Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:48])[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:29](OS(C)(=O)=O)[CH3:30])[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:36])[C@H:12]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([CH3:48])[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:29]=[CH2:30])[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:36])[C@H:12]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 4-nitrobenzyl 2-[(3R,4R)-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methanesulfonyloxy-2-butenoate (XVc, 0.0714 g, 0.00010 mole) in chloroform (1 mL) was treated with triethylamine (0.014 mL, 0.00010 mole) at room temperature. After a period of 1 h, reverse-phase C-18 HPLC indicated consumption of the starting material with formation of a single new peak (eluting phase 65% acetonitrile and 35% 0.01M phosphate pH 6.5 buffer). Dilute hydrochloric acid (chilled at 0° C.) and ethyl acetate were added. The organic layer was washed with cold water, dried (sodium sulfate) and concentrated to give 0.0615 g (ca. 100%) of the title compound as a foam. The product was characterized by its 1H-NMR spectrum.
Reaction SMILES: [Cl:1][CH:2]([Cl:23])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:22])[CH3:21])=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.C([O-])(=O)C.[Na+].O[NH:42][C:43](=[NH:53])[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>CN(C)C=O.C(OC(=O)C)C.C1(C)C=CC=CC=1>[Cl:23][CH:2]([Cl:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16]3[O:17][N:53]=[C:43]([CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[N:42]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:22])[CH3:21])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=N)NO
Reactant: CC1(C)O[C@H](c2ccc(C(=O)O)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1noc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
To a solution of the product of Step 2, Example 8 (525 mg, 1.4 mmol) in dimethylformamide (15 mL) is added 1,1′-Carbonyldiimidazole (286 mg, 1.7 mmol). The resulting solution is stirred at room temperature for 30 minutes at which time sodium acetate (140 mg, 1.7 mmol) and commercially available tert-butyl 2-(hydroxyamino)-2-iminoethylcarbamate (325 mg, 1.7 mmol) are added. The reaction is then stirred at room temperature for 72 hours. Next, the reaction is diluted with ethylacetate (75 mL) and washed with water (3×75 mL). The organic phase is dried (Na2SO4) and concentrated under vacuum. To the residue is added toluene (15 mL) and sodium acetate (140 mg, 1.7 mmol). The resulting mixture is heated to reflux for 18 hours while stirring, then cooled to room temperature and concentrated under vacuum. The residue is chromatographed on silica gel eluting from 100% hexanes to 50:50 EtOAc:hexanes to afford the title compound (280 mg): 1H NMR (400 MHz, CDCl3) 8.19 (d, 2H, J=8.0 Hz), 7.64 (d, 2H, J=8.0 Hz), 6.33 (m, 1H), 5.16 (m, 2H) 4.88-4.52 (m, 4H), 1.75 (s, 3H), 1.59 (s, 3H), 1.50 (s, 9H). m/z (Cl) 461 [M-(CH3)2CO].
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([O:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[CH2:24][C@@H:25]([OH:27])[CH3:26])[CH:19]=[N:20][CH:21]=1)([CH3:14])[CH3:13]>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:27][C@H:25]([CH2:24]/[CH:23]=[CH:22]/[C:18]2[CH:19]=[N:20][CH:21]=[C:16]([O:15][CH:12]([CH3:14])[CH3:13])[CH:17]=2)[CH3:26])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)Oc1cncc(/C=C/C[C@H](C)O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cncc(OC(C)C)c2)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, p-toluenesulfonyl chloride (11.45 g, 60.06 mmol) was added to a stirring solution of (2S)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol (7.00 g, 31.63 mmol) in dry triethylamine (30 mL) at 0° C. After stirring and warming to ambient temperature over 18 h, the mixture was concentrated on a rotary evaporator. The crude product was stirred with saturated NaHCO3 solution (100 mL) for 1 hour and extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford 10.00 g (84.2%) as a dark-brown oil, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][S:13][C:14](=[N:17][C:18]#[N:19])SC>C(O)C>[C:18]([NH:17][C:14](=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])[S:13][CH3:12])#[N:19]
Reactant: CSC(=NC#N)SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: CSC(=NCCSCc1[nH]cnc1C)NC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
(i) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (23.4 g.) in ethanol was added slowly to a solution of dimethylcyanodithioimidocarbonate (20.0 g.) in ethanol, with stirring at room temperature. The mixture was set aside overnight at room temperature. Filtration afforded N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.0 g.) m.p. 148°-150°. The filtrate was concentrated under reduced pressure and the mixture was triturated with cold water and the solid obtained, filtered off and recrystallised twice from isopropyl alcohol/ether to yield further product (27 g.), m.p. 148°-150°.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:35][C:36]2[O:40][N:39]=[C:38]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[CH:37]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[C:8]=2[N:34]=1)[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:35][C:36]2[O:40][N:39]=[C:38]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[CH:37]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:15])[C:8]=2[N:34]=1)[CH3:2]
Reactant: CCOCc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1Cc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (3.55 g, 5.58 mmol) in trifluoroacetic acid (30 mL) was stirred at room temperature for three days. The trifluoroacetic acid was removed under reduced pressure, and the residue was triturated with hydrochloric acid (50 mL of a 6 N in ethanol) and water (10 mL) for 30 minutes. The resulting mixture was adjusted to pH 14 with the addition of 50% (w/w) aqueous sodium hydroxide and stirred for 30 minutes. The volatiles were removed under reduced pressure, and the residue was recrystallized from aceotnitrile after a hot filtration. Three crops of crystals were collected to provide 1.35 g of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine. A portion of this material was diluted with dichloromethane. The resulting solution was washed sequentially with aqueous potassium carbonate, water, and brine; purified by column chromatography on silica gel (250 g, eluting with 15% CMA in chloroform); and dried to provide 0.657 g of an analytically pure sample as a white powder, mp 246.0-247.0° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[C:14]([OH:15])=[C:13]([O:16][CH3:17])[C:12]([CH3:18])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH2:22]([O:15][C:14]1[C:9]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=2)=[O:19])=[CH:10][N:11]=[C:12]([CH3:18])[C:13]=1[O:16][CH3:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1O
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of the compound 22 (100 g, 344 mmol), benzyl alcohol (46 ml, 447 mmol), and tributylphosphine (128 ml, 516 mmol) in tetrahydrofuran (1000 ml) was added a 40% diisopropyl azodicarboxylate-toluene solution (280 ml, 516 mmol) under ice-cooling over 30 minutes. After stirred for 30 minutes under ice-cooling, a temperature was raised to room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, to the residue were added toluene (100 ml) and hexane (2000 ml), and precipitated crystals were filtered. The solvent was distilled off under reduced pressure, to the residue were added diethyl ether (200 ml) and hexane (2000 ml), and precipitated crystals were filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). 4-Benzyloxy-N-(4-fluorobenzyl)-5-methoxy-6-methylnicotinamide 23 (68.5 g, 52%) was obtained as a colorless crystal.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14](O)=[CH:13][C:12](O)=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.C1C(C2C(=O)C3C=CC(O)=CC=3OC=2)=CC=C(O)C=1.CO>O>[O:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[C:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[CH:8]1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Agent: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Solvent: CO
Solvent: O
Product: O=c1c(-c2ccccc2)coc2ccccc12

Procedure:
Standard solutions were prepared by dissolving 0.500 mg of genistein, and daidzein into a 100 ml volumetric flask with 80 parts methyl alcohol, and 20 parts water. This provides a concentration of each individual isoflavone in the standard solution of 5 micrograms/ml.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:24]([O:26]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:30][NH:31][C:24](=[O:26])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccs1)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(F)cc1)C2c1nccs1
Temperature: 45 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-4-oxo-3-(thiazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (180 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give the title compound (3 mg, yield: 2%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 4.88 (d, J=8.0 Hz, 1H), 5.09 (d, J=8.0 Hz, 1H), 7.01 (t, 2H), 7.21 (d, 1H), 7.36-7.40 (m, 2H), 7.47 (d, 1H), 7.59 (d, 1H), 7.65 (t, 1H), 7.74 (d, 1H); 19F-NMR (400 MHz, CD3OD) δ (ppm): −116.36 (s); LC-MS (ESI) m/z: 365 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:41]5[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][OH:46])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(CCO)CC1
Temperature: 60 °C
Yield: 25.7 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 27B (225 mg, 0.427 mmol) in DMF (3 mL) was added 2-piperazin-1-yl-ethanol (0.157 mL, 1.281 mmol) followed by diisopropylethylamine (0.223 mL, 1.281 mmol) and tetrabutylammonium iodide (157.72 mg, 0.427 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenyl-hexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea (68 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.45 (brs, 2H), 8.55 (s, 1H), 7.55 (d, 2H), 7.35 (d, 2H), 7.25 (d, 1H), 6.85 (d, 1H), 6.45 (s, 1H), 4.20 (m, 2H), 3.88 (s, 3H), 3.45 (m, 2H), 2.50-2.25 (m, 12H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI)m/z 620 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH:5]1[C:4]2[C:9](=[N:10][C:11]3[C:16]([C:3]=2[CH2:2][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1c2ccccc2nc2ccccc12
Product: CCOP(=O)(Cc1c2ccccc2nc2ccccc12)OCC
Temperature: 25 °C
Yield: 94 %

Procedure:
The mixture of 10 (1.5 g, 5.5 mmol) and triethyl phosphite (2 mL) was heated to reflux for 4 h. After cooling down to room temperature, the excess triethyl phosphite was removed under vacuum to afford 11 (1.7 g) in 94% yield. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.8 Hz, 2H), 8.17 (d, J=8.8 Hz, 2H), 7.72 (t, J=7.2 Hz, 2H), 7.54 (t, J=7.2 Hz, 2H), 4.13 (d, J=24 Hz, 2H), 3.92-3.77 (m, 4H), 1.04 (t, J=7.2 Hz, 6H). 13C NMR (400 MHz, CDCl3) δ 148.4, 148.3, 135.8, 135.7, 129.9, 129.8, 125.8, 125.3, 125.2, 124.9, 124.8, 62.4, 27.5, 26.1, 16.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1OCc1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1cc(-c2ccc(F)c(OCc3ccccc3)c2)cn1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a solution of 2-benzyloxy-4-bromo-1-fluoro-benzene [CAS: 1036724-54-5](1250 mg, 4.45 mmol) in MeCN (40 mL) and water (10 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 h-pyrazole (925.18 mg, 4.45 mmol), sodium carbonate (1414.18 mg, 13.34 mmol) and bis(triphenylphosphine)palladium (II) dichloride (157.92 mg, 0.2200 mmol). The reaction was then heated at 100° C. for 4 hours. The reaction mixture was poured into EtOAc (100 mL) and aq NaOH (0.5M, 200 mL). The organics were separated, and washed with brine (75 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified over silica (25 g, SNAP cartridge), eluting with between 0% and 40% EtOAc in isohexane. Fractions containing the desired product were combined and concentrated in vacuo to give 4-(3-benzyloxy-4-fluoro-phenyl)-1-methyl-pyrazole (D78) (760 mg, 2.5575 mmol, 57.6% yield) as a colourless oil;
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 75 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
To a solution of 15.0 g (99.8 mmol) of 2-amino-N-methyl-benzamide in DMF (300 mL) are added 2,4,5-trichloropyrimidine (23.8 g, 130 mmol) and potassium carbonate (17.9 g, 130 mmol). The reaction mixture is stirred at 75° C. for 5 hours, cooled to room temperature, and then poured into H2O (600 mL). The resulting precipitate is collected by a filtration followed by washing with 50% aqueous CH3CN (200 mL) and dried under reduced pressure (40° C., 10 hours) to give desired 2-(2,5-dichloro-pyrimidin-4-yl-amino)-N-methyl-benzamide as ivory solid (26.4 g, 88.9 mmol, 89%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH2:17][CH3:18])[C:12]([OH:14])=O)[N:10]=1)=[O:4].[NH2:19][CH:20]1[C:46](=[O:47])[N:22]2[C:23]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:24]([CH2:27][O:28][CH3:29])[CH2:25][S:26][C@H:21]12>>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH2:17][CH3:18])[C:12]([NH:19][CH:20]2[C:46](=[O:47])[N:22]3[C:23]([C:30]([O:32][CH:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:24]([CH2:27][O:28][CH3:29])[CH2:25][S:26][C@H:21]23)=[O:14])[N:10]=1)=[O:4]
Reactant: CCON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC)CS[C@H]12)c1csc(NC(=O)CCl)n1
Yield: 84 %

Procedure:
Following the method of Preparation 3, 225 mg of 2-(2-chloroacetamidothiazol-4-yl)-2-ethoxyiminoacetic acid and 200 mg of benzhydryl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate were reacted to give 280 mg of benzhydryl 7-[2-(2-chloroacetamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate, in the form of a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[CH2:5][CH:6]([OH:10])[C:7](O)=[O:8].S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[CH2:5][CH:6]([OH:10])[C:7]([Cl:17])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(CC(O)C(=O)O)c1
Product: Cc1cc(C)cc(CC(O)C(=O)Cl)c1

Procedure:
3,5-Dimethyl benzyl glycolic acid (5.59 g) was cooled to 0° C. Thionyl chloride (5 ml) was added and the stirred solution was refluxed for 2 h. The solvent was removed in vacuo to afford 3,5-dimethyl benzyl glycolic acid chloride as an oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]4)=[O:30])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3ccc(C4CCCCC4)cc3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-cyclohexylphenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH2:1]([C:4]1[O:8][C:7]([CH2:9][C:10]2[CH:15]=[C:14]([NH:16]C(=O)C(F)(F)F)[CH:13]=[CH:12][C:11]=2[S:23](Cl)(=[O:25])=[O:24])=[N:6][N:5]=1)[CH2:2][CH3:3].[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[CH2:35][O:34][B:33]([OH:36])[C:32]=2[CH:37]=1.N1C=CC=CC=1>C(#N)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([S:23]([NH:27][C:28]2[CH:29]=[CH:30][C:31]3[CH2:35][O:34][B:33]([OH:36])[C:32]=3[CH:37]=2)(=[O:24])=[O:25])=[C:10]([CH2:9][C:7]2[O:8][C:4]([CH2:1][CH2:2][CH3:3])=[N:5][N:6]=2)[CH:15]=1
Reactant: CCCc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)o1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a stirred solution of 2-((5-propyl-1,3,4-oxadiazol-2-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (430 mg, 1.05 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (234 mg, 1.57 mmol) in 5 mL of ACN was added pyridine (253 uL, 3.13 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow solid (410 mg, yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH2:14].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22](Cl)=[O:23]>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14][C:22](=[O:23])[CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: O=C(Cl)Cc1cccs1
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1cccs1
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a suspension of 2-amino-4-chloro-5-nitrobenzoic acid methyl ester (221 mg in 2.5 mL of dry 1,2-dichloroethane) was added a solution of thiophen-2-yl-acetyl chloride (169 mg in 3.0 mL dry 1,2-dichloroethane) and the mixture heated at reflux on an oil bath. After 18 hours, the reaction was cooled and the solvent removed in vacuo. Recrystallization of the crude product from methanol gave the title compound (230 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[N:7]1)=[O:5])[CH3:2].[CH2:17](OC(N1C2C(=C(Br)C=CC=2)C(OC)=N1)=O)C>>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:15])=[CH:12][CH:13]=2)[C:8]([O:16][CH3:17])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Reactant: CCOC(=O)n1nc(O)c2cc(Br)ccc21
Product: CCOC(=O)n1nc(OC)c2cc(Br)ccc21

Procedure:
5-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CCIX was prepared from 5-bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester using the procedure described for preparation of 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV (Example 37).