.37 g, 2.4 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The mixture was diluted with EtOAc (40 mL), then washed with water (2×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. The crude material was purified by chromatography on silica gel, eluting with Hex:EtOAc=70:30 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=1.55 (t, J=7.3 Hz, 3H), 4.22 (q, J=7.3 Hz, 2H), 8.07 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:14]2[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15]2)=[C:6]2[CH2:13][CH2:12][CH2:11][C:7]2=[N+:8]([O-])[CH:9]=1)([O-:3])=[O:2].[CH3:32][C:33]([O:35]C(C)=O)=[O:34]>>[C:33]([O:35][CH:11]1[C:7]2=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([N:14]3[CH2:19][C@H:18]([C:20]([F:21])([F:23])[F:22])[CH2:17][C@H:16]([NH:24][C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[CH2:15]3)=[C:6]2[CH2:13][CH2:12]1)(=[O:34])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 90 °C
Yield: 73.6 %

Procedure:
To tert-butyl [(3S,5R)-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (114.7 mg, 0.2569 mmol) was added Ac2O (2.0 mL, 21 mmol). The reaction mixture was heated at 90° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM, and poured into a saturated aqueous solution of Na2CO3 at 0° C. The separated aqueous layer was further extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a brown foamy solid (92.3 mg, 74%). LCMS calc. for C21H28F3N4O6 (M+H)+: m/z=489.2. found 489.2.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Si:13]([N:20]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21]1=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CI.Cl>C1COCC1.CCCCCC.CCOCC>[Si:13]([N:20]1[C@H:23]([C:24]([OH:26])=[O:25])[C@@H:22]([CH3:1])[C:21]1=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 27.5 ml of diisopropylamine in 150 ml of THF at -20° C. was added 73.5 ml of 2.4N n-butyl lithium in hexane. After 15 minutes, the solution was cooled to -70° C. and a solution of 20 gm of (4S)-1-t-butyldimethylsilylazetidin-2-one-4-carboxylic acid in 75 mL of THF was added. The solution was warmed to -20° C. for 15 minutes before a solution of 13.5 mL of methyl iodide in 20 mL of THF was added. After 30 minutes at -20° to 0° C., the reaction was diluted with 300 mL of ether and then poured into a mixture of ice and 400 mL of 1N HCl. The layers were separated and the aqueous layer extracted with ether. The ether layers were washed with brine, dried over sodium sulfate and evaporated. The residue was crystallized from hexane to give 12-15 gms of (3R,4S)-1-t-butyldimethylsilyl-3-methylazetidin-2-one-4-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([N:26]([C:34]1[N:39]=[C:38]2[N:40]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:41]=[C:42]([CH2:43][CH2:44][OH:45])[C:37]2=[C:36]([Cl:57])[N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:45][CH2:44][CH2:43][C:42]2[C:37]3[C:38](=[N:39][C:34]([N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:35][C:36]=3[Cl:57])[N:40]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:41]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COc1c(C)cnc(Cn2nc(CCO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc(CCOS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reaction time: 12 h
Yield: 91 %

Procedure:
Triethylamine (0.048 mL), p-toluenesulfonyl chloride (43 mg) and 4-dimethylaminopyridine (0.7 mg) were added to a mixture composed of di-tert-butyl{4-chloro-3-(2-hydroxyethyl)-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate of 8) above (64 mg) and dehydrated dichloromethane (1 mL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate and sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (74 mg, 91%) as an amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][N:18]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:20]3[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][CH:21]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: CN1CCc2[nH]c3ccc(Br)cc3c2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(CCn2c3c(c4cc(Br)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
Tetra butyl ammonium chloride (0.026 g, 0.094 mmol) was taken in 15 ml, 50% aq. NaOH solution (7 ml) and stirred for 15 minutes at RT. 8-bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.500 gm, 1.89 mmole) was added and further stirred for 10 min. at RT. 2-methyl-5-vinylpyridine (0.247 gm, 2.08 mmole) was added and reaction mixture was heated at 100° C. for 12-15 hrs. The reaction mixture was cooled at RT, extracted with ethyl acetate, dried over anhydrous sodium sulphate, concentrated and purified by Reverse Phase HPLC to get 63 mg 8-bromo-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as TFA Salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.Cl.C[OH:26]>[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCC/C(=C\c1ccc(OC2CCCCC2)c(Br)c1)[N+](=O)[O-]
Reactant: CO
Agent: [Fe]
Agent: Cl
Product: CCCCC(=O)Cc1ccc(OC2CCCCC2)c(Br)c1
Temperature: 25 °C

Procedure:
2-Bromo-1-cyclohexyloxy-4-((E)-2-nitro-hex-1-enyl)-benzene (8.3 mmol, 3.2 g), and iron powder (41.8 mmol, 2.3 g) were dispersed in methanol (20 mL), 3.0 N HCl (20 mL) and heated to reflux for 3.0 h. Cooled the reaction mixture to room temperature, filtered through celite washed with ether. Organic layer separated, dried (Na2SO4) filtered and concentrated under reduced pressure to provide 1-(3-Bromo-4-cyclohexyloxy-phenyl)-hexan-2-one (2.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[N:17]([CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+]>CCO.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[N:17]([CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3ccccn3c2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CCO
Product: Nc1ccc(-c2cc3ccccn3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a suspension of 2-(4-nitrophenyl)indolizine (0.2 g, 0.84 mmol) and Cu(OAc)2 (0.16 g, 0.88 mmol) in EtOH (50 mL) was added NaBH4 (0.64 g, 16.8 mmol). The resulting mixture was stirred at room temperature for 3 hrs and concentrated in vacuo. The residue was dissolved in H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo to give a solid (0.092 g, 53%). 1H NMR (CDCl3, 400 MHz) δ: 7.87 (dd, J=6.8, 1.2 Hz, 1H), 7.44-7.95 (m, 3H), 7.31 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.59-6.64 (m, 2H), 6.42 (td, J=6.8, 1.2 Hz, 1H), 3.67 (br s, 2H). MS: m/z=209 (M+H+).
Reaction SMILES: O[C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.CCN(S(F)(F)[F:28])CC.C(OCC)(=O)C>C(Cl)Cl>[F:28][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (MG Bursavich et al; Organic Letters 2001, 3, 2317, 150 mg, 0.51 mmol) in 5 mL of DCM at −78° C. under nitrogen was added DAST (0.2 mL, 1.5 mmol). The mixture was allowed to warm up to rt with stirring over 3 h. To the mixture was added 100 mL of ethyl acetate and the organic layer was separated, washed with a saturated NaHCO3 solution, and then evaporated under vacuum. The residue was purified via silica gel chromatography eluting with 0-100% ethyl acetate/hexanes to give (3R,4R)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41 mmol); LCMS (Method T) RT 3.09 min, m/z 294.3. (M−H)−; 1H NMR (500 MHz, chloroform-d) δ 7.11 (d, J=8.5 Hz, 2H), 6.93 (br. s., 1H), 6.89-6.82 (m, 2H), 4.56-4.47 (m, 1H), 4.45-4.38 (m, 1H), 4.16 (d, J=7.2 Hz, 1H), 2.89-2.69 (m, 3H), 1.89-1.83 (m, 1H), 1.76-1.65 (m, 1H), 1.53 (s, 9H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:36])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:15]=[N:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:8][C:7]=1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C=O.O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][C:5](=[O:36])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:40])[CH2:23][CH2:24]3)[N:15]=[N:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=[CH:8][C:7]=1[O:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester dihydrochloride in DCM (6 mL) was added formaldehyde solution in water (37%, 2.26 mmol, 0.168 mL) and 2 drops of acetic acid. Sodium triacetoxyborohydride (3.02 mmol, 674 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1 h and partitioned between ethyl acetate (40 mL) and saturated aq. sodium bicarbonate solution (40 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on basic alumina using 0-4.5% MeOH in DCM to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester. This was converted to the title compound using 4 N HCl in dioxane (296 mg). LCMS: m/z 483 [M+1] 1H NMR (400 MHz, CD3OD) δ 7.86-7.93 (2H, m), 7.65-7.71 (1H, m), 7.34-7.38 (1H, m), 5.38-5.55 (1H, m), 4.61-4.65 (1H, m), 3.89 and 3.89 (3H, s), 3.11-3.65 (6H, m), 2.94 (3H, s), 1.16-2.57 (18 H, m), 0.83 (3 H, dt).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(OC2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a mixture of 308 mg (purity: 98.0%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 823 mg (5.50 mmol) of 2-cyclopropyl-6-methylphenol were added diphenyl ether (2.76 g) and 328 mg (5.56 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 295 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 58%) and 3.1 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)[CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][CH3:37])=[O:4].[OH-].[K+].Cl>CO.C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][O:25][C:21]1[CH:20]=[C:19]([C@H:17]2[CH2:16][O:15][C:11]3=[CH:12][C:13]4[CH2:14][C@@H:5]([C:3]([OH:4])=[O:2])[N:6]([C@H:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH3:37])[CH2:7][C:8]=4[CH:9]=[C:10]3[O:18]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (0.14 g, 0.22 mmol) was taken in 1 mL of MeOH:THF (4:1) and cooled to 0° C.; KOH (0.54 mL, 2.5 N) was added and stirred at room temperature for 12 hours. KOH (0.36 mL, 2.5 N) was added and stirred for 24 hours. Then, HCl (2.4 mL, 1 N) was added to the reaction and the product was extracted with EtOAc. The ethyl acetate layer was separated and washed with water and brine, and then dried over Na2SO4, filtered, and evaporated to get (3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (0.11 g). LCMS (m/z): 605.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:34][CH3:35])=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:7]=2)[C:17]=1[O:34][CH3:35])(=[O:25])=[O:24]
Reactant: CC(C)CN
Reactant: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(C(C)C)sc1-c1ccnc(NCC(C)C)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-[3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzenesulfonamide (150 mg, 0.279 mmol) and isobutylamine (0.140 mL, 1.397 mmol) the title compound was obtained as an off-white foam (86.3 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 7.94 (d, J=4.9 Hz, 1H), 7.54-7.73 (m, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.15-7.32 (m, 3H), 6.99-7.17 (m, 2H), 5.74 (dd, J=2.2, 1.1 Hz, 1H), 3.24-3.28 (m, 1H), 3.12 (s, 3H), 3.01 (br. s., 2H), 1.81 (dt, J=13.3, 6.6 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H), 0.85 (d, J=6.6 Hz, 6H). MS (ESI): 574.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)[nH]n1
Yield: 77.8 %

Procedure:
In a 20 mL vial, to a solution of 3-tert-butyl-1H-pyrazol-5-amine (150 mg, 1.078 mmol) in dichloromethane (2 mL) and triethylamine (0.180 mL, 1.293 mmol) was added (chloromethanetriyl)tribenzene (300 mg, 1.078 mmol). The reaction was stirred at 20° C. for 10 hours before toluene (5 mL) and ethyl acetate (10 mL) were added. The solid was filtered and the filtrate was concentrated to provide the crude title compound (320 mg). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.02 (m, 9H) 4.82 (s, 1H) 5.75 (s, 1H) 7.15-7.37 (m, 15H) 11.13 (s, 1H); MS (DCI/NH3) m/z 382 (M+H)+.
Reaction SMILES: C(OC([C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1)=O)C.BrC1SC2C=[C:42]([O:44]C)C=CC=2N=1>>[CH3:42][O:44][C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:15][CH:14]=3)[S:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1
Reactant: COc1ccc2nc(Br)sc2c1
Product: COc1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1

Procedure:
Tert-butyl 4-[5-(6-Methoxy-1,3-benzothiazol-2-yl)pyridin-2-yl]piperazine-1-carboxylate was prepared according to the method used for the preparation of 2-[6-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]-3-pyridinyl]-6-benzothiazolecarboxylic acid ethyl ester, from 2-bromo-6-methoxybenzothiazole (Yang et al. J. Biological Chem. 1989, 2, 891-898) (0.20 g), and obtained as a solid (0.23 g). 1H NMR δ 8.74 (s, 1H) 8.12 (d, 1H) 7.87 (d, 1H) 7.67 (s, 1H) 7.09 (dd, 1H) 6.98 (d, 1H) 3.84 (s, 3H) 3.64 (br. s., 4H) 3.45 (br. s., 4H) 1.43 (s, 9H); MS m/z M+H 427.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21]Br>CS(C)=O.O>[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[C:7]3([CH2:21][CH2:20][CH2:19]3)[C:6]=2[CH:5]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc2c(c1)C1(CCC1)c1cc(Br)ccc1-2
Reaction time: 120 h

Procedure:
Powdered KOH (983 mg, 17.5 mmol) was added in batches over 1 minute to a heterogeneous mixture of 2,7-dibromo-9H-fluorene (1.31 g, 4.04 mmol) and 1,3-dibromopropane (837 mg, 4.15 mmol) in DMSO (20 mL), and stirred at ambient condition for ˜5 days. The mixture was diluted with water (200 mL) and extracted with 10% CH2Cl2/hexanes (100 mL, 2×). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified with a column chromatography (sample was loaded as a silica gel mesh; hexanes, with gravity elution) to afford 2′,7′-dibromospiro[cyclobutane-1,9′-fluorene] as a white fluffy solid (600 mg). 1H NMR (CDCl3, δ=7.24, 400 MHz): 7.86 (d, J=1.8, 2H), 7.48 (d, J=8.0, 2H), 7.44 (dd, J=8.1, 1.8, 2H), 2.61 (app t, J=8.1, 4H), 2.42-2.34 (m, 2H).