Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:21]([O:23]C)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C:16]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)O)CCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclopentane carboxylate (5.5 g, 15.6 mmol) in methanol:THF (4:1, 100 ml) 10 N sodium hydroxide (15 ml) was added at room temperature. It was stirred for 16 h and evaporated to dryness in vacuo, the residue was dissolved in 100 mL water, pH adjusted to 7 with 5N hydrochloric acid solution. It was extracted with chloroform;methanol (3:1) washed with water, dried and concentrated to give 1-({[4-(2- butynyloxy)phenyl]sulfonyl}amino)cyclopentane carboxylic acid. Yield 4.5 g (86%); White solid, mp.108-110° C. Electrospray Mass Spec 336 (M−H)−.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]=[O:11].[CH:12](OC(=O)C)=[O:13]>C1COCC1>[CH:10]([N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH:12]=[O:13])=[O:11]
Reactant: CC(=O)OC=O
Reactant: O=CNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CN(C=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (10.8 g, 60 wt %, 0.27 mol) in 50 mL of THF was added dropwise a solution of N-(pyridine-2-yl)formamide (22.4 g, 0.18 mol) in 250 mL of THF. When the addition was complete, the reaction was stirred at room temperature for 30 minutes and then cooled in an ice/salt bath. The acetic formic anhydride ethereal solution from the previous step was added in one portion. The resulting mixture was stirred in the ice bath for 30 minutes and then overnight at room temperature. The mixture was poured into 1 L of ice/water and extracted with 3×250 mL of CH2Cl2. The combined organic extracts were washed with 2×250 mL of H2O, dried and evaporated to give 33.2 g of solid. The crude product was column chromatographed (silica gel) eluting with 100% CH2Cl2 followed by 90:10 CH2Cl2:EtOAc. 14.2 g of product was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([O:19]C)[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].Cl.C(OC(=O)C)C>C1C=CC=CC=1>[Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:5]
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(Cl)c2)c(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)c(Cl)c1)c1ccc(O)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 53 g of 2,3-dichloro-4-methoxy-3',4'-dichlorobenzophenone and 40 g AlCl3 in 400 ml of benzene is refluxed for five hours and then cooled to room temperature and maintained there for about 18 hours. The mixture is then poured over 200 ml of concentrated HCl and 200 ml of ice and then stirred at room temperature for one half hour. Ethylacetate is added to the mixture and the ethyl acetate/benzene layer is washed with water, dried over Na2SO4 and then evaporated to yield 2,3-dichloro-4-hydroxy-3',4'-dichlorobenzophenone, mp 179°-180° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:12]I>C(OCC)(=O)C>[CH3:12][N:5]1[CH2:6][CH:7]=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:4]1
Reactant: CCOC(=O)c1ccncc1
Reactant: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CCN(C)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of ethyl isonicotinate (151 g) in ethyl acetate (1000 mL) was added methyl iodide (126 mL), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was cooled, and an orange precipitate was collected by filtration. The precipitate was suspended in ethanol (1000 mL), sodium borohydride (37.8 g) was added with cooling at −40° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and ethanol was evaporated under reduced pressure. The residue was extracted with ethyl acetate-THF, the organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to give ethyl 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (85.8 g, 51%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][CH:34]1[CH2:36][O:35]1>[I-].[K+].CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:33][CH:34]5[CH2:36][O:35]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCC4CO4)cc32)nc1-c1cccc(Cl)c1
Yield: 75 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.5 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.012 mL (0.15 mmole) of 2-chloromethyl-oxirane was heated at 100 degrees for 3 hours. The mixture was concentrated under reduced pressure, diluted with 20 mL of water and the resulting precipitate collected by filtration. The solid was triturated with diethyl ether to give 0.032 g of 4-(3-chloro-phenyl)-2-(6-oxiranylmethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.39a) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH:12]2[OH:25])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[C:27]1[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][CH:28]=1.[I-].[Na+]>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13][CH:12]2[O:25][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[N:32]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)C1
Reactant: COC(=O)c1cccc(Cl)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC2CN(C(=O)OC(C)(C)C)CCOC2c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
Under ice-cooling, sodium hydride (60% in oil, 53 mg) was added to a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (400 mg) in DMF (5 mL). After stirring at room temperature for 20 min, methyl 6-chloropicolinate (280 mg) and sodium iodide (330 mg) were added, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (207 mg).
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[C:6]([O:10][CH:11]([F:13])[F:12])=[C:5]([Cl:14])[N:4]=1>O1CCCC1>[NH2:1][C:3]1[N:4]=[C:5]([Cl:14])[C:6]([O:10][CH:11]([F:13])[F:12])=[C:7]([F:9])[N:8]=1
Reactant: N
Reactant: Fc1nc(F)c(OC(F)F)c(Cl)n1
Solvent: C1CCOC1
Product: Nc1nc(F)c(OC(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.8 g (0.578 mol) of gaseous ammonia were passed into a mixture of 62.5 g (0.289 mol) of 2,4-difluoro-6-chlorodifluoromethoxypyrimidine in 300 ml of tetrahydrofuran at from -75° to -70° C. in the course of one hour while stirring. Stirring was continued for one hour at -70° C., after which the mixture was warmed up to room temperature. The precipitate which had separated out was filtered off under suction and partitioned between ethyl acetate and water and the organic phase was dried over mangesium sulfate. The reaction filtrate was evaporated down, the residue was dissolved in the above ethyl acetate phase, the solution was chromatographed over silica gel using 5:1 petroleum ether/ether and the eluate was evaporated down. 46.5 g (75.3% of theory) of the title compound were obtained as colorless crystals of melting point 77°-80° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:35])([C:31]([F:34])([F:33])[F:32])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[ClH:37]>C1COCC1>[ClH:37].[NH2:7][C:8]1[C@:9]([CH3:35])([C:31]([F:34])([F:32])[F:33])[O:10][CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)CO[C@@]1(C)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@]1(c2cccc(NC(=O)c3ccc(Br)cn3)c2)CO[C@@](C)(C(F)(F)F)C(N)=N1

Procedure:
((2R*,5R*)-5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (0.113 g, 0.194 mmol) was dissolved in THF (1 ml) and 4N HCl (5 ml) and the reaction mixture was stirred for 2 h at 25° C. and 3 h at 40° C. The solvents were removed under reduced pressure and the resulting residue was titurated with Et2O to provide the title compound as a white amorphous solid: TLC (EtOAc/MeOH 9:1): Rf=0.56; HPLC RtH5=1.147 min; 1H NMR (600 MHz, DMSO-d6): δ 11.45 (s, 1H), 10.81 (s, 1H), 9.74 (d, 2H), 8.88 (dd, 1H), 8.34 (dd, 1H), 8.10 (d, 1H), 8.01 (d, 1H), 7.95 (s, 1H), 7.46 (t, 1H), 7.27 (d, 1H), 4.13 (d, 1H), 4.05 (d, 1H), 1.81 (s, 3H), 1.69 (s, 3H); ESIMS: 471, 473 [(M+H)+].
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15]O>>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][Br:1]
Reactant: Br
Reactant: OCCc1ccccc1F
Agent: O=S(=O)(O)O
Product: Fc1ccccc1CCBr
Temperature: 0 °C

Procedure:
To a mixture of aqueous hydrobromic acid (48%, 360 mL) and concentrated sulfuric acid (103.6 mL) at room temperature was added dropwise 2-(2-fluorophenyl)ethanol (250 g, 1.78 mol, Aldrich). The reaction mixture was refluxed for 7 h, poured onto 600 ml of ice and the mixture was extracted with diethyl ether. The diethyl ether extracts were washed successively with saturated sodium carbonate and brine. The organic phase was dried (MgSO4) and concentrated in vacuo to give 359.9 g (99%) of 2-(2-fluorophenyl-ethylbromide as a brown oil. This product was used without further purification. NMR (CDCl3 : d 7.6-6.9 (m, 4H, ArH), 3.6 (t, 2H, CH2), 3.2 (t, 2H, CH2).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2.N1CCCCC1>C(O)C>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:15]\[C:12]1[NH:11][C:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:18][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:5](=[O:17])[C:6]=2[C:13]=1[CH3:14]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Temperature: 45 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexa hydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 5-bromo-1,3-dihydro-indol-2-one (25 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-2-((5-bromo-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinoprop yl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 80 (51 mg, yield 81%) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:4][CH:3]1[NH:5][C:6](=[O:21])[C:7]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[O:19][CH3:20].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br>>[CH3:20][O:19][C:8]1[CH:9]=[C:10]([C:15]([F:17])([F:18])[F:16])[CH:11]=[C:12]([S:13][CH3:14])[C:7]=1[C:6]([NH:5][CH:3]1[CH2:4][CH:2]1[N:1]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CC1N
Reactant: BrCCCCBr
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CC1N1CCCC1

Procedure:
The title compound, light yellow solid, MS: m/e=375.2 [(M+H)+], was prepared in accordance with the general method of example 10 from N-((1SR,2RS)-2-amino-cyclopropyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate AC) and 1,4-dibromobutane.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:9].C([N+]1[CH:18]=[CH:17][N:16]([CH2:19][CH:20]([CH3:22])C)[CH:15]=1)C(C)C>>[Br-:9].[CH:1]1([N+:8]2[CH:18]=[CH:17][N:16]([CH:19]3[CH2:20][CH2:22][CH2:3][CH2:2][CH2:1][CH2:7]3)[CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Cn1cc[n+](CC(C)C)c1
Reactant: NC1CCCCCC1
Agent: [Br-]
Product: c1c[n+](C2CCCCCC2)cn1C1CCCCCC1
Yield: 63 %

Procedure:
Using cycloheptylamine (2×110.4 mmol) the procedure used in Example 1 for synthesizing compound 1 was followed yielding 23.60 g white solids after drying under high vacuum (69.1 mmol, 63% yield). 1H NMR (300 MHz, DMSO-d6): 9.44, 7.93, 4.50, 2.08-1.97, 1.95-1.97, 1.77-1.69, 1.65-1.56, 1.54-1.46. 13C NMR (75 MHz, DMSO-d6): 133.5, 120.8, 61.1, 34.7, 26.8, 23.3. Analysis calculated for C17H29BrN2: C, 59.82; H, 8.56; N, 8.21 (C/N=7.29). Found: C, 59.45; H, 8.33; N, 8.08 (C/N=7.36).
Reaction SMILES: CN(C)C=O.O[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:16]([F:19])([F:18])[F:17].S(Cl)([Cl:22])=O>>[Cl:22][C:13]1[CH:14]=[C:15]2[NH:7][C:8]([C:16]([F:19])([F:18])[F:17])=[N:9][C:10]2=[N:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: On1c(C(F)(F)F)nc2ncccc21
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc2ncc(Cl)cc2[nH]1

Procedure:
Dimethylformamide (2 milliliters) was added to 4 grams of 1-hydroxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine in 10 milliliters of thionyl chloride. The resulting reaction mixture was heated on a steam bath overnight. Solvent was removed and the residue shaken with 50 milliliters of water and filtered. The residue was then taken up in sodium hydroxide solution, filtered and acidified to pH 3, shaken with three 150-milliliter portions of diethyl ether, and dried over magnesium sulfate. Solvent was evaporated, yielding the desired 6-chloro-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine, m.p., 290°-2° C., with sublimation from 260° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH:8]([OH:11])[C:9]#[N:10].Cl.[OH2:22]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH:8]([OH:11])[C:9]([NH2:10])=[O:22]
Reactant: O
Reactant: Cc1ccc(C)c(OCc2ccccc2C(O)C#N)c1
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(OCc2ccccc2C(O)C(N)=O)c1
Temperature: 50 °C
Yield: 65.7 %

Procedure:
To 10.0 g of 2-(2,5-dimethylphenoxymethyl)-mandelonitrile (content: 96% by weight), 30 g of xylene, 3.66 g of hydrogen chloride and 0.648 g of water were added. The obtained mixture was heated to 50° C., stirred and maintained at the same temperature for 3 hours to obtain a xylene solution containing 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetamide (yield: 65.7%). The formation of by-products generated by the hydrolysis of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetamide was not recognized.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([N:30]([C:34]([O:36][CH2:37]I)=[O:35])[CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:37][O:36][C:34]([N:30]([CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33])=[O:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCCN(CCC)C(=O)OCI
Agent: [Na+]
Product: CCCN(CCC)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 84.4 %

Procedure:
In the same manner as in Example 81, 179 mg of the title compound was prepared from 159 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 135 mg of N,N-di(propan-1-yl)aminocarbonyloxymethyl iodide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([C:18]#[C:19][Si](C)(C)C)[N:10]=1>CO>[C:18]([C:11]1[N:10]=[C:9]([O:8][CH3:7])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1)#[CH:19]
Reactant: COc1nc(C#C[Si](C)(C)C)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc([N+](=O)[O-])c(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Potassium carbonate (0.020 g, 0.148 mmol) was added to a solution of 2-methoxy-3-nitro-6-((trimethylsilyl)ethynyl)pyridine (Preparation 201, 0.37 g, 1.478 mmol) in MeOH (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and diluted with EtOAc. The solution was washed with water and the organic layer was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a brown solid (248 mg, 94%).
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH2:18][C:19]2[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:21][O:22][C:23]=2[CH3:24])=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8].[CH3:31]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[CH3:31][C:2]1[C:3]([O:17][CH2:18][C:19]2[C:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:21][O:22][C:23]=2[CH3:24])=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC2CCOCC2)cc1Br
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: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cc(C(=O)NC2CCOCC2)cnc1OCc1c(-c2ccccc2)noc1C
Yield: 50.8 %

Procedure:
To a suspension of 5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide (200 mg, 0.42 mmol) in 1,2-dimethoxyethane (1 mL) was added trimethylboroxine (88 μL, 0.64 mmol), aqueous sodium carbonate (1 M, 0.64 mL, 0.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (49 mg, 0.04 mmol). The reaction mixture was then irradiated in the microwave for 20 min at 140° C. under an argon atmosphere. It was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Trituration from tert-butylmethylether afforded the title compound (87 mg, 50%) which was obtained as a white solid. MS: m/e=408.4 [M+H]+
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:23](O)=[O:24])[N:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1>>[CH3:1][NH:2][C:23]([C:12]1[N:13]([CH3:22])[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)[N:11]=1)=[O:24]
Reactant: CN
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: CNC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 9, Step B, but using methylamine (0.20 mL of 2N methylamine in THF), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound. HPLC/MS: 320 (M+1); Rt=3.28 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1Cl
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccccn2)c(Cl)cc1Cl
Temperature: 110 °C
Yield: 93.6 %

Procedure:
To a solution of methyl 2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Preparation 45, 5 g, 15 mmol) in dioxane (30 mL) and water (10 mL) was added 2-bromopyridine (1.73 mL, 18 mmol), tetrakis(triphenylphosphine)palladium (0) (1.75 g, 1.51 mmol) and potassium carbonate (4.18 g, 30 mmol). The reaction was heated to 110° C. The reaction was cooled, extracted into EtOAc and separated. The organic layer was washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10-50% EtOAc in heptanes followed by trituration with TBME to afford the title compound (3.96 g, 93%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5](=O)[C:4]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=1
Reactant: CCOC(=O)c1c(CC)c2cc(OC)c(F)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)nc2cc(F)c(OC)cc2c1CC

Procedure:
A suspension of ethyl 4-ethyl-7-fluoro-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate (19.4 g, 0.066 mol) in phosphoryl chloride (243 ml) is heated at reflux for 6 hours. The phosphoryl chloride is distilled off. The reaction mixture is decanted into ice-cooled water, then taken up in dichloromethane to solubilize. The organic phase is washed with water, then with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate and the solvent is evaporated off. The residue is suspended in ether and the non-converted starting product (4 g) is filtered out. The filtrate is evaporated and the residue is purified by column chromatography (SiO2, AcOEt/Hpt: 5/95 to 20/80). 10.9 g of a white solid is obtained.