Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH:9]([CH3:13])[CH2:10]C#N)=[O:8])=[CH:5][CH:4]=1.Br.[OH-].[Na+].[C:19](=[O:22])(O)[O-:20].[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]([CH3:10])[CH2:13][C:19]([OH:20])=[O:22])=[O:8])=[CH:14][CH:15]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(C(=O)C(C)CC#N)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)C(=O)c1ccc(O)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 78185.6 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a reflux condenser connected to a base trap, a glass rod air driven stirrer, and a thermometer was charged with 192.0 g (0.946 mmol) of (±)-3-(4'-methoxybenzoyl)-3-methylpropionitrile from Example G and 48% aqueous hydrogen bromide (1.0 L). The reaction mixture was heated over 1 hr to 65° C. then stirred at this temperature for 45 min (this effected complete hydrolysis of the nitrile moiety). The reaction temperature was increased to 110° C. and the solution was stirred for 3.5 hrs to effect demethylation. The solution was cooled to 23° C., diluted with water (1250 ml), cooled to 0° C. and the pH was adjusted to pH 8.5 with sodium hydroxide pellets (325 g) and powdered sodium bicarbonate (50 g). The aqueous solution was washed with EtOAc (2.5 L), transferred to a 4 L beaker in an ice/water bath and the pH was adjusted to pH 2 with 36% concentrated hydrochloric acid (Fisher, 150 ml). The aqueous solution was extracted with EtOAc (1L) and the organic layer was separated. The aqueous solution was saturated with solid sodium chloride (200 g) then extracted again twice with EtOAc (1×1L, 1×0.5L). The combined organic extracts were dried over anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo to provide 154.0 g (78%) of pure (±)-3-(4'-hydroxybenzoyl)-3-methylpropanoic acid, m.p. 122°-126° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH:13]([CH3:15])[CH3:14])[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:24]=[O:25])C.[Cl-].[NH4+]>C1COCC1>[CH:24]([C:2]1[CH:3]=[C:4]([C:8]2([CH:13]([CH3:15])[CH3:14])[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CN(C)C=O
Reactant: CC(C)C1(c2cccc(Br)c2)OCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C1(c2cccc(C=O)c2)OCCO1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
110 mg of 2-(3-bromophenyl)-2-isopropyl-1,3-dioxolane was dissolved in 1 mL of THF, and cooled to −78° C., and 0.36 mL of n-butyl lithium (1.5 M hexane solution) was added thereto, followed by stirring for 15 minutes. Thereafter, DMF (0.53 mL) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction liquid, followed by extraction with diethyl ether. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 57 mg (yield 61%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:4][C:5]([C:22](F)([F:24])[F:23])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([CH2:14][CH2:15][CH3:16])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:24][CH:22]([F:23])[C:5]1[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH2:14][CH2:15][CH3:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:27])([F:1])[F:26])[N:4]=1
Reactant: CCCC1C(C(=O)OCC)=C(C(F)(F)F)NC(C(F)(F)F)=C1C(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(C(=O)OCC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 0 °C
Yield: 64.7 %

Procedure:
A mixture of 20.0 g (0.05 mole) of diethyl 2,6-bis(trifluoromethyl)-l,4-dihydro-4-n-propyl-3,5-pyridinedicarboxylate, 7.62 g (0.05 mole) of DBU, and 200 ml of THF is held at reflux for 9 hours, cooled an poured into 500 ml of ice water. The mixture is extracted with ether (2×200 ml). The ether extract is washed with diluted hydrochloric acid, dried (MgSO4), and concentrated to give 12.4 g (64.5%) of the desired product, nD25 1.4436.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:10][N:9]2[CH:22]=1)=[O:4].FC(F)(F)C(OO)=[O:26].FC(F)(F)C(OC(=O)C(F)(F)F)=O.OO>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:26])=[O:15])=[CH:10][N:9]2[CH:22]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(S(=O)c3ccccc3)ccc2n1
Reactant: O=C(OO)C(F)(F)F
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)Nc1cn2cc(S(=O)(=O)c3ccccc3)ccc2n1

Procedure:
Portionwise, with cooling, 0.500 g. (0.0015 mole) of 2(methoxycarbonylamino)-6-(phenylsulfinyl) imidazo [1,2-a] pyridine is added to 5 ml. of a methylene chloride solution of trifluoroperacetic acid prepared from 415 μl. trifluoroacetic anhydride and 65 μl. of 90% hydrogen peroxide. The solution is heated at reflux for 20 hours. The cooled reaction mixture is washed with 10 ml. of a saturated aqueous sodium bicarbonate solution, the organic layer is separated and chromatographed on silica gel. Elution with 50% ethyl acetate-methylene chloride yields 2-(methoxycarbonylamino) 6-(phenylsulfonyl) imidazo [1,2-a] pyridine, m.p. 300° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[C:5](Br)=[CH:6][CH:7]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13](=[CH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][C:4]=2[CH:3]=1
Reactant: COC(=O)/C=C/CCN(Cc1cc(N)ccc1Br)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)Cc2cc(N)ccc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a stirring solution of methyl (2E)-5-{N-[(3-amino-6-bromophenyl)methyl](tert-butoxy)carbonylamino}pent-2-enoate (1 eq) in toluene (0.08 M) at room temperature was added tetrakis(triphenylphosphine) palladium(0.03 eq) and triethylamine (3 eq). The reaction mixture was stirred at 100° C. for 18 hr and filtered through celite. The reaction solvent was removed by rotary evaporation. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc/Hexane). EI-MS m/z 333 (M+H)+.
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9]2)[CH2:5][CH2:4]1)=O>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)(=O)C.O.[Zn]>[NH2:1][N:3]1[CH2:4][CH2:5][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9]2)[CH2:7][CH2:8]1
Reactant: O=NN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: NN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 7.1 g of 1'-nitroso-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], Example 1, in 75 ml of glacial acetic is added to a stirring suspension pf 7.1 g of zinc dust in 50 ml of glacial acetic acid and 50 ml of water while maintaining the reaction temperature between 10° and 20° C. The reaction mixture is stirred for 15 minutes at ambient temperature and then at 80° C. for 5 minutes; an additional 4.7 g of zinc dust are introduced and stirring is continued for an additional 10 minutes. The heated mixture is filtered, the precipitate is washed with hot 1N hydrochloric acid and the combined filtrate and washings are basified and extracted with chloroform. The organic solution is dried and the solvent is removed, leaving a white crystalline solid, 1'-amino-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], which is recrystallized from ethanolto to give the pure product, mp 143°-145° C.
Reaction SMILES: Cl[C:2]([CH3:20])([CH3:19])[C:3]([C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]([CH3:20])([CH3:19])[C:3]([C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(Cl)C(=O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C(=O)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
28.7 g of 4-(2-chloro-2-methyl-propanoyl)-benzophenone and 5.4 g of sodium methoxide are boiled in 120 ml of methanol for 4 hours. After cooling, the mixture is filtered, the filtrate is evaporated and water is added to the residue. The mixture is extracted with ether and, after drying and evaporating the combined extracts, 4-(2-methoxy-2-methyl-propanoyl)-benzophenone is obtained as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10](Br)=[CH:9][C:8]=1[Cl:15].[C:35]([O:39][C:40]([N:42]1[CH:46]=[CH:45][CH:44]=[C:43]1B(O)O)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:43]2[N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH:46]=[CH:45][CH:44]=2)=[CH:9][C:8]=1[Cl:15]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(-c2cccn2C(=O)OC(C)(C)C)cc1Cl
Yield: 92.1 %

Procedure:
N-(4-Bromo-2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.410 g) was coupled with 1-tert-butoxycarbonyl-2-pyrroleboronic acid (0.930 g) in THF (10 mL) as described in Example 7-2) to give 0.435 g of N-[4-(1-tert-butoxycarbonyl-2-pyrrolyl)-2,6-dichlorobenzoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester ESMS: m/z 653 (MH+).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]([CH:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH3:47]>CN(C=O)C>[C:49]1([CH:48]([NH:55][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH2:46][CH3:47])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CCC(N)c1ccccc1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(NC(=O)c1ccc2[nH]cnc2c1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a mixture of 5-benzimidazole-carboxylic acid in DMF was added DIPEA (1.3 equiv) and HATU (1.2 equiv). The mixture was stirred for 5 min, and then α-ethylbenzylamine (1.1 equiv) was added. The reaction mixture was stirred at rt. for 1 h. After the reaction was completed, the solvent was removed in vacuo to obtain the crude which was purified by flash chromatography to obtain the title compound. LC-MS 280 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].Cl.[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36](/[C:38](=[N:42]/[O:43][CH3:44])/[C:39](Cl)=[O:40])[N:37]=1)=[O:31].Cl>O.O1CCCC1>[Cl:28][CH2:29][C:30]([NH:32][C:33]1[S:34][CH:35]=[C:36](/[C:38](=[N:42]/[O:43][CH3:44])/[C:39]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:40])[N:37]=1)=[O:31]
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1

Procedure:
7β-Amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, 157 g, is suspended in a mixture consisting of 500 ml of tetrahydrofuran and 500 ml of water, and to this, 141 g of sodium hydrogen carbonate is added in small portions with stirring. With stirring at 5° C., 150 g of 2-(2-chloroacetamidothiazol-4-yl)-2(Z)-methoxyiminoacetylchloride hydrochloride is added over 20 minutes, and the reaction mixture is stirred for further 1 hour at the same temperature. After completion of the reaction, the pH is adjusted to 3.0 with 10% hydrochloric acid, and the reaction mixture is extracted twice with 1 liter each of a mixture of ethyl acetate-tetrahydrofuran (1:1). The extract is dried over anhydrous magnesium sulfate, the solvent is evaporated off under reduced pressure to leave colorless powder, which is washed with 200 ml of ethyl acetate and filtered, to give 253 g of the desired compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[NH:17][C:18]3=[O:19])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cc(-c2ccccc2)cs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cc(-c2ccccc2)cs1
Yield: 87.1 %

Procedure:
A solution of 4-phenyl thiophene-2-carboxaldehyde (1 g, 5.3 mmol) and rhodanine (700 mg, 5.3 mmol) in 10 mL of glacial acetic acid was heated with anhydrous sodium acetate (1.22 g, 14.8 mmol) for 2 h. The reaction mixture was then poured into cold water. The precipitate was filtered, washed with water and dried under reduced pressure to get 5-((4-phenylthiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (1.4 g, yield 87%). MS (ESI) m/z: Calculated for C14H9NOS3: 302.98. found: 302.0 (M−H)−. The crude product was carried through without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:18]([CH2:20][CH3:21])[CH3:19])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:22][N:23](C)[CH:24]=O>>[CH3:22][N:23]([CH3:24])[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([N:18]([CH2:20][CH3:21])[CH3:19])[C:3]=1[C:1]#[N:2])=[O:17]
Reactant: CN(C)C=O
Reactant: CCN(C)c1nsc(NC(=O)Oc2ccccc2)c1C#N
Product: CCN(C)c1nsc(NC(=O)N(C)C)c1C#N
Temperature: 25 °C

Procedure:
A solution of 10.6 g of phenyl (4-cyano-3-(ethylmethylamino)-5-isothiazolyl)carbamate and 25 ml of dimethylformamide was placed in a pressure bottle. This solution was cooled and 5 ml of dimethylamine (previously collected in a dry-ice trap) were added. The pressure bottle was sealed and allowed to warm slowly to room temperature. The reaction mixture was then heated at 80° for approximately 16 hours. The reaction mixture was cooled in a dry ice bath and the vessel was opened. The reaction mixture was concentrated under reduced pressure until a small amount of material crystallized. Collection of the crystals produced 2.3 g of 1,1-dimethyl-3-(4-cyano-3-(ethylmethylamino)-5-isothiazolyl)urea, mp 115°-130° (decomposes). The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[C:29]([O:33][CH3:34])=[CH:30][CH:31]=[CH:32][C:25]=2[S:24]1(=[O:36])=[O:35]>>[O:35]=[S:24]1(=[O:36])[C:25]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: COc1cccc2c1C(=O)N(CCCCBr)S2(=O)=O
Reactant: O=c1ccc2ccccc2n1C1CCNCC1
Product: COc1cccc2c1C(=O)N(CCCCN1CCC(n3c(=O)ccc4ccccc43)CC1)S2(=O)=O

Procedure:
From the hydrochloride salt of 1-(4-piperidyl)-2(1H)-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-4-methoxy-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 7.80 (t, J=8.1 Hz, 2H), 7.60 (d, J=9.33 Hz, 2H), 7.51 (m, 2H), 7.25 (m, 3H), 6.66 (d, J=9.27 Hz, 1H), 4.06 (s, 2H), 3.80 (t, J=6.9 Hz, 2H), 3.09 (dd, J=9.8, 1.8 Hz, 2H), 2.84 (m, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.19 (t, J=11.6 Hz, 2H), 1.89 (br m, 2H), 1.69 (br m, 3H), 1.58 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH2:16][OH:17].C(Cl)(Cl)Cl>CO>[OH:17][CH2:16][CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Add 6.0 g (0.03 moles) 4-chloro-3-nitrobenzamide to 60 ml 2-aminoethanol and stir at ambient temperature. When TLC (silica support; 9:1 CHCl3 :MeOH eluent) shows no starting material, ca. 3 hrs., pour onto ice. Filter, wash (3×15 ml) with cold H2O, and recrystallize from MeOH/IPA. Yield is 4.5 g (66%) of orange crystals.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([Cl:28])[CH:27]=1)[CH2:24][CH:23](N1CCCC1)[CH2:22][CH2:21]2>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:17][C:18]1[CH:27]=[C:26]([Cl:28])[C:25]2[C:24]3[CH2:3][CH2:2][C:1](=[O:4])[NH:5][C:23]=3[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: C=CC(N)=O
Reactant: Clc1cc(Cl)c2c(c1)CCC(N1CCCC1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1CCC2=C(CCc3cc(Cl)cc(Cl)c32)N1

Procedure:
16.2 g of acrylamide and 0.9 g of anhydrous p-toluenesulphonic acid were added to 30.6 g of 1-(6,8-dichloro3,4-dihydro-2(1H)-naphthyl)pyrrolidine. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. After cooling, the reaction mixture was stirred at room temperature in 80 ml of a mixture of chloroform-ethyl acetate (1:1). There was obtained 8,10-dichloro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one which melts at 212°-214° after recrystallization from ethyl acetate.
Reaction SMILES: CC(C)(C)[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4](NC)=O.FC1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F.[OH:56][CH:57]1CCN[CH2:59][CH2:58]1>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][C:19]=3[N:11]([C:9]([N:8]3[CH2:59][CH2:58][CH:57]([OH:56])[CH2:4][CH2:3]3)=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: OC1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Product: CN1CCc2c(c(-c3ccc(F)c(F)c3)nn2C(=O)N2CCC(O)CC2)C1

Procedure:
Compound 45 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methyl amide with 4-hydroxypiperidine. 1H NMR (CDCl3) δ 7.46-7.51 (m, 1H), 7.32-7.36 (m, 1H), 7.20 (q, J=8.9 Hz, 1H), 3.96-4.08 (m, 3H), 3.60 (s, 2H), 3.41-3.47 (m, 2H), 3.08 (t, J=5.6 Hz, 2H), 2.78 (t, J=5.8 Hz, 2H), 2.54 (s, 3H), 1.97-2.01 (m, 2H), 1.63-1.72 (m, 2H). LCMS (+ESI) m/z=377 [M+H]+.
Reaction SMILES: S([O-])(O)=O.[Na+].[NH2:6][C:7]1[C:12]([CH:13]=O)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:9][N:8]=1.[NH2:21][C:22]1[CH:23]=[C:24]([C:29]2[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=2)[CH:25]=[CH:26][C:27]=1[NH2:28].O>CN(C=O)C>[NH2:6][C:7]1[C:12]([C:13]2[NH:21][C:22]3[CH:23]=[C:24]([C:29]4[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=4)[CH:25]=[CH:26][C:27]=3[N:28]=2)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:9][N:8]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Reactant: Cn1cc(-c2cnc(N)c(C=O)c2)cn1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3cc(-c4cnn(C)c4)cnc3N)[nH]c2c1
Temperature: 25 °C

Procedure:
1.2 300 μl (1.485 mmol) of 38-40% sodium hydrogensulfite solution are added to a solution of 100 mg (0.495 mmol) of 2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbaldehyde and 108 mg (0.495 mmol) of 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one in 4 ml of DMF, and the resultant suspension is stirred at 50° C. for 72 hours. The reaction mixture is cooled to RT, water is added, and the precipitated product is filtered off with suction, washed with water and dried, giving 6-{2-[2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]-3H-benzimidazol-5-yl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one as yellow solid; APCI-401;
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br)#[N:2].[OH:11][C:12]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20]>>[OH:11][C:12]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=3[C:1]#[N:2])=[CH:27][CH:26]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(O)cc1
Reactant: N#Cc1ccccc1CBr
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCc2ccccc2C#N)cc1
Yield: 71 %

Procedure:
The title compound is prepared in a manner analogous to the procedure set forth in Example 48 from 2-cyanobenzyl bromide and [2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine to provide 501 mg as a brown oil. This material was purified via silica gel chromatography employing the Chromatotron® using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 9:1 to yield the title compound (291 mg, 71%) as a white solid. Ion spray M.S. 427.4 (M*−1). Calculated for C23H28N2O4S-½H2O: Theory: C 63.12, H 6.70, N 6.40. Found: C 63.20, H 6.64, N 6.28.
Reaction SMILES: [C:1]1([N:7]2[C:11]([B:12]([OH:14])[OH:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1.ClCCl>[C:1]1([N:7]2[C:11]([B:12]3[O:13][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:14]3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1ccnn1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Temperature: 40 °C
Reaction time: 48 h
Yield: 55.1 %

Procedure:
(1-Phenyl-1H-pyrazol-5-yl)boronic acid (25.0 g) was dissolved in toluene (700 mL), pinacol (18.0 g) was added thereto at room temperature, and the mixture was stirred at 40° C. for 2 days. The reaction mixture was diluted with dichloromethane, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was collected by filtration, and washed with hexane to give the title compound (19.8 g).