Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][CH:24]1[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][N:13]2[CH2:14][CH2:15][C:10]([C:8](=[O:9])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([OH:16])[CH2:11][CH2:12]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(F)cc1)C1(O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCC(CCN2CCC(O)(C(=O)c3ccc(F)cc3)CC2)CC1

Procedure:
The title compound was prepared from ((4-Fluoro-phenyl)-(4-hydroxy-piperidin-4-yl)-methanone and trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester according to the procedure described for the synthesis of (4-{2-Trans-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (intermediate E, example 1) in 1,2 dichloroethane using triacetoxyborohydride. MS (m/e): 451.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:59][O:60][C:61]1[N:66]=[CH:65][C:64](B(O)O)=[CH:63][CH:62]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:64]2[CH:65]=[N:66][C:61]([O:60][CH3:59])=[CH:62][CH:63]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Yield: 68 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 96 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (68%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]12[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[CH2:52][NH:51][CH2:50][CH2:49]2>CN(C)C(=O)C.CC1CCCO1>[CH2:52]1[N:51]([C:16]([C:15]2[CH:14]=[C:13]([S:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:12])[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:50][CH2:49][N:48]2[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]12
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Reactant: C1CCN2CCNCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1)N1CCN2CCCCC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid (4.35 g, 12.6 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (5.27 g, 13.9 mmol) in N,N-dimethylacetamide (30 mL) and 2-methyltetrahydrofuran (90 mL) was added 1,4-diazabicyclo[4.4.0]decane (2.47 g, 17.6 mmol). The reaction was stirred at ambient temperature for 2.5 hours, and then it was diluted with 2-methyltetrahydrofuran (57 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (35 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL). The organic layer was washed with 6% NaHCO3/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×50 mL), and then it was concentrated. The residue was concentrated from ethanol (2×50 mL) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(N(CC)CC)C.[F:39][C:40]([F:48])([F:47])[CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[C:9]1[C:25]1[CH:26]=[CH:27][C:28]([O:31][S:43]([CH2:42][CH2:41][C:40]([F:48])([F:47])[F:39])(=[O:45])=[O:44])=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 8.8 %

Procedure:
To a solution of 1-(2-chlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one (0.54 g, 1.24 mmol) in dichloromethane (30 ml) at 0° C. was added triethylamine (0.20 ml, 1.50 mmol) followed by 3,3,3-trifluoropropane sulfonyl chloride (295 mg, 1.50 mmol). The reaction mixture was subsequently stirred at room temperature for 2.5 hours. Concentration and purification by flash chromatography (heptane:EtOAc gradient) afforded 65 mg (9%) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26]1[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:17][CH2:25][C:26]3[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COc2ccc3c(c2)nc(N)c2nc(CC)sc23)o1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.0 eq., 1.0 mmol) and anhydrous DMF (2 mL). The mixture was warmed until a solution was obtained. An additional amount of DMF (1 mL) was added. To this stirred orange solution was added cesium carbonate (3.0 eq., 3.0 mmol) and a solution of ethyl 5-(chloromethyl)-2-furancarboxylate (1.0 eq., 1.0 mmol) dissolved in DMF (2 mL). Additional DMF (1 mL) was used to rinse the vial. The vial was capped and heated to 60° C. overnight. The reaction was monitored by HPLC. The reaction was quenched by adding the reaction mixture drop-wise to water (60 mL) with stirring. A precipitate formed. Crude ethyl 5-{[(4-amino-2-ethylthiazolo[4,5-c]quinolin-7-yl)oxy]methyl}-2-furoate was isolated as a solid by vacuum filtration. The solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated to provide a solid which analysis indicated was the methyl ester. This material was recrystallized from acetonitrile to provide methyl 5-{[(4-amino-2-ethylthiazolo[4,5-c]quinolin-7-yl)oxy]methyl}-2-furoate as a light yellow crystalline solid, mp 184-186° C. MS (APCI) m/z 384 (M+H)+. Anal. calcd for C19H17N3O4S.0.30CH3CN: C, 59.49; H, 4.56; N, 11.68. Found: C, 59.35; H, 4.22; N, 11.71.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=1.CC(C)([O-])C.[K+].Br[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl>C(O)(C)(C)C>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:12]([CH:13]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)CCBr
Reactant: CCOC(=O)CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)CCC(C(=O)OCC)C(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Ethyl 3-(3-(2,6-dimethylbenzyloxy)phenyl)-3-oxopropanoate (Step A, 5 g, 16.02 mmol) in t-butyl alcohol (50 ml) was added a solution of potassium tert-butoxide (1M in t-butyl alcohol, 1.988 g, 17.7 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. Ethyl 3-bromopropionate was added drop wise to the reaction mixture and stirring continued for another 2 hours and then poured into 1M HCl, extracted with ethyl acetate (2×), washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography eluted with hexane:ethyl acetate (2:1) to give the title compound.
Reaction SMILES: [Mg].[CH2:2]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[O:18][B:19]([O:22]C)[O:20]C.Cl>O1CCCC1>[CH2:2]([C:10]1[CH:15]=[CH:14][C:13]([O:18][B:19]([OH:22])[OH:20])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(OB(O)O)cc1
Temperature: -78 °C

Procedure:
50 ml of THF (tetrahydrofuran) was added to 2.91 g (0.12 mol) of metallic magnesium, and the mixture was stirred. 100 ml of a solution of 26.89 g (0.1 mol) of p-octylbromobenzene in THF was added dropwise thereto, and the mixture was heated. After the initiation of the reaction was confirmed, the mixture was refluxed for one hr. The mixture was cooled to −78° C., 12.46 g (0.12 mol) of trimethylboric acid was added dropwise thereto, and the mixture was stirred for 30 min. The temperature was returned to room temperature, followed by stirring for additional one hr. Dilute hydrochloric acid was added thereto, and the mixture was stirred for one hr. The aqueous layer was extracted with ether, and the oil layer was washed with water and then with an aqueous sodium hydrogencarbonate. The oil layer was then dried over sodium sulfate, the solvent was removed by distillation, and the resultant crude product was purified by chromatography on silica gel to give p-octylphenylboric acid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[OH:15].C(N(C(C)C)CC)(C)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[OH:15])#[N:5]
Reactant: OC1CCCN1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCCC1O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-fluorobenzonitrile (4.03 g, 33.2 mmol) and pyrolidin-2-ol (2.92 g, 33.5 mmol) was treated with diisopropylethylamine (4.37 g, 33.8 mmol) at room temperature. The mixture was stirred at room temperature (5 d). The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6 mm, 20% EtOAc-80% hexane) afforded the title compound (57).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][C:7]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:21]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]2[C:32]([CH2:33]Cl)=[CH:31][N:30]=[CH:29]2)=[CH:25][CH:24]=1)#[N:22].C(N(C(C)C)CC)(C)C>C(#N)C>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:28]2[C:32]([CH2:33][N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:17]=[CH:18][CH:19]=[C:3]([CH3:2])[CH:4]=4)([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]3)=[CH:31][N:30]=[CH:29]2)=[CH:35][CH:36]=1)#[N:22]
Reactant: COC(=O)C1(Cc2cccc(C)c2)CCNCC1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
A solution of methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (142 mg, 0.5 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (135 mg, 0.5 mmol; Example 52, Step D), and diisopropylethylamine (0.26 mL, 1.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. After collection and concentration of appropriate fractions, the residue was recrystallized from a mixture of ethyl acetate and hexane to provide the title compound as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17])([O-])=O.[CH3:26]O>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:17]
Reactant: CO
Reactant: O=C(NCC1CCNCC1)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: CN1CCC(CNC(=O)Nc2cc(-c3cccs3)ccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 1-(2-nitro-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.045 g, 0.12 mmol, 1.0 equiv.) in methanol was added Pd/C (0.02 g, 0.02 mmol, 0.16 equiv.). The reaction mixture was stirred at room temperature under H2 balloon pressure for 1h. The reaction was filtered through celite and concentrated under reduced pressure. The crude solid was washed with ether to obtain of pure 1-(2-Amino-5-(thiophen-2-yl)phenyl)-3-((1-methylpiperidin-4-yl)methyl)urea (0.03 g, 67% yield). ESI+ MS: m/z 345 ([M]+). 1H NMR (500 MHz, d6-DMSO): δ 7.66 (d, J=1.5 Hz, 1H), 7.56 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.10 (dd, J=3.5 Hz, 1H), 7.03 (t, J=4.0 Hz, 1H), 6.71 (d, J=7.5 Hz, 1H), 6.27 (t, J=5.5 Hz, 1H), 4.88 (bs, 2H), 2.98 (t, J=5.5 Hz, 2H), 2.77 (d, J=11.0 Hz, 2H), 2.16 (s, 3H), 1.85 (m, 2H), 1.63 (d, J=4.5 Hz, 2H), 1.36-1.33 (m, 1H), 1.20-1.13 (m, 3H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([N:20]1[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([N:20]1[C:24]([CH:25]([OH:26])[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)=[CH:23][N:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cncn1Cc1ccccc1
Reactant: Fc1ccc(CCCBr)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
5,4 g of magnesium turnings are covered with 50 ml of dry tetrahydrofuran. A solution of 1-bromo-3-(4-fluorophenyl)propane (48,7 g) in 200 ml of dry tetrahydrofuran is then added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. To the reaction mixture is then added dropwise the solution of 1-benzyl-5-imidazolecarbaldehyde (20,9 g) in 200 ml of tetrahydrofuran. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold saturated ammonium chloride solution. Tetrahydrofuran phase is removed and the water phase is extracted three times with ethyl acetate. Organic phases are combined, dried and evaporated to dryness. The residue is suspended with diethyl ether and filtered. Yield 86%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([Br:12])=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH3:13]>C(O)C(C)C>[CH3:1][N:2]1[C:6]2[C:7]([Br:12])=[C:8]([NH:11][C:1]3[NH:13][CH2:5][CH2:6][N:2]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: N
Reactant: Cn1cnc2ccc(N)c(Br)c21
Solvent: CC(C)CO
Product: Cn1cnc2ccc(NC3=NCCN3)c(Br)c21
Yield: 93 %

Procedure:
A solution of 3-methyl-4-bromo-5-aminobenzimidazole (0.31 g, 1.4 mmol) and ISA (0.6 g, 4.5 mmol) in 10 ml of isobutanol was stirred at reflux for 12 h. Oily residue obtained was subjected to column chromatography (NH3 sat'd 20% isopropanol/EtOAc) to yield 0.39 g (1.3 mmol, 93%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.50 g (68%) of the product as a white solid: mp 209-210° C. Anal. Calc. For C11H12N5Br.2.0C4H4O4. requires C, 43.36; H, 3.83; N, 13.31 Found: C, 43.66; H, 3.84; N, 13.10.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[OH-].[K+].[N+:17]([CH3:20])([O-:19])=[O:18]>C1COCC1.CO>[N+:17]([CH2:20][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:14][CH:13]=1)[OH:12])([O-:19])=[O:18]
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1ccc(-c2ccccn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a cooled (0° C.) solution consisting of 4-pyridin-2-yl-benzaldehyde (346 mg, 1.9 mmol) in THF (5 mL) and NO2CH3 (0.3 mL) and MeOH (2.5 mL) was added KOH (2.5 M, 1.13 mL). The reaction mixture was stirred at 0° C. for 30 min. and then quenched with a saturated NH4Cl solution. The aqueous mixture was extracted with EtOAC. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (257 mg, 60%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH+:12]([O-:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCCC1>[C:20]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[NH+:12]([O-:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(O)CC(C)(C)[NH+]1[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC1CC(C)(C)[NH+]([O-])C(C)(C)C1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution in which 30.3 g (300 mmol) of triethylamine and 34.4 g (200 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxide (TEMPOL) were dissolved in 200 mL of tetrahydrofuran (THF), 25.5 g (250 mmol) of acetic anhydride was added at 0° C. The temperature was raised to 25° C. to carry out a reaction for 12 hours, and it was then concentrated by a rotary evaporator. The residue was supplied to 1 liter of iced water, and the precipitated orange solid was collected by filtration to obtain 33.8 g of 4-acetyloxy-2,2,6,6-tetramethylpiperidine-N-oxide.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[I-].[K+].C1(C)C=CC=CC=1>[C:12]1([NH:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)c1cccnc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
5.0 g (31.7 mmol) of 2-chloronicotinic acid, 5.9 g (63.5 mmol) of aniline, and 0.1 g of potassium iodide were heated up 140° C., and toluene (30 mL) was added to this reaction mixture. The resulting mixture was stirred for 2 hours at 100° C. The reaction mixture was cooled, and then the solvent was distilled off. Chloroform was added to the residue, and insoluble materials were filtered off. The filtrate was concentrated, and thus 7.5 g of the title compound was obtained as crude pale yellow crystals (yield: quantitative).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OCC)=[NH:19])[CH3:9].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:8]([O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:19])=[N:33][NH:32][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:9]
Reactant: CCOC(=N)CCCCCCC(=O)OCC
Reactant: NNC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCCCCC(N)=NNC(=O)c1ccccc1
Reaction time: 12 h
Yield: 65 %

Procedure:
Add triethylamine (5.6 mL, 40 mmol) to a solution of 7-ethoxycarbonimidoylheptanoic acid ethyl ester (11.0 g, 41 mmol) and benzoic acid hydrazide (5.5 g, 40 mmol) in ethanol (110 mL) at room temperature under nitrogen and stir the mixture for 12 hours. Remove the solvent under reduced pressure, dissolve the residue in ethyl acetate (200 mL), wash with saturated NaHCO3 (200 mL) and brine (200 mL) solutions, and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 8-amino-8-(benzoylhydrazono)octanoic acid ethyl ester (8.3 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cccc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A 3-L flask equipped with a nitrogen (N2) inlet, thermometer and addition funnel was charged with dichloromethane (CH2Cl2, 1400 mL) and 2-amino-6-methylpyridine (130 g, 1.2 mol, Aldrich). After cooling the reaction to 0° C. in a wet ice/water bath, triethylamine (Et3N, 151.5 g, 1.5 mol) was added. Trimethylacetyl chloride (159.15 g, 1.32 mol) was diluted with CH2Cl2 (100 mL) and added dropwise to the reaction over 1.5 h. The reaction was stirred for an additional 30 min at room temperature. The salts were filtered from the reaction and the filtrate was washed twice with H2O. Drying the filtrate with anhydrous magnesium sulfate (MgSO4) and stripping all solvent in vacuo left a yellowish colored solid. Recrystallization from diethyl ether (Et2O)/hexanes (Hex) provided 167.3 g (73%) of pure product. The identity of this material and that of subsequent examples were confirmed by NMR (300 MHZ), microanalysis, and infrared spectroscopy, unless otherwise noted.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2].[OH-].[Na+].O.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[C:6]([F:27])[C:5]=1[F:28])[CH3:2]
Reactant: CCOC(=O)c1ccccc1-c1ccc(-c2ccc(OCC)c(F)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc(-c3ccccc3C(=O)O)cc2)c(F)c1F
Temperature: 30 °C
Yield: 48.2 %

Procedure:
The compounds (3) (29.1 g), sodium hydroxide (11.4 g), Solmix A-11 (100 ml) and water (100 ml) were mixed, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 30° C., and then aqueous 6N-hydrochloric acid solution (100 ml) and toluene (200 ml) were added hereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate, giving 13.0 g of 4-ethoxy-2,3-difluoro-4′-biphenylbenzoic acid (44). The yield based on the compound (3) was 49.2%.