Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37]O)([CH3:34])[CH3:33].O1C2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:37][CH2:36][N:35]([CH:39]([CH3:41])[CH3:40])[CH:32]([CH3:34])[CH3:33])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: CC(C)N(CCO)C(C)C
Agent: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN(C(C)C)C(C)C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(diisopropylamino)ethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(diisopropylamino)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](OC(OCC)N(C)C)C>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:19][CH2:18][N:17]2[CH2:16][CH2:15][N:14]3[CH2:13][CH2:12][N:11]([CH:20]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCCNCCNCC2)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: c1ccccc1
Product: c1ccc(CN2CCN3CCN4CCN(CC2)C34)cc1
Yield: 96 %

Procedure:
A solution of 1-benzyl-1,4,7,10-tetraazacyclododecane (4 g; 0.015 mol ) and dimethylformamide diethylacetal (6.88 g; 0.0467 mol) in benzene (40 ml ) is heated at 80° C. and the azeotropic mixture ethanol-benzene is distilled away. When the conversion is ended, the solvent is evaporated under reduced pressure and the final product is obtained as a yellow oil (4.0 g). Yield 96%
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1cccc(C2(O)CCC(=O)CC2)n1
Product: COc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methoxy-pyridin-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[Si]([I:23])(C)(C)C.[CH3:24][N:25]1[C:29](=O)[CH2:28][CH2:27][CH2:26]1.I[Si](C)(C)C.I>CC(O)C>[IH:23].[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([O-:18])=[O:17])=[C:6]([CH2:5][N+:25]3([CH3:24])[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C[Si](C)(C)I
Reactant: CN1CCCC1=O
Agent: I
Solvent: CC(C)O
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)CCCC1
Temperature: 37 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
The silylated 7-ACA slurry was added to the TMSI/NMP slurry and the mixture was agitated for 30 minutes at 15°-20° C. Next, iodotrimethylsilane (TMSI, 4.2 ml, 29.5 mmol) was added and the reaction mixture was warmed to about 37° C. for 40 hours under a slight stream of nitrogen. The thick product slurry was then cooled to about 5° C. and 2-propanol (10 ml) was added dropwise keeping the temperature at or below 10° C. After agitating the mixture for 15 minutes with continued cooling, a solution of hydriodic acid (20 ml of 57% HI in 30 ml of water) was added. The temperature was allowed to rise to 20° C. and the two-liquid phase mixture was agitated for 15 minutes at about 20° C. The rich aqueous phase was separated and the spent cyclohexane phase was washed with water (10 ml). The combined aqueous extract was treated with diatomaceous earth (3 g), agitated for 5 minutes at 20°-25° C. then treated with decolorizing carbon (4 g). After agitating for 30 minutes at 20°-25° C., the mixture was filtered and the spent cake was washed with water (40 ml). The filtrate was diluted with 2-propanol (500 ml) to crystallize the product. The resulting product slurry was cooled to 0°-5° C. and was agitated for 1 hour. The slurry was filtered and washed with 80 ml of 2-propanol:water (4:1) and 80 ml of 2-propanol. Further drying in vacuo at 45° C. afforded 18.5 g (59.2%) of crystalline (6R, 7R)-7-amino-3-[(1-methyl-1-pyrrolidinio)methyl]ceph-3-em-4-carboxylate monohydriodide. Purity as determined by HPLC was 97.3%. The 1H NMR spectrum observed with the title compound is the same as an authentic sample prepared by the method in the art using Freon TF (U.S. Pat. No. 4,714,760): 1H NMR (D2O, 360 MHz) δ: 2.14-2.32 (envelope, 4H, --N(CH3)CH2CH2 --), 3.00 (s, 3H, NCH3), 3.46-3.67 (m, 5H, --N(CH3)CH2CH2 ; SCH2), 3.96 (d, 1H, J=16.9 Hz, --SCH2), 4.09 (d, 1H, J=13.9 Hz, =CCH2N--), 4.73 (d, 1H, J=13.9 Hz, =CCH2N--), 5.21 (d, 1H, J=5.1 Hz, --COCHCHS--), 5.41 (d, 1H, J=5.1 Hz, --COCHCHS).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Ni].CCO>[N:13]1([CH2:12][CH2:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(NCCN2CCCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(NCCN2CCCC2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A 25 mL round bottom flask was charged with (4-Nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine (0.352 g, 1.50 mmol mmol) and EtOH (5 mL). Hydrazine Hydrate (0.326 mL, 10.5 mmol) was then added to the solution. Excess RaNi was then added in dropwise until gas evolution ceased. The suspension was then allowed to stir for an additional 1 h at 65° C. The suspension was cooled to room temperature and then was filtered over celite. The celite was washed with MeOH (˜20 mL) and the combined organic solutions were then concentrated in vacuo affording pure N-(2-Pyrrolidin-1-yl-ethyl)-benzene-1,4-diamine as a light purple oil (0.219 g, 1.07 mmol, 71% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.Cl.O>[C:1]([C:3]1[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:5]([C:14]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CS(N)(=O)=O
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a mixture of 4-cyano-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylic acid (291 mg, 0.732 mmol), in DCM (5.0 mL) was added methanesulfonamide (87.1 mg, 0.916 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (176 mg, 0.916 mmol), and N,N-dimethylaminopyridine (103 mg, 0.842 mmol) and the resulting solution was stirred at room temperature overnight. The reaction was diluted with DCM (10 mL), 1N HCl (3 mL) and with water (3 mL). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=0/100→20/80) to give 250 mg of crude product. This material was purified by preparative reverse phase chromatography to give 70 mg (20% yield) of the title compound as a white solid. LC/MS (FA) ES+ 474, 476. 1H NMR (400 MHz, MeOH-d4) δ: 7.45 (d, 1H, J=2.0 Hz)), 7.38 (d, 1H, J=8.4 Hz), 7.25 (dd, 1H, J=8.0, 2.0 Hz), 4.38 (s, 2H), 3.82-3.80 (m, 4H), 3.57-3.55 (m, 4H), 3.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=23)=[C:4]([F:22])[CH:3]=1.Cl.Cl.N1C2C(=NC=CC=2OC2C=CC(N[C:42]([NH:44][C:45](=[O:55])[CH2:46][C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3Cl)=[S:43])=CC=2F)C=C1.C1(CC(N=C=S)=O)C=CC=CC=1>>[ClH:53].[F:22][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:44][C:45](=[O:55])[CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:43])[CH:21]=[CH:20][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: Cl
Agent: O=C(Cc1ccccc1)N=C=S
Product: COC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Yield: 72 %

Procedure:
Starting from the amine 287, following the procedure described above for the synthesis of compound 269b (scheme 561, example 222) and replacing 2-(2,6-dichlorophenyl)acetyl isothiocyanate with 2-phenylacetyl isothiocyanate, title compound 288 was obtained in 72% yield as a yellowish solid. 1H NMR (d-DMSO) δ (ppm): 12.51 (s, 1H), 11.84 (s, 1H), 8.64(dd, 1H, J1=5.1 Hz, J2=0.4 Hz), 8.24 (s, 1H, J=0.4Hz), 8.02(dd, 1H, J1=1.8 Hz, J2=13.4 Hz), 7.56-7.54 (m, 2H), 7.36-7.31 (m, 1H), 7.28-7.25 (m, 1H), 6.81 (d, 1H, J=5.5 Hz), 3.91 (s, 3H), 3.81 (s, 2H). MS (m/z): 496.3 (M+H) (found).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N:12]=[S:13]=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(=NS(C)(=O)=O)=O.N1C=CC=CC=1.O>C1C=CC=CC=1>[N:12]1[S:13][CH:1]=[C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: COC(=O)c1cccc(N=S=O)c1C
Agent: CS(=O)(=O)N=S=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cccc2nscc12
Yield: 36.4 %

Procedure:
To a solution of methyl 2-methyl-3-(sulfinylamino)benzoate (15.0 g, 71.0 mmol) in benzene (200 mL) was added a solution of N-sulfinylmethanesulfonamide (10.0 g, 71.0 mmol) and pyridine (9.19 mL, 114 mmol) in benzene (80 mL) at 0° C. The reaction mixture was heated under reflux for 18 hr, water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (5.0 g, yield 36%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:32])([F:31])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][NH:28][CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1.Cl[C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[Cl:40][C:39]1[C:34]([N:28]2[CH2:29][CH2:30][C:20]3[C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([C:11]([F:31])([F:10])[F:32])=[CH:13][CH:14]=4)=[N:24][C:23]([S:25][CH3:26])=[N:22][C:21]=3[CH2:27]2)=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Reactant: Clc1cccnc1Cl
Agent: CCN(CC)C(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 180 °C
Yield: 17 %

Procedure:
A mixture of diisopropylethylamine (252 mg, 1.95 mmol), N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (443 mg, 1.3 mmol) and 2,3-dichloropyridine (386 mg, 2.6 mmol) in dioxane (5 mL) and N,N-diethylacetamide (0.5 mL) was heated via microwave in a sealed tube at 180° C. for 10 h. Solvent was removed in vacuo and residue was purified by column chromatography. The product was obtained as a beige solid (100 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)O1.Br[C:21](=[CH2:25])[CH2:22][CH2:23][OH:24].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:21](=[CH2:25])[CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Reactant: C=C(Br)CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(CCO)c1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Palladium acetate (100 mg, 0.6 mmol) was added to a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (8.0 g, 31 mmol) and 3-bromo-3-buten-1-ol (6.2 g, 41 mmol) in toluene (118 mL) and water (12 mL) followed by addition of 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (500 mg, 1 mmol). The mixture was stirred at 100° C. for 6 h. After cooling to RT, the mixture was diluted with EtOAc, washed with water and brine. The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in methylene chloride (0-50%) to afford the desired product.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.NCC([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:69]=[CH:68][CH:67]=[CH:66][C:63]=2[C:64]#[N:65])[CH2:57][CH2:56]1)=O>CN(C=O)C.O>[C:64]([C:63]1[CH:66]=[CH:67][CH:68]=[CH:69][C:62]=1[O:61][CH:58]1[CH2:59][CH2:60][N:55]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:56][CH2:57]1)#[N:65]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: N#Cc1ccccc1OC1CCN(C(=O)CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.03 h
Yield: 6 %

Procedure:
DIPEA (1.3 g, 0.01 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (720 mg, 2.9 mmol) in DMF (4 mL) followed by HOBt (459 mg, 3.4 mmol) and EDCI.HCl (664 mg, 3.4 mmol). After 2 minutes of stirring, 2-[1-(2-amino-acetyl)-piperidin-4-yloxy]-benzonitrile hydrochloride (prepared by method used for the synthesis of Intermediate 15) (600 mg, 2.9 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in CHCl3 as eluent) afforded 87 mg (6% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-cyano-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 430.18, 96.4%, 1H NMR (300 MHz, DMSO-d6): δ8.0 (m, 1H), 7.8 (m, 3H), 7.2 (m, 1H), 7.4 (m, 4H), 7.2 (m, 2H), 4.9 (m, 1H), 4.2 (bs, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:13][Br:14])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(Br)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)c(Br)cc1CBr
Yield: 92 %

Procedure:
A mixture of methyl 4-bromo-5-fluoro-2-methylbenzoate (1.0 g, 4.0 mmol) (Ellanoval Laboratories Cat. No. 38-0304), N-bromosuccinimide (900. mg, 5.06 mmol) and benzoyl peroxide (50 mg, 0.2 mmol) in carbon tetrachloride (50 mL) was refluxed under a nitrogen atmosphere for 4 h. After cooling the mixture was diluted with methylene chloride. The organic solution was washed with brine, then dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]#[C:9][NH2:10].Cl.O1CCOCC1>O.C(OCC)C>[C:2]1([NH:1][C:9]([NH2:10])=[NH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)Nc1ccccc1
Temperature: 80 °C

Procedure:
Aniline (30 mmol, 1 equiv.), cyanamide (1.3 g, 31 mmol, 1.03 equiv.), and 4N hydrogen chloride in dioxane (8 mL, 32 mmol) was stirred for 10 minutes at room temperature and heated to 80° C. for 18 hours. The mixture was diluted with water (30 mL) and diethyl ether (50 mL). The aqueous layer was washed with ether (30 mL) and the organic layers were discarded. The aqueous layer was neutralized with 6N aqueous HCl (6 mL) and diluted with ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL) four times. The combined organic layers were concentrated under reduced pressure to afford a solid compound. The solid was washed with diethyl ether (30 mL) to provide pale yellow title compound. The compound was characterized by LC/MS and HPLC.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>C1COCC1>[CH2:11]1[O:12][C:13]2([CH2:18][CH2:17][C:16]([OH:19])([C:3]3[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=3)[CH2:15][CH2:14]2)[O:20][CH2:10]1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Yield: 83.6 %

Procedure:
To a 500 ml round-bottom flask equipped with a mechanical stirrer, condenser and addition funnel were added magnesium turnings (3.50 g, 140 mmol) and enough THF to cover the Mg. A solution of 1-bromo-4-fluorobenzene (12.45 g, 70.43 mmol) in THF (90 ml) was added dropwise at such a rate that the reaction maintained a gentle reflux following reaction-initiation (the initiation may be accomplished by warming the flask). After the mixture was refluxed for an additional 2.5 h, a solution of 1,4-cylohexanedione monoethylene ketal (10.00 g, 64.03 mmol) in THF (75 ml) was added dropwise. The mixture was kept at refluxing for an additional 2 h before being quenched with saturated ammonium chloride solution (7 ml). After removal of the magnesium salts by filtration, the filtrate was concentrated to dryness. The residue was dissolved in CHCl3 and washed with water and brine. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (30% ether in petroleum ether) to afford the desired alcohol (13.50 g, 87%) as a colorless solid. mp 133-134° C. 1H NMR (500 MHz, CDCl3) δ 1.69 (d, J=11.7 Hz, 2H), 1.79 (d, J=12.2 Hz, 2H), 2.05-2.18 (m, 4H), 3.98 (m, 4H), 7.02 (t, J=8.3, 2H). 7.47-7.50 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])=[CH:22][N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:22][N:21]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:20]=3)=[CH:37][CH:38]=2)[N:10]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)cc1
Yield: 91.7 %

Procedure:
To a mixture of ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoate (0.38 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid as colorless crystals (0.33 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 144-145° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4cccnc4)cc3)cc21
Yield: 70.1 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), nicotinoylchloride (195 mg), triethylamine (354 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (297 mg).