Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[C:4](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5](/[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][CH:10]=2)\[C:6](O)=[O:7])[CH2:3][CH2:2]1.Cl.Cl.[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:6](=[O:7])/[C:5](/[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:13][CH:14]=2)=[C:4](\[CH:1]2[CH2:3][CH2:2]2)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:34][CH:33]=1
Reactant: COCOc1ccc(/C(C(=O)O)=C(\c2ccccc2)C2CC2)cc1
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(\c2ccccc2)C2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 7 (65 mg, 0.200 mmol), 4-(2-(dimethylamino)ethoxy)benzenamine dihydrochloride (42.6 mg, 0.168 mmol), 4-Dimethylaminopyridine (1.2 mg, 0.00982 mmol) in CH2Cl2 (3 ml) was added O-Benzotriazoyl-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (83.4 mg, 0.220 mmol) under ice cooling, and the mixture was stirred at 0° C. for 10 min. Then N,N-Diisopropylethylamine (90.4 mg, 0.701 mmol) was added under ice cooling. The mixture was stirred at 0° C. for 5 min, and at room temperature for 15 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by silica gel flash column chromatography (eluent: CH2Cl2 to CH2Cl2/MeOH, 6:1) gave the colorless solid (100%). The solid was triturated with hexane to give 8 (80%). 8: colorless powder; 1H-NMR (CDCl3) δ 0.45 (2H, m), 0.79 (2H, m), 2.36 (6H, s), 2.55 (1H, m), 2.76 (2H, t, J=5.5 Hz), 3.41 (3H, s), 4.07 (2H, t, J=5.5 Hz), 5.05 (2H, s), 6.74 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz), 6.95-6.99 (4H, m), 7.10-7.20 (4H, m), 7.44 (2H, d, J=8.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:18][C:19](=[O:36])[C@@H:20]([CH2:28][S:29]([C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([OH:17])=O)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ON1C(=O)CCC1=O>[C:32]([S:29]([CH2:28][C@@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C@H:14]([C:15](=[O:17])[NH:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41])[CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:12]=1)=[O:36])(=[O:30])=[O:31])([CH3:35])([CH3:33])[CH3:34]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1
Reaction time: 17 h
Yield: 87.2 %

Procedure:
89 g (170 mmol) of (S)-1-(t-butoxycarbonyl)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionic acid, 1 g (8.5 mmol) of N-hydroxysuccinimide, 35.5 g (155 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-butane-1,2-diol and 800 ml of ethyl acetate were stirred at 20°. A solution of 37 g (178 mmol) of dicyclohexylcarbodiimide in 110 ml of ethyl acetate was added within 10 minutes. The reaction had finished after stirring at 20° for 17 hours. The solid (dicyclohexylurea) was filtered off and the filtrate was treated while stirring firstly with 68 ml of deionized water and then with 1100 ml of hexane. After one hour at 0° the crystallizate was filtered off under suction and triturated in methanol at 20°. The suspension was cooled to -15° and the product was filtered off. 98.8 g (86%) of t-butyl 4-[(S)-2 -[(S)-2-t-butanesulphonylmethyl-3-phenylpropionylamino]-2-[(1S,2R,3S)-1-cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxy-propylcarbamoyl]ethyl]-1H-imidazole-1-carboxylate were obtained.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (232) (1.0 g, 1.46 mmol) in tetrahydrofuran (10 mL) was added HCl (37% aqueous, 1.70 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. After completion of the reaction, the mixture was diluted with ethyl acetate (30 mL), washed with water, separated and the organic phase dried over Na2SO4. After evaporation of the solvent, the crude product was purified by 100-200 silica gel column chromatography using 60% ethyl acetate in hexane followed by 5% methanol in dichloromethane as the eluent to obtain 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (233) (0.7 g, 84%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([CH:13]=1)[O:7][CH2:8][C:9](OC)=[O:10]>[Pd].CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:9](=[O:10])[CH2:8][O:7][C:6]=2[CH:13]=1
Reactant: COC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: O=C1COc2cc(F)ccc2N1
Reaction time: 2 h

Procedure:
To 500 mg of 5% Pd/C in a Parr bottle was added 100 ml of EtOH followed by 5.0 g (21.8 mmol) of methyl 5-fluoro-2-nitrophenoxyacetate. The flask was placed in a Parr Apparatus, evacuated and then charged with hydrogen. The suspension was then shaken for 2 hours. After evacuating the flask and recharging with nitrogen, the solids were removed by vacuum filtration through Celite®. Since some product does precipitate, the filter cake is repeatedly rinsed with EtOAc (200 ml). The filtrate is refluxed for 4 hours and then evaporated to dryness in vacuo to give the desired material, 7-fluoro-2H-1,4-benzoxazin-3(4H)-one, as a white solid (m.p. 201°-202° C.) in quantitative yield.
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:27]=[C:24]([CH:25]=[O:26])[C:23]([OH:28])=[CH:22][CH:21]=1.[Cl:29][CH2:30]/[CH:31]=[CH:32]/[CH2:33]Cl.[OH-].[Na+]>O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:28][CH2:33]/[CH:32]=[CH:31]/[CH2:30][Cl:29])=[C:24]([CH:27]=1)[CH:25]=[O:26]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: ClC/C=C/CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cc(Cl)ccc1OC/C=C/CCl

Procedure:
To 1.2 lt of refluxing water, 1 ml of 40% aqueous tetrabutylammonium hydroxide, 160 g of 5-chloro-salicylaldehyde and 140 ml of trans-1,4-dichloro-2-butene are added while vigorously stirring, followed by the dropwise addition of the solution of 42 g of sodium hydroxide in 200 ml of water at such a rate that the pH of the mixture is kept between 7 and 8. Thereafter the mixture is refluxed until the pH is about 7, cooled and extracted with methylene chloride. The extract is washed with 5% aqueous sodium hydroxide, dried, evaporated and the residue heated to 30°/0.1 mmHg in order to remove the excess of 1,4-dichloro-2-butene. The residue is taken up in 1 lt of diethyl ether, the solution filtered, the filtrate evaporated and the residue recyrstallized from ethyl acetate, to yield the 5-chloro-2-(4-chloro-trans-2-butenyloxy)-benzaldehyde melting at 62°-63°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][N:15]3[CH2:18][C@@H:19]([OH:21])[CH2:20][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH:24]1([C:27]2[N:28]=[CH:29][C:30](O)=[N:31][CH:32]=2)[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>O1CCCC1>[CH:24]1([C:27]2[N:28]=[CH:29][C:30]([O:21][C@H:19]3[CH2:18][N:15]4[CH2:16][CH2:17][N:12]([S:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=5)(=[O:11])=[O:10])[CH2:13][C@H:14]4[CH2:20]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](O)C[C@@H]2C1
Reactant: Oc1cnc(C2CC2)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A mixture of (7S,8aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol (Example 17, 103 mg, 0.294 mmol), 5-cyclopropylpyrazin-2-ol (40 mg, 0.294 mmol) and triphenylphosphine (154 mg, 0.588 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature for 1 hour. Then (E)-diisopropyl diazene-1,2-dicarboxylate (119 mg, 0.588 mmol) was added, and the reaction was continued at room temperature overnight. The solution was concentrated, and the residue was purified by chromatography on silica gel (ethyl acetate/hexane=3:2) to give the title compound (68 mg, 48% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (m, 4H), 1.22 (m, 2H), 2.12 (m, 4H), 2.41 (m, 2H), 3.01 (m, 2H), 3.67 (m, 1H), 3.83 (m, 1H), 5.25 (m, 1H), 7.94 (m, 1H), 8.03 (m, 1H), 8.15 (m, 4H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH2:12][NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[N:7][C:6]=2[CH:19]=1.OO.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C.C(Cl)Cl.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH2:11][CH2:12][NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[O:23])=[N:7][C:6]=2[CH:19]=1
Reactant: O=C([O-])O
Reactant: CCNC(=O)NCCSc1nc2cc(Cl)ccc2s1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)NCCS(=O)c1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Dissolved in a mixed solution of 5.8 ml of acetic acid and 5.8 ml of methylene chloride were 1.15 g (3.65 mmol) of the compound obtained in Example 21, and 0.41 ml (4.02 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic quantity of sodium tungstate were successively added to the solution, which was stirred at room temperature for 1 hour. The reaction solution was poured in 116 ml of water, neutralized with sodium hydrogencarbonate and extracted with 116 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 0.96 g of white crystalline powders (79% yield).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:17][N:16]([C:18]([C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:23][N:24]=3)=[O:19])[CH2:15]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:2][N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][CH:14]2[CH2:17][N:16]([C:18]([C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:23][N:24]=3)=[O:19])[CH2:15]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CCl)cc2)C1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1ccc(SC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.6 %

Procedure:
Dimethylamine hydrochloride (0.10 g, 1.24 mmol) and 60B (0.16 g, 0.41 mmol) were mixed in DCM (5 ml). Triethylamine (0.290 ml, 2.07 mmol) was added and the mixture was stirred at RT for 2.5 h. More of triethylamine (0.290 ml, 2.07 mmol) and dimethylamine hydrochloride (0.10 g, 1.24 mmol) were added. The mixture was stirred overnight at RT and then diluted with DCM (10 ml). The mixture was washed with water, filtered through a phase separator and then evaporated. The residue was purified by column chromatography eluting with NH3 in MeOH (2M)/DCM (1:99, 2:98). There was obtained 0.14 g (84%) of 60 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.20 (s, 6H), 3.38 (s, 2H), 4.16 (m, 2H), 4.61 (m, 2H), 5.07 (m, 1H), 7.50 (t, 2H), 7.56 (t, 1H), 8.12 (d, 2H), MS (APCI+) m/z 395 [M+H]+, LC purity: 97%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].O1CC[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH:11]=[CH2:12]
Reactant: O=Cc1ccccc1Br
Reactant: C1CCOC1
Product: C=CC(O)c1ccccc1Br

Procedure:
To 2-bromobenzaldehyde (27 g; 0.146 mmol.) in dry tetrahydrofuran cooled to -78° C. in a dry ice/isopropyl alcohol bath was added 175 ml of a 1.0M solution of vinyl Grignard reagent in tetrahydrofuran dropwise and the reaction allowed to slowly warm overnight to room temperature. The reaction mixture was quenched with saturated NH4Cl and the tetrahydrofuran was concentrated off. The reaction mixture was poured into water and extracted twice with diethylether, washed with water and then brine and dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[CH:21]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:4]([N+:22]([O-])=O)[CH:3]=1.P(OCC)(OCC)(OCC)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:21]([NH:22][C:4]=2[CH:3]=1)=[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=31
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1cc2ccccc2c2ccccc12
Solvent: CCOP(=O)(OCC)OCC
Product: Brc1ccc2c(c1)[nH]c1c3ccccc3c3ccccc3c21
Yield: 62 %

Procedure:
A 250 mL round bottom flask was charged with 9-(4-bromo-2-nitrophenyl)phenanthrene (26.36 g, 69.69 mmol), and triethyl phosphate (84.84 mL, 487.86 mmol), and the mixture was heated under reflux at 160° C. to 165° C. for 14 hours. After the reaction was completed, the remaining triethyl phosphate was removed by vacuum distillation. The resultant product was diluted with a mixed solvent of MeOH:H2O=1:1, and the produced solid was filtered. The obtained solid was washed with a mixed solvent of MeOH:H2O=1:1, and petroleum ether. The solid was dissolved in methylene chloride, dried with MgSO4, and concentrated, and purified by silica gel column (petroleum ether:methylene chloride=2:1). Then, 14.96 g of a product (62%) was obtained.
Reaction SMILES: [C:1](N)(=[O:3])[CH3:2].C=O.O.Cl.C(=O)=O.[NH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].C(NCC(O)=O)(=O)C>COCCOC>[C:1]([N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: O=C(O)CNCC(=O)O
Agent: C=O
Agent: CC(=O)NCC(=O)O
Agent: Cl
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 110 °C
Yield: 87 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole), 37% HCl (1.8 g, 0.018 mole) , DME (90 mL), and CO2 (CO) 1 (4. 1 g, 0.012 mole) and pressurized to 4000 psi (27,580 kPa) CO at 25° C. This mixture was heated to 110° C. for 30 min. HPLC analysis of this stream gave an 87% yield of (XVI), 0.5% (XIV), and 4.0% (XVIII).
Reaction SMILES: FC(F)(F)[C:3]([N:5](C)[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=4)[CH:16]=3)[N:14]=2)[N:11]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:3][NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[N:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[O:23][N:22]=4)[CH:16]=3)[N:14]=2)[N:11]=1
Reactant: CN(C(=O)C(F)(F)F)c1ccc2nc(-c3cccc(-c4noc(C(F)(F)F)n4)c3)cn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1ccc2nc(-c3cccc(-c4noc(C(F)(F)F)n4)c3)cn2n1
Temperature: 60 °C

Procedure:
A mixture of 2,2,2-trifluoro-N-methyl-N-(2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)acetamide(0. 15 mmol) and K2CO3 (0.3 mmol)in 20 mL methanol -water(4:1) was heated at 60° C. for 1 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give the N-methyl-2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazin-6-amine.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:20])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=O.[CH:21]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:27]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:28](=[O:29])[NH:2][C:3]=2[CH3:20])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NC1CCCCC1
Reactant: CC(N)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1[nH]c(=O)n(C2CCCCC2)c1-c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
2-Amino-4'-benzyloxypropiophenone hydrochloride (349 mg, 1.20 mmol) was suspended in acetone (30 ml) under ice-cooling, and cyclohexyl isocyanate (204 mg, 1.62 mmol) was added thereto. Triethylamine (377 mg, 3.73 mmol) was then added, and the mixture was stirred for one hour under ice-cooling. After addition of trifluoroacetic acid (2 ml), the mixture was stirred for 6 days at room temperature. The solvent was removed by evaporation in vacuo, and the residue was extracted with dichloromethane. The extract was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Evaporation of the solvent provided a crude product, which was purified by column chromatography (chloroform/ ethanol=50/1 (v/v)) and recrystalization (ethanol-chloroform) to give the title compound. Yield: 240 mg (55%), m.p. 262° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(Br)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A solution of 2-bromo-1-fluoro-4-nitrobenzene (0.94 g, 4.3 mmol) in N,N-dimethylformamide (10 mL) was treated with potassium carbonate (1.5 g, 11 mmol) followed by morpholine (0.56 mL, 6.4 mmol) and stirred at 20° C. for 3 h. The reaction mixture was diluted with sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (1.0 g, quantitative) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[NH2:32][C:33]1[N:38]=[CH:37][N:36]=[C:35]2[NH:39][N:40]=[CH:41][C:34]=12.[H-].[Na+]>ClCCl.CN1CCCC1=O.C1(C)C=CC=CC=1>[NH2:32][C:33]1[N:38]=[CH:37][N:36]=[C:35]2[N:39]([C@@H:13]3[O:16][C@H:17]([CH2:11][O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@H:18]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@:12]3([CH3:30])[OH:29])[N:40]=[CH:41][C:34]=12
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: Nc1ncnc2[nH]ncc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ncc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To the compound from Step C of Example 62 (1.00 g, 2.02 mmol) in dichloromethane (20 mL) was bubbled HBr gas for 5 min until it was saturated. The resulting solution was stirred at room temperature for 10 min, evaporated in vacuo and coevaporated with anhydrous toluene (10 mL). 4-Amino-1H-pyrazolo[3,4-d]pyrimidine (Aldrich, 0.43 g, 3.18 mmol) and NaH (60%, 150 mg, 3.8 mmol) were stirred in 1-methyl-2-pyrrolidinone (10 mL) for 30 min. The resulting solution was poured into the above bromo sugar residue and the mixture was stirred overnight. The mixture was diluted with toluene (50 mL), washed with brine (10%, 3×50 mL) and concentrated under reduced pressure. The residue was chromatographed on silica gel (EtOAc as eluent) to afford a solid (400 mg).
Reaction SMILES: C1(=O)[N:5]([CH:6]([CH3:23])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)C(=O)C2=CC=CC=C12.O.NN.[OH-].[K+]>O>[NH2:5][CH:6]([CH3:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccc(-c2ccc(CC(C)N3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(-c2ccc(CC(C)N)cc2)cc1

Procedure:
1.0 g (2.6 mmol) of 4'-(2-phthalimido-propyl)-4-acetyl-biphenyl are stirred into 25 ml of glycol with 0.5 ml of hydrazine hydrate and 0.9 g (0.016 mol) of potassium hydroxide for 3 hours at 200° C. The mixture is then diluted with water, extracted with ether and the extracts are concentrated by evaporation.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH:13]C(=O)OC(C)(C)C)=[O:6].[ClH:23].O1CCOCC1.C(OCC)C.CCOCC.CCCCCC>O1CCOCC1>[ClH:23].[NH2:13][C@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:5]([NH:4][CH2:3][C:2]([F:1])([F:21])[F:22])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)NCC(F)(F)F
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@H]1CCCC[C@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl {(cis)-2-[(2,2,2-trifluoroethyl)carbamoyl]cyclohexyl}carbamate, I-5a (2.55 g, 7.86 mmol) in Dioxane (10 ml) was added 4 M HCl/Dioxane (19.66 ml, 79 mmol) and the mixture allowed to stir at RT for 60 min. The reaction was concentrated in vacuo and resulting solid slurried with diethyl ether (100 mL). Re-concentration of the mixture and re-slurry of the solid with ether/hexane gave a free flowing solid. Final concentration of the mixture gave a white solid, I-5b, (2.1 gm) which was stored under nitrogen.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][CH2:33][O-:34].[Na+]>C(O)C>[CH2:33]([O:34][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH3:32]
Reactant: CC[O-]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: [Na+]
Solvent: CCO
Product: CCOCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
The mixture of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (23 mg, 0.050 mmol), NaOEt (10 mg) in ethanol (1 mL) was refluxed at 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (15.0 mg, 64%).