Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH2:27]([SH:31])[CH2:28][CH2:29][SH:30].B(F)(F)F>>[S:30]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2][S:31][CH2:27][CH2:28][CH2:29]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: SCCCS
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCCCS4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.3 mmol) with 1,3-propanedithiol (0.330 mmol), BF3.etherate (catalytic) in tetrahydrofuran (10 ml) at 70-80° C. for 14 hours followed by silica gel column chromatographic purification to provide title compound in 50% yield.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[C:5]([OH:7])=[O:6].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[C:5]([O:7][CH2:12][CH3:13])=[O:6]
Reactant: CCI
Reactant: CC(C)(CF)C(=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C(C)(C)CF
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a solution of 4-fluoro-3,3-dimethyl-2-oxobutanoic acid (2.3 g, 15.53 mmol) in DMF (30 mL) was added iodoethane (1.880 mL, 23.29 mmol) and K2CO3 (5.36 g, 38.8 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc and stirred for 10 min. The solid was filtered. The filtration was partitioned between EtOAc and water. The organic phase was washed water, sat. NaCl, and concentrated. The residue was diluted with hexane (˜100 mL) and washed with water (2×30 mL), dried over MgSO4, filtered and concentrated to yield ethyl 4-fluoro-3,3-dimethyl-2-oxobutanoate (2.3 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:25])=[C:14]([C:16](=[O:24])[NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:15]=2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[NH2:25][C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:26])=[O:2])=[CH:9][CH:8]=2)=[CH:15][C:14]=1[C:16](=[O:24])[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1

Procedure:
190 mg of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid methyl ester are dissolved in 20 ml of MeOH. 175 mg Na2CO3 in 6 ml of water are added.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Li+].Cl[CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[N:18][C:17]=1[CH2:16][S:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: O=S([O-])c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C(F)(F)F)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A mixture of lithium 4-(trifluoromethyl)benzenesulfinate (700 mg, 3.24 mmol, 1.72 equiv, 100%), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (500 mg, 1.89 mmol, 1.00 equiv) and potassium carbonate (0.35 g) in N,N-dimethylformamide (25 mL) was stirred overnight at 70° C. The reaction mixture was cooled to room temperature then quenched by the addition of 60 mL of water and ice. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to yield 0.7 g (85%) of methyl 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a white solid. LC-MS: (ES, m/z): 481 [M+CH3CN+H]+, 440 [M+H]+, 271, 146, 105.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[N+:17](=[CH:19][CH3:20])=[N-:18]>CCOCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[C:19](=[N+:17]=[N-:18])[CH3:20])=[CH:10][CH:9]=1
Reactant: CC=[N+]=[N-]
Reactant: O=C(Cl)c1ccc(Oc2ccccn2)cc1
Solvent: CCOCC
Product: CC(=[N+]=[N-])C(=O)c1ccc(Oc2ccccn2)cc1

Procedure:
To a solution of 4-(2-pyridyloxy)benzoyl chloride in ether, a solution of diazoethane in ether is added dropwise, and the reaction is effected as in Example 8 (2) to give 4-(2-pyridyloxy)-1-(2-diazopropionyl)benzene (4.72 g). This substance is recrystallized from ethyl acetate to give crystals melting at 101° to 102°C (decomp.). IR (CCl4): 2070, 1630, 1590 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][CH3:15])=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26])(=[O:21])=[O:20].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]([CH3:15])[C:25](=[O:26])[C:24]3[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=3)=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1
Reactant: CNc1cnncc1-c1ccc(F)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1cnncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 26.7 %

Procedure:
To a solution of 5-(4-fluoro-2-methoxyphenyl)-N-methylpyridazin-4-amine (27 mg, 116 μmol) in dichloromethane (1 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.4 mg, 232 mmol) and N,N-diisopropylethylamine (60 mg, 80.9 μL, 463 μmol). The clear, light brown solution was stirred at room temperature for 1.75 h and then poured on saturated aqueous ammonium chloride solution and dichloromethane and the layers were separated. The aqueous layer was extracted three times with dichloromethane. The organic layers were dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to give the desired compound as a light brown solid (15 mg; 25%). MS (ESI+): m/z=483.09 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: NCC/C=C\c1cccc(Cl)c1
Agent: O=[Pt]=O
Solvent: CO
Product: NCCCCc1cccc(Cl)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
To a solution of (Z)-4-(3-chlorophenyl)but-3-en-1-amine (1.80 g, 9.91 mmol) in methanol (30 mL) was added platinum(IV) oxide (0.18 g, 0.79 mmol), and to the resulting stirred mixture at ambient temperature was fitted a balloon of hydrogen. The flask was purged and refilled five times with hydrogen, and the resulting mixture was stirred at ambient temperature under a balloon of hydrogen for 1 hour. The catalyst was removed by filtration through a glass microfibre filter, and the filtrate was concentrated to afford 4-(3-chlorophenyl)butan-1-amine as a light yellow oil (1.78 g, 98% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]3[CH:27]=[CH:26][O:25][C:22]=3[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]5[O:25][CH:26]=[CH:27][C:21]=5[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc3ccoc3cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc3occc3cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:49][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(S(=O)(=O)CC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(S(=O)(=O)CC)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-ethanesulfonyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C36H53N4O4SCl2 [(M+H)+] 763.2152, observed 763.2150.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3Cl)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[CH:30]=[CH2:31])[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1ncnc2c1ncn2[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Yield: 67.2 %

Procedure:
To a solution of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-9H-purine (330 mg, 0.74 mmol) and tributyl(vinyl)stannane (0.26 mL, 0.88 mmol) in 1,2 dichloroethane (10 mL) was added Pd(Ph3P)2Cl2 (26 mg, 0.03 mmol) and the r×n mixture was heated at reflux overnight. The solvent was removed and the residue purified by flash chromatography (0 to 20% EtOAc/hexanes) to yield 215 mg (67%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([Br:25])=[CH:4][N:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:25])[C:6]=3[S:10][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(Br)cnc(N)c23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2csc3c(Br)cnc(N)c23)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of Example 76B (0.5 g, 1.1 mmol) in TFA (4 mL) and dichloromethane (5 mL) was stirred at 0° C. for 5 minutes, warmed to room temperature for 2 hours, then concentrated. The residue was dissolved in dichloromethane, washed with brine, dried (Na2SO4), filtered, and concentrated to provide 0.332 g of the desired product. MS (ESI(+)) m/e 321 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([S:19][CH3:20])[C:16]([Cl:21])=[CH:15][C:14]=1[OH:22].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:22][C:14]2[CH:15]=[C:16]([Cl:21])[C:17]([S:19][CH3:20])=[CH:18][C:13]=2[Cl:12])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reactant: CSc1cc(Cl)c(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CSc1cc(Cl)c(Oc2cc(Cl)nc(Cl)c2)cc1Cl
Reaction time: 3 h

Procedure:
Quantities of 19.3 gm (0.1 mol) of 2,6-dichloro-4-nitropyridine and 23.1 gm (0.11 mol) of 2,5-dichloro-4-methylmercaptophenol were dissolved in 100 ml of acetone, 13.8 gm (0.1 mol) of K2CO3 were added, and the resulting mixture was stirred for 3 hours under reflux. It was then stirred into 500 ml of water, and the precipitate formed was recovered by suction filtration.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:14])[NH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15]C1(Br)C(=O)NC(=O)NC1=O>O1CCCC1>[Br:15][CH2:2][C:1]([C:4]1[C:5](=[O:14])[NH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Reactant: CC(=O)c1ccc(C(C)(C)C)[nH]c1=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)CBr)c(=O)[nH]1
Yield: 71.7 %

Procedure:
To a tetrahydrofuran (5.0 mL) solution of 3-(acetyl)-6-tert-butylpyridin-2(1H)-one (0.50 g), 5,5-dibromobarbituric acid (0.41 g) was added, and the resultant was heated to reflux for 2 hours. A deposit formed during the course of concentration of the reaction solution under reduced pressure was filtered to obtain the title compound (0.28 g) as a light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11](C(O)=O)=[N:12][CH:13]=1)([O-:3])=[O:2].C1(P([N:34]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:34])=[N:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Nc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
A mixture of 5-(3-nitrophenoxy)pyridine-2-carboxylic acid (10.4 g, 40.0 mmol), diphenylphosphoryl azide (10.8 mL, 50.0 mmol), triethylamine (6.92 mL, 50.0 mmol) and tert-butanol (200 mL) was stirred at room temperature for 3 hr, and then stirred with heating under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (20 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (70 mL) was added to the residue, and the mixture was stirred with heating under refluxing conditions for 3 hr. After extraction with ethyl acetate (×3), the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (5.80 g, 63%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([NH2:15])=[N:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](O)(=O)[CH3:31]>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[N:15]=[C:30]([CH3:31])[O:14][N:13]=2)[CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: NC(=NO)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(OCc3ccccc3)c(OCc3ccccc3)c([N+](=O)[O-])c2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3,4-bis-benzyloxy-N′-hydroxy-5-nitro-benzamidine (1.0 g, 2.54 mmol) in dimethylformamide (5 mL) at room temperature was added 1,1-carbonyldiimidazole (0.494 g, 3.048 mmol) in one portion and the mixture was stirred at room temperature for ninety minutes. Thereupon, acetic acid (0.184 g, 3.067 mmol) was added dropwise and the mixture was allowed to stir for two hours at room temperature, then at 155° C. for three hours. The mixture was allowed to cool to room temperature, and poured onto ice-water (100 mL). Brine (10 mL) was added and the resulting precipitate was removed by filtration, washed with water and dried in air. The solid was then dissolved in dichloromethane (20 mL) and a spatula tip of activated charcoal was added. After stirring for twenty minutes, the suspension was filtered through celite and the filtrate was evaporated to leave a yellow oil that solidified on standing. After recrystallisation from dichloromethane/petroleum ether, 3-(3,4-bis-benzyloxy-5-nitrophenyl)-5-methyl-[1,2,4]oxadiazole was obtained as a pale yellow solid (0.537 g, 51%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1.[N:19]1([CH2:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>Cl.C(O)(C)C>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[N:7][C:2]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:25]([CH2:24][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:26]=2)=[N:3][CH:4]=1
Reactant: NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: CC(C)O
Product: NC(=O)c1ccccc1Nc1nc(Nc2cccc(CN3CCCC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]benzamide (200 mg, 0.6 mmol) and 3-(1-pyrrolidinylmethyl)aniline (134mg, 0.75 mmol) were combined in a vessel with 5 mL isopropanol and 2 drops of 12N HCl. The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with isopropanol to give 178 mg (65% yield) of an orange solid as the HCl salt. MS: M(C22H23ClN6O)=422.92, (M+H)+=423 and 425.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:46]([CH3:58])=[N:47][O:48][C:49]=2[C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][C:51]=2[OH:57])=[CH:41][CH:40]=1.C(OCC)(=O)C>ClCCl>[Br:1][C:54]1[CH:55]=[C:50]([C:49]2[O:48][N:47]=[C:46]([CH3:58])[C:45]=2[C:42]2[CH:41]=[CH:40][C:39]([O:38][CH3:37])=[CH:44][CH:43]=2)[C:51]([OH:57])=[CH:52][C:53]=1[OH:56]
Reactant: [Br-]
Reactant: COc1ccc(-c2c(C)noc2-c2ccc(O)cc2O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2c(C)noc2-c2cc(Br)c(O)cc2O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyltrimethylammonium tribromide (3.95 g, 10 mmol) was added portion-wise to an ice cooled suspension of 4-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzene-1,3-diol (Example 1) (2.95 g, 10 mmol) in dichloromethane (50 ml) and the mixture stirred for ˜60 mins, at room temperature. Ethyl acetate (300 ml) was added and the mixture washed with water (3×200 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale brown solid. Crude product was purified by column chromatography, on silica, eluting with ethyl acetate/hexane (1:2), to give 4-bromo-6-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzene-1,3-diol as a white solid, dried in vacuo, (3.42 g)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>>[N:18]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: c1cn[nH]c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(-n2cccn2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (74 mg, 0.285 mmol) and pyrazole (28 mg, 0.425 mmol) similar to Example 166 and was isolated as a white solid (mp 151–152° C., 67 mg, 0.230 mmol, 81%). 1H NMR (CDCl3) 9.71 (s, 1H), 8.77 (m, 3H), 8.19 (s, 1H), 7.88 (m, 1H), 7.47 (m, 1H), 6.61 (dd, J=1.5, 2.7 Hz, 1H).
Reaction SMILES: O[CH2:2][CH:3]([CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1.C(Br)(Br)(Br)[Br:34].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Br:34][CH2:2][CH:3]([CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(CO)CCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(CBr)CCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(9-(9-Hydroxy-8-methylnonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 283, step b) (100 mg), carbon tetrabromide (143 mg) and imidazole (30 mg) were dissolved in DCM (5 mL). The solution was cooled to 0° C. and a solution of triphenylphosphine (85 mg) in DCM (1 mL) was added dropwise. The reaction mixture was stirred at this temperature for 1 hour then at room temperature for 2 hours. A further amount of carbon tetrabromide (150 mg) was added, the mixture cooled to 0° C. and triphenylphosphine (114 mg) in DCM (1 mL) added dropwise. Stirred at room temperature for 1 hour then water was added and the phases separated. The organic phase was evaporated and the product purified by silica gel chromatography eluting with 0-10% methanol in DCM to afford the subtitled compound as an orange gum. Yield 0.088 g.
Reaction SMILES: O=[C:2]([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Br[C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:2]1[C:3]([OH:5])=[O:4]
Reactant: Nc1cccnc1Br
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc2ncccc2[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.22 mL 2-oxo-propionic acid, 0.26 g palladium acetate and 3.20 mL triethylamine were added to a solution of 1.00 g 2-bromo-pyridin-3-yl amine and 1.21 g triphenyl-phosphine in 10 mL N,N-dimethylformamide. The reaction mixture was stirred for 4 hours at 100° C. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel with dichloromethane/methanol as eluent. Yield: 260 mg MS(ES+): m/e=163.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:27][C:28]1([C:33]2([CH:36]=O)[CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30][O:29]1>>[CH:36]([C:33]1([C:28]2([CH3:27])[O:29][CH2:30][CH2:31][O:32]2)[CH2:34][CH2:35]1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC1(C2(C=O)CC2)OCCO1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCC=CC1(C2(C)OCCO2)CC1

Procedure:
1.93 g of hexyltriphenylphosphonium bromide and 900 mg of aldehyde 7 are reacted analogously to 193., and 879 mg of title substance 203 is obtained as a colorless oil (1:3 E,Z mixture that cannot be separated).