Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:10][S:11][C:12]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:10][S:11][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)nsc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Temperature: 100 °C

Procedure:
Starting material 9 (1.12 g) is dissolved in DME (12 ml) and to this are added 439 mg of 10, water (5 ml) and 954 mg of Na2CO3. The mixture is degassed with argon for 5 min. Pd(dppf)Cl2 (121 mg) is added, the tube is sealed and the reaction mixture is heated at 100° C. in the microwave for 15 min. TLC (Hep/EtOAc, 80/20) shows a good conversion into a slower moving spot. The reaction mixture is diluted with EtOAc and washed with water and brine. The organic layer is dried and concentrated. The residue is purified by flash column chromatography using 5% diisopropyl ether in heptane as eluent. Isothiazole 11 is obtained in good yield as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].I[CH2:33][CH2:34][O:35][CH2:36][CH2:37]I.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: ICCOCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.4 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1-iodo-2-(2-iodoethoxy)ethane (1.2 g, 3.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]2[NH:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[N:3]1.[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22](F)[CH:23]=2)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]1)[CH3:14]>N1C=CC=CC=1>[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:9]3[CH2:10][CH2:11][NH:12][CH:7]([C:4]4[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=4)[CH2:8]3)[CH:23]=2)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]1)[CH3:14]
Reactant: Cn1ccc(C2CNCCN2)n1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccn(C)n4)C3)cc21

Procedure:
A 1.0 g portion of 3-(1-methyl-1H-pyrazol-3-yl)piperazine and 508 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid were dissolved in 5 ml of pyridine and heated at 85°-95° C. for 18 hours, in a pressure bottle which had been evacuated and filled with argon. Methanol was added and the solid collected, giving 610 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-(1-methyl-1H-pyrazol-3-yl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]2[C:9]3[C:14]([N:15]=[C:16]4[C:21]=2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:9]3[C:14]([N:15]=[C:16]4[C:21]=2[CH:20]([OH:22])[CH2:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:23][CH:24]=1
Reactant: Cc1ccc(CNc2c3c(nc4ccccc24)CCCC3=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CNc2c3c(nc4ccccc24)CCCC3O)cc1
Temperature: 0 °C

Procedure:
3,4-Dihydro-9-(4-methylbenzylamino)acridin-1(2H)-one (5.71 g) was dissolved in 100 ml of dry THF, chilled with ice-water, and then 9.0 ml of 1M lithium aluminum hydride in THF was added. After 15 minutes the reaction was quenched by the sequential addition of 0.4 ml of water, 0.4 ml of 15% sodium hydroxide, and 1.2 ml of water. The inorganic salts were filtered off and washed with warm THF and then the combined organic phase was evaporated and the residue recrystallized from dichloromethane-pentane to obtain 4.77 g of analytically pure product, mp 176°-178° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])[CH3:2].[I:14]N1C(=O)CCC1=O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([I:14])[C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ccc(N)nc1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(I)c(N)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To a solution of 2,6-diamino-nicotinic acid ethyl ester described in Preparation Example A-14 (1.4 g, 7.7 mmol) in N,N-dimethylformamide (15 mL) was added N-iodosuccinimide (2.09 g, 9.3 mmol), and the solution was stirred for 1 hour at room temperature. The reaction mixture was poured into an aqueous solution of saturated sodium thiosulfate pentahydrate, and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and the title compound (0.84 g, 2.7 mmol, 35.5%) was obtained.
Reaction SMILES: CC(S([NH:7][C:8]1([CH:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[N:18]=2)[CH3:13])[CH2:11][O:10][CH2:9]1)=O)(C)C.Cl.C(=O)([O-])O.[Na+]>CO.O1CCOCC1>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([CH:12]([C:8]3([NH2:7])[CH2:9][O:10][CH2:11]3)[CH3:13])[NH:15][CH:16]=2)=[CH:20][CH:21]=1
Reactant: CC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(NS(=O)C(C)(C)C)COC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(c1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1)C1(N)COC1
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 2-methyl-N-[3-(1-{4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}-ethyl)oxetan-3-yl]propane-2-sulfinamide (Preparation 9, 0.320 g, 0.74 mmol) in methanol (4 mL) at 0° C. was added 4M hydrogen chloride in 1,4-dioxane (4 mL) and the reaction left to stir for 2 hours. Solid sodium hydrogen carbonate was added to the reaction, followed by a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.243 g, 91% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].C1(C2C=CC=CC=2)C=CC=CC=1.ClCCC(Cl)=O.ClCCC(C1C=CC(C2C=CC=CC=2)=CC=1)=O.C[Mg]I.BrCCC(C1C=CC=CC=1C1C=CC=CC=1)(O)C.C1(C)C=CC(S(OCCC(C2C=CC=CC=2C2C=CC=CC=2)(O)C)(=O)=O)=CC=1.[CH3:103][NH2:104]>CO>[CH3:103][NH:104][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5]
Reactant: CN
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Agent: CC(O)(CCBr)c1ccccc1-c1ccccc1
Agent: C[Mg]I
Agent: Cc1ccc(S(=O)(=O)OCCC(C)(O)c2ccccc2-c2ccccc2)cc1
Solvent: CO
Solvent: c1ccc(-c2ccccc2)cc1
Product: CNCCC(C)(O)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.6 g of 1-chloro-3-p-biphenylylbutan-3-ol [m.p. 68° - 70°; obtainable by a Friedel-Crafts reaction of biphenyl with 3-chloropropionyl chloride to give 4-(3-chloropropionyl)-biphenyl and reaction with CH3MgI; or 3.05 g of 1-bromo-3-p-biphenylyl-butan-3-ol or 3.96 g of 1-p-toluenesulfonyloxy-3-p-biphenylyl-butan-3-ol] and 30g of methylamine in 100 ml of methanol is heated at 120° for 2 hours in an autoclave. After cooling and working up in the customary manner, 1-methylamino-3-p-biphenylyl-butan-3-ol is obtained.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4N(C)N=C(C)C=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:39])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[CH3:23])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[CH3:39]
Reactant: Cc1ccc(N)cc1O
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 29, 70 mg, 0.217 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (32 mg, 0.260 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜2 mL of i-prOH affording the title compound in 69% yield (0.064 g, 0.1497 mmol).
Reaction SMILES: C(Cl)(Cl)=O.ON=C(C(OCC)=O)C(OCC)=O.CN(C)C1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][OH:34])=[CH:31][CH:30]=1.Cl[C:38]([O:40][N:41]=[C:42]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:39].Cl>C1C=CC=CC=1.O.N1C=CC=CC=1>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:34][C:38]([O:40][N:41]=[C:42]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:39])=[CH:31][CH:30]=1
Reactant: COc1ccc(CO)cc1
Reactant: CCOC(=O)C(=NOC(=O)Cl)C(=O)OCC
Agent: CCOC(=O)C(=NO)C(=O)OCC
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOC(=O)OCc1ccc(OC)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzene (20 ml.) was added to a solution of phosgene 2.5 g.) in benzene (11.4 ml.). A solution of diethyl 2-hydroxyiminomalonate (4.73 g.) and N,N-dimethylaniline (3.03 g.) in benzene (30 ml.) was added dropwise to the solution over 40 minutes at 5° C in a nitrogen stream. The mixture was stirred for 1 hour at the same temperature and overnight at room temperature. A solution of 4-methoxybenzylalcohol (3.11 g.) and pyridine (4.04 ml.) in benzene (30 ml.) was added dropwise to the resultant mixture containing diethyl 2-chlorocarbonyloxyiminomalonate over a period of 40 minutes at 5° C. The mixture was stirred for 2 hours at the same temperature, for 3 hours at room temperature and allowed to stand overnight. Cold water (100 ml.) was added to the reaction mixture to dissolve an insoluble material and cooled 1N-hydrochloric acid (20 ml.) was added thereto, after which the mixture was shaken. The organic layer was then washed 3 times with 1N hydrochloric acid (20 ml.), 3 times with a 5% sodium carbonate aqueous solution (20 ml.) and a sodium chloride aqueous solution, and then dried over magnesium sulfate. After drying, the solvent was distilled off to give diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (6.89 g.), a pale brown oil, which was solidified on standing at ambient temperature.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@@H:25]2[C:29]([CH3:31])([CH3:30])[CH2:28][O:27][C:26]2=[O:32])[CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@@H:25]2[C:29]([CH3:30])([CH3:31])[CH2:28][O:27][C:26]2=[O:32])[CH2:14]1)=[O:11]
Reactant: CC1(C)COC(=O)[C@@H]1N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)COC(=O)[C@@H]1N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
Dimethylsulfoxide (0.121 mL, 1.7 mmol) was added to a solution of oxalyl chloride (0.07 mL, 0.8 mmol) in 10 mL of CH2Cl2 at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 20 min., then a solution of dihydro-3-(R)-(3-(R)-(hydroxymethyl)-4-(S)-(3-fluorophenyl)-pyrrolidin-1-yl)-4,4-dimethyl-2(3H)furanone (200 mg, 0.65 mmol) in 1 mL of CH2Cl2 was added. The mixture was stirred at −78° C. for an additional 45 min., then triethylamine (0.46 mL, 3.3 mmol) was added and the cold bath was removed. After the reaction mixture had warmed to room temperature, it was diluted with CH2Cl2 and washed with 1N NaOH and brine. The solution was dried over Na2SO4, filtered and concentrated to afford 100 mg (50% yield) of the title compound. 1H NMR (400 MHz, CDCl3). δ1.17 (s, 3H), 1.24 (s, 3H), 3.08-3.24 (m, 4H), 3.35 (t, 1H, J=8.4 Hz), 3.55 (dd, 1H, J=5.9, 9.6 Hz), 3.66 (dd, 1H, J=7.9, 16 Hz), 3.91 (d, 1H, J=9.0 Hz), 3.98 (d, 1H, J=9.0 Hz), 6.95-6.97 (m, 1H), 7.04 (dt, 1H, J=2.1, 10 Hz), 7.10 (d, 1H, J=7.8 Hz), 7.27-7.32 (m, 1H), 9.71 (d, 1H, J=2.0 Hz). ESI-MS. M/z; (M+H)=306.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:24]C1C(Cl)=NC(Cl)=NC=1.NC1C=C(O)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([Br:24])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(Br)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine and 3-aminophenol were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.99 (bs, 1H), 9.34 (bs, 1H), 8.30 (s, 1H), 7.15 (t, 1H, J=8.4 Hz), 7.06-6.97 (m, 2H), 6.94-6.92 (m, 2H), 6.80 (bs, 1H), 6.62 (s, 1H, J=8.1 Hz), 6.43 (d, 1H, J=7.8 Hz); LCMS: ret. time: 18.48 min.; purity: 97%; MS (m/e): 374 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([CH2:19]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([CH2:19][Cl:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2ccccc2)c2c1OCCO2
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(OCc2ccccc2)c2c1OCCO2
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a solution, cooled to -10° C., of 10 g (0.037 mole) of 5-benzyloxy-8-hydroxymethyl-1,4-benzodioxane (XIp), code number 760 701, in 100 ml of chloroform were slowly added 4.6 g (0.039 mole) of thionyl chloride. They were left in contact for 15 minutes, then the solvents were evaporated, the residue was taken up in chloroform, washed with a solution of sodium bicarbonate, dried and the solvent was evaporated. 10.4 g of unstable product were obtained which, after checking by chromatography on a thin silica layer, was used in the synthesis of the compound of formula (XIm), code number 770 119.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[C:34](O)=[O:35])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])=[CH:27][CH:28]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Product: COc1ccc(-c2ocnc2C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)cc1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS (basic): tR=1.31 min; [M+H]+=476.1.
Reaction SMILES: [C:1]1([N:7]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:34]1[CH:39]=[N:38][C:37]([Br:40])=[CH:36][N:35]=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>[Br:40][C:37]1[N:38]=[CH:39][C:34]([C:4]2[CH:3]=[CH:2][C:1]([N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)=[N:35][CH:36]=1
Reactant: Brc1cnc(Br)cn1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: Brc1cnc(-c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)cn1
Temperature: 85 °C
Yield: 70.4 %

Procedure:
A mixture of N-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)naphthalen-1-amine (Compound 7) (2.91 g, 6.91 mmol), 2,5-dibromopyrazine (3.56 g, 13.8 mmol), Pd(PPh3)4 (0.346 g, 0.3 mmol), K2CO3 (1.93 g, 14 mmol) in dioxane/water (80 mL/15 mL), was degassed and heated at about 85° C. overnight. The resulting mixture was diluted with ethyl acetate (250 mL), washed with brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 4:1 to 2:1 to 3:2). The desired fraction was collected, after removal of solvent to give a yellow solid (Compound 8) (2.2 g, in 70.4% yield).
Reaction SMILES: C(O[CH:4]=[C:5]([S:11]([CH3:14])(=[O:13])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=1>ClC1C=CC=CC=1>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([NH:22][CH:4]=[C:5]([S:11]([CH3:14])(=[O:12])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:20][CH:21]=1
Reactant: CCOC=C(C(=O)OCC)S(C)(=O)=O
Reactant: Nc1ccc(Cl)nc1
Solvent: Clc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(Cl)nc1)S(C)(=O)=O
Temperature: 135 °C
Yield: 84.1 %

Procedure:
A mixture of ethyl 3-ethoxy-2-(methylsulfonyl)acrylate (7.0 g, 32 mmol) and 2-chloro-5-aminopyridine (4.1 g, 32 mmol) in chlorobenzene (16 mL) was stirred with heat at 135° C. for 3 h in a round bottomed flask that was equipped with a short path distillation apparatus to collect the ethanol generated during the reaction. The reaction was cooled, concentrated and the residue was purified by chromatography (silica, methylene chloride/ethyl acetate) to afford the desired product (8.2 g, 84%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 10.61 (d, 13.4 Hz, 1H), 8.34 (d, J=13.4 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 7.50 (dd, J=8.6, 3.0 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.18 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); ESI MS m/z 305 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(#N)N(C)C>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)cc1
Solvent: CN(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(-c2ccc(CBr)cc2)cc1)c1ccc(Cl)cc1Cl
Yield: 89.3 %

Procedure:
A mixture of 5.0 g of 2,4-dichlorophenyl 4'-methyl-4-biphenylyl ketone, 2.7 g of N-bromosuccinimide and 20 mg of azaisobutyronitrile in 70 mL of carbon tetrachloride was heated to boiling under reflux for 4 hours. The precipitated material was filtered off and the filtrate was evaporated. The residue was recrystallized from toluene/cyclohexane. There were obtained 5.5 g (89%) of 2,4-dichlorophenyl 4'-bromomethyl-4-biphenylyl ketone as a colorless solid with a m.p. of 92° C.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:5]OS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)[CH2:4][O:3]1.[OH:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[NH:28][C:29](=[O:31])[CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:27][O:26][C:24]1[CH:23]=[CH:22][C:21]([NH:28][C:29](=[O:31])[CH3:30])=[C:20]([O:19][CH2:1][C@:2]2([CH3:5])[CH2:4][O:3]2)[CH:25]=1
Reactant: COc1ccc(NC(C)=O)c(O)c1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(C)=O)c(OC[C@]2(C)CO2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (2.04 g, 7.46 mmol), N-(2-hydroxy-4-methoxyphenyl)acetamide ((1.04 g, 5.74 mmol) and Cs2CO3 (2.80 g, 8.61 mmol) in DMF (12 mL) was kept on stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (ethyl acetate:hexane 1:1) to give the subtitled compound (1.19 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]#[N:5].C(=NO)C=CC1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>O1CCCC1.O>[CH3:25][S:26]([O:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]#[N:5])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(C=Cc1ccccc1)=NO
Agent: ON=CC=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(C#N)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
3.44 g (0.02 mol) of 2-hydroxyimino-4-phenyl-but-3-enenitrile, (mp 127-129° C., prepared from cinnamaldoxime according to C. Trione et al, J. Org. Chem. 1993, 58, 2075) are dissolved in 20 ml of anhydrous tetrahydrofuran and cooled to 0° C. Methanesulfonyl chloride (1.7 ml, 0.022 mol) is added at once, followed by triethylamine (4.2 ml, 0.03 mol) dropwise over 15 min, keeping the temperature of the mixture at 5° C. The mixture is then stirred at 25° C. for two hours, and poured into 150 ml of iced water. The off-white precipitate is washed with ether, dried and recrystallyzed from 70 ml of ethanol, yielding 2.74 g (55%) of 2-methylsulfonyloxyimino-4-phenyl-but-3-enenitrile as colorless crystals, mp. 144-148° C. No attempt is made to recover more material from the ether extract.