Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:37])C.Cl>CC(C)=O>[CH:4]([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:37])=[O:3]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: Cl
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Yield: 96.4 %

Procedure:
To a solution of 0.227 g of (+)-1-(2,2-diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N′-(4-methylphenyl)ureido)indolin-2-one in 5 ml of acetone was added 5 ml of 6N hydrochloric acid, followed by heating under reflux for 10 minutes. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and washed twice with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 0.189 g of the title compound as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(O)c1)C(=O)O
Reaction time: 2 h
Yield: 102.1 %

Procedure:
Methyl 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (0.91 g, 3.1 mmol) was taken up in methanol (30 mL) at rt and the lithium hydroxide monohydrate (0.51 g, 12.3 mmol) in water (10 mL) was added. The reaction was complete after stirring for 2 h. The methanol was removed under reduced pressure to give an aqueous layer which was partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoic acid (0.89 g, 100%). Analytical LCMS (M+H-Boc)+: m/z=181.9.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[N:13][CH:12]=1.[Li]CCCC.CN([CH:32]=[O:33])C>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([CH:32]=[O:33])=[N:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cncc1-c1ccc2c(c1)CCCC2
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1c(-c2ccc3c(c2)CCCC3)cnc1C=O
Yield: 56.8 %

Procedure:
Reaction of 5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1-(2-trimethylsilanyl ethoxymethyl)-1H-imidazole (268 mg, 0.82 mmol), 2.5 M n-BuLi (424 uL, 1.06 mmol), and DMF (253 uL, 3.27 mmol) for 2 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (166 mg, 57%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 1.80-1.85 (m, 4H), 2.80-2.83 (m, 4H), 3.60 (t, 2H, J=9.0 Hz), 5.81 (s, 2H), 7.13 (d, 1H, J=6.0 Hz), 7.51 (d, 1H, J=6.0 Hz), 7.57 (s, 1H), 7.60 (s, 1H). 9.88 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>CC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 84.9 %

Procedure:
To a mixture of 4-nitrobenzene (3.0 g, 14.8 mmol) and 3-methylphenylboronic acid (2.06 g, 15.1 mmol) in 35 mL of acetone and 40 mL of water was added K2CO3.1.5H2O (5.93 g, 37.5 mmol) and Pd(OAc)2 (101 mg, 0.50 mmol). The deep black mixture was refluxed for 6 hr and then cooled. The mixture was extracted with ether and the organic layer was passed through a layer of celite. The pale yellow solution was dried over Na2SO4 and evaporated to dryness. The residue was recrystallized from hot methanol to give pale yellow crystals (2.68 g, 85%). m.p.59-60° C.1H NMR (CDCl3) δ 8.26 (d, 8.7 Hz, 2H), 7.70 (d, 8.7 Hz, 2H), 7.41 (m, 3H), 7.26 (d, 7.1 Hz, 1H), 2.43 (s, 1H). 13C NMR (CDCl3) δ 147.6, 146.8, 138.8, 138.6, 129.6, 128.9, 128.0, 127.6, 124.4, 123.9, 21.4. LRMS (EI) for C13H11NO2 213 (M+, intensity 100); HRMS (EI) calcd 213.0789, obsd 213.0778.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation see Intermediate 107) (20 mg, 0.047 mmol) in ethanol (0.5 mL) was added NaOH (1M in water, 0.188 mL, 0.188 mmol) and the resulting mixture was stirred at room temperature for 3 h then concentrated in vacuo. Purification of the residue using MDAP gave 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (12 mg, 0.029 mmol, 62%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].[CH:11]1([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][OH:21])[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:11]1([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19][CH2:20][O:21][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc([N+](=O)[O-])cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of 4 nitrophenol (0.32 g, 2.3 mmol) in anhydrous DCM (100 ml) at 0° C. was added (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid cyclopentyl ester (1 g, 3.5 mmol) (Scheme 9) in DCM (100 ml), triphenyl phosphine (2.5 g, 9.5 mmol) followed by slow addition of DIAD (1.9 ml, 9.6 mmol). The reaction was allowed to warm to room temperature and stirred for 16 h. The solvent was removed and the crude material purified by column chromatography to furnish the desired product. (EtOAc:heptane, 1:9), (0.45 g, 48%). LCMS purity 97%, m/z 309 [M++H-boc]+.
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][C@H:17]2[CH2:21][CH2:20][C:19]([Cl:22])=[C:18]2[C:23]2[CH:28]=[CH:27][C:26]([C@H:29]([O:35]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:24]=2)=[CH:12][CH:13]=1)=[O:8].Cl>C1COCC1>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][C@H:17]2[CH2:21][CH2:20][C:19]([Cl:22])=[C:18]2[C:23]2[CH:24]=[CH:25][C:26]([C@H:29]([OH:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:27][CH:28]=2)=[CH:12][CH:13]=1)=[O:8]
Reactant: CCCCC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(C2=C(Cl)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC[C@@H](O)c1ccc(C2=C(Cl)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of 5% NaOH/MeOH (0.25 mL, 0.31 mmol), ester 14 (18 mg, 0.029 mmol) and THF (0.05 mL) was allowed to stir at room temperature. After 30 min., 10 mL 1 M HCl solution was added and the resulting mixture was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solution was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (0%→50% ethyl acetate/hexanes) gave compound 15 (11 mg, 0.024 mmol, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1ccccc1F
Product: C[C@@H](CCl)COc1ccccc1F

Procedure:
Prepared by Procedure U and Scheme AK using 2-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)cc1

Procedure:
2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-morpholine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst to give the title compound. LCMS (PS-A3) Rt 6.88 min [M+H]+ 340. 1H NMR (Me-d3-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m), 3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d), 7.92 (2H, br. s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
7-Fluoro-5-nitro-2,3-dihydro-1,4-benzodioxin (6.96 g, 35 mmol) and 5% Pd/C (4 g) in MeOH (500 ml) was stirred overnight in the presence of hydrogen at atmospheric pressure at rt. The catalyst was filtered off and solvent removed; the residue was dissolved in MeOH (100 ml), more 5% Pd/C (paste, 3 g) was added and mixture stirred overnight in presence of hydrogen (45 psi) at rt. The catalyst was filtered off and solvent removed; the residue treated with DCM (20 ml), the solid filtered off and compound in DCM loaded on silica (pre-wet with petroleum ether) and purified using a 10%-50% EtOAc: 40-60 petroleum ether gradient to provide the desired compound (3 g, 51%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:16][C:17]([CH3:22])([CH3:21])[C@@H:18]1[O:20][CH2:19]1.C(N(CC)CC)C>C(O)(C)C>[CH3:16][C:17]([CH3:22])([CH3:21])[C@H:18]([OH:20])[CH2:19][N:11]1[CH:12]=[CH:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:8][CH:7]=2)=[N:10]1
Reactant: FC(F)(F)c1ccc(-c2cc[nH]n2)cc1
Reactant: CC(C)(C)[C@H]1CO1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)[C@H](O)Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 85 °C
Yield: 48.2 %

Procedure:
A mixture of 4.11 g (19.4 mmol) of 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole, 2.0 g (19.9 mmol) of (S)-3,3-dimethyl-1,2-epoxybutane, 3.1 mL (22.3 mmol) of triethylamine, and 10 mL of isopropyl alcohol was placed in a sealed tube and heated at 85° C. for 48 h. Solvent was evaporated and the residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (1:7) to give 2.92 g (49%) of (2S)-3,3-dimethyl-1-{3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol as a pale yellow solid and 0.4 g (7%) of its isomer (2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol. Data for (2S)-3,3-dimethyl-1-{3-[4-(tifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol: 1H-NMR (DMSO-d6): δ 7.96 (d, J 8 Hz, 2H), 7.75 (s, 1H), 7.69 (d, J=8 Hz, 2H), 6.76 (d, J=2 Hz, 1H), 4.86 (d, J=6 Hz, 1H), 4.26 (dd, J=14 Hz, J=2 Hz, 1H), 3.88 (dd, J=14 Hz, J=10 Hz, 1H), 3.45–3.50 (m, 1H), 0.88 (s, 9H); ES-LCMS m/z 313 (M+H). Data for (2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol: 1H-NMR (DMSO-d6): δ 7.87 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H), 7.52 (d, J=2 Hz, 1H), 6.42 (d, J=2 Hz, 1H), 5.01 (d, J=6 Hz, 1H), 4.10 (dd, J=14 Hz, J=2 Hz, 1H), 3.92 (dd, J=14 Hz, J=10 Hz, 1H), 3.62–3.67 (m, 1H), 0.82 (s, 9H); ES-LCMS m/z 313 (M+H).
Reaction SMILES: [I:1]I.[C:3]([O:7][C:8](=[O:33])[NH:9][CH2:10][CH2:11][CH:12]1[N:17]2[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:20]=[C:16]2[C:15](=[O:32])[NH:14][CH2:13]1)([CH3:6])([CH3:5])[CH3:4]>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[C:3]([O:7][C:8](=[O:33])[NH:9][CH2:10][CH2:11][CH:12]1[N:17]2[C:18]([I:1])=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:22]=3)[CH:20]=[C:16]2[C:15](=[O:32])[NH:14][CH2:13]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)cn21
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(I)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Iodine (450 mg 1.77 mmol) was added portion wise to a solution of tert-butyl(2-{1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate (780 mg 1.77 mmol) and silver trifluoroacetate (392 mg, 1.77 mmol) in dry DCM (100 ml), at 5° C. The reaction mixture was stirred at the same temperature for 1 hour, then the ice bath removed and left to warm to rt (1 h). The solid was filtered, the organic phase washed with Na2S2O5 (5% aq. solution) until decolouration occurred and finally washed with water. The organic was dried over Na2SO4 to obtain the title compound 1.0 g (99%) as a white solid.
Reaction SMILES: CS([C:5]1[C:6]2[CH2:16][CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:7]=2[N:8]=[C:9]([NH2:11])[N:10]=1)(=O)=O.C(O[C:29]([N:31]1[CH2:35][CH2:34][CH:33]2[CH2:36][NH:37][CH2:38][CH:32]12)=O)C1C=CC=CC=1>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[CH3:29][N:31]1[CH2:35][CH2:34][C@@H:33]2[CH2:36][N:37]([C:5]3[C:6]4[CH2:16][CH2:15][CH2:14][C:13]5[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=5[C:7]=4[N:8]=[C:9]([NH2:11])[N:10]=3)[CH2:38][C@H:32]12
Reactant: CS(=O)(=O)c1nc(N)nc2c1CCCc1ccccc1-2
Reactant: O=C(OCc1ccccc1)N1CCC2CNCC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: CN1CC[C@@H]2CN(c3nc(N)nc4c3CCCc3ccccc3-4)C[C@@H]21

Procedure:
The title compound was prepared using the procedure described in Example 1F, substituting the product from Example 3A for the product from Example 1C, and substituting the product from Example 15B for the product from Example 1E. The resulting intermediate was refluxed for 16 hours in 4.4% formic acid in methanol with the presence of Pd(OH)2 (5% mol). The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with 3% (9:1 MeOH: NH4OH) in dichloromethane to provide the title compound. 1H NMR (CDCl3) δ 1.71-1.84 (m, 1H), 2.04-2.10 (m, 1H), 2.15-2.20 (m, 3H), 2.31-2.40 (m, 1H), 2.38 (s, 3H), 2.51-2.56 (m, 1H), 2.64 (t, J=6.44 Hz, 2H), 2.83 (m, 2H), 3.14-3.21 (m, 1H), 3.60-3.77 (m, 4H), 4.85 (s, 2H), 7.18-7.21 (m, 1H), 7.31-7.34 (m, 2H), 7.73-7.77 (m, 1H). MS (M+H)+ m/z 336.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([CH3:27])[CH:18]=3)[N:8]=2)[CH:6]=1.[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[C:19]([CH3:27])[CH:18]=4)[N:8]=3)[CH:6]=2)=[CH:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)ccc1C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c3)n2)ccc1C(F)(F)F

Procedure:
N-tert-Butyl-4-{1-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example E.73) (0.50 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.057 g), which was subsequently deprotected.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-nitrobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-nitrophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[O:3]1)=[O:2].[CH3:15]O>Cl>[C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[O:3]1)=[O:2]
Reactant: CO
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Agent: Cl
Product: COC(=O)CC1OC(=O)c2ccccc21

Procedure:
Phthalide-3-acetic acid (XCI, 9.6 g, 50 mmol) is dissolved in methanol (50 ml) saturated with anhydrous hydrochloric acid and the mixture is cooled to 0-5° for 18 hr. The solvent is concentrated under reduced pressure, treated with sodium bicarbonate, and extracted with methylene chloride (800 ml). The organic phase is washed with saturated aqueous sodium bicarbonate, saline, dried over magnesium sulfate, filtered and concentrated to give the title compound, mp 62-63°; NMR (CDCl3, TMS) 7.94-7.50, 5.90, 3.77 and 2.92 δ.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CN1CCC(c2ccccc2)C1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-phenyl-pyrrolidine.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([O:19][CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][NH2:29])=[C:24]([CH3:32])[CH:23]=1)[CH3:18]>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]([NH:29][CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])=[CH:23][C:24]=2[CH3:32])=[N:3][CH:4]=[N:5][C:6]=1[CH3:9]
Reactant: Cc1ncnc(Cl)c1Cl
Reactant: CCOCCc1ccc(OCCN)c(C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOCCc1ccc(OCCNc2ncnc(C)c2Cl)c(C)c1
Yield: 75.7 %

Procedure:
1.6 g of 4,5-dichloro-6-methylpyrimidine was dissolved in 50 ml of toluene. 1.0 g of triethylamine and 2.2 g of 2-[4-(2-ethoxyethyl)-2-methylphenoxy]ethylamine were added to the solution, and the reaction mixture was heated under reflux for 5 hours, whilst stirring. At the end of this time, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The toluene was removed by distillation under reduced pressure, and the oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate) to isolate the product. The crystals thus obtained were recrystallized from hexane to afford 2.6 g of the title compound as colorless needles melting at 57°-58° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[C:10]=1[Cl:17])[CH2:6]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:20])=O>>[CH2:1]([CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[C:10]=1[Cl:17])[CH2:6][Cl:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CO)Cc1ccc(Cl)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: CCCCC(CCl)Cc1ccc(Cl)c(Cl)c1Cl
Temperature: 140 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
332 g of (XX) were added dropwise to 148 g of thionyl chloride, and the mixture was stirred for 14 hours at room temperature and for 2 hours at 140° C. Distillation gave 278 g of (XXI) of boiling point 142°-145° C./0.1 mbar.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:12]2[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[S:24])[CH:15]=[CH:16][C:17]=2[O:18][CH2:19][CH2:20][CH3:21])[NH:7][C:8](=[O:11])[C:9]=1[Br:10])([CH3:3])[CH3:2].I[CH3:29]>CO>[CH:1]([C:4]1[N:5]=[C:6]([C:12]2[CH:13]=[C:14]([NH:22][C:23](=[N:25][CH2:26][CH3:27])[S:24][CH3:29])[CH:15]=[CH:16][C:17]=2[O:18][CH2:19][CH2:20][CH3:21])[NH:7][C:8](=[O:11])[C:9]=1[Br:10])([CH3:2])[CH3:3]
Reactant: CCCOc1ccc(NC(=S)NCC)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reactant: CI
Solvent: CO
Product: CCCOc1ccc(NC(=NCC)SC)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Yield: 85.6 %

Procedure:
The compound (2.7 g, 6 mmol) of example 35 was suspended in methanol (20 ml), and added with iodomethane (1.0 g, 7 mmol). After refluxed for 3 h, the reaction mixture was concentrated to dryness. The resultant solid was recrystallized from ethylether to obtain the title compound (2.4 g, yield: 85%). 1H NMR (DMSO-d6) δ: 7.16 (1H, d), 6.99 (1H, dd), 6.87 (1H, d), 4.00 (2H, t), 3.37 (1H, m), 2.94 (2H, q), 2.56 (3H, s), 1.74 (2H, m), 1.18 (6H, d), 1.11 (3H, t), 0.98 (3H, t).