Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1]I(=O)(=O)=O.[Na+].[CH3:7][C:8]([CH3:29])([Si:10]([CH3:28])([CH3:27])[O:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH3:26])([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:9]>O.CO>[CH3:9][C:8]([CH3:29])([Si:10]([CH3:28])([CH3:27])[O:11][CH2:12][CH2:13][CH2:14][S:15](=[O:1])[CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH3:26])([CH3:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCCSCCCO[Si](C)(C)C(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCS(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium (meta)periodate (7.751 g, 1.1 eq) in water (40 mL) was slowly poured into a solution of 2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane, (12.32 g, 1 eq) in methanol (150 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered through a pad of celite and silica gel which was washed with methanol. The filtrate was concentrated under reduced pressure at a temperature below 25° C. The residue was diluted with brine and extracted a couple of times with chloroform. All organic solvents were combined, dried with anhydrous sodium sulfate, and concentrated to give a clear oil as crude 2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane 8-oxide, in amount of 12.84 g.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1.O.[NH4+:28]>C(O)C>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:28])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1cccc2nc(-c3cccc(CNCCN(C)C)c3)oc12
Reactant: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)CCNCc1cccc(-c2nc3cccc(C(N)=O)c3o2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
Methyl 2-(3-((2-(dimethylamino)ethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (100 mg, 0.28 mmol) and ammonium water (58.8 mg, 1.68 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. Evaporation under reduced pressure and purification with pre-HPLC gave 2-(3-((2-(dimethylamino)ethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide (10.0 mg, yield 11%). 1H-NMR (400 MHz, DMSO-d6) δ 2.85 (s, 6H), 3.37-3.42 (d, J=20 Hz, 4H), 4.36 (s, 2H), 7.48-7.52 (t, J=8 Hz, 1H), 7.71-7.97 (m, 6H), 8.35-8.37 (d, J=8 Hz, 1H), 8.43 (s, 1H); LC-MS (ESI) m/z 339 [M+1]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:13])[CH3:16]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: CCOC(=O)Cl
Product: CCOC(=O)ON=C(C#N)C(=O)OCC
Yield: 74.3 %

Procedure:
The reaction of ethyl 2-hydroxyimino-2-cyanoacetate (8.5 g) with ethyl chloroformate (6.0 g) is carried out as in Example 3 to give ethyl 2-ethoxycarbonyloxyimino-2-cyanoacetate (8.8 g) as an oil.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:16][C:17]1[C:23]([OH:24])=[C:22]([F:25])C=C[C:18]=1O>>[Cl:6][CH2:7][C:8]1[C:14]2[C:13](=[C:22]([F:25])[C:23]([OH:24])=[C:17]([F:16])[CH:18]=2)[O:12][C:10](=[O:11])[CH:9]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1ccc(F)c(O)c1F
Agent: O=S(=O)(O)O
Product: O=c1cc(CCl)c2cc(F)c(O)c(F)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
Sulfuric acid (2 mL) in a flask was cooled to 0° C. After ethyl 4-chloroacetoacetate (0.62 g, 3.8 mmol) was added thereto, 2,4-difluororesorcinol (0.5 g, 3.4 mmol) was added dropwise thereto. The mixture was stirred at room temperature for 2 hours, and the reactant was placed in ice water. The precipitate was filtered, washed with water, and dried by nitrogen gas to obtain the title compound (0.2 g, 24%).
Reaction SMILES: [CH:1]([C:3](O)([CH3:5])[CH3:4])=[CH2:2].[C:7](OC)([O:11]C)([O:9][CH3:10])[CH3:8]>C(O)(=O)CC>[CH3:4][C:3]([CH3:5])=[CH:1][CH2:2][CH2:8][C:7]([O:9][CH3:10])=[O:11]
Reactant: COC(C)(OC)OC
Reactant: C=CC(C)(C)O
Solvent: CCC(=O)O
Product: COC(=O)CCC=C(C)C
Temperature: 115 °C
Reaction time: 12 h
Yield: 271.5 %

Procedure:
A distillation column-provided four-necked flask having a volume of one liter, which was equipped with a dropping funnel, a thermometer, a stirring device and a reflux ratio regulator, was charged with 50.0 g (580.5 mmoles) of 2-vinyl-2-propanol, 139.5 g (1,161.0 mmoles) of trimethyl orthoacetate and 1.3 g (17.4 mmoles) of propionic acid, and the internal temperature was raised to 115° C. Heating was continued for 12 hours while removing a fraction of not higher than 65° C. from a column top of the distillation column. After confirming the disappearance of 2-vinyl-2-propanol by a gas chromatographic analysis of the reaction solution, the reaction solution was distilled in vacuo. Fractions of from 60 to 65° C./1.2 kPa were collected to obtain 62.2 g (437.1 mmoles) of methyl 5-methyl-4-hexenate. The yield was 75.3%.
Reaction SMILES: [OH:1][C:2]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C:39]([NH:41][CH3:42])=[O:40])[CH:33]=[CH:32]2)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[CH:3]=[CH2:4]>C(OCC)(=O)C.[C].[Pd]>[OH:1][C:2]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C:39]([NH:41][CH3:42])=[O:40])[CH:33]=[CH:32]2)([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)[CH2:3][CH3:4]
Reactant: C=CC(O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(O)(c1ccc2cc(C(=O)NC)ccc2c1)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 143.7 %

Procedure:
A mixture of 6-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)-2-propenyl]-N-methyl-2-naphthamide (444 mg) and 10% palladium carbon (50% wet; 100 mg) in ethyl acetate (6 mL) was stirred for 12 h at room temperature under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated and crystallized from ethyl acetate to give the titled compound (359 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1ccccc1I
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccccc4C(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-iodo-2-trifluoromethyl-benzene.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[OH:18][CH:17]([C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: CNC(=O)c1ccccc1Br
Reactant: O=Cc1ccc(F)cc1
Product: CNC(=O)c1ccccc1C(O)c1ccc(F)cc1

Procedure:
Reaction of 2-bromo-N-methylbenzamide with 4-fluorobenzaldehyde as described in the preparation of Intermediate 2A gave the title material as a white solid: mp: 133-134° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.81 (3H, d, J=5.1 Hz, NCH3), 5.89 (2H, broad s, CH and NH), 7.01 (2H, m, aromatics), 7.28-7.45 (6H, m, aromatics). Anal. Calcd for C15H14FNO2: C, 69.49; H, 5.44; N, 5.40. Found: C, 69.46; H, 5.44; N, 5.41.
Reaction SMILES: CCCCCC.[H-].[Na+].[OH:9][CH2:10][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([Cl:26])([Cl:25])[Cl:24])[CH:20]=[C:19](Cl)[N:18]=1>C(COC)OC.O>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([Cl:24])([Cl:25])[Cl:26])[CH:20]=[C:19]([O:9][CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:18]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: OCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Solvent: O
Product: Clc1cc(C(Cl)(Cl)Cl)cc(OCc2ccco2)n1
Temperature: 50 °C
Yield: 58.3 %

Procedure:
To 5.5 grams (0.115 mole) of hexane washed sodium hydride in 100 mls of dimethoxyethane was added over a 25 minute period, 11.28 grams (0.115 mole) of 2-(hydroxymethyl)furan dissolved in 30 mls of dimethoxyethane. An additional 25 mls of dimethoxyethane was added and the mixture heated to 50° C. for about 10 minutes. To this mixture was added 26.54 grams (0.1 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine dissolved in 100 mls of dimethoxyethane. The mixture was heated under reflux (83° C.) for about 2.5 hours and the reaction mixture added to 600 mls of water and extracted with methylene chloride. The methylene chloride was evaporated from the extract leaving a black oil. This oil was distilled under reduced pressure to obtain 19.05 grams of the desired 2-chloro-6-(2-furanylmethoxy)-4-(trichloromethyl)pyridine product. The product, an oil, had a refractive index of n 25/d = 1.5722 and upon analysis was found to have carbon, hydrogen, nitrogen and chlorine contents of 41.19, 2.50, 4.23 and 42.49 percent, respectively, as compared with the theoretical contents of 40.40, 2.16, 4.28 and 43.37 percent, respectively, as calculated for the above named compound.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[O:40])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: CC(C)(N)CO
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC(C)(C)CO)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using (S)-phenyl(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate)(intermediate 32) (100 mg, 0.18 mmol) and 2-amino-2-methylpropan-1-ol (24 mg, 0.27 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound as a yellow solid. (45 mg, 45%)
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].I([Cl:26])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClC(Cl)C.CO>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Cl:26])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reaction time: 8 h

Procedure:
25.2 g (86 mmol) 5-acetyl-8-benzyloxy-1H-quinolin-2-one (European Journal of Medicianl Chemistry 1984, 19(4), 341) and 50 g (142 mmol) benzyltrimethylammonium dichloriodate in 500 mL dichloroethane and 300 mL methanol are stirred overnight at reflux temperature. The reaction mixture is evaporated down and the residue is stirred overnight in THF and 1 N hydrochloric acid. After the THF has been distilled off the precipitated solid is suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([CH2:11][C:12]1[CH:20]=[C:19]([CH3:21])[C:18]2[C:14](=[CH:15][N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:17]=2)[CH:13]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O.CO>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([CH2:11][C:12]1[CH:20]=[C:19]([CH3:21])[C:18]2[C:14](=[CH:15][N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:17]=2)[CH:13]=1)[CH:9]=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CC(CO)NC(=O)OC(C)(C)C)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(CC(C=O)NC(=O)OC(C)(C)C)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 5 °C
Reaction time: 0.02 h

Procedure:
tert-Buty-1-hydroxy-3-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)propan-2-ylcarbamate (0.3 g, 0.69 mmol) was dissolved in anhydrous dimethyl sulfoxide (2.5 mL). Triethylamine (0.29 mL, 2.07 mmol) was then added and the reaction mixture cooled to ca. 5° C. using an ice bath. A solution of sulfur trioxide pyridine complex (0.33 g, 2.07 mmol) in dimethyl sulfoxide (2 mL) was added in one portion. After 1 min, the ice bath was removed and the reaction mixture stirred at room temperature for 20 min. The reaction mixture was poured into an ice slurry and extracted with ethyl acetate (3×). The combined organic extracts were washed with 10% citric acid (2×), water (2×), 5% sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded 0.2 g (74%). Mass spec. (in methanol): 466.25 (M+MeOH+H)+.
Reaction SMILES: Br.[C:2]1([NH:8][C:9]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([B:19]4[O:23]C(C)(C)C(C)(C)[O:20]4)=[CH:15][N:14]3[CH:28]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].C1(B(O)O)C=CC=CC=1>C(#N)C>[ClH:29].[C:2]1([NH:8][C:9]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([B:19]([OH:23])[OH:20])=[CH:15][N:14]3[CH:28]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)OC1(C)C
Agent: Br
Agent: Cl
Agent: OB(O)c1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)c1cn2cc(B(O)O)ccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2°) A solution of 0.19 g of N-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide hydrobromide (1:1) in 9 mL of acetonitrile is treated with 0.5 mL of hydrochloric acid and 1 g of polymer-supported benzeneboronic acid (Alfa-Aesar L19459, ˜3 mmol/g). The reaction mixture is stirred for 16 hours at 25° C. and then refluxed for 1 hour. The resin is filtered off, washed with acetonitrile and then with methanol and the combined filtrates are evaporated to dryness under reduced pressure to give 160 mg of 2-phenylcarbamoylimidazo[1,2-a]pyridine-6-boronic acid hydrochloride (1:1) in the form of an orange-coloured solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[C:13]([NH:21][NH:22][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: CC(C)O
Product: O=C(CCNNC(=O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
Benzylacrylate (1.13 ml, 7.34 mmol) was added to a stirred suspension of benzoylhydrazine (285) (1.0 g, 7.34 mmol) in isopropanol (28 ml). The mixture was refluxed for 20 h, cooled to room temperature then concentrated. The residue was purified by flash chromatography (20% EtOAc in CH2Cl2) to afford 259 (1.098 g, 50%) as an oil which crystallized on standing: mp 65° C.; IR (KBr) 3283, 1723, 1644, 1316, 1201, 1156; 1H NMR (CDCl3) 5 8.32-8.18 (1H, m), 7.81-7.70 (2H, m), 7.57-7.23 (8H, m), 5.36-4.92 (1H, brm), 5.11 (2H, s), 3.26 (2H, t, J=6.5), 2.59 (2H, t, J=6.5); 13C NMR (CDCl3) δ 172.12, 167.27, 135.65, 132.54, 131.66, 128.45, 128.10, 128.06, 126.84, 66.31, 47.33, 33.31;
Reaction SMILES: [CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]2[N:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][O:22]C3CCCCO3)=[O:20])=[N:15][CH:16]=2)[CH2:6]1.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]2[N:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][OH:22])=[O:20])=[N:15][CH:16]=2)[CH2:6]1
Reactant: Cc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)NOC4CCCCO4)cn3)C2)c1C
Agent: Cl
Solvent: CCO
Product: Cc1cccc(CN2CC[C@@H](Nc3cnc(/C=C/C(=O)NO)cn3)C2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2E)-3-(5-{[(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (46 mg) in ethanol (1 mL) was added 2N hydrogen chloride in ethanol (0.26 mL). After stirring at room temperature for 2 hours, the reaction mixture was evaporated in vacuo and triturated with ethyl acetate to give (2E)-3-(5-{[(3R)-1-(2,3-dimethylbenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride (31 mg).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH:10]1[CH2:13][N:12]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:15]=2)[CH2:11]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][CH:10]1[CH2:11][N:12]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:15]=2)[CH2:13]1
Reactant: CCOC(=O)c1cnc(N2CC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CC(N)C2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4M HCl in dioxane (15 ml) was added to ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}pyrimidine-5-carboxylate (323 mg, 1 mmol) and the reaction stirred at r.t. for 30 min. The suspension was concentrated in vacuo to give the title compound as a white solid (323 mg, quant.). LCMS purity 78%, m/z 223 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>O>[CH3:22][O:21][C:19]([NH:1][C@@H:2]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)[C:3]([OH:5])=[O:4])=[O:20]
Reactant: N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reaction time: 18 h

Procedure:
To (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid (505 mg; 3.18 mmol; obtained from Astatech) in water (15 ml) was added sodium carbonate (673 mg; 6.35 mmol), and the resultant mixture was cooled to 0° C. and then methyl chloroformate (0.26 ml; 3.33 mmol) was added dropwise over 5 minutes. The reaction was allowed to stir for 18 hours while allowing the bath to thaw to ambient temperature. The reaction mixture was then partitioned between 1N HCl and ethyl acetate. The organic layer was removed and the aqueous layer was further extracted with 2 additional portions of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford Cap-170 a colorless residue. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.65 (1H, br s), 7.44 (1H, d, J=8.24 Hz), 3.77-3.95 (3H, m), 3.54 (3H, s), 3.11-3.26 (2H, m), 1.82-1.95 (1H, m), 1.41-1.55 (2H, m), 1.21-1.39 (2H, m); LC/MS: Anal. Calcd. for [M+H]+ C9H16NO5: 218.1. Found 218.1.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C/C=C/C=O
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 90.1 %

Procedure:
First, 8.20 g (115 mmol) of crotonaldehyde and 9.55 g (57.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.33 g (5.78 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to SoC or lower. Then the crystals were dried for 2 hours in vacuo to give 11.3 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 99%, yield of 89% based on benzenesulfonyl cyanide).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:28])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CSc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Product: CSc1ccc(NC(=S)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
A suspension of 4-chloro-N-(4-(methylthio)phenyl)benzamide (1 g, 3.60 mmol) and Lawesson's reagent (875 mg, 2.16 mmol) in toluene (25 mL) was heated to 11 0° C. for 16 h. After cooling, toluene was removed in vacuo and the resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v) to afford 503 mg (48%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(COC)OC>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:1]=[C:2]2[CH:11]=1
Reactant: COc1cc(N)nc2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(OC)c3ccccc32)n1

Procedure:
350 mg of 2-amino-4-methoxyquinoline [Grout et al., J. C. S. Perkin I, (1973), p. 1314] were dissolved in 10 ml dimethoxyethane and 390 mg of ethyl bromopyruvate were added thereto. The crystalline intermediate thus formed was filtered off, washed with ether and then was dissolved in ethanol. The solution obtained was refluxed for 1 hour and then the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel--chloroform as eluant) and was crystallized from chloroform/ether to give colorless needles of ethyl 5-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 178°-179° C.