Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[Cl:13])[CH:7]=1
Reactant: COc1cc(Br)cn2nccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1cc(Br)cn2ncc(Cl)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (1010 mg, 4.43 mmol) in acetonitrile (40 ml) was added N-chlorosuccinimide (1180 mg, 8.86 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was partitioned between dichloromethane (100 ml) and 1N aqueous sodium hydroxide (100 ml). The organic layer was washed with brine (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 6-bromo-3-chloro-4-methoxypyrazolo[1,5-a]pyridine as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H); 8.03 (s, 1H); 6.84 (s, 1H); 3.94 (s, 1H). LRMS (ESI) calculated for C8H6BrClN2O [M+H]+, 260.9; found 261.0.
Reaction SMILES: C(OC(=O)[N:7]([CH:15]1[CH2:17][CH2:16]1)[C@H:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[F:14])(C)(C)C.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1>>[CH:15]1([NH:7][C@H:8]2[CH2:13][CH2:12][N:11]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:10][C@H:9]2[F:14])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@H]1CCNC[C@H]1F
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CC[C@H](NC3CC3)[C@H](F)C2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[(3R,4S)-3-fluoro-piperidin-4-yl]-carbamic acid tert-butyl ester and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described for Intermediate 73.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23]([O:27][C:28](=[O:58])[N:29]([CH2:31][CH:32]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)[CH3:30])([CH3:26])([CH3:25])[CH3:24]>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>[C:23]([O:27][C:28](=[O:58])[N:29]([CH2:31][CH:32]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH2:33][O:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:3]=[C:4]([Cl:16])[CH:5]=[C:6]([N:8]([CH3:15])[CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:7]=2)[CH:40]=1)[CH3:30])([CH3:24])([CH3:26])[CH3:25]
Reactant: CN(CC(COc1cccc(B2OC(C)(C)C(C)(C)O2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reactant: CN(c1cc(Cl)nc(Cl)n1)C1CCOCC1
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: C1COCCO1
Solvent: O
Product: CN(CC(COc1cccc(-c2nc(Cl)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of (2,6-dichloro-pyrimidin-4-yl)-methyl-(tetrahydro-pyran-4-yl)amine (0.4 g, 1.5 mmol) in degassed dioxane and H2O (4/1, 25 mL) was added Na2CO3 (315 mg, 3.0 mmol); Pd(PPh3)4 (86 mg, 0.075 mmol) and {2-(tert-Butyl-dimethyl-silanyloxy)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propyl}-methyl-carbamic acid tert-butyl ester (703 mg, 1.35 mmol). The system was purged with N2 stream and the mixture was stirred at 100° C. for 2 h., cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to give [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro-pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (373 mg, 40% yield) as major product. ESI-LCMS (m/z): 411.2 [M+1]+along with the minor product [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{2-chloro-6-[methyl-(tetrahydro-pyran-4-yl)-amino]-pyrimidin-4-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (140 mg, 15% yield). ESI-LCMS (m/z): 411.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([S:7][CH3:8])[S:4][C:3]=1[C:9]([O:11]CC)=O.[CH:14]([NH2:16])=O>>[CH3:8][S:7][C:5]1[S:4][C:3]2[C:9](=[O:11])[NH:16][CH:14]=[N:1][C:2]=2[CH:6]=1
Reactant: CCOC(=O)c1sc(SC)cc1N
Reactant: NC=O
Product: CSc1cc2nc[nH]c(=O)c2s1
Temperature: 155 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of ethyl 3-amino-5-(methylthio)-thiophene-2-carboxylate (2 g) and formamide (20 mL) was stirred at 150-160° C. for 6 h. The reaction mixture was allowed to rt and poured into ice cold water. The solution was stirred for 15 min. and the precipitated solid was filtered, washed with ice cold water and dried to give the product as a light brown color solid (1.2 g, 61%), mp 216-218° C. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (1H, s), 8.11 (1H, s), 7.26 (1H, s), 2.68 (3H, s); LC-MS (negative ion mode): m/z 197 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:5]([C:7]1C=CC=CC=1)=[O:6].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=1)(=[O:6])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(=O)c2ccccc2)cc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Amino-5-nitrobenzophenone (4 g; synthesized by the process reported by Berend et al., J. Prakt. Chem., vol. 69, p. 471 (1904)) was dissolved in pyridine (40 mL), and the temperature was maintained at 50° C. Methanesulfonyl chloride (1.9 mL) was added, followed by stirring for 2 hours. Additional methanesulfonyl chloride (1.7 mL) was added, followed by stirring at 50° C. for 2 hours. The reaction mixture was cooled down to room temperature and then poured into water (200 mL). The deposited precipitation was collected by filtration and dried under reduced pressure to yield N-(3-acetyl-5-nitrophenyl)methanesulfonamide (5.4 g) as a crude product. The whole quantity of the crude product was dissolved in ethanol (40 mL), and zinc dust (20 g) was added. After further adding concentrated hydrochloric acid (2 mL), the mixture was heated to reflux for 4 hours. The reaction mixture was filtered. To the filtrate, ethyl acetate (100 mL) was added. The mixture was washed with water (100 mL) three times and the organic layer was dried-over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (95:5 chloroform/methanol) to yield the title compound (3.9 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH:4]([N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[Cl:5]>[Pt]=O.C(OCC)(=O)C>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[Cl:5]
Reactant: COC(OC)C(Cl)N=Cc1cccc(Cl)c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(OC)C(Cl)NCc1cccc(Cl)c1
Reaction time: 7 h

Procedure:
A solution of 80 g. (0.305 m.) of 2,3-dichlorobenzylidenaminoacetaldehyde dimethyl acetal in 300 ml. of ethyl acetate was divided into two equal parts. Platinum oxide (300 mg.) was added to each and the mixtures were shaken under 20 psi H2 for about seven hours. Filtration, evaporation, and distillation afforded 2,3-dichlorobenzylaminoacetaldehyde dimethyl acetal, b.p. 100°-125° C. (0.005 mm.).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([OH:17])=[O:16])[C:10](=[O:13])[NH:11][N:12]=1.[CH2:18](O)[CH3:19]>>[CH2:18]([O:16][C:15](=[O:17])[CH2:14][C:9]1[C:10](=[O:13])[NH:11][N:12]=[C:7]([OH:6])[CH:8]=1)[CH3:19]
Reactant: O=C(O)Cc1cc(O)n[nH]c1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(O)n[nH]c1=O
Temperature: 88 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
Concentrated sulfuric acid (0.04 mL, 0.75 mmol) was added to a solution of (6-hydroxy-3-oxo-2,3-dihydro-pyridazin-4-yl)-acetic acid (Example 182-(1); 259 mg, 1.52 mmol) in ethanol (3.2 mL), and the mixture was heated while stirring at an external temperature of 84 to 92° C. for four hours. The mixture was left to stand at room temperature overnight. Then, the resulting solid was collected by filtration and sequentially washed with water and ether to give the title compound (246 mg, 82%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C=O)C.[Na+].[I-]>[O:1]1[CH2:2][CH2:3][CH:4]([S:20][C:18](=[O:21])[CH3:19])[CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCOCC1
Temperature: 50 °C
Yield: 81.3 %

Procedure:
To a solution of 300 g (1.175 mol) of toluene-4-sulfonic acid tetrahydropyran-4-yl ester in DMF (3 L) are added 268 g (2.35 mol) potassium thioacetate, followed by a catalytic amount of NaI (0.12 g, 10 mol %) at room temperature. After complete addition, the reaction is heated to 50° C. for 20 h. The reaction mixture is partitioned between TBME (3 L) and water (3 L), the aqueous layer is extracted with TBME (2 L), then saturated with NaCl and extracted again with TBME (2×2 L). The combined organic extracts are dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 153 g of thioacetic acid S-(tetrahydro-pyran-4-yl)ester. Yield: 81%; ES-MS: m/z 161 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=C)=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:13].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=[O:13])=[N:6][CH:7]=1
Reactant: C=Cc1ncc(Cl)cc1CF
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ncc(Cl)cc1CF
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a solution of 5-chloro-3-(fluoromethyl)-2-vinylpyridine (65 mg, 0.38 mmol) in THF (2.3 mL) and water (3.5 mL) was added a solution of osmium tetroxide (2.5 wt % in 2-methyl-2-propanol, 80 μl, 0.038 mmol, Aldrich). After 5 min, sodium meta-periodate (122 mg, 0.568 mmol, Aldrich) was added in one portion and the reaction mixture was allowed to stir for 1 h. The reaction mixture was partitioned between brine and EtOAc. The organic phase was separated and dried over MgSO4. The filtrate was absorbed onto a plug of silica gel and purified by chromatography, eluting with a gradient of 5% to 45% EtOAc in hexane, to provide the title compound as grey solid (55 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH:22]2[CH2:24][CH2:23]2)[C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[C:34]([C:35]([C:38]#[N:39])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([N:8]([CH:22]3[CH2:24][CH2:23]3)[C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([C:38]#[N:39])([CH3:37])[CH3:36])[C:26]=4[Cl:25])[CH:7]=[CH:6][CH:5]=3)[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc2cnc(N(c3cccc(N)c3)C3CC3)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)C3CC3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of N-{5-[(3-aminophenyl)(cyclopropyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 353 μmol) produced in Example D21(v), 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (95 mg, 424 μmol) produced in Example D18(v) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (201 mg, 530 μmol) in pyridine (3 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→97/3), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (137 mg, 71%) as colorless crystals.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Pd].O>[ClH:1].[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 139.2 %

Procedure:
In this reference example, 31.8 g of 1-benzyl-4-[N-(o-nitrobenzyl)-amino]-piperidine dihydrochloride, 3.2 g of 10% Pd-C and 500 ml of water are mixed and stirred at room temperature. Then, about 6 l of hydrogen gas is absorbed by the mixture. Then the reaction is discontinued and the Pd-C is removed by filtration. The aqueous solution is adjusted to pH 11 with an aqueous sodium hydroxide and then extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated. The resulting oily product is dissolved in 140 ml of ethanol. Then, 70 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate is added thereto. The white crystals deposited are separated by filtration, washed with ethyl acetate and dried to obtain 23.5 g of a crude product. The crude product is recrystallized from a mixed solvent of methanol and ethyl acetate to obtain 15.0 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28].N>CCO.CO.C(Cl)Cl>[O:20]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[NH:28])[CH:3]=2)[N:8]1[CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCN1CCCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCN1CCCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (225 mg, 0.82 mmol) in 10 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (470 mg, 1.65 mmol) and stirred overnight at room temperature. A TLC analysis indicated that the starting amine is still present. An additional 235 mg of methyl thiophene-2-carbimidothioate hydroiodide was added and stirring was continued for 1 day. Argon was bubbled through the mixture for 20 minutes then it was concentrated to give a brownish oil. This residue was partitioned between CH2Cl2 (50 mL) with 10% MeOH and saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a brown residue which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 to 10% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid which contained a mixture of starting amine and the desired product. This mixture was then subjected to preparative TLC using 10% MeOH:10% Et3N:80% EtOAc as eluant. A small amount of product was obtained in pure form (analyzed by HPLC). This compound was converted to the dihydrochloride salt by dissolving in 10 mL of a 10% MeOH/CH2Cl2 solution, cooled to 0° C. and treated with 0.5 mL of a 1M HCl in Et2O solution. The solution was stirred for 20 minutes then concentrated to give a yellow-brown oil. A yellow solid was obtained after drying under high vacuum overnight. Yield: 12 mg of compound 1. HPLC analysis indicated that the product is >99% pure. 1H-NMR (MeOH-d4) δ: 8.08-8.05 (m, 2H), 7.40-7.38 (m, 4H), 4.42 (t, J=6.7 Hz, 2H), 3.77-3.73 (m, 2H), 3.41 (t, J=6.7 Hz, 2H), 3.32-3.02 (m, 4H), 2.76-2.72 (m, 2H), 2.00-1.53 (m, 6H); MS (ESI): 383.2 (M+1), 30%, 192.1 (M+2), 100%. ESI-HRMS calculated for C21H27N4OS (MH+): 383.1900, Observed: 383.1908.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[C:20]([NH:2][CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:26])[CH3:25]
Reactant: CC(C)(C)C(=O)CN
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)NCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a mixture of 1-amino-3,3-dimethylbutan-2-one hydrochloride salt (35 g, 231 mmol) in CH2Cl2 (500 mL) at 0° C. are added N,N-diisopropylethylamine (74 g, 577 mmol) and ethyl chloro(oxo)acetate (31.5 g, 231 mmol) slowly over a period of 15 min. The reaction mixture is stirred at room temperature for 2 h and is filtered through Celite. The filtrate is concentrated to afford the title compound (40 g, 81%).
Reaction SMILES: C1(S([C:10]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)(=O)=O)C=CC=CC=1.[C:25]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26].N#N.[Li+].[OH-].C(O)(=O)C.[OH:42][P:43]([OH:46])([OH:45])=[O:44]>C(Cl)Cl.CS(C)=O>[P:43]([OH:46])([OH:45])([OH:44])=[O:42].[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([C:15]1[C:10]([CH:26]=[C:25]([OH:27])[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:17]
Reactant: CC(=O)c1ccncc1
Reactant: O=C(c1ccccc1Cl)c1cccnc1S(=O)(=O)c1ccccc1
Agent: N#N
Agent: O=P(O)(O)O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(c1ccccc1Cl)c1cccnc1C=C(O)c1ccncc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The title compound may also be prepared by an alternative process, which is described below. Add (2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone (15 g) and 4-acetylpyridine (7.59 g; 1.5 eq) to DMSO (150 mL) under an inert atmosphere of N2. Heat the solution to 70° C., then add LiOH (4 g, 4 eq) in one portion. Stir the reaction mixture for 4 hours at that temperature. The mixture turns from red to dark brown during the reaction. Completion of the reaction may be checked by HPLC. After completion of the reaction, cool the reaction mixture to 15° C. with a cold-water bath, and add CH2Cl2 (150 mL). Quench the reaction mixture in 10 min with 10% NaCl (150 ml) containing acetic acid (9.58 mL; 4 eq). At the end of the addition, the temperature reaches approximately 27° C. Re-extract the aqueous layer with CH2Cl2 (150 ml). Combine the organic layers and wash with 10% NaCl (3×300 mL). Concentrate the combined organic layers to dryness under vacuum and re-dissolve the residue in MeOH (4.3 volumes). Cool the reaction mixture to 20° C., and add H3PO4 (85% w/w in water; 2.88 mL; 1 eq). Stir the suspension for 4 h at 20° C., filter, wash the precipitate with MeOH (2×15 mL) and dry under vacuum at 50° C. to yield the title compound as an orange solid.
Reaction SMILES: P(O[CH2:6][C@@H:7]([OH:12])[C@@H:8]([OH:11])[CH:9]=[O:10])(O)(O)=O.[C:13]([O-:18])(=[O:17])[C:14]([CH3:16])=O.[Na+].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[CH2:16]1[C:14]([C:13]([OH:18])=[O:17])=[CH:6][C:7](=[O:12])[C@@H:8]([OH:11])[C@@H:9]1[OH:10]
Reactant: O=C[C@H](O)[C@H](O)COP(=O)(O)O
Reactant: CC(=O)C(=O)[O-]
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: [Na+]
Product: O=C(O)C1=CC(=O)[C@@H](O)[C@H](O)C1
Reaction time: 2 h
Yield: 90 %

Procedure:
D-Erythrose 4-phosphate (0.45 mL, 12 mM, pH 7.0), sodium pyruvate (0.054 mL, 100 mM, pH 7.0), CoCl2 (0.027 mL, 10 mM), NAD (0.054 mL, 1 mM), DHQ synthase (2 units) and DHQ dehydratase (2 units) are incubated with KDPGal aldolase (100 units) from E. coli at room temperature for 2 h. Protein is subsequently removed by ultrafiltration using Millipore PM-10 membrane. 3-Dehydroshikimate was formed in 90% yield, as determined by 1H NMR analysis.
Reaction SMILES: [OH-].[Na+].C1(=O)OC(=O)C=C1C.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH2:19]1[C:24](=[O:25])[N:23]([O:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[C:40](=[O:41])[CH:39]=[CH:38][C:36]3=[O:37])[CH:30]=2)=[O:28])[C:21](=[O:22])[CH:20]1S(O)(=O)=O.SCCO>O>[CH2:19]1[C:24](=[O:25])[N:23]([O:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[C:36](=[O:37])[CH:38]=[CH:39][C:40]3=[O:41])[CH:30]=2)=[O:28])[C:21](=[O:22])[CH2:20]1
Reactant: O=C(ON1C(=O)CC(S(=O)(=O)O)C1=O)c1cccc(N2C(=O)C=CC2=O)c1
Agent: CC1=CC(=O)OC1=O
Agent: O=P([O-])([O-])[O-]
Agent: OCCS
Solvent: O
Product: O=C(ON1C(=O)CCC1=O)c1cccc(N2C(=O)C=CC2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 500 μl of H2O were added 5 mg of the peptide and the pH was adjusted to 8.5 with NaOH, to obtain a final concentration of 10 mg/ml. Citraconic anhydride was diluted in H2O to a concentration of 10 mg/ml. 500 μl of the anhydride solution were added to the peptide solution 100 μl at a time with adjustment of the pH to 8.5 between each addition. The solution was then stirred constantly at room temperature for 1 hour. This was followed by the addition of 100 μl of 1M sodium phosphate buffer (pH 7.2) and then 900 μl of 100 mM sodium phosphate buffer (pH 7.2). Sulfo-MBS was diluted in H2O to a concentration of 25 mg/ml and 400 μl of this solution were added to the peptide solution to obtain an MBS concentration of about 5 mg/ml. This solution was stirred constantly at room temperature for 30 minutes. 6 μl of β-mercaptoethanol were added for a final β-mercaptoethanol concentration of 35 mM. The solution was stirred constantly at room temperature for 1 hour. KLH was dissolved in PBS at 3 mg/ml and 2.5 ml were added to the peptide solution. The solution was stirred constantly at room temperature for 3 hours and then dialysed against 1 litre of PBS, with three changes of the PBS. The final peptide concentration was about 1 mg/ml and the final KLH concentration was about 1.5 mg/ml.