Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([Cl:13])=[C:9]([NH:11]N)[CH:10]=1)([OH:4])=O.[C:14]([CH:22]([CH2:26][CH3:27])C(O)=O)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[Cl:13][C:8]1[C:9]2[NH:11][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:22]3[CH2:26][CH2:27][C:2](=[O:4])[C:5]([C:10]=23)=[CH:6][CH:7]=1
Reactant: CCC(C(=O)O)C(=O)c1ccccc1
Reactant: NNc1cc(C(=O)O)ccc1Cl
Agent: Cl
Solvent: O
Product: O=C1CCc2c(-c3ccccc3)[nH]c3c(Cl)ccc1c23
Yield: 107.5 %

Procedure:
(5-carboxy-2-chlorophenyl)hydrazine hydrochloride (46 g) and benzoylbutyric acid (39.6 g) were suspended in water (500 ml) and the suspension was heated to reflux for 1 hour and allowed to cool. The crystals precipitated were collected by filtration, washed with methanol and ether, and air-dried to yield 62.4 g (84%) of the titled compound as pale brown crystals.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH:19]1([CH:22]([OH:36])[C:23]2[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32]([OH:34])=O)[N:25]([CH3:35])[N:24]=2)[CH2:21][CH2:20]1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([Cl:50])=[C:42]([CH:49]=1)[C:43]([NH:45][CH:46]1[CH2:48][CH2:47]1)=[O:44]>O1CCCC1>[Cl:50][C:41]1[CH:40]=[CH:39][C:38]([NH:37][C:32]([C:26]2[N:25]([CH3:35])[N:24]=[C:23]([CH:22]([CH:19]3[CH2:20][CH2:21]3)[OH:36])[C:27]=2[C:28]([F:29])([F:30])[F:31])=[O:34])=[CH:49][C:42]=1[C:43](=[O:44])[NH:45][CH:46]1[CH2:48][CH2:47]1
Reactant: Cn1nc(C(O)C2CC2)c(C(F)(F)F)c1C(=O)O
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1nc(C(O)C2CC2)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
515 mg (1.86 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride are added to a solution of 410 mg (1.55 mmol) of 3-[cyclopropyl(hydroxy)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid and 327 mg (1.55 mmol) of 5-amino-2-chloro-N-cyclopropylbenzamide in tetrahydrofuran (10 ml) and the mixture is stirred for six hours at room temperature. The reaction mixture is concentrated by evaporation, admixed with water, extracted with dichloromethane and the combined organic phases are dried over sodium sulphate. Following concentration by evaporation in vacuo, the solid is washed with dichloromethane to give 308 mg of (N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-3-[cyclopropyl(hydroxy)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15](S(C)(=O)=O)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:29])=[CH:4][CH:3]=1.[C:30]1([CH:36]2[O:41][C@H:40]3[CH2:42][C@@H:43]([OH:46])[CH2:44][O:45][C@@H:39]3[CH2:38][O:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:46][C@H:43]4[CH2:44][O:45][C@H:39]5[C@@H:40]([O:41][CH:36]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[O:37][CH2:38]5)[CH2:42]4)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: O[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-bromophenyl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (2.6 g, 5.03 mmol), (4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (1.307 g, 5.53 mmol), and cesium carbonate (4.92 g, 15.09 mmol) were dissolved in DMF (25.1 mL). The reaction mixture was stirred overnight at rt, then diluted with EtOAc and saturated NH4C/water (50:50). The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with sat. NaHCO3 and brine, then dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 100 g column by eluting with 10% EtOAc:Hexane to 70% EtOAc:Hexane to yield the desired product. LC-MS: calculated for C31H35BrClN3O5Si 671.12 observed m/e: 671.83 (M+H)+ (Rt 1.37/2 min).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:29]#[N:30])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.C[Si]([N:42]=[C:43]=[O:44])(C)C.Cl>C(Cl)Cl.CCOC(C)=O.O>[C:29]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=2)[C:20]([OH:21])=[C:11]([C:9]([NH:8][CH2:7][CH2:6][C@@H:2]([NH:1][C:43]([NH2:42])=[O:44])[C:3]([OH:5])=[O:4])=[O:10])[N:12]=1)#[N:30]
Reactant: C[Si](C)(C)N=C=O
Reactant: N#Cc1nc(C(=O)NCC[C@@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc(C(=O)NCC[C@@H](NC(N)=O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-2-Amino-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)butanoic acid (21 mg, 0.04 mmol) in CH2Cl2 (1.5 mL) was cooled to 0° C. To the solution were added triethylamine (0.05 mL, 0.32 mmol) and (trimethylsilyl)isocyanate (0.02 mL, 0.16 mmol). After stirring for 16 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid (1 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2 with 0.5% formic acid) to give the title compound in 5 mg. MS: (−) m/z 448.29 (M−1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][NH:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][N:35]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH3:34])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CNCCS(C)(=O)=O
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Agent: Cl
Product: CN(CCS(C)(=O)=O)Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 38.8 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.217 g, 0.474 mmol) was reacted with N-methyl-N-(2-methanesulphonyl-ethyl)amine (0.411 g, 3.0 mmol). Purification by silica gel chromatography, eluting with 2-3% MeOH/CHCl3, followed by trituration with ether, gave the title compound as a pale yellow solid (0.100 g, 0.184 mmol, 39%); δH [2H6]DMSO 9.84 (1H, s), 8.63 (1H, s), 8.48 (1H, s), 8.12 (1H, d), 7.78 (1H, d), 7.68 (2H, d), 7.13-7.52 (5H, m), 7.02-7.10 (3H, m), 6.55 (1H, d), 5.14 (2H, s), 3.70 (2H, s), 3.35-3.44 (2H, obscured by water), 3.05 (3H, s), 2.84 (2H, t), 2.28 (3H, s).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([C@H:16]2[CH2:19][CH2:18][C@H:17]2[C:20]([OH:22])=[O:21])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>[OH-].[Na+]>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([C@@H:16]2[CH2:19][CH2:18][C@H:17]2[C:20]([OH:22])=[O:21])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CC[C@H]1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 68 %

Procedure:
5.0 g of cis-2-[(3,5-bistrifluoromethyl phenyl)-aminocarbonyl]-cyclobutane carboxylic acid was reacted at a temperature of 50° C. for three hours in 10% aqueous caustic soda solution. The products were neutralized with dilute hydrochloric acid, extracted with ethyl acetate and then recrystallized from acetonitrile to give 3.4 g of the title compounds (yield: 68%).
Reaction SMILES: C([C:4]1(C(C)CC(O)=O)[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])C=C.C1(N=C=NC2CCCCC2)CCCCC1.C1C([N+]([O-])=O)=CC=C(O)C=1>CN(C)C=O>[NH:6]1[C:5](=[O:12])[CH2:4][C:9](=[O:10])[NH:8][C:7]1=[O:11]
Reactant: C=CCC1(C(C)CC(=O)O)C(=O)NC(=O)NC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CN(C)C=O
Product: O=C1CC(=O)NC(=O)N1
Reaction time: 8 h

Procedure:
5-Allyl-5-(β-carboxy-α-methyl-ethyl)-barbituric acid (10 mg.) was dissolved in 0.5 ml. dimethyl formamide (DMF) and was treated first with a solution of 5 mg. dicyclohexyl carbodiimide (DCC) in 0.5 ml. DMF and then with a solution of 12 mg. p-nitrophenol in 0.5 ml. DMF at 4° C. After standing overnight at this temperature, the mixture was evaporated to dryness and then dissolved in 1.5 ml. of a 1:1 mixture of glycerine-water. Bovine serum albumin (20 mg.) was added and the mixture was allowed to react for eight hours at room temperature and then overnight at 4° C. The product was then dialyzed against distilled water for two days to remove unreacted barbituric acid derivative and the p-nitrophenol which was displaced from the barbituric acid by the protein, to afford the bovine serum albumin-barbituric acid conjugate. The degree of substitution was estimated to be 2-3 moles of barbiturates per mole of protein, calculated from the extinction coefficient of the absorbtion at 202 mμ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C@H:13]1[C@:17]([CH3:22])([CH2:18][C:19]([OH:21])=[O:20])[C@@H:16]([OH:23])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2.[CH:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH2:25].CS(O)(=O)=O>C1COCC1>[CH2:27]([O:26][CH:24]([O:23][CH:16]1[CH2:15][CH2:14][CH:13]([CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[C:17]1([CH3:22])[CH2:18][C:19]([O:21][CH:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:25])=[O:20])[CH3:25])[CH2:28][CH2:29][CH3:30]
Reactant: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](O)[C@@]1(C)CC(=O)O)C2
Reactant: C=COCCCC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CCCCOC(C)OC(=O)CC1(C)C(OC(C)OCCCC)CCC1C1CCc2cc(OC)ccc2C1

Procedure:
Contacting (1S, 2S, 5S) -5-(1,2,3,4 -tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclopentaneacetic acid with butyl vinyl ether in THF containing methanesulfonic acid affords the stereochemically corresponding α-butoxyethyl 2-(α-butoxyethoxy)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-1 -methylcyclopentaneacetate, in which the ester linkage is cleaved and the carboxyl reduced to hydroxy by contacting with lithium tetrahydroaluminate (1-) in THF. From the resultant alcohol, on esterification with acid chloride or anhydride in pyridine, followed by cleavage of the ether linkage via hydrochloric acid in acetone, the corresponding mono ester of the invention wherein the ester grouping is on the ethanolic side chain eventuates. Contacting such a mono ester with acid chloride or anhydride affords a di-ester of the invention.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([OH:25])[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2].Cl[C:27]1[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)[O:25][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2]
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Reactant: CC[C@@H]1COC(c2ccc(-c3cc(O)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC[C@@H]1COC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.4 %

Procedure:
3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (272 mg, 0.79 mmol) synthesized in Example (108b) was dissolved in acetonitrile (5.0 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (220 mg, 1.14 mmol) synthesized in Example (97c) and cesium carbonate (640 mg, 1.96 mmol) were added at room temperature, followed by stirring at room temperature for 3.5 hours under nitrogen atmosphere. To this reaction solution, water (20 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (417 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CC>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[CH:3]=2)=[CH:19][CH:18]=1)([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: COc1ccc2cc(-c3ccc(C(=O)O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an 100 mL three-necked RB flask equipped with a magnetic bar, a condenser and a nitrogen gas inlet, 2-bromo-6-methoxynaphthalene (4.74 g, 20 mmol), 4-carboxybenzene boronic acid (3.50 g, 20 mmol) and 1-propanol (40 mL) were mixed and stirred at room temperature for approximately 30 min. Palladium acetate (0.014 g, 0.003 equiv., 0.06 mmol), triphenylphosphine (0.047 g, 0.009 equiv., 0.18 mmol), Na2CO3 solution (2M, 12 mL, 1.20 equiv., 24 mmol) and water (8 mL) were added and the mixture was refluxed for 1.5 h. When the mixture was still hot, 25 mL of water was added and the mixture was stirred and cooled to room temperature. The resultant crystals were filtered, washed with water and refluxed with 50 mL of acetic acid for 3–4 h. A white solid was obtained (5.08 g) and recrystallization from acetone showed the title compound as white crystals (4.63 g, 83%). mp 288–289° C. 1H NMR (500 MHz, DMSO) δ 3.90 (s, 3H), 7.2–8.3 (m, 10H), 12.99 (s, 1H). IR (KBr) ν (cm−1): 2500–3000 (COO—H, very broad, m), 1030 (OCH3, s), 1678 (C═O, s). Anal. Calcd for C18H14O3: C, 77.68; H, 5.07. Found: C, 77.56; H, 5.08.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:35][O:34][C:32](=[O:33])[NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reaction time: 24 h
Yield: 26.4 %

Procedure:
A Mixture of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.1 g 0.23 mmol), methyl chloroformate (Aldrich) (0.028 g 0.3 mmol) and potassium carbonate (0.07 g 0.05 mmol) were stirred and heated at reflux under nitrogen in acetone (10 ml) for 18 hr. Additional methyl chloroformate (0.028 g) and potassium carbonate (0.07 g) were added and heating continued for a further 24 hr. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (30 ml), dried (MgSO4) and the solvent removed. The residues were purified by SPE chromatography, elution with cyclohexane:ethyl acetate (3:1) gave the title compound as a white solid (0.03 g 26%). MH− 492
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[Br:13][C:14]1[CH:15]=[C:16]([CH2:21][NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:17]([NH2:20])=[N:18][CH:19]=1>O1CCOCC1>[Br:13][C:14]1[CH:19]=[N:18][C:17]2[NH:20][C:6](=[O:7])[N:22]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH2:21][C:16]=2[CH:15]=1
Reactant: CN1CCN(CCNCc2cc(Br)cnc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CN1CCN(CCN2Cc3cc(Br)cnc3NC2=O)CC1
Reaction time: 8 h

Procedure:
CDI (815 mg, 5.0 mmol) was added to a solution of 5-bromo-3-((2-(4-methylpiperazin-1-yl)ethylamino)methyl)pyridin-2-amine (550 mg, 1.67 mmol) in dioxane (13 mL). The reaction mixture was stirred overnight at reflux. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (10:0:0.1 to 9:1:0.1) as eluent. The title product was obtained as a yellow solid (430 mg, 72%).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[CH3:22])C1=S)C=C>ClCCl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([CH3:22])=[C:15]([NH:11][CH2:12][CH2:13][CH2:14][NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH:20]=1
Reactant: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Reactant: NC1CCC1
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1NCCCNC1CCC1
Yield: 58.5 %

Procedure:
To neat cyclobutylamine (10.0 mL) was added the hydrobromide salt of Example 8, Step B in two equal portions (2×4.3 g) 15 minutes apart at ambient temperature. The mixture was heated at reflux under nitrogen for 30 minutes, then cooled and partitioned between dichloromethane and 1N sodium hydroxide The aqueous layer was extracted with dichloromethane, the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 98:2 dichloromethane-methanol to 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.7 g, 58.5%) as a brown solid, which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)[CH2:13][CH3:14]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: CCCc1ncc[nH]1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CN(C)C=O
Product: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Temperature: 65 °C
Reaction time: 20 h
Yield: 72.3 %

Procedure:
2,6-Dichloropurine (0.38 g, 2 mmol) and 2-propylimidazole (1.32 g, 12 mmol) were dissolved in freshly distilled DMF (10 mL), and the mixture was stirred at 65° C. for 20 h. Volatiles were evaporated in vacuo, and the residue was dissolved in 0.1 N NaOH/H2O//CH2Cl2 (100 mL/50 mL). The organic phase was extracted with 0.1 N NaOH/H2O (3×50 mL). The combined aqueous phase was washed with CH2Cl2 (2×50 mL) and neutralized with CO2. The precipitated solid was filtered and washed (H2O) to give 2-chloro-6-(2-propylimidazol-1-yl)purine (0.38 g, 72%): mp 224.5-225° C.; UV (MeOH) max 215, 288 nm (∈ 25 800, 16 700), min 332, 241 nm (∈ 2500, 4500); 1H NMR (500 MHz, DMSO-d6) δ 14.04 (br s, 1H), 8.69 (s, 1H), 8.43 (s, 1H), 7.06 (s, 1H,), 3.12 (t, J=7.5 Hz, 2H), 1.72 (sext, J=7.3 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 157.3, 151.7, 150.2, 147.2, 146.6, 128.9, 122.5, 121.1, 32.4, 21.5, 14.5; HRMS m/z 262.0723 (M+[C11H11ClN6]=262.0734). Anal. Calcd for C11H11ClN6: C, 50.29; H, 4.22; N, 31.99. Found: C, 50.02; H, 4.28; N, 31.64.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[C:19]([O:24][CH2:25][CH3:26])(=[O:23])[CH:20]([CH3:22])[CH3:21].I[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([C:39]1[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[C:42]([CH3:48])=[C:41]([CH3:49])[C:40]=1[O:50][CH3:51])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.C(OC(C)C)(C)C.[Cl-].[Na+]>O1CCCC1>[CH3:51][O:50][C:40]1[C:41]([CH3:49])=[C:42]([CH3:48])[C:43]([O:46][CH3:47])=[C:44]([CH3:45])[C:39]=1[CH:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:31][CH2:30][CH2:29][CH2:28][C:20]([CH3:22])([CH3:21])[C:19]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCI)c2ccccc2)c1C
Reactant: CCOC(=O)C(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCC(c1ccccc1)c1c(C)c(OC)c(C)c(C)c1OC
Temperature: -12.5 °C
Reaction time: 0.17 h
Yield: 247.6 %

Procedure:
A 2.1 ml (3.0×1.1 mmole) portion of n-butyllithium·hexane solution was added dropwise to a solution of 0.50 ml (3.0×1.2 mmole) of diisopropylamine in anhydrous tetrahydrofuran (5 ml) under an atmosphere of argon at -20° C. over the period of 5 minutes, followed by stirring at -20 to -5° C. for 10 minutes. The mixed solution was cooled at -20° C. and a solution of 0.38 g (3.0×1.1 mmole) of ethyl isobutyrate in tetrahydrofuran (4 ml) was added dropwise to it over the period of 5 minutes, followed by stirring at -20° to -5° C. for 20 minutes. A solution of 1.36 g (3.0 mmole) of 1-iodo-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-phenylpentane in tetrahydrofuran (14 ml) was added dropwise to the mixed solution over the period of 5 minutes, followed by stirring at -20° to -10° C. for 1.5 hours. After the reaction solution was cooled with ice, the reaction was suspended by adding 1N hydrochloric acid, and isopropyl ether and sodium chloride were added to extract the product. The organic layer was separated out, washed with aqueous saturated sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to perform purification (elution with hexane/isopropyl ether) to thereby give 1.20 g (91%) of ethyl 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2,2-dimethyl-7-phenylheptanoate. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[CH:12]1[CH2:16][CH:15]=[CH:14][CH:13]=1>>[Cl:7][C:6]12[C:2]([Cl:11])([Cl:1])[C:3]([Cl:10])([C:4]([Cl:9])=[C:5]1[Cl:8])[CH:15]1[CH:16]2[CH:12]=[CH:13][CH2:14]1
Reactant: C1=CCC=C1
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Product: ClC1=C(Cl)C2(Cl)C3CC=CC3C1(Cl)C2(Cl)Cl

Procedure:
In particular, the condensation reaction is a Dieis-Alder addition of hexachlorocyclopentadiene and cyclopentadiene to yield 4,5,6,7,8,8,-hexachloro-3a,4, 7,7a-tetrahydro-4,7-methanoindene which is oxidized with selenium dioxide to 1-exo-hydroxy-4,5,6,7,8,8-hexachloro-3a,4,7,7,a-tetrahydro-4,7-methanoindene. The composition of the heptachlor-hapten was verified by physical analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].[Br:13]Br>CC(O)=O.C(OCC)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:13])[C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11]
Reactant: BrBr
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(Cl)cc1N
Temperature: 25 °C
Yield: 78.6 %

Procedure:
To a solution of 2-Amino-4-chloro-benzoic acid methyl ester (1.85 g, 10.0 mmole) in HOAc (20.0 ml) was injected bromine (0.512 ml, 10.0 mmole) dropwise. The reaction was stirred at room temperature for an hour. The mixture was diluted with ethyl ether (200 ml) and then the solvents were decanted. The residue was partitioned between ethyl acetate (200 ml) and 0.100N NaOH(aq) (200 ml). After separated the two layers, the organic layer was dried over Na2SO4, filtered and concentrated to provide the crude product (2.08 g, 78%), which was used directly for the next step without further purification. MS (ES+): 264, 266 (M+H).