Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([N:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Fc1ccc(Nc2ccc(Cl)c(Cl)c2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N(c2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
Sodium hydride (0.19 g, 60% in oil) was added to 10 ml of dimethyl sulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 1.0 g of (3,4-dichlorophenyl)-(4-fluorophenyl)amine was added to the mixture and stirred at 60° C. for one hour. A DMSO solution containing 2.0 g of 3-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture and stirred at 60° C. for 15 hours. Ethyl acetate was added to the reaction solution. The solution was then washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The eluent solvent was distilled off under reduced pressure to thereby obtain 0.29 g of oily brown 3-[(3,4-dichlorophenyl)-(4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([O:14][CH3:17])=[O:13])=[O:7])=[CH:15][CH:16]=1
Reactant: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(Br)cc1
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
Step 2 To a solution of trans-2-(4-bromobenzoyl)cyclobutanecarboxylic acid (8.2 g, 28.94 mmol) in MeOH (250 mL) was added 2,2-dimethoxypropane (3.65 g, 35.02 mmol) and HCl (4.0 M in dioxane) (2.0 mL). The resulting solution was stirred at rt for 3 days, and then evaporated to dryness. The resulting residue was purified with flash chromatography (Biotage Flash 40M) using 4 to 11% ethyl acetate in hexanes to afford methyl trans-2-(4-bromobenzoyl)cyclobutanecarboxylate (6.21 g, 78%). 1H NMR (400 MHz, CD2Cl2) δ 2.14-2.39 (m, 4H), 3.62 (m, 1H), 3.68 (s, 3H), 4.24 (m, 1H), 7.63 (m, 2H), 7.80 (m, 2H).
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:43])[N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]3)[CH3:31])[CH:23]=2)=[C:19]([F:46])[CH:18]=1.[F:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][C:55]([N:57]=[C:58]=[S:59])=[O:56])=[CH:50][CH:49]=1>C(O)C>[CH3:41][N:40]([CH3:42])[CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]([CH3:31])[C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:20]3[CH:44]=[CH:45][C:17]([NH:16][C:58]([NH:57][C:55](=[O:56])[CH2:54][C:51]4[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=4)=[S:59])=[CH:18][C:19]=3[F:46])[N:27]=[CH:26][N:25]=2)=[O:43])[CH2:33][CH2:34]1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.6 %

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (101 mg) to a solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (110 mg) in ethanol (2.0 ml), the mixture was stirred for 15 minutes at room temperature. After adding 2-(4-fluorophenyl)acetyl isothiocyanate (3.06 ml, 0.25 M solution in toluene) thereto, the mixture was further stirred at room temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate (10 ml) and ethyl acetate (30 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated. Diethyl ether:hexane=1:1 was added to the obtained solid to produce a suspension. The precipitate was filtered and then washed with diethyl ether to provide the title compound (50.5 mg, 31.6%) as pale yellow powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[F-:14].[K+]>CC(C)=O.O.CCOC(C)=O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([S:10]([F:14])(=[O:12])=[O:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(C2CC2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)(F)c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
Crude compound 45 (13.3 g) was dissolved in 200 mL of acetone and 60 mL of water. Potassium fluoride (7.12 g, 122 mmol) was added and the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried with Na2SO4, filtered, and concentrated to dryness to give 9.80 g (97%) of crude p-cyclopropyl benzenesulfonyl fluoride (Compound 46).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>O1CCCC1>[CH3:13][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCOCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCOCC1
Reaction time: 3 h
Yield: 91.8 %

Procedure:
Into a 500-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl tetrahydro-2H-pyran-4-carboxylate (8 g, 50.6 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of LDA (50 mL, 101.1 mmol, 2M in THF) dropwise at −78° C. and stirred for 3 h. To this was added a solution of CH3I (9.5 mL, 151.9 mmol) in tetrahydrofuran (50 mL) dropwise at −78° C. The reaction mixture was stirred for 3 h at −78° C., then carefully quenched with 400 mL of NH4Cl (sat.). The aqueous phase was extracted with 300 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 8 g (92%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][C:14]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[N:24]=[C:6]2[CH2:5][O:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:36].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][C:14]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15][CH:16]=4)[N:11]=[C:10]([NH2:36])[C:9]=3[N:24]=[C:6]2[CH2:5][O:4][CH2:3]1
Reactant: [NH4+]
Reactant: C[C@H]1COCc2nc3cnc4cc(CCS(C)(=O)=O)ccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1COCc2nc3c(N)nc4cc(CCS(C)(=O)=O)ccc4c3n21
Temperature: 25 °C

Procedure:
A 200-mL, round-bottomed flask was charged with (11S)-11-methyl-3-[2-(methylsulfonyl)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (0.45 g, 1.31 mmol) and CH2Cl2 (75 mL). The mixture was stirred at ambient temperature and MCPBA (0.45 g, 50% purity) was then added slowly in portions. The reaction was stirred at ambient temperature for 2 hours. Concentrated aqueous NH4OH solution (25 mL) was then slowly added to the reaction mixture followed by careful addition of p-toluenesulfonyl chloride (0.27 g, 1.44 mmol). The reaction was stirred rapidly at ambient temperature overnight. The reaction was then treated with H2O (100 mL) and vigorous stirring was maintained for 2 hours. The layers were then separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid that was crystallized from acetonitrile to give 0.12 g of (11S)-11-methyl-3-[2-(methylsulfonyl)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a white, crystalline solid, mp 205-206° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.[CH2:21]([NH:28][C:29]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=[C:31](Cl)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1>[CH2:21]([NH:28][C:29]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=[C:31]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1cnc(Cl)nc1NCc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
A 5 ml NMP solution of 352 mg of 4-morpholinoaniline was mixed with 0.95 ml of 4 M hydrogen chloride/1,4-dioxane solution and 400 mg of 4-benzylamino-2-chloropyrimidine-5-carboxamide, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled down to room temperature, and then the precipitate was collected by filtration. The collected solid was mixed with saturated sodium bicarbonate aqueous solution and extracted with a mixed solution of THF-ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was crystallized by adding methanol and then recrystallized (methanol-THF) to obtain 264 mg of 4-benzylamino-2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidine -5-carboxamide as colorless crystals.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:25][C@H:26]1[C:34]2[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:32][CH:31]=[N:30][C:29]=2[C@H:28]([OH:41])[CH2:27]1.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([CH2:53][NH:54][CH2:55][C:56]([OH:59])([CH3:58])[CH3:57])[C:50](O)=[O:51])=[CH:45][CH:44]=1.C(Cl)Cl>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([C@@H:49]([CH2:53][NH:54][CH2:55][C:56]([OH:59])([CH3:57])[CH3:58])[C:50]([N:38]2[CH2:37][CH2:36][N:35]([C:33]3[C:34]4[C@H:26]([CH3:25])[CH2:27][C@@H:28]([OH:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:40][CH2:39]2)=[O:51])=[CH:47][CH:48]=1
Reactant: CC(C)(O)CNC[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@H](CNCC(C)(C)O)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.100 g, 0.265 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (31 mg, 0.13 mmol), N,N-diisopropylethylanine (0.231 mL, 1.32 mmol) and (S)-2-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropylamino)propanoic acid (43 mg, 0.16 mmol) in methylene chloride (1.2 mL, 19 mmol). The mixture was stirred for 1 hour at room temperature, after which the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted with DCM (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by reverse phase HPLC to give (S)-2-(4-chlorophenyl)-3-(2-hydroxy -2-methylpropylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (33 mg, 51%). 1HNMR (CDCl3, 500 MHz) δ 8.59 (s, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 5.06 (m, 1H), 4.48 (m, 1H), 3.92 (m, 2H), 3.15 (m, 2H), 2.94 (m, 2H), 2.02 (m, 2H), 1.19 (m, 6H), 1.06 (d, 3H). LCMS M+1 488.3
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].[CH2:31](I)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:31]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:28])=[O:2])[CH2:14][CH2:15]2)=[CH:20]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCI
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 0.119 g (0.31 mmol) of 2-(2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester, 0.022 g (0.52 mmol) of NaH in 60% of mineral oil and 0.058 mL (0.41 mmol) of hexyl iodide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.047 g (34% of yield) of the desired product.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4].ClCCl.C(N(CC)CC)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O>[C:44]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4])(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)ccc1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)c2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 0.025 g of tert-butyl {1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate (Example 36b) and 0.8 ml of dichloromethane is admixed successively with 0.006 ml of triethylamine and 0.007 ml of benzoyl chloride and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.74 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.01 (gradient I).
Reaction SMILES: [NH2-:1].[Na+].[CH3:3][N:4]1[CH2:8][CH:7](O)[CH2:6][N:5]1[CH3:10].[C:11]1(S(Cl)(=O)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH:1]([CH:7]1[CH2:8][N:4]([CH3:3])[N:5]([CH3:10])[CH2:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [NH2-]
Reactant: CN1CC(O)CN1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CC(Nc2ccccc2)CN1C
Reaction time: 4.5 h

Procedure:
A stirred suspension of 40 g. (1.02 mole) of sodamide in dry toluene was treated dropwise with 116 g. (1.0 mole) of 1,2-dimethyl-4-pyrazolidinol at 80° C. After 4.5 hrs. at reflux the mixture was cooled and maintained below 20° C. while 161.0 g. (1.0 mole) of benzenesulfonyl chloride was added dropwise. After stirring 1.0 hr. the reaction mixture was shaken with dilute sodium hydroxide, the separated toluene layer dried over sodium sulfate and concentrated at reduced pressure. The residue was dissolved in 300 ml. of aniline, the mixture heated 2.5 hrs. on the steam bath and refluxed for 3.0 hrs. The cooled mixture was extracted with dilute sodium hydroxide solution and the separated aqueous layer extracted with isopropyl ether. The combined organic layers after drying over sodium sulfate were concentrated and the residue distilled to a pot temperature of 140° C./80 mm. The residue which would not crystallize was distilled at 110°-125° C./0.1 mm. to give 86 g. of product.
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6][OH:7].N([Cl:14])=O.CC[O:17][CH2:18]C>>[CH3:18][O:17][C:10]1[CH:11]=[CH:3][C:4]([C:5]([Cl:14])=[N:6][OH:7])=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: COc1ccccc1C=NO
Reactant: O=NCl
Product: COc1ccc(C(Cl)=NO)cc1

Procedure:
By the method of Example I-B, 43.6 g of methoxybenzaldoxime in 510 ml of ether was treated with 21.0 g of nitrosyl chloride. After removal of the ether, the product oil was triturated with benzene-hexane and crystallized from benzene-hexane. The filtrate from the crystallization was concentrated to about one-third of its original volume and placed in the refrigerator. The solid which formed and the first crop of crystals were combined and recrystallized from hexane-ether to give 13.2 g of 4-methoxybenzohydroximoyl chloride, m.p. 87.5°-89.5°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(C(F)(F)F)cc3)c(-c3ccc(C(F)(F)F)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 29.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-trifluoromethylphenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 g, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 12 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (15 mg, 0.038 mmol) as a yellow solid. MS: [M+H]+=394.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[NH:17][C:18]1[C:19](=O)[CH2:20][CH2:21][CH2:22][CH:23]=1)([CH3:7])[CH3:6]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:4])/[N:3]=[C:19]1\[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]\1[NH:17][C:9]1[C:10]([CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=[CH:13][C:8]=1[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)c1cccc(C(C)C)c1NC1=CCCCC1=O
Reactant: CN(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC1=CCCC/C1=N\N(C)C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Follow a procedure similar to that of Example C except use toluene (12 mL); 1,1-dimethylhydrazine (0.81 mL, 10.6472 mmol); a solution of titanium(IV) chloride (0.2011 g, 1.0600 mol) in toluene (5 mL); stir for 1 hour; then add 2-(2,6-diisopropylphenylamino)cyclohex-2-enone (0.4889 g, 1.8014 mmol, Preparation 3); followed by 1 mL of rinse toluene; stir the resulting reaction mixture overnight; to give after isolation 0.5222 g (92.5%) of the product (K) as a yellow oil containing about 7% of a minor isomeric product.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].[C:14](Cl)(=[O:17])[CH2:15][CH3:16].C(N(CC)CC)C>CC(C)=O>[CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:14](=[O:17])[CH2:15][CH3:16])(=[O:3])=[O:4]
Reactant: CCC(=O)Cl
Reactant: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O
Reaction time: 20 h
Yield: 46.3 %

Procedure:
To a stirred solution of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (1.25 g, 0.005 mol) and propionyl chloride (3.20 g, 0.035 mol) in dry acetone (20 mL), triethylamine (0.014 mol) was added dropwise at room temperature. A precipitate was formed immediately. After an additional 20 h, the reaction mixture was filtered and the filtrate evaporated in dryness in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed with dilute hydrochloric acid (3×15 mL), followed by water (2×10 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated to dryness in vacuo. The residue was triturated with petroleum ether to give a solid which, on recrystallization from absolute ethanol, afforded 0.71 g (46.4%) of the title compound: mp 97°-98° C.; 1H NMR (acetone-d6) δ 3.8-4.2 (m, 4 H, CH2CH2), 3.5 and 3.3 (2 s, 6 H, 2 CH3SO2), 2.8 (q, 2 H, COCH2), 1.1 (t, 3 H, COCCH3). Anal. (C7H15C1N2O5S2) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: Oc1c(Cl)cc(Cl)cc1I
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCNCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A solution of 2,4-Dichloro-6-iodo-phenol [2040-83-7] (2.0 g, 6.9 mmol), 4-Methoxyphenylacetylene (0.91 g, 6.9 mmol), PdCl2P(PH3)2 (0.15 g), and Cul (50 mg) in DMF/Diethylamine (26 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH, filtered to give 85 as a solid (0.80 g, 42%): Mp=1.72–174° C.; 1H NMR (CDCl3) δ 7.82 (d, 2 H, J=8.1 Hz), 7.41 (d, 1 H, J=1.8 Hz), 7.24 (d, 1 H, J=1.9 Hz), 7.00 (d, 2 H, J=8.8 Hz), 6.84 (s, 3 H), 3.87 (s, 3 H); MS 293/295 [M+H]+
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][O:11]1)=[O:10].[CH:19](=[O:21])[CH3:20]>O1CCCC1>[OH:21][CH:19]([CH:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:9](=[O:10])[O:11]1)[CH3:20]
Reactant: O=C1OCc2ccccc21
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1OC(=O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A dry tetrahydrofuran solution (100 mL) of lithium diisopropyl amide (26.9 mmol) was cooled to −78 degree in a current of nitrogen, and a tetrahydrofuran solution (100 mL) of phthalide (3.0 g, 22.4 mmol) was dripped in. After stirring at −78° C. for 30 minutes, acetaldehyde (1.19 g, 26.9 mmol) was slowly added and stirred at −50° C. for 4 hours. After the temperature had risen to room temperature, distilled water was added and the mixture extracted with ethyl acetate. The organic phase was washed with distilled water and saturated brine, and dried with anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/6), and the target compound (1.96 g, 49%) was obtained as a yellow oily residue.