Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[C:8]([C:9]([CH3:15])=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)=[N:7][O:6][CH:5]=2)[CH3:2].C(=O)(O)[O-].[Na+].[CH2:21]([OH:23])[CH3:22]>>[NH2:7][C:8]1[C:9]([CH3:15])=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:5]([O:23][CH2:21][CH3:22])=[O:6]
Reactant: CCO
Reactant: CCc1cc([N+](=O)[O-])c(C)c2nocc12
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1c(CC)cc([N+](=O)[O-])c(C)c1N
Yield: 76 %

Procedure:
A solution of 4-ethyl-7-methyl-6-nitro-anthranil (300 mg, 0.000146 mol.) in absolute ethanol was mixed with sodium bicarbonate (160 mg, 0.0019 mol.) and was refluxed for 4 hrs. The solution was evaporated to dryness, the residue partitioned between ethyl acetate and 5% hydrochloric acid solution. The organic layer was dried over magnesium sulphate and evaporated to give a solid. This solid was further purified by column chromatography (10% ethyl acetate: pet. ether 30-60) to give ethyl 2-amino-6-ethyl-3-methyl-4-nitro-benzoate as an oil (yield: 276 mg, 76%). IR (neat): 3500, 3400, 2980, 1700, 1620, 1580, 1530 cm-1. H-NMR (CDCl3): 1.20 (t, 3H, CH3), 1.40 (t, 3H, CH3), 2.18 (s, 3H, CH3) 2.78 (q, 3H, CH2), 4.40 (q, 2H, CH2O), 5.05 (br.s, 2H, NH2), 6.91 (s, 1H, ArH).
Reaction SMILES: [O:1]1[CH2:5][CH2:4]CC1.[CH:6](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:24][C:25]1[N:30]=[C:29]([CH3:31])[CH:28]=[CH:27][CH:26]=1>O.CC(C)=O>[Br:24][C:25]1[N:30]=[C:29]([CH2:31][C:5]([CH3:4])([OH:1])[CH3:6])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(Br)n1
Reactant: CC(C)NC(C)C
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C)(O)Cc1cccc(Br)n1
Reaction time: 0.58 h

Procedure:
In a nitrogen atmosphere, 400 mL of tetrahydrofuran containing 31 mL of diisopropylamine was cooled in a dry ice/acetone bath, and 82.7 mL of 2.66 M n-butyllithium/hexane solution was added thereto, and 50 mL of tetrahydrofuran containing 34.4 g of 6-bromopicoline was dropwise added thereto at −70° C. or lower. After the addition, 29.4 mL of acetone was added thereto at −60° C. or lower. After stirred for 35 minutes, water was added to the reaction liquid, and the organic solvent was concentrated under reduced pressure. This was extracted with diethyl ether, washed with saturated saline water, and dried with anhydrous magnesium sulfate. After concentrated under reduced pressure, the residue was purified through distillation to obtain 27.60 g of the entitled compound as a colorless oily substance.
Reaction SMILES: C(O)=O.[NH:4]1[CH2:7][CH:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1.CCN(CC)CC.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>CN(C=O)C>[C:22]([N:4]1[CH2:7][CH:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC1CNC1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 20 h
Yield: 39.9 %

Procedure:
A stirred solution of 131 (10.3 mmol), DMF (50 mL), and NEt3 (5.0 mL, 36.0 mmol) at 0° C. was treated with BOC2O (2.5 g, 11.3 mmol) followed by removal of the cooling bath. After 20 h, the reaction mixture was diluted with EtOAc and then washed with H2O, 5% KHSO4, sat. NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 132 (1.0 g) as a colorless oil. Rf 0.44 (silica, EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) δ 4.13 (q, J=7 Hz, 2H), 4.01 (m, 2H), 3.60 (dd, J=9 and 6 Hz, 1H), 2.88 (m, 1H), 2.61 (d, J=8 Hz, 2H), 1.44 (s, 9H) 1.25 (t, J=7H, 3H). ##STR57##
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[CH3:15])=O.[C:16]([O:20]C)(=[S:19])[NH:17][NH2:18]>C(#N)C>[O:20]=[C:16]1[NH:17][N:18]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH:8]3[CH3:15])[CH2:2][S:19]1
Reactant: COC(=S)NN
Reactant: CC1C(=O)Nc2ccc(C(=O)CCl)cc21
Solvent: CC#N
Product: CC1C(=O)Nc2ccc(C3=NNC(=O)SC3)cc21

Procedure:
1.0 g 5-(2-chloroacetyl)-1,3-dihydro-3-methyl-2H-indol-2-one, 0.37 g O-methyl thiocarbazate, and 20 ml acetonitrile were refluxed for 2 hrs. The precipitate was isolated by filtration and washed with hot acetonitrile to yield a yellowish powder, 450 mg.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)C(CC1CC1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1ccc(-c2c(C(CC3CC3)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 90 °C
Yield: 77.1 %

Procedure:
To a suspension of ethyl 2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoate (0.035 g; 0.080 mmol) in a mixture methanol-ethanol (2:1) (2.4 mL) was added a 5% sodium hydroxide solution (1.94 mL; 2.42 mmol) and the reaction mixture was heated to 90° C. for 6 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified with HCl (1N) until pH 2. The white precipitate was filtered and dried to furnish 0.025 g (76%) of the title compound as a white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([OH:24])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[Cl:33][C:34]([Cl:38])([Cl:37])[CH2:35]O>CN(C1C=CC=CN=1)C.C(Cl)Cl>[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:35][C:34]([Cl:38])([Cl:37])[Cl:33])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
A mixture of 6.2 g of dicyclohexylcarbodiimide, 7.15 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(2-carboxy-ethynyl)-cyclopropane-carboxylate, 80 mg of dimethylaminopyridine and 35 ml of methylene chloride was stirred for 10 minutes and 4.5 g of 2,2,2-trichloroethanol were added thereto. The mixture was stirred for one hour and was filtered and the filtrate was washed with N hydrochloric acid and then with water until the wash water was neutral, dried and evaporated to dryness. The 14 g of oil residue were chromatographed over silica gel and eluted with a 97-3 benzene-ethyl acetate mixture to obtain 9 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[2,2,2-trichloroethoxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 70°-71° C.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C@:6]2([C@@H:11]([O:12][C:13]([CH3:15])=[O:14])[C@:10]3([OH:32])[CH2:16][C@@:17]45[S:29][S:28]SS[C@@:21]([CH2:30][OH:31])([N:22]([CH3:25])[C:23]4=[O:24])[C:19](=[O:20])[N:18]5[C@@H:9]3[CH2:8]2)[C:4](=[O:5])[C:3]1([CH3:34])[CH3:33].S(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:1][CH:2]1[O:7][C:6]2([CH:11]([O:12][C:13]([CH3:15])=[O:14])[C:10]3([OH:32])[CH2:16][C:17]45[S:29][S:28][C:21]([CH2:30][OH:31])([N:22]([CH3:25])[C:23]4=[O:24])[C:19](=[O:20])[N:18]5[CH:9]3[CH2:8]2)[C:4](=[O:5])[C:3]1([CH3:34])[CH3:33]
Reactant: CC(=O)O[C@H]1[C@]2(O)C[C@]34SSSS[C@](CO)(C(=O)N3[C@@H]2C[C@@]12OC(C)C(C)(C)C2=O)N(C)C4=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1C2(CC3N4C(=O)C5(CO)SSC4(CC31O)C(=O)N5C)OC(C)C(C)(C)C2=O
Reaction time: 0.25 h

Procedure:
Sirodesmin B (50 mg.) in dry pyridine (1.0 ml.) was treated with thionyl chloride (0.1 ml.) for 12 minutes at 0°C., then added to iced-water (25 ml.) and left for 15 minutes. The solution was adjusted to pH 2 with 2N.sulphuric acid, then extracted with chloroform (3 × 20 ml.). The extracts were dried over sodium sulphate, then concentrated to an oil (29.4 mg.) which was essentially Sirodesmin A but contained traces of Sirodesmin B and C. The crude product was purified by preparative t.l.c. on silica gel G.F. (solvent, formic acid: methanol: chloroform, 1:4:95) to yield Sirodesmin A as an oil (12.5 mg.).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:42])[N:24]([CH2:31][CH2:32][O:33][CH2:34][CH:35]2[CH2:39][O:38]C(C)(C)[O:36]2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([Cl:43])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[Cl:43][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:31][CH2:32][O:33][CH2:34][CH:35]([OH:36])[CH2:39][OH:38])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:42]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOCC2COC(C)(C)O2)c2ccccc2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCOCC(O)CO)c1ccccc1
Reaction time: 3 h

Procedure:
A solution of [2-(3-chloro-5-{[2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-ethyl]-phenyl-carbamoyl}-phenoxy)-ethyl]-pyridin-4-yl-carbamic acid tert-butyl ester (0.037 g) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room temperature for 3 h and then the solvent removed under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.010 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([F:43])([F:42])[C:39](O)=[O:40])[CH:35]=[CH:36][CH:37]=2)[CH:25]=1.[CH2:44]([S:46]([NH2:49])(=[O:48])=[O:47])[CH3:45]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([F:42])([F:43])[C:39]([NH:49][S:46]([CH2:44][CH3:45])(=[O:48])=[O:47])=[O:40])[CH:35]=[CH:36][CH:37]=2)[CH:25]=1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(F)(F)C(=O)O)c2)n1
Reactant: CCS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC(=O)C(F)(F)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (43 mg, 0.22 mmol) is added to a stirred ice cold solution of (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-difluoro-acetic acid [100 mg, 0.21 mmol, Example 81 (a)], ethanesulfonamide (24.5 mg, 0.22 mmol) and 4-dimethylaminopyridine (26.1 mg, 0.21 mmol) in dry DCM under nitrogen. The reaction mixture is stirred at room temperature overnight at 60° C. The mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography to afford ethanesulfonic acid [2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2,2-difluoro-acetyl]-amide [35 mg, Example 81(b)]. LCMS: RT=2.31 minutes; MS: 559, 561 (M+H); 1H NMR [300 MHz, CD3OD]: □8.18 (1H, b), 8.05 (1H, b), 7.75 (1H, d, J=4 Hz), 7.5 (1H, t, J=4 Hz), 7.42 (1H, s), 7.28 (2H, q, J=4 Hz), 6.55 (1H, s), 3.95 (3H, s), 3.7 (2H, b), 3.18 (2H, q, J=4 Hz), 3.08 (2H, t, J=3.5 Hz), 1.15 (3H, t, J=4 Hz). IC50=0.1 nM
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(OCC)C>CN(C)C=O.O>[CH2:14]([O:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[CH:16]1[O:18][CH2:17]1
Reactant: ClCC1CO1
Reactant: Oc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: c1ccc2c(OCC3CO3)cccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of sodium hydride (4.0 g of 60% NaH in mineral oil, 100 mmol) in dimethylformamide (DMF, 100 ml) was treated with 1-naphthol (14.42 g, 100 mmol). After stirring for 1 hour at ambient temperature (room temperature), the reaction was treated with epichlorohydrin (10.18 g, 110 mmol) and stirred for 1 hour at 100° C. The reaction was diluted with water and transferred to a separatory funnel using diethyl ether (500 ml). The organic phase was washed with 10% aqueous NaHCO3 (3×200 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. Kugelrohr distillation (˜100 microns) yielded 1-naphthyl glycidyl ether as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 200 (M+, 61), 184 (1), 169 (5), 157 (12), 144 (79), 129 (16), 115 (100), 101 (3), 89 (16).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[Na].Br[CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO>[OH:4][CH2:3][CH2:2][S:1][CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCCCCC(CCCC(Br)CCCCCCC(=O)OCC)OC(C)=O
Reactant: OCCS
Agent: [Na]
Solvent: CO
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCO)OC(C)=O

Procedure:
2-Mercaptoethanol (31.2 g., 0.4 mole) is dissolved in a solution of sodium (9.2 g., 0.4 mole) in methanol (300 ml.). Ethyl 8-bromo-12-acetoxy-heptadecanoate (Example 1, Step E) (43.5 g., 0.1 mole) is added and the resulting solution is heated at reflux for 5 hours. Most of the methanol is then removed by evaporation in vacuo. Water (350 ml.) is added to the residue and the oily product taken up in ether, washed with water and brine and dried over sodium sulfate. Evaporation of the ether leaves the title compound as a yellow residual oil which is used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]1[CH:12]2[CH:13]3[CH:17]=[CH:16][CH:15]([CH:11]2[CH:10]=[CH:9]1)[CH2:14]3.[OH2:18]>>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:18])=[O:5].[CH2:8]1[CH:12]2[CH:13]3[CH:17]=[CH:16][CH:15]([CH:11]2[CH:10]=[CH:9]1)[CH2:14]3
Reactant: O=C1C=CC(=O)O1
Reactant: O
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: O=C(O)/C=C\C(=O)O

Procedure:
196 parts maleic anhydride, 278 parts (95% pure) dicyclopentadiene and 36 parts demineralized water were placed into a four-necked flask, and addition reaction was performed under nitrogen stream at 130° C. for 3 hours to obtain an addition product of maleic acid to dicyclopentadiene. Next, 392 parts maleic anhydride, 592 parts phthalic anhydride and 718 parts propylene glycol were added and mixed. Then the mixture was dehydrated and condensed in a widely-used manner under nitrogen stream at 200° C. for 8 hours to obtain a dicyclopentenyl-group-containing unsaturated polyester having an acid value of 25 mgKOH/g. This dicyclopentenyl-group-containing unsaturated polyester was dissolved at 80° C. in a solution in which 0.31 parts hydroquinone is dissolved in 1094 parts styrene monomer. A dicyclopentenyl-group-containing unsaturated polyester resin (III) of a viscosity of 4.5 stokes/25° C. was thus obtained.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C(N(C(C)C)CC)(C)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)#[CH:33]>[Cu]I>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:32]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([C@@H:10]4[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]4)=[CH:6][CH:5]=3)[CH:33]=2)=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N=[N+]=[N-])cc2)C1
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-n3cc(-c4ccc(F)cc4)nn3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
(S)-tert-Butyl 2-(4-azidophenyl)morpholine-4-carboxylate (76 mg, 0.25 mol) was dissolved in diisopropylethylamine (800 mg, 6.24 mmol). 1-Ethinyl-4-fluorobenzene (30 mg, 0.25 mmol) was added, followed by copper(I)-iodide (48 mg, 0.25 mmol). The mixture was stirred for 2 h at room temperature. The green mixture was concentrated on the rotavap, silica gel (0.5 g) was added and after short grinding the mixture was put on a silica gel column for purification. Flash chromatography (5 g silica gel, 10 to 30% ethyl acetate in heptane) yielded a white solid (17 mg, 16%), MS (ISP): 425.2 ([M+H]+).
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]1[CH:10]2[CH2:11][C:12]3([NH2:15])[CH2:14][CH:8]([CH2:9]2)[CH2:7][CH:6]1[CH2:13]3.[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](Cl)=[O:27])[C:20]=2[O:19][CH2:18][CH2:17]1>O>[C:12]12([NH:15][C:26]([C:25]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:21]=4[CH:22]=[CH:23][CH:24]=3)=[O:27])[CH2:14][CH:8]3[CH2:9][CH:10]([CH2:5][CH:6]([CH2:7]3)[CH2:13]1)[CH2:11]2
Reactant: O=C(Cl)c1cccc2c1OCCO2
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cccc2c1OCCO2
Yield: 25.7 %

Procedure:
200 ml of chloroform and 37.5 g of adamantamine were introduced into a balloon flask provided with an agitator and a thermometer, and then 50 g of 1,4-benzodioxane-5-carbonyl chloride was added in portions at a temperature of from 5°-10° C. After agitation at abmient temperature 1500 ml of water was added and then chloroform was removed under vacuum. The base which was precipitated by ammonia was extracted by means of methylene chloride. After removal of the solvent the residue was dissolved in hydrochloric ethanol. The crystals formed by cooling were dried off, washed and then dried. 20 g of N-(1-adamantyl)-1,4-benzodioxane-5-carboxamide was produced (M.P.: 137° C.; yield: 25%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])/[CH:5]=[N:6]/[OH:7].[Cl:14]N1C(=O)CCC1=O>CN(C)C=O>[OH:7]/[N:6]=[C:5](\[Cl:14])/[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(/C=N/O)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1cc(/C(Cl)=N/O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-3-methyl-4-nitrobenzaldehyde oxime (1.0 equiv.) in dimethylformamide, N-chlorosuccinimide (1.2 equiv.) was added in 3 portions over the period of 1 hr and the reaction mixture was stirred at r.t. for 5 hours. DMF was evaporated and the residue was diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether (60-80), to provide the title compound as a creamish solid (78%); 1H NMR (300 MHz, DMSO-d6) δ: 2.55 (s, 3H), 7.81-7.84 (d, J=8.7 Hz, 2H), 7.86 (s, 1H), 8.04-8.07 (d, J=8.4 Hz, 1H), 12.86 (s, 1H); IR (KBr) 3320, 3105, 2925, 1607, 1583, 1521, 1440, 1387, 1358, 1310, 1259, 1183, 1010, 860 cm−1.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36](Cl)(Cl)([Cl:38])[Cl:37]>>[Cl:37][C:36]([Cl:38])=[C:11]([C:8]1[CH:7]=[N:6][C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[N:10][CH:9]=1)[C:12]([F:15])([F:14])[F:13]
Reactant: CC(C)(C)c1ncc(C(=O)C(F)(F)F)cn1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)c1ncc(C(=C(Cl)Cl)C(F)(F)F)cn1

Procedure:
2-(1,1-dimethylethyl-5-trifluoroacetylpyrimidine (0.9 g) was dissolved in dry carbon tetrachloride (15 cm3) containing triphenylphosphine (2.5 g). The reaction mixture was stirred under a nitrogen atmosphere and heated at the reflux temperature for 30 hours to give a deep red-brown solution. The reaction mixture was fractioned by filtering the cooled solution through a short column of silica gel and eluting with a mixture of hexane/dichloromethane (3:1 by volume). On evaporation of the solvents the product was obtained as a colourless solid (0.9 g)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH2:9])=[O:8])[N:5]=[CH:4][CH:3]=1.CO[C:12](OC)(OC)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:12]1[NH:1][C:2]2[N:6]([N:5]=[CH:4][CH:3]=2)[C:7](=[O:8])[N:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(OC)(OC)OC
Reactant: NC(=O)n1nccc1N
Product: CCCCc1nc(=O)n2nccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 3.0 g of the product of Example 14 in 10 ml of trimethylorthovalerate is heated at 130° C. for 1 hour. The reaction mixture is cooled to room temperature and diluted with hexanes. The resulting solid is collected, washed with hexanes and dried to give 2.0 g of the desired product as a solid. M+H=193.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[CH:14]=O)[CH3:9].[C:22]([NH:25][CH2:26][C:27]([OH:29])=[O:28])(=O)[CH3:23].C([O-])(=O)C.[Na+]>O>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[CH:14]=[C:26]1[C:27](=[O:28])[O:29][C:22]([CH3:23])=[N:25]1)[CH3:9]
Reactant: CC(=O)NCC(=O)O
Reactant: CCOc1ccc(C=O)cc1OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOc1ccc(C=C2N=C(C)OC2=O)cc1OCC
Yield: 45 %

Procedure:
To acetic anhydride (193 ml) are added 3,4-diethoxybenzaldehyde (234.4 g), N-acetylglycine (95.4 g) and sodium acetate (49.5 g), and the mixture is heated under reflux for one hour, and the reaction mixture is allowed to stand for cooling. The reaction mixture is further allowed to stand in a refrigerator overnight, and then thereto is added water. The mixture is extracted with chloroform, and the extract is washed, dried and concentrated. The residue is crystallized from ethanol to give 4-(3,4-diethoxybenzylidene)-2-methyloxazol-5(4H)-one (100.9 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[Li].BrC1C(F)=CC=CC=1F>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[C:18]([F:17])=[CH:23][CH:22]=[CH:21][C:20]=2[F:24])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: [Li]c1c(F)cccc1F
Agent: Fc1cccc(F)c1Br
Product: CCSc1ncc(C(=O)c2c(F)cccc2F)c(N)n1
Yield: 70 %

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (200 mg, 0.830 mmol, Example 1) and a solution of 2,6-difluorophenyl lithium (˜3 equiv, freshly prepared from 1-bromo-2,6-difluorobenzene (Aldrich), as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,6-difluoro-phenyl)-methanone as a white solid (170 mg, 70% yield). HRMS, observed:296.0667; Calcd for (M+H)+: 296.0664.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][NH:18][CH3:19]>CCO>[CH3:17][N:18]([CH3:19])[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CNC
Solvent: CCO
Product: CN(C)CC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), N-methylmethanamine (2.0 M in MeOH, 0.50 ml, 1.0 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 271 (M+, 1), 77 (4), 59 (4), 58 (bp), 51 (3).