Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)COc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of 15.16 g of methyl (2-hydroxyphenoxy)acetate, 29.23 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene, 11.5 g of anhydrous potassium carbonate, and 160 ml of N,N-dimethylformamide was stirred at room temperature for 30 minutes and then at 70° C. for 3 hours. Another 5 g of methyl (2-hydroxyphenoxy)acetate was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 17.8 g of methyl [2-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}phenoxy]acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1=COCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
7.65 g of N-t-butoxycarbonyl-L-serine and 3.88 g of 3,4-dihydro-2H-pyrane were dissolved in 60 ml of dichloromethane followed by the addition of 0.47 g of pyridinium p-toluene sulfonate and the solution was stirred for 3 hours at room temperature. After the reaction solution was washed with water and saturated brine, the solvent was distilled off under reduced pressure to obtain 9.90 g of the target compound. Yield: 92%
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[N:26]1[C:30]([NH2:31])=[CH:29][C:28]([CH3:32])=[N:27]1.ClCCl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:31][C:30]2[N:26]([C:21]3[C:20]4[C:25](=[C:16]([F:15])[CH:17]=[CH:18][CH:19]=4)[N:24]=[CH:23][CH:22]=3)[N:27]=[C:28]([CH3:32])[CH:29]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2ccnc3c(F)cccc23)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2ccnc3c(F)cccc23)n1
Temperature: 80 °C
Yield: 2 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.13 g, 0.55 mmol) and crude 1-(8-fluoroquinolin-4-yl)-3-methyl-1H-pyrazol-5-amine (0.14 g, 0.55 mmol) in pyridine (1 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.005 g, 0.011 mmol, 2%). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=4.8 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.47-7.41 (m, 5H), 7.13 (d, J=4.8 Hz, 1H), 6.20 (s, 1H), 2.35 (s, 3H), 1.35 (s, 9H); MS: (ES) m/z calculated for C23H24FN4O2S [M+H]+ 439.5. found 439.3.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 66.7 %

Procedure:
A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester, the titled compound, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH:16](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH:16]=[N:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in the next step. 1H NMR (CDCl3, 400 MHz) δ 8.09 (s, 1), 7.75 (d, J=1.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m, 2H), 1.27-1.24 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([CH2:37][S:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([CH2:37][S:38]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccn4)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccccn4)cc2)CCN3CCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.30 g) was dissolved in methylene chloride (15 ml), m-chloroperbenzoic acid (83 mg) was added to the solution at −30° C., and the mixture was stirred for 1 hour at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 181) (97 mg).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:48])[NH:31][C@H:32]4[CH2:35][C@@H:34]([C:36]([N:38]5[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:47])[CH3:46])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:51])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH2:44]([N:41]1[CH2:42][CH2:43][N:38]([C:36]([C@@H:34]2[CH2:35][C@H:32]([NH:31][C:30]([C@:14]34[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]3[C@@H:16]3[C@@:11]([CH3:49])([CH2:12][CH2:13]4)[C@@:10]4([CH3:50])[C@@H:19]([C@:20]5([CH3:23])[C@@H:7]([CH2:8][CH2:9]4)[C:6]([CH3:51])([CH3:52])[C@@H:5]([OH:4])[CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:48])[C:33]2([CH3:46])[CH3:47])=[O:37])[CH2:39][CH2:40]1)[CH3:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
A solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1S,3R)-3-(4-ethylpiperazine-1-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 66, 0.760 g) in MeOH:THF (2:1) (45 ml) at 0° C., 2N NaOH (15 ml) were added and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated, the aqueous layer extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as a white solid. Wt: 0.500 g: Yield: 69.9%; 1H NMR (300 MHz, CDCl3): δ 5.90 (d, J=8.1 Hz, 1H), 4.728 (s, 1H), 4.57 (s, 1H), 4.10 (m, 1H), 3.80-3.41 (m, 4H), 3.20-3.10 (m, 2H), 2.9 (m, 1H), 2.60-2.295 (m, 9H), 2.1 (m, 2H), 1.90 (m, 1H), 1.80-1.02 (m, 22H), 0.95, 0.92 (s, 6H), 0.83 (s, 3H), 0.80 (s, 3H). Mass: [M+H+]+ 679 (100%); IR (KBr, cm−1): 3445, 2946, 2867, 1634, 1459, 1463, 1376, 1270, 1242, 1126, 1043, 983, 883, 768, 656; M.R: 122.0° C.-155.1° C.; HPLC: 94.8%.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C@@H:15]4[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1.C(OCC)C>[C:24]([O:21][C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C@@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:11]2[CH2:10][CH2:9][C@@:8]2([CH3:23])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:2](=[O:3])[CH3:1])[CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a stirred suspension of 5α-pregnan-3β-ol-20-one (110) (200 g; 0.628 mol) in pyridine (1750 mL) was added acetic anhydride (593 mL; 6.28 mol). Solid was dissolved after 2 hours and the reaction was left for overnight at room temperature. The reaction mixture was diluted with diethyl ether (5 L) and transferred into a 12 L separatory funnel. The mixture was stirred, while 10% HCl (150 mL) was added by careful monitoring of temperature (maximum temp 35° C.) by an ice bath. The organic layer was washed with ice cold 10% HCl (8×500 mL), with saturated NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The pale yellow solid was dried at 40° C. overnight to give the 3-acetylated compound 111 (223 g; 99%). 1H NMR (300 MHz, CDCl3) δ: 0.58(s, 3H), 0.81(s, 3H), 2.01(s, 3H), 2.10(s, 3H), 2.51(t, 1H, J=9 Hz), 4.67(sept, 1H, J=5 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:14][N:15](C(OCC1C=CC=CC=1)=O)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH3:24])[C@@H:9]([OH:13])[CH2:10][CH2:11][CH3:12])(C)(C)C>CO.[Pd]>[NH2:7][C@H:8]([C@@H:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH2:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH3:24]
Reactant: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCC[C@H](O)[C@@H](N)CNCc1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.8 %

Procedure:
A solution of (1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamic acid tert-butyl ester (600 mg, 1.2 mmol, see procedure 12a) in MeOH was charged with 5% Pd/C, Degussa style (120 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in methylene chloride (6 mL) and the resultant solution was charged with trifluoroacetic acid (6 mL). The mixture was stirred for 3 h at RT and concentrated in vacuo. The residue was dissolved in benzene and the resultant solution was concentrated in vacuo; this procedure was repeated to provide (2S,3S)-2-amino-1-(2,4-dimethyl-benzylamino)-hexan-3-ol (321 mg). MS found: (M+H)+=251.4.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: C1CCOC1
Product: C=Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of Ph3PCH3Br (57 g) in THF (240 mL) at 0° C. was dropwise added n-BuLi (1.6 N, 100 mL). The resulting mixture was allowed to warm to room temperature and stirred for 1 h. After recooling to 0° C., a solution of 3-bromo-4-fluoro-benzaldehyde (20.3 g) in THF (20 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with water, concentrated, and extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate, concentrated under vacuum. The crude product was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to give the title compound as an oil (18 g).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C(=O)[C:2]1=[O:3].[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC>C(O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH2:20]([O:19][C:12]1([O:16][CH2:17][CH3:18])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3])[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CCOC1(OCC)C(=O)Nc2ccccc21
Yield: 128.9 %

Procedure:
In 500 ml of ethanol were dissolved 14.7 g of isatin and 10.6 g of triethyl orthoformate, and 100 mg of camphorsulfonic acid was added thereto. The mixture was heated under reflux for 12 hours, followed by concentration. To the residue was added chloroform, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1) to give 20.4 g (92%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:10]=[CH:9]2>C1C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH:12]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1ccc2cc(CO[Si](C)(C)C(C)(C)C)ccc2c1
Agent: [Pd]
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc2cc(CO[Si](C)(C)C(C)(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
The compound (2.54 g) obtained in Example 121-4 was dissolved in anhydrous benzene (80 ml) and added with palladium black, followed by stirring at room temperature for 1 hour under a nitrogen atmosphere. After completion of the reaction, the solution was filtrated through Celite. Then, the solvent was distilled off, thereby obtaining the subject compound (2.62 g) as a white solid.
Reaction SMILES: O=[C:2]1[NH:7][CH2:6][C:5]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:4][CH2:3]1.B.C1COCC1.CSC.B>C1COCC1>[O:4]1[C:5]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:7][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)CO2
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of tert-butyl 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step a) (8.2 g) in THF (100 mL) was treated dropwise with borane THF complex (1M in THF, 91 mL) and the resultant mixture heated at 55° C. for 2 hours. Borane dimethylsulfide complex (2M in THF, 15.17 mL) was added and the resultant mixture heated at 55° C. for 2 hours. The mixture was cooled to room temperature and quenched with methanol, then the solvents were evaporated under reduced pressure. The residue was dissolved in methanol (250 mL) and the solution treated with N1,N2-dimethylethane-1,2-diamine (10 g) and the resultant mixture was heated at reflux for 6 hours. Further N1,N2-dimethylethane-1,2-diamine (3 g) was added and heated at reflux continued for 6 hours. The mixture was cooled to room temperature and the solvents evaporated under reduced pressure, the residue was purified by flash silica chromatography eluting with 1% triethylamine and 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 7.40 g.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]3[N:17]([CH:31]=[CH:32][N:33]=3)[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26]C)=[O:25])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCOCC1.O>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]3[N:17]([CH:31]=[CH:32][N:33]=3)[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([OH:26])=[O:25])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4CO)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(-c2cc(Nc3cccc(N4CCCC4CO)n3)c3nccn3n2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
To a solution of methyl 3-(8-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (185 mg, 0.416 mmol) in dioxane (5 mL) and water (4.5 mL) was added NaOH (167 mg, 4.16 mmol), then the mixture was heated to 40° C. with stirring for 4 h. The solution was concentrated in vacuo then water (10 mL) was added and the solution was washed with dichloromethane (10 mL×3). The aqueous layer was adjusted to pH=4 by addition of concentrated HCl. The solid formed was filtered to give 3-(8-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.096 g, 54%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.84 (s, 1H), 9.19 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.31 (s, 1H), 8.23 (d, 1H, J=7.5 Hz), 8.13 (d, 1H, J=7.5 Hz), 7.71 (t, 1H, J=7.8 Hz), 7.53 (t, 1H, J=7.8 Hz), 6.72 (d, 1H, J=7.5 Hz), 6.27 (d, 1H, J=8.1 Hz), 3.96 (brs, 2H), 3.61 (brs, 1H), 3.46-3.37 (m, 2H), 2.07-1.95 (m, 4 h). LC-MS: [M+H]+, 431, tR=1.459 min, HPLC: 99.27% at 214 nm, 99.49% at 254 nm, tR=5.08 min.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CCC)c1
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol), in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes propane-sulfonylchloride (0.16 ml, 202 mg, 1.42 mmol). The mixture was stirred for 48 hours, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with ethyl acetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (40 mg, 14%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:31])[C:15](=[O:30])[C:16]([CH3:29])=[C:17](OS(C4C=CC(C)=CC=4)(=O)=O)[C:12]=3[C:11](=[O:32])[N:10]([CH:33]3[CH2:35][CH2:34]3)[C:9]2=[O:36])=[CH:4][CH:3]=1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)C.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:31])[C:15](=[O:30])[C:16]([CH3:29])=[C:17]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:12]=3[C:11](=[O:32])[N:10]([CH:33]3[CH2:35][CH2:34]3)[C:9]2=[O:36])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(Br)cc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1c(Nc2ccccc2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(Br)cc3)c2n(C)c1=O
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To toluene-4-sulfonic acid 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 39 (100 mg) obtained in Step 6 was added aniline 40 (0.64 ml), and the mixture was stirred at 150° C. for 2.5 hrs. After allowing to cool to room temperature, diethyl ether-hexane [1:1 (volume ratio), 30 ml] was added to the reaction mixture, and the crystals were collected by filtration. The obtained crystals were purified by column chromatography (chloroform:acetone=15:1) to give 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 41 (81 mg, yield 93%) as pale-yellow crystals.