Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[CH:36])#[N:29]>CN(C)C=O.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>[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[C:36][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[N:29]
Reactant: C#CCCCCCC#N
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 199.3 %

Procedure:
Under argon, to a solution of 2-iodoadenosine (200 mg, 0.51 mmol) and bis(triphenylphosphine)palladium dichloride (36 mg, 10 mol %) dissolved in N,N-dimethylformamide (5 mL), triethylamine (0.09 mL, 0.61 mmol, 1.2 eq.) and 7-cyano-1-heptyne (74 mg, 0.1 mmol, 1.2 eq.) were added, and, under ice-cooling conditions, cuprous iodide (10 mg, 5 mol %) was added thereto, followed by stirring at 60° C. for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by dry packed silica gel column chromatography (chloroform:methanol=10:1), to thereby yield the above-titled compound as a pale yellow powder (yield: 77 mg, percent yield: 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:14][CH2:13][C:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][S:10][C:11]=1[C:15]([F:16])([F:18])[F:17])(=[O:29])=[O:28]
Reactant: OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (80 mg, 0.27 mmol, 1.00 equiv), dichloromethane (2.0 mL), triethylamine (83 mg, 0.82 mmol, 3.01 equiv). This was followed by the addition of MsCl (62 mg, 0.54 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 30° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.12 g of [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a yellow solid. This crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C12H9ClF3NO3S2, 372.0 (M+H). found 372.0.
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][SH:26])[CH3:22].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][S:26][CH2:1][CH:2]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])[CH3:22]
Reactant: CCN(CC)CCS
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Product: CCN(CC)CCSCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The oil prepared in Step 10 (1.5 g, 5.95 mmol) is dissolved under argon in methanol (22 mL). To this solution is added 2-diethylaminoethanethiol hydrochloride (1 g, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol) , and the mixture is stirred at room temperature for 16 hours. The solvent is removed on a rotary evaporator and then the residue is purified by flash chromotography on silica gel to give the pure title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>[Ni].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(Cl)c(Cl)c2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CCc2ccc(Cl)c(Cl)c2)cc1
Yield: 86.2 %

Procedure:
4-[2-(3,4-dichlorophenyl)ethenyl]nitrobenzene (34.0 g, 116 mmol) and 2 g of Raney nickel in 510 ml of tetrahydrofuran were shaken under hydrogen at 15 psi (103.4 kPascal) until four equivalents of hydrogen were consumed. The catalyst was removed by filtration, and the resulting filtrate evaporated in vacuo to yield a residual tan solid. Recrystallization from hexane yielded 26.6 g (86%) of 4-[2-(3,4-dichlorophenyl)ethyl]benzenamine, mp 72°-74° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([Cl:20])[CH:10]=2)[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28][C:27]=2[CH:35]=1>>[Cl:20][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:24]=[CH:25][C:26]4[O:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28][C:27]=4[CH:35]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]([F:19])([F:18])[F:17]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)c(Cl)c1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC(F)(F)F)c(Cl)c4)n3)ccc2O1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.99 (bs, 1H), 9.49 (bs, 1H), 8.18 (d, 1H, J=4.5 Hz), 8.08 (t, 1H, J=2.4 Hz), 7.81-7.74 (m, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.42 (s, 1H), 7.20 (d, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.7 Hz), 5.36 (m, 1H), 3.80-3.47 (m, 4H), 3.20 (dd, 1H, J=6.0 and 16.5 Hz); LCMS: purity: 100%; MS (m/e): 500 (MH+).
Reaction SMILES: [CH2:1]([C:5]1C=CC=C[C:6]=1[OH:11])[CH2:2]CC.[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Cl)(Cl)(Cl)=O>C(Cl)CCl>[CH3:12][NH:13][C:14](=[O:15])[O:11][CH2:6][CH2:5][CH2:1][CH3:2]
Reactant: CCCCc1ccccc1O
Reactant: CCOC(=O)NC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)NC

Procedure:
To a solution of 2-sec butylphenol (1.5 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) in ethylene dichloride (6 ml) was added phosphoryl chloride (0.77 g, 0.05 mole) and the reaction mixture was refluxed under stirring for twenty hours. It was poured onto ice-cold water. The organic layer separated and aqueous layer was extracted with dichloroethane. The combined organic layer was washed with water, dried (Na2SO4) and distilled to give liquid residue, which was further purified by distillation to give 2-sec butyl N-methylcarbamate of the formula (III) [96% by GLC, DV-101 (3%), 150° C., nitrogen, 30 ml/min.] as a liquid, b.p. 110° C. (vap.)/4 mm; IR: 3320 (N--H), 1730 (--COO--), 1535,1490 and 750 (aromatic); PMR (CDCl3, 90 MHz): 0.81 (3H,t, primary methyl of side chain, 1.58 (2H, m, methylene protons of side chain), 2.88 (4H, doublet overlapping a multiplet, NH--CH3 and benzylic proton), 4.97 (1H, br s, N--H) and 6.95 to 7.25 (4H, m, aromatic).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl.[O:40]([NH2:42])[CH3:41]>O1CCCC1>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:42][O:40][CH3:41])=[O:31])[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CON
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)n3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NOC)n3)ccc21
Temperature: 25 °C
Yield: 21.5 %

Procedure:
Similarly to Production example 27-2, a crude product of phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyrimidyl)carbamate (546 mg, 1.31 mmol, 56.3%) was obtained as pale brown powder from N1-ethyl-5-(2-amino-4-pyrimidyl)oxy-1H-1-indolecarboxamide (691 mg, 2.32 mmol) and phenyl chlorocarbonate. The crude carbamate product (273 mg, 0.65 mmol) was dissolved in tetrahydrofuran (7.0 ml); and triethylamine (0.91 ml, 6.53 mmol) and methoxylamine hydrochloride (273 mg, 3.27 mmol) was added thereto while stirred at room temperature. After the reaction mixture was stirred overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:1). The crystals were precipitated from ethyl acetate-hexane (1:10), filtered off, and dried under aeration to yield the title compound (52.5 mg, 0.14 mmol, 21.7%) as white crystals.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=1>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[C:19]([CH3:24])[CH:18]=1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(N)c(C)c1
Product: COc1ccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(C)c1
Yield: 46.5 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (2.0 g) and 4-methoxy-2-methylaniline (1.29 g) to give the title compound as a white solid (1.37 g).
Reaction SMILES: Cl[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[K+].Cl.C(O)(C(F)(F)F)=[O:18]>O.O.CO>[OH:18][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Yield: 66 %

Procedure:
To a 250 mL flask were added 3-chloro-2-nitrobenzoic acid (10 g, 49.6 mmol) and a potassium hydroxide solution (40 g, 727 mmol) in water (70 mL). The thick slurry was heated to reflux for 12 hours. The solution was cooled in ice and cautiously brought to pH 3 with concentrated HCl. The aqueous mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The crude product mixture was dissolved in dichloromethane and the resulting yellow precipitate was filtered to afford Intermediate A-15A (6 g, 32.8 mmol, 66.0% yield). HPLC: RT=0.85 min (H2O/MeOH with TFA, Sunfire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=206 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.56-7.35 (m, 1H), 7.23 (dd, J=7.9, 1.5 Hz, 1H).
Reaction SMILES: O.NN.[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([N+:22]([O-])=O)=[CH:17][C:16]=2[CH3:25])[CH:11]=[CH:12][CH:13]=1)([CH3:7])[CH3:6]>C(O)CC.[Pd]>[CH3:7][C:5]([C:8]1[CH:9]=[C:10]([O:14][C:15]2[C:16]([CH3:25])=[CH:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])[CH3:6]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(C)(C)C)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCCO
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N
Temperature: 90 °C

Procedure:
Hydrazine hydrate (4.3 ml) is added dropwise to a mixture of 1-{[3-(1,1-dimethylethyl)phenyl]oxy}-2,5-dimethyl-4-nitrobenzene (8.65 g) and 5% palladium-on-charcoal (100 mg) in n-propanol (60 ml) heated to 90° C. The reaction mixture is maintained at 90° C. for 2 h and then filtered through Celite. Concentration gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:11]([OH:13])=O)[CH2:7][C@H:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OC(N1C[C@H](O)C[C@H]1C(=O)N[C@@]1(C(OCC)=O)C[C@@H]1C=C)=O)(C)(C)C>>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C@:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][C@H:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Reactant: COC(=O)C1=C[C@@H](O)C[C@H]1C(=O)O
Agent: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C

Procedure:
Reaction of compound 63 (50 mg, 37 mmol) with (1R,2S)-1-amino-2-vinyl-cyclo-propane carboxylic acid tert-butyl ester according to the method described for the preparation of 59 provided the title compound as a slightly yellow oil (50 mg, 38%).
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7](O)[C@H:5]([OH:6])[C@H:3]1O.[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][C@H:17]1[O:19][C@H:7]([CH2:5][O:6][C:11](=[O:12])[CH3:9])[C@@H:9]([O:10][C:2](=[O:1])[CH3:3])[C@H:11]([O:12][C:5](=[O:6])[CH3:7])[C@H:18]1[O:10][C:2](=[O:1])[CH3:3])(=[O:15])[CH3:14]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 88 %

Procedure:
Analogously, as described in the synthesis of title compound Aa), the reaction of 100 g (555.0 mmol) of α-D-glucopyranose with a mixture of 1000 ml of absolute pyridine and 1000 ml of acetic acid anhydride after working-up and recrystallization from 95% aqueous ethanol yields 190.6 g (88.0%) of the above-mentioned title compound as a colorless and crystalline compound. By 1H-NMR-spectroscopic study of the title compound that is thus obtained, it was possible to determine the α to β-ratio of two possible anomers with ≧98:2. Accordingly, the title compound is the exclusively α-configured anomer.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[O:5][C@H:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C@@H:3]1[CH2:24][CH2:25][N:26]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]=[N:27]1.[O:37]1CCCC1.I([O-])(=O)(=O)=O.[Na+].[K]>C(O)(C)(C)C>[CH:6]([O:5][C@H:4]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C@H:3]([CH2:24][CH2:25][N:26]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]=[N:27]1)[C:2]([OH:37])=[O:1])=[O:7]
Reactant: C1CCOC1
Reactant: COc1ccc(-c2ccc(CC[C@H]3O[C@@H](O)[C@@H](O)[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1
Agent: [K]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Product: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the compound obtained from step d above (8 g) in tert-butanol:tetrahydrofuran (40 mL:40 mL) at 0° C., a solution of sodium metaperiodate (14 g in 40 mL of water) was added. The reaction mixture was stirred for 2 hours at the same temperature, and potassium permangnate (518 mg) was added at 0° C. After stirring the reaction mixture for an additional 6 hours at room temperature, the reaction mixture was evaporated on a rotary evaporator. The residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under the reduced pressure, to afford the title compound (8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28]>>[OH:28][NH:27][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:16][C:17]#[CH:18]
Reactant: NO
Reactant: C#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Product: C#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 25 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 m, 10 mmol), 0.065 g of the product was isolated. Yield 25%; off-white solid; mp 70° C.; MS: 375.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.19 (brs, 1H), 2.90-3.00 (m, 2H), 3.55 (d, J=13.8 Hz, 1H), 3.67 (d, J=13.8 Hz, 1H), 3.89 (s, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.80-7.89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm−1): 3168m, 3095s, 1670m, 1593s.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:25][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][C:6]1=O)C.C(O)(=O)C.Cl.[C:32]([NH:36][NH2:37])([CH3:35])([CH3:34])[CH3:33]>C(O)C>[C:32]([N:36]1[C:6]2[CH:7]=[CH:8][C:9]3([CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:13][CH2:14]3)[CH2:25][C:5]=2[CH:4]=[N:37]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CN(C)C=C1CC2(C=CC1=O)CCN(C(=O)OCc1ccccc1)CC2
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)n1ncc2c1C=CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Benzyl 10-((dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (59.2 g, 167 mmol) was dissolved in ethanol (835 mL). To the solution was added acetic acid (20 mL, 345 mmol) and tert-butylhydrazine hydrochloride (29.1 g, 234 mmol). The reaction was heated to reflux for 1 hour. The reaction was cooled to room temperature and concentrated to an orange oil. Purification by flash column chromatography (20-40% ethyl acetate/heptanes) afforded the title compound (50 g, 79%) as a pale yellow solid. +ESI (M+H) 380.5; 1H NMR (400 MHz, CDCl3, δ): 7.26-7.40 (m, 5 H), 7.17 (s, 1 H), 6.66 (d, J=9.95 Hz, 1 H), 5.77 (d, J=10.15 Hz, 1 H), 5.12 (s, 2 H), 3.38-3.64 (m, 4 H), 2.58 (s, 2 H), 1.60 (s, 12 H), 1.50 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.[Mg].[C:11]([CH:13]1[CH2:15][CH:14]1[C:16](N(OC)C)=[O:17])#[N:12]>C(OCC)C.BrC(Br)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:16]([CH:14]1[CH2:15][CH:13]1[C:11]#[N:12])=[O:17]
Reactant: CON(C)C(=O)C1CC1C#N
Reactant: Fc1ccc(Br)c(Cl)c1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC1CC1C(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 24.0 g (115 mmol) of 2-chloro-4-fluorobromobenzene in 20 ml of diethyl ether was added dropwise to 2.92 g (120 mmol) of magnesium turnings in 780 ml of diethyl ether, activated by adding a few drops of dibromoethane, and the reaction mixture was heated under reflux overnight. The reaction solution was added dropwise under argon to a solution of 17.7 g (68.8 mmol) of the compound from Example 73A in 300 ml of THF, and the reaction mixture was stirred initially at RT overnight and then under reflux for 8 h. It was concentrated and taken up in ethyl acetate and saturated aqueous ammonium chloride solution, the phases were separated, and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.20 g (14% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11](=[O:29])[NH:12][C:13]3[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[O:18])=[CH:15][CH:14]=3)[CH:7]=[CH:6][C:5]=12.[Cl:30]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:30][C:3]1[N:4]2[CH:9]=[C:8]([NH:10][C:11]([NH:12][C:13]3[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[O:18])=[CH:15][CH:14]=3)=[O:29])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C(Nc1ccc(C(=O)NCC2CCCCO2)cc1)Nc1ccc2nccn2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(C(=O)NCC2CCCCO2)cc1)Nc1ccc2ncc(Cl)n2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(3-imidazo[1,2-a]pyridin-6-ylureido)-N-((tetrahydro-2H-pyran-2-yl)methyl)benzamide (0.016 g, 0.041 mmol) in chloroform (0.813 ml) was treated with N-chlorosuccinimide (5.70 mg, 0.043 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under a stream of nitrogen and purified using normal phase chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1H), 9.02 (s, 1H), 8.89-8.85 (m, 1H), 8.35 (t, J=5.8 Hz, 1H), 7.85-7.79 (m, 2H), 7.69-7.60 (m, 2H), 7.58-7.52 (m, 2H), 7.19 (dd, J=9.5, 2.0 Hz, 1H), 3.91-3.83 (m, 1H), 3.46-3.19 (m, 4H), 1.80-1.73 (m, 1H), 1.66-1.57 (m, 1H), 1.49-1.36 (m, 3H), 1.26-1.09 (m, 1H); MS (ESI(+)) m/e 428 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]#[N:24]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:22][C:23]#[N:24])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCC#N)c1csc(N)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
54 g of ethyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dissolved in 500 ml of dimethylformamide. After the addition of 138 g of potassium carbonate, there are added dropwise within 1 hour 47 ml of chloroacetonitrile and the mixture is then stirred at room temperature for 20 hours. The dark solution obtained is poured into ice-water and extracted with ethyl acetate. The organic phase is washed with water, treated with active carbon, dried over magnesium sulphate and concentrated. After recrystallization from toluene, there are obtained 38 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetate of melting point 167°-168° C.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:9]=1[OH:21])#[N:7].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([C:31]12[CH2:38][CH2:37][C:34]([CH2:39]Br)([CH2:35][CH2:36]1)[CH2:33][CH2:32]2)[CH2:29][CH3:30]>O>[C:6]([C:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:9]=1[O:21][CH2:39][C:34]12[CH2:35][CH2:36][C:31]([CH2:28][CH2:29][CH3:30])([CH2:38][CH2:37]1)[CH2:32][CH2:33]2)#[N:7]
Reactant: CCCCCc1ccc(O)c(C#N)c1C#N
Reactant: CCCC12CCC(CBr)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCc1ccc(OCC23CCC(CCC)(CC2)CC3)c(C#N)c1C#N
Temperature: 80 °C
Reaction time: 48 h

Procedure:
50 ml of dimethylformamide were added to 0.04 mole of 2,3-dicyano-4-pentylphenol, 0.2 mole of potassium carbonate and 0.04 mole of 4-propyl-1-bicyclo(2,2,2)-octylmethyl bromide. The mixture was stirred at 80° C. for 48 hours. The mixture was then cooled to room temperature and poured into 200 ml of water and the organic phase was extracted. The organic extract was washed with water and dried over magnesium sulfate. After the solvent had been evaporated off, the crude product was recrystallized several times. The pure product has a high melting point of 133.1° C. and a negative DCA.