Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[NH:7][C:6]2=[O:14].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>C(#N)C>[C:15]1([CH:2]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[NH:7][C:6]3=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1nc[nH]n1
Reactant: O=c1[nH]c(=O)c2cc(C(Cl)c3ccccc3)ccc2[nH]1
Solvent: CC#N
Product: O=c1[nH]c(=O)c2cc(C(c3ccccc3)n3cncn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A mixture of 5.8 parts of 6-(chlorophenylmethyl)-2,4(1H,3H)-quinazolinedione, 10 parts of 1H-1,2,4-triazole and 158 parts of acetonitrile was stirred for 1 hour at room temperature and for 2 hours at reflux temperature. The solvent was evaporated and the residue was washed with water. The precipitate was filtered off and purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the first fraction was evaporated and the residue was washed with ethyl acetate and dried, yielding 2.2 parts (34.1%) of 6-[phenyl(1H-1,2,4-triazol-1-yl)methyl]-2,4(1H,3H)-quinazolinedione; mp. 280.9° C. (comp. 40).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:39])[CH:19]([C:24]1[CH:29]=[C:28](O)[CH:27]=[C:26]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=1)[CH2:20][C:21]([CH3:23])=[CH2:22].N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:39])[CH:19]([C:24]1[CH:29]=[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:27]=[C:26]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=1)[CH2:20][C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)CC(C(=O)OC)c1cc(O)cc(OCc2ccccc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.7 %

Procedure:
Trifluoromethanesulfonic anhydride (3.3 mL, 10.1 mmol) was added dropwise to a stirred solution of 2-(3-benzyloxy-5-hydroxyphenyl)-4-methyl-pent-4-enoic acid methyl ester (4.5 g, 13.8 mmol) and pyridine (3.0 mL, 38.7 mmol) in DCM (80 mL) at 0° C. then warmed to room temperature. After 1 h, the mixture washed with 1M HCl (50 mL), dried (MgSO4) and concentrated in vacuo to afford the title product as an orange oil (6.10 g, 96%). 1H-NMR (400 MHz, CDCl3): δ 7.42-7.30 (m, 5H), 6.97 (s, 1H), 6.85 (s, 1H), 6.78 (s, 1H), 5.05 (s, 3H), 4.75 (s, 1H), 4.64 (s, 1H), 3.77 (t, 1H), 3.66 (s, 3H), 2.77 (dd, 1H), 2.40 (dd, 1H), 1.69 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[Cl:9][C:10]1[CH:15]=[C:14]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccc(Cl)c2)ncn1
Temperature: 125 °C
Yield: 91.4 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), 3-chlorophenylboronic acid (0.489 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in a mixture of DME/EtOH/water (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (30-70% ethyl acetate in hexanes) to afford: 6-(3-chlorophenyl)pyrimidin-4-amine (0.47 g, 2.286 mmol, 91% yield) as a yellow solid. LCMS R.T.=1.45; [M+2H]+=208.05.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:78])[CH2:15][C@@H:16]([NH:67]C(OCC1C=CC=CC=1)=O)[CH2:17][CH2:18][CH2:19][NH:20][C:21]([C@H:23]1[NH:41][C:40](=[O:42])[C@H:39]([CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[NH:38][C:37](=[O:54])[C@@H:36]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:35][C:34]2[CH:63]=[C:30]([CH:31]=[CH:32][C:33]=2[OH:64])[C:29]2=[CH:65][C:25](=[C:26]([OH:66])[CH:27]=[CH:28]2)[CH2:24]1)=[O:22])C1C=CC=CC=1>[Pd].C(O)(=O)C.O.C(O)C>[C:50]([O:49][C:47](=[O:48])[NH:46][CH2:45][CH2:44][CH2:43][C@@H:39]1[NH:38][C:37](=[O:54])[C@@H:36]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:35][C:34]2[CH:63]=[C:30]([CH:31]=[CH:32][C:33]=2[OH:64])[C:29]2=[CH:65][C:25](=[C:26]([OH:66])[CH:27]=[CH:28]2)[CH2:24][C@@H:23]([C:21]([NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH2:67])[CH2:15][C:14]([NH:13][CH2:12][CH2:11][NH2:10])=[O:78])=[O:22])[NH:41][C:40]1=[O:42])([CH3:51])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)NC1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)NCCC[C@H](N)CC(=O)NCCN)NC1=O
Reaction time: 15 h

Procedure:
12 mg (0.011 mmol) of benzyl(2-{[(3S)-3-{[(benzyloxy)carbonyl]amino}-6-({[(8S,11S,14S)-14-[(tert-butoxycarbonyl)amino]-11-{3-[(tert-butoxycarbonyl)amino]propyl}-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-8-yl]carbonyl}amino)hexanoyl]amino}ethyl)carbamate (Example 190A) are added into 3 ml of a 4:1:1 acetic acid/water/ethanol mixture. 1.5 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated at RT under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr and washed with ethanol, and the filtrate is concentrated on a rotary evaporator in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1C=O)[CH3:2].[O-][CH2:28]C.[Na+].Cl>C(=O)(OCC)OCC.C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:28]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(OCC)cc2)cc1C=O
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C1=Cc2cc(-c3ccc(OCC)cc3)ccc2OCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 4-[(4′-ethoxy-3-formyl-1,1′-biphenyl-4-yl)oxy]butyric acid ethylester (0.50 g) in diethyl carbonate (5 ml) was added a solution of 20% sodium ethoxide in ethanol (0.57 g) at room temperature, and the mixture was then heated to 50° C. and stirred for 1 hour. The solution was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed, and concentrated. The concentrate was purified by silica gel chromatography (n-hexane/ethyl acetate=10/1) and subsequent concentration of the appropriate eluate gave white crystal of the title compound (0.39 g, yield 82%).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:32]([O:34][C:35](=[O:40])[CH2:36][C:37]([O-:39])=O)[CH3:33].FC(F)(F)C(O)=O.[CH3:48][O:49][C:50]1[CH:70]=[CH:69][C:53]([O:54][C:55]2[CH:68]=[CH:67][C:58]([CH2:59][NH:60][C:61]([C:63]3([NH2:66])[CH2:65][CH2:64]3)=[O:62])=[CH:57][CH:56]=2)=[C:52]([C:71]([F:74])([F:73])[F:72])[CH:51]=1>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:40])[CH2:36][C:37]([NH:66][C:63]1([C:61](=[O:62])[NH:60][CH2:59][C:58]2[CH:57]=[CH:56][C:55]([O:54][C:53]3[CH:69]=[CH:70][C:50]([O:49][CH3:48])=[CH:51][C:52]=3[C:71]([F:73])([F:74])[F:72])=[CH:68][CH:67]=2)[CH2:65][CH2:64]1)=[O:39])[CH3:33]
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)NC1(C(=O)NCc2ccc(Oc3ccc(OC)cc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
87 μL (0.50 mmol) of DIPEA and 80.9 mg (0.25 mmol) of TBTU were added to a solution of 33.27 mg (0.25 mmol) of monoethylmalonate in 100 μL DMF and the mixture was stirred for 5 min at RT. Then 83 mg (0.17 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) was added and the mixture was stirred for 1.5 h at ambient temperature. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[C:21](/[CH3:41])=[CH:22]/[CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C@H:32]([O:38][CH2:39][CH3:40])[C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[C:21](/[CH3:41])=[CH:22]/[CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C@H:32]([O:38][CH2:39][CH3:40])[C:33]([OH:35])=[O:34])=[CH:29][CH:30]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 131) (400 mg, 0.72 mmol) and sodium hydroxide (1M, 2.9 ml, 2.9 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2propionic acid (315 mg, 83%) as a colourless gum.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:15]=2)[C:10]([CH:26]=[O:27])=[CH:9]1)(OC(C)(C)C)=O.I[C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH2:38])[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:38][C:36]1[N:35]=[CH:34][N:33]=[C:32]2[N:31]([CH:39]([CH3:41])[CH3:40])[N:30]=[C:29]([C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[NH:8][CH:9]=[C:10]4[CH:26]=[O:27])[C:37]=12
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3[nH]cc(C=O)c3c2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of N-Boc-3-formyl-5-indoleboronic acid pinacol ester (40 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). The TFA from purification hydrolyzed the Boc to yield BA43. ESI-MS (M+H)+ m/z calcd 321.1, found 321.0.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:33])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:33])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:22]=1
Reactant: COc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCCc2ccc(F)cc21
Product: COc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(F)cc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl)methyl](4-methoxyphenyl)amine (0.54 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This compound was dissolved in ethyl acetate, and 4 mol/L-HCl/dioxane was added. The precipitated solid was collected by filtration to give N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride ½ hydrate (0.52 g). melting point: 125.4° C.
Reaction SMILES: [O:1]1CCC[CH2:2]1.C[Li].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][CH:17]1[C:37](=[O:38])[N:19]2[C:20]([C:29]([O:31][CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:30])=[C:21]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:22][S:23][C@H:18]12)=[O:15].C(OCl)(C)(C)C>CCOCC.C(O)(=O)C.CO>[CH3:2][O:1][C:17]1([NH:16][C:14](=[O:15])[CH2:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[C:37](=[O:38])[N:19]2[C:20]([C:29]([O:31][CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:30])=[C:21]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:22][S:23][C@H:18]12
Reactant: C1CCOC1
Reactant: CC(=O)OCOC(=O)C1=C(COC(C)=O)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Agent: CC(C)(C)OCl
Agent: [Li]C
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OCOC(C)=O)=C(COC(C)=O)CS[C@@H]21
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To 25 ml of tetrahydrofuran was added 2 ml of a 1.8 molar solution of methyl lithium in ether. The solution was cooled to 0° C. and 4 ml of methanol were added to the solution. The solution was then cooled to -80° C and 468 mg of acetoxymethyl 7-[2-(2-thienyl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate were added, followed by the addition of 0.143 ml of t-butylhypochlorite. The cold reaction mixture was stirred for 25 minutes and was thereafter diluted with 4 ml of glacial acetic acid. The acidified reaction mixture was evaporated to dryness and the residual reaction product mixture was dissolved in dichloromethane. The solution was washed consecutively with a saturated solution of sodium chloride, a dilute solution of sodium thiosulfate, a saturated solution of sodium bicarbonate, and finally with a saturated solution of sodium chloride. The washed solution was dried and was then evaporated to dryness. The residue was chromatographed on preparative thin layer silica gel plates using benzene-ethyl acetate (7:3). The location of separated materials on the chromatogram was determined with an ultraviolet lamp. The reaction product was eluted from the silica gel with acetone. The acetone was evaporated to yield 202 mg of acetoxymethyl 7-methoxy-7-[2-(2-thienyl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15]C)=[CH:10][C:9]=2[F:17])=[N:6][CH:7]=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[C:9]([F:17])=[CH:10][C:11]([OH:15])=[CH:12][C:13]=2[F:14])=[N:4][CH:3]=1
Reactant: COc1cc(F)c(-c2ncc(Br)cn2)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1cc(F)c(-c2ncc(Br)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 5-bromo-2-(2,6-difluoro-4-methoxyphenyl)pyrimidine (0.887 g, 2.95 mmol) in DCM at 0° C., was added dropwise a solution of BBr3 (1M in DCM) (22 ml, 22 mmol) and the reaction mixture was stirred overnight at room temperature. This mixture was then poured over cold MeOH and solid NaHCO3 was added slowly until pH=4-5. The suspension obtained was filtered and the filtrate evaporated. The solid obtained was redissolved in ethyl acetate, washed with water and brine, dried and concentrated to give the desired compound as a white solid (0.817 g, 85% of yield).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([OH:8])([CH3:7])[CH3:6])=[O:3].[OH:9][CH2:10][C:11]([C@H:13]([C@@H:15]([C@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])=[O:12].Cl[O-].[Na+]>[Ni](Cl)Cl>[CH3:1][C:2]([CH2:4][C:5]([OH:8])([CH3:7])[CH3:6])=[O:3].[CH2:19]([OH:20])[C@H:17]([OH:18])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C:11]([C:10]([OH:3])=[O:9])=[O:12]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl[Ni]Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)CC(C)(C)O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
To an 150 l-capacity reaction vessel kept at a reduced pressure of 300 Torr were fed 450 kg of a 33.3% by weight of an aqueous solution of diacetone-L-sorbose, 9 l of a 5% by weight of an aqueous solution of nickel chloride and a 12.5% by weight aqueous solution of sodium hypochlorite in amounts shown in Table 3 concurrently with each other in 1 hour. The reaction started at once, and boiled at 75° C. An amount of about 160 l of water was distilled off as the reaction proceeds, when the reaction concluded. The reaction mixture was worked up in the same manner as in Example 1, to provide diacetone-2-keto-L-gulonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([Cl:17])[N:14]=[C:13](Cl)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:19][N:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[OH-].[Na+].O>CC(C)=O>[OH-:8].[NH4+:10].[N:20]1([NH:19][C:13]2[N:12]=[C:11]([NH:10][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=3)[N:16]=[C:15]([Cl:17])[N:14]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NN1CCCCCC1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc(NN3CCCCCC3)n2)cc1Cl
Product: [NH4+]
Yield: 31.3 %

Procedure:
To 101 (6.03 g, 20.0 mmol) dissolved in acetone (75 mL) was added a solution of 1-aminohomopiperidine (2.3 mL, 20.0 mmol) in acetone (10 mL) followed by addition of NaOH (8.0 mL 2.5 N NaOH solution, 20.0 mmol) and 20 mL of water. The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The sample was concentrated on a rotary evaporator and the resulting oil was dried overnight under vacuum. Column chromatography (96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded a light purple solid 152 (1.2 g, 16%), mp 139° C.; TLC (silica gel, 96:3:1, CH2Cl2, CH3OH, conc. NH4OH), Rf 0.31; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 52.5 min, 94.9% purity; MS (ESI): m/z 383 (M+H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]=[C:24]=[O:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1.O.Cl>N1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:25])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(Oc1ccc(NC(=O)Nc2cc(Cl)cc(Cl)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 4.95 g (0.025 mole) of 2-(4-aminophenoxy)-2-methylpropionic acid in 50 ml dry pyridine, 4.95 g (0.025 mole) of 3,5-dichlorophenyl isocyanate were added. After 1 hour stirring at room temperature, 150 ml water was added and the mixture was acidified with concentrated HCl. The precipitate was filtered, washed several times with cold water and dried. Recrystallization from aqueous acetone gave small plates 1.81 g (94%) MP 182-184°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH2:7].Cl.[NH2:9]O.[Cl:11][C:12]1[C:13]([O:22][CH3:23])=[C:14]([C:18]([Cl:21])=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C(OCC)C>[Cl:11][C:12]1[C:13]([O:22][CH3:23])=[C:14]([C:18]([Cl:21])=[CH:19][CH:20]=1)[C:15]([NH:9][OH:7])=[O:16]
Reactant: O
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1c(Cl)ccc(Cl)c1C(=O)NO
Reaction time: 1 h

Procedure:
To a solution of 360 g. of potassium carbonate in 350 ml. of water was added 2.5 diethyl ether and 181 g. hydroxylamine hydrochloride. The mixture was cooled to 5°-1O° C. and 477 g. of 3,6-dichloro-2-methoxybenzoyl chloride was added dropwise at a rate that maintained the reaction temperature below 10° C. After addition was complete, the reaction mixture was stirred for 1 hour and allowed to stand overnight at ambient temperature. The crude white solid product was obtained by filtration. The crude solid was washed with water, then treated with 1.5 of 4.5 M. HCl, filtered, washed again with H2O and dried to give 3,6-dichloro-2-methoxybenzohydroxamic acid as a white solid, m.p. 150° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:13](N=N[N:17]=2)[CH:14]=1)[OH:8])([CH3:4])[CH3:3].Cl.Cl[Sn]Cl.[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26]>CO.C(Cl)Cl.C(O)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[NH2:17][C:12]1[N:13]=[CH:14][C:9]([C@H:7]([CH2:6][NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])[OH:8])=[CH:10][CH:11]=1
Reactant: CC(C)(C)NC[C@H](O)c1ccc2nnnn2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)NC[C@H](O)c1ccc(N)nc1
Yield: 92.6 %

Procedure:
A solution of 538 mg (2.29 mmol) of (R)-α-[[(1,1-dimethylethyl)amino]methyl]tetrazolo[1,5-a]- pyridine-6-methanol in 15 ml of methanol was treated with 0.19 ml (2.29 mmol) of concentrated hydrochloric acid and 1.03 g (4.58 mmol) of SnCl2 ·2H2O. The reaction mixture was heated at reflux for one hour at which point tlc (silica gel) indicated completion. The mixture was reduced in volume under reduced pressure and then diluted with methylene chloride. The organic solution was washed with 15 ml of 2.5 N NaOH solution. The aqueous layer was back washed with a 20% methanolic methylene chloride solution until all product had been recovered. The combined organic layers were washed with saturated sodium chloride solution (2X), dried with anhydrous magnesium sulfate, and concentrated to dryness. The crude product was chromatographed on silica gel with 80:20:2 methylene chloride:methanol:concentrated aqueous ammonia as eluent to five 434 mg of pure product. To a solution of this free base (2.07 mmol) in 3 ml of absolute ethanol, a solution of 506 mg (4.36 mmol) of maleic acid in 5 ml of absolute ethanol was added slowly. The heterogeneous mixture was permitted to stir for an additional hour. The precipitate was collected by filtration and washed with ethanol-ether and then ether to give 690 mg of salt. The filtrate was diluted with ether to afford additional solid which was collected and rinsed with ethanol-ether and ether to afford 110 mg of product (total yield, 88%). A sample was recrystallized from ethanol, m.p. 167°-68° C. (dec.); [α]25D=-35.0 (MeOH); Analysis: Calc'd. for C11H19N3O·2C4H4O4 :
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[C:11]([N+:15]#[C-:16])([CH3:14])([CH3:13])[CH3:12].[CH:17](=O)[CH3:18]>Cl(O)(=O)(=O)=O>[C:11]([NH:15][C:16]1[N:6]2[C:2]([S:3][CH:4]=[C:5]2[CH2:7][C:8]([OH:10])=[O:9])=[N:1][C:17]=1[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC=O
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1nc2scc(CC(=O)O)n2c1NC(C)(C)C

Procedure:
Compound 39 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) (2-amino-thiazol-4-yl)-acetic acid solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) acetaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.