Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:10][N:9]=[C:8]2[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:36]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Cl)#[N:37].C1C[O:49]CC1>CCCCCC>[CH2:21]([C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:49])[C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[C:36]#[N:37])=[CH:26][CH:25]=2)[C:11]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:10][N:9]=1)[CH2:22][CH2:23][CH3:24]
Reactant: N#Cc1ccccc1CCl
Reactant: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(N)cc1
Reactant: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(NC(=O)c2ccccc2C#N)cc1
Yield: 36 %

Procedure:
A solution of 450 mg (1.16 mmole) of 4-(4- aminobenzyl)-3-n-butyl-5-(4-chlorobenzylthio)-4H-1,2,4-triazole (Step B), 438 μl (325 mg, 2.52 mmole) of N,N-diisopropylethylamine and 418 mg (2.53 mmole) of 2-cyanobenzyl chloride [R. Scholl and W. Neuberger, Monatsh. Chem. 33, 507 (1911)] in 10 ml of dry THF was stirred overnight at room temperature under N2. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in 50 ml of ethyl acetate and washed with 2×60 ml of saturated NaHCO3 solution followed by 50 ml of saturated NACl. The organic phase was then dried (MgSO4), filtered, and concentrated. A solution of the residue in CH2Cl2 was treated with approximately 2 g of silica gel, and the mixture was evaporated to give a dry powder, which was added as a slurry in hexane to the top of a silica gel column packed in the same solvent. The column was eluted briefly with hexane and then with a stepwise gradient from 1:1 hexane-EtOAc to 100% EtOAc. Two major products were eluted, the second of which correspond to the desired product. Fractions containing this material were combined and concentrated to give 229 mg (36%) of the title compound as a solid, mp 75°-77° C. dec., homogeneous by TLC in 1:3 hexane-EtOAc; mass spectrum (FAB) m/e 516 (M+1)+.
Reaction SMILES: Cl.[C:2]([CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)#[N:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:2]([CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6]1)#[N:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N#CCC1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#CCC1CCN(S(=O)(=O)c2ccc(Cl)cc2)C1
Yield: 101.1 %

Procedure:
Acylation, in chloroform, of 36.6 g (0.25 mol) of 3-cyanomethylpyrrolidine hydrochloride with 52.7 g (0.25 mol) of para-chlorophenylsulfonic acid chloride, in the presence of 50.5 g (0.5 mol) of triethylamine makes it possible to obtain 72 g of a solid which is purified by chromatography on silica, Merck 70-230 mesh, using as eluent a dichloromethane/methanol mixture (99/1 v/v).
Reaction SMILES: C(O[N:6]([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])C=O)(C)(C)C.[ClH:25]>CO.C(OCC)(=O)C>[ClH:24].[ClH:25].[NH2:6][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(C)(C)ON(C=O)CC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butoxy-N-[2-[4-(4-chlorophenyl)-1-piperazinyl]-2-oxoethyl]formamide (31 g) in methanol (60 ml) was added 4N hydrogen chloride in ethyl acetate (219 ml) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour and diluted with ethyl acetate. The resulting solid was collected by filtration and washed with ethyl acetate. The solid was dried to give the title compound (29 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>O1CCOCC1>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Product: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (120 mg, 0.66 mmol) in 1.5 ml dioxane was added 3-chloroaniline (35 μL, 3.31 mmol). The mixture was heated in Microwave 10 minutes at 120° C. The solid formed was isolated by filtration and air dried to give 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde as orange solid. LCMS (M+1=273)
Reaction SMILES: [OH-:1].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:8][C@H:9]([C@@H:16]([C:15]1[CH:14]=[CH:18][CH:12]=[CH:6][CH:7]=1)[OH:17])[CH2:10][O:4][S:3]([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:1])=[O:5].[S:3]([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)([OH:17])(=[O:5])=[O:4]
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)[C@H](O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a stirred solution of diol (2S,3S)-2-Methyl-3-phenyl-3-hydroxy-propanol (2.5 g,15 m.mole) in THF (20 ml) was added NaOH (1 g, 40 m.mole) and Tosyl chloride (5 g, 25 m.mole) in THF (5 ml). The cloudy solution was stirred at room temperature for 6 hours and then THF was evaporated under vaccu, diluted with ether (50 ml) washed with water (2×10 ml) and dried over anhydrous MgSO4. Evaporation gave crude tosylate (2S,3S)-2-Methyl-3-phenyl-3-hydroxy-1-tosyloxy-propane (4.1 g, 85%) sufficiently pure for the next step as a yellow viscous oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[C:5]([CH:23]=[CH2:24])[N:4]=1.CN1CC[O:31]CC1.[OH2:34]>CO.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[OH:34][CH:23]([C:5]1[N:4]=[C:3]([C:2]([F:1])([F:25])[F:26])[N:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH:6]=1)[CH2:24][OH:31]
Reactant: C=Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Reactant: O
Reactant: CN1CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CO
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(O)CO)nc(C(F)(F)F)n2)CC1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-{[2-(trifluoromethyl)-6-vinylpyrimidin-4-yl]oxy}piperidine-1-carboxylate (614 mg, 1.64 mmol) in methanol (7 mL) and tert-butyl alcohol (5.2 mL) was added TV-methylmorpholine TV-oxide (212 mg, 1.81 mmol) and water (5.2 mL). To this solution was then added osmium tetraoxide (20.9 mg, 0.0822 mmol). After stirring for 3 hours, another equivalent of TV-methylmorpholine TV-oxide was added. The reaction was stirred at room temperature overnight. The solution was concentrated and diluted with water and extracted with ethyl acetate twice, washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography on a silica gel column to give the desired product. LCMS (M+H)+: 408.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[C:9]([NH2:16])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:17]([N:3]1[CH:4]=[N:5][C:6]2[C:2]1=[N:1][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:16][C:7]=2[NH2:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: ClCc1ccccc1
Reactant: CCCCCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 210 °C

Procedure:
A mixture of 4-amino-5-cyanoimidazole (1.09 g, 11 mmol) and hexaneamide (4.39 g, 38 mmol) was heated at 210° C. for 15 h under N2 atmosphere. After cooling, the residue was dissolved in a mixture of DMF (200 ml) and water (50 ml). Benzyl chloride (3 ml) and K2CO3 (3 g) was added to the mixture, and heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by CH2Cl2. The resulting organic layer was evaporated under vacuum. 9-benzyl-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1-50:1). Bromine (2 ml) was added to the mixture of 9-benzyl-2-hexyladenine and NaOAc (5 g) in ACOH (40 ml) within an ice bath, and the mixture was heated at 70° C. for 6 h. Solvent was evaporated under vacuum, the residue was extracted by EtOAc. The resulting organic layer was evaporated under vacuum, 9-benzyl-8-bromo-2-pentyladenine was obtained by the purification of the residue by column chromatography (CH2Cl2 :MeOH=100:1). A mixture of 9-benzyl-8-bromo-2-pentyladenine and conc.HCl (20 ml) was refluxed for 6 h. After cooling, aqueous NH3 was added to neutralize and crystallize the product (pH=8), and the desired compound was collected by filtration (0.25 g, Yield: 8%).
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[F:56][C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][CH:65]=1)[C:60](Cl)=[O:61]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:12][CH:13]=5)[C:5]([OH:4])=[O:55])=[O:24])[N:26]([C:60](=[O:61])[C:59]5[CH:63]=[CH:64][CH:65]=[C:57]([F:56])[CH:58]=5)[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:40][CH:41]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3cccc(F)c3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexa hydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and 3-fluorobenzoyl chloride (3 eq.) were added. After stirring at room temperature for 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified by over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 861.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][C:14]=2[CH:23]2[CH2:25][CH2:24]2)[C:8]2[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:7]=2[N:6]([C:32]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[C@H:5]1[CH3:40].[C:41]([N:48]([CH3:54])[C@H:49]([C:51](O)=[O:52])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:30]([C:28]1[CH:27]=[CH:26][C:8]2[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][C:14]=3[CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:11])[C@@H:4]([NH:3][C:51](=[O:52])[C@@H:49]([N:48]([CH3:54])[C:41](=[O:42])[O:43][C:44]([CH3:45])([CH3:47])[CH3:46])[CH3:50])[C@H:5]([CH3:40])[N:6]([C:32]([CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[O:33])[C:7]=2[CH:29]=1)#[N:31]
Reactant: C[C@H]1[C@H](N)C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N1C(=O)C1CCOCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a 0° C. solution of (3S,4S)-3-amino-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile dihydrochloride (60 mg, 103 μmol) in DMF (343 μl) was added Boc-N-methyl-L-alanine (23.0 mg, 113 μmol), N,N-diisopropylethylamine (89.1 μl, 515 μmol), and HBTU (43.0 mg, 113 μmol). The reaction was stirred at rt for 30 min, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55.3 mg, 77%) as a white solid. MS m/z 695 (MH)+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:8]3=[C:7]([CH3:19])[C:6]=2[CH:5]=1.[Br:20]Br>>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:8]3=[C:7]([CH3:19])[C:6]=2[C:5]=1[Br:20]
Reactant: Cc1c2c(nc3ccc(N)cc13)CCNCC2
Reactant: BrBr
Agent: Cl
Product: Cc1c2c(nc3ccc(N)c(Br)c13)CCNCC2

Procedure:
9-Amino-10-bromo-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline dihydrochloride was prepared from 9-amino-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline dihydrochloride by bromination with an equimolar quantity of bromine analogous to Example 148.
Reaction SMILES: C[O:2][C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[Cl:11][C:8]1[S:7][C:6](/[CH:5]=[CH:4]/[C:3]([OH:12])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a mixture of 3-(5-chloro-thiophen-2-yl)-(E)-acrylic acid methyl ester (0.60 g, 2.96 mmol) in 15 mL of 1:1:1 THF/MeOH/H2O at 0° C. is added lithium hydroxide monohydrate (0.62 g, 14.7 mmol). The mixture is stirred at 0° C. for 1 h, then at room temperature for 1 h and concentrated in vacuo. The residue is diluted with EtOAc and washed with 1N HCl. The aqueous layer is extracted with EtOAc and the combined organics are washed with water (2×), dried, filtered and concentrated to provide the title compound (0.54 g, 2.86 mmol) as a white solid. The crude material can be used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ7.65 (d, 1H), 7.05 (d, 1H), 6.90 (d, 1H), 6.10 (d, 1H).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([CH2:22][NH2:23])[CH2:10]2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:35])=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:30]=1>>[Cl:1][C:28]1([CH3:35])[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]1[S:31]([NH:23][CH2:22][C:11]1[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[N:12]=1)(=[O:33])=[O:32]
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Cl
Reactant: NCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Product: CC1(Cl)C=CC(F)=CC1S(=O)(=O)NCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Yield: 88 %

Procedure:
According to general sulfonamide coupling procedure, [5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]methyl amine hydrochloride was reacted with 5-fluoro-2-methylbenzenesulfonyl chloride. The reaction yield was 88% of 2-Chloro-N-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-ylmethyl]-5-fluoro-2-methyl-benzenesulfonamide as a solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:42][CH2:43][CH2:44][OH:45]>C(Cl)Cl>[OH:45][CH2:44][CH2:43][NH:42][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:20][CH:21]=1)=[O:24]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: NCCO
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (50 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride(0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. And then, triethylamine (0.7 ml) and 2-aminoethanol(1.27 g) were added in order, the solution was stirred at 0~5° C. for 2 hours and heated slowly to 20~25° C. and stirred for 30 minutes. The reaction mixture was washed with water twice and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and further recrystallized using isopropanol and ether. The recrystallized product was filtered and dried to give 1.34 g (yield: 80%) of the desired compound as a white powder.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[CH2:15]([C@@H:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]1)[CH2:16][CH3:17]
Reactant: CCC[C@H]1CC[C@@H](NCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCC[C@H]1CC[C@@H](N)CC1

Procedure:
To a solution of cis-1-benzylamino-4-propylcyclohexane (Preparation 52) (1.59 g, 6.87 mmol) in EtOH (90 mL) was added cyclohexene (10 mL) and 10% palladium-on-carbon (550 mg). The mixture was refluxed for 12 h. After cooling the mixture was filtered through celite. Solvent was removed in vacuo to give the title compound: δH (CD3OD): 0.95 (3H, t), 1.28-1.74 (13H, m), 2.95 (1H, m).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]([CH2:4][C:5]([O-:7])=[O:6])=[CH2:3].[NH4+].[NH4+].C(=O)([O-])[O-].[NH4+].[NH4+]>>[C:5]([OH:7])(=[O:6])[CH:4]=[CH2:2].[C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3]
Reactant: C=C(CC(=O)[O-])C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [NH4+]
Product: C=C(CC(=O)O)C(=O)O
Product: C=CC(=O)O

Procedure:
The partially neutralized ammonium salt of 95 weight % acrylic acid and 5 weight % itaconic acid was prepared as described in Example II except that ammonium itaconate was used instead of sodium itaconate and ammonium carbonate was used instead of soda ash.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(C)C>[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:28]2[CH2:29][CH2:30][CH:25]([NH:24][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:26][CH2:27]2)=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(OCC(O)CN2CCC(NC(=O)c3ccccc3)CC2)cc1

Procedure:
A solution of 2,3-epoxy-1-(4-acetamidophenoxy)-propane (5.18 g.) and 4-benzamidopiperidine (6.13 g.) in isopropanol (250 ml.) was refluxed for 24 hours, cooled and a white crystalline solid was filtered off (8.90 g.).This was recrystallised from isopropanol to give 7.41 g. of the title compound as a quarter hydrate, m.p. 226°-8° C. (Found: C, 66.35; H, 7.1; N, 10.1. C23H29N3O4.1/4 H2O requires C, 66.4; H, 7.15; N, 10.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][C:4]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)=[CH:42][C:41]=1[O:57][CH3:58]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:58][O:57][C:41]1[CH:42]=[C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)[CH:44]=[CH:45][C:40]=1[O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:26][C:4]1[CH:5]=[C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C2=NOC(c3cc(OC)c(OC)c(OC)c3)C2)cc1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(C2=NOC(c3cc(OC)c(OC)c(OC)c3)C2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 79.8 %

Procedure:
2-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenol (1a) (359.37 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (3d) (557 mg, 80% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.[N-:17]=[N+:18]=[N-:19]>C1COCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([N:17]=[N+:18]=[N-:19])=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: [N-]=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1cnccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of Pyrazine-2-carboxylic acid (295 mg, 2.1 mmol, 1 eq) and triethylamine (765 ul, 5.4 mmol, 2.6 eq) in THF (6 ml) at 0° C. was added dropwise diphenylphophoryl azide (1.4 ml, 2.8 mmol, 1.3 eq). The mixture was stirred under nitrogen at 0° C. for 30 minutes, then warmed to RT and stirring continued for a further 2 hours. The reaction mixture was concentrated under vacuum and purified by flash chromatography (90/10-60/40 Iso-hexane/EtOAc) to afford the title compound as white solid (265 mg, yield=78%). 1H NMR (400 MHz, CDCl3) δ 9.14 (d, 1H, J=1.2); 8.50 (dt, 1H, J=1.2, 0.4), 2.62 (s, 3H, broad).