Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16](=[O:25])[N:17]([CH3:24])[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:15][C:16](=[O:25])[N:17]([CH3:24])[CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 85.5 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (4.74 g, 23.3 mmol), methyl-piperidin-4-yl-carbamic acid tert-butyl ester (5 g, 23.3 mmol), and triethylamine (5 mL) in N,N-dimethylformamide (30 mL) was stirred at 90° C. for 14 h. Upon completion of the reaction, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized from methanol and water to give methyl (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-carbamic acid tert-butyl ester (6.7 g, 85.5%) as brown crystals. LCMS calcd for C16H24N4O4 (m/e) 336, obsd 337 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)[N:15]([CH:17]([CH3:18])[CH3:19])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(Cc1ccccc1)C2
Yield: 27.7 %

Procedure:
The title compound (72 mg) was prepared according to Example 287 using 300 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 146 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C22H24FN3, 349.20; found, m/z 350.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60-7.57 (m, 2H), 7.55-7.53 (m, 3H), 7.43-7.40 (m, 2H), 7.32-7.27 (m, 2H), 4.59-4.34 (m, 5H), 3.81-3.79 (m, 1H), 3.46-3.40 (m, 1H), 2.90-2.85 (m, 2H), 1.43-1.36 (m, 6H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(N)cc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-1-benzyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (80 mg, 0.23 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.0 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2 h. The reaction mixture was filterd and the filterarte was concentrated. The residue was triturated with ethanol to obtain 63 mg of N1-benzyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 264-265° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([Cl:21])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C(=O)Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-Bromo-phenyl)-propionic acid (0.500 g, 2.18 mmol) in dichloromethane (20 mL) was treated with dimethylformamide (0.03 mL, 0.44 mmol), followed by oxalyl chloride (0.248 mL, 2.8 mmol) dropwise over 5 minutes, and the reaction was stirred at room temperature for 1 hour. The mixture was then concentrated and dried under vacuum to give the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28]O)[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH3:28])[CH2:30][CH2:31][N:38]4[C:34](=[O:44])[C:35]5=[CH:43][CH:42]=[CH:41][CH:40]=[C:36]5[C:37]4=[O:39])[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CCN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butanol (6.9 g, 23.6 mmol), phthalimide (4.16 gm, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped and the residue was stirred in ether (200 ml). The insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g; eluted with dichloromethane, DCM, and 1-2%CH3OH in DCM) and SiO2, 100 g; eluted with DCM, 1 l; and 1%CH3OH in DCM, 1.2 l). Two close compounds were separated. The lower compound on TLC 3.66 g) was treated with HCl/ether in ethanol, and the solid salt was precipitated with hexane. Recrystallization from ethanol and isopropyl ether yielded white crystals 3.26 g, m.p. 210°-214° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[C:14](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: Oc1ccc(OC(F)(F)F)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
To a stirred suspension of 3-Bromo-4-trifluoromethoxy-phenol (20.0 g, 82.6 mol) and potassium carbonate (46.3 g, 330.4 mmol) in acetone (600 ml) was added drop-wise iodomethane (46.9 g, 330.4 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature then filtered and the filtrate was evaporated in vacuo to afford the title compound as a colourless oil (19.8 g, 93%).
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[NH:4][C@H:3]1[CH2:7][O:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].N([C@H]1C(=O)N(CC2C=CC(OC)=CC=2OC)[C@H]1C(OC)=O)=[N+]=[N-].O(CC(Cl)=O)C1C=CC=CC=1>>[CH2:23]([O:22][C:20]([NH:1][C@H:2]1[C:5](=[O:6])[NH:4][C@H:3]1[CH2:7][O:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N)cc1
Agent: COC(=O)[C@H]1[C@@H](N=[N+]=[N-])C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=C(Cl)COc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)OCc2ccccc2)cc1

Procedure:
Reaction of cis-3-amino-4-oxo-2-p-toluenesulfonyloxymethylazetidine with benzyl chloroformate according to the procedure described in Preparation 2 for reaction of methyl cis-3-azido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate and phenoxyacetyl chloride gives cis-3-benzyloxycarbonylamino-4-oxo-2-p-toluenesulfonyloxymethylazetidine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.[CH3:9][N:10]([CH3:14])[C:11](=O)[CH3:12].[Br:15][C:16]1[CH:17]=[C:18]([C:22]2C=C([CH:26]=[CH:27][CH:28]=2)N)[CH:19]=[N:20][CH:21]=1>O>[Br:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:12]=[C:11]([CH:26]=[CH:27][CH:28]=2)[N:10]([CH3:14])[CH3:9])[CH:19]=[N:20][CH:21]=1
Reactant: CC(=O)N(C)C
Reactant: Nc1cccc(-c2cncc(Br)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CN(C)c1cccc(-c2cncc(Br)c2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (83 mg) and methyl iodide (62 W) were added to an N,N-dimethylacetamide (1 ml) solution containing 3-(5-bromopyridin-3-yl)aniline (50 mg), followed by stirring at 80° C. for 4 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and a white solid of 3-(5-bromopyridin-3-yl)-N,N-dimethylaniline (7.1 mg) was thus obtained.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]1([C:20]([NH:33][C@@H:34]([CH2:37][C:38]2[N:42]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:41]=[N:40][CH:39]=2)[CH2:35][OH:36])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Si:6]([O:36][CH2:35][C@@H:34]([NH:33][C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:37][C:38]1[N:42]([C:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:41]=[N:40][CH:39]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OC[C@H](Cc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](Cc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 101.4 %

Procedure:
Imidazole (12.269 g, 0.180 mol) and tert-butyldimethylsilyl chloride (TBDMSCl) (20.37 g, 0.135 mol) were added to a solution of the compound (XXI) (56.390 g, 0.0901 mol) in dry DMF (560 ml) under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water, extracted with Et2O, washed with water and a saturated NaCl aqueous solution, then dried over Na2SO4, and concentrated to obtain a light-yellow foamy material (67.602 g). This crude product was purified by silica gel column chromatography (hexane/acetone=5/1) to obtain the objective compound (XX) (58.770 g; yield: 88.1%) as a white foamy material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH:16][CH2:15][CH2:13][OH:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: NCCO
Product: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Yield: 57.8 %

Procedure:
Prepared by general procedure III from 5-Bromo-2-methyl-benzenesulfonyl chloride (1.6 g, 6 mmol, synthesized according to J. Am. Chem. Soc., 1940, 62, 511–514) and ethanolamine (1.0 mL, 17 mmol) to give the title compound (1.02 g, 58%) as a pale-yellow solid. MS (ISP) 294.1[(M+H)+], 296.2[(M+2+H)+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nccc(NC2CCCC2)n1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(COc2ccc(-c3nccc(NC4CCCC4)n3)cc2)cc1
Yield: 93.1 %

Procedure:
(2-chloro-pyrimidin-4-yl)-cyclopentylamine (100 mg, 0.51 mmol) was reacted with (4-benzyloxyphenyl)boronic acid (173 mg, 0.76 mmol), tetrakis(triphenylphosphino)palladium (44 mg, 0.04 mmol), and aq. 2 N sodium carbonate (1.01 mmol, 0.51 mL) as described in general procedure Q, method Q2, to give 164 mg of [2-(4-benzyloxy-phenyl)-pyrimidin-4-yl]-cyclopentyl-amine. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 4:1 then 1:1. LCMS m/z: 346 (M+1)+.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[C:11]([CH3:23])[N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[C:9]2[C:8](=[O:24])[N:7]([CH3:25])[C:6]1=[O:26])[CH:2]([CH3:4])[CH3:3].[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:27][C:13]1[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:11]([CH3:23])=[C:10]2[C:9]=1[C:8](=[O:24])[N:7]([CH3:25])[C:6](=[O:26])[N:5]2[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(Cn2cc3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(Cl)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Temperature: 25 °C
Yield: 64 %

Procedure:
1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (103 mg, 0.29 mmol) and hexachloroethane (400 mg, 1.7 mmol) are dissolved in anhydrous THF, and then 1.0M LiHMDS in THF (1.4 mL, 1.4 mmol) is added dropwise. The reaction mixture is stirred at room temperature for an hour, and then quenched with saturated ammonium chloride aqueous solution. The mixture is purified by silica-gel column chromatography to give pure product as off-white solids (yield: 64%). MS (ESI) m/z 390.2 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[C:4]=1[OH:12])=[O:2].P([O-])(O)(O)=[O:14].[Na+].Cl([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([C:1]([OH:14])=[O:2])=[C:4]([OH:12])[C:5]=1[CH3:11])#[N:8]
Reactant: Cc1c(C#N)ccc(C=O)c1O
Reactant: O=P([O-])(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Product: Cc1c(C#N)ccc(C(=O)O)c1O
Temperature: 17 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a solution of 4-formyl-3-hydroxy-2-methylbenzonitrile (3.90 g) in DMSO (21.0 mL) were added sodium dihydrogenphosphate (7.26 g) and an aqueous solution (16.0 mL) of sodium chlorite (5.46 g) under ice-cooling, and the mixture was stirred at 17° C. for 16 hr. The reaction mixture was poured into saturated aqueous sodium carbonate solution, and the mixture was extracted with tert-butyl methyl ether. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.00 g: containing DMSO).
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C([O:26][N:27]1N=N[C:29]2[CH:30]=[CH:31]C=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.CC1ON=C(N)C=1>ClC(Cl)C.CO>[CH3:31][C:30]1[O:26][N:27]=[C:28]([NH:33][C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]4[C:11]=3[CH:12]=2)=[O:18])[CH:29]=1
Reactant: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Agent: Cc1cc(N)no1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CC(Cl)Cl
Product: Cc1cc(NC(=O)c2ccc3nc4n(c3c2)CCCNC4=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
A mixture of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate B, 51 mg, 0.21 mmol) and HATU (89 mg, 0.23 mmol) in dichloroethane (3 mL) is stirred at room temperature for 1 h. 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (64 mg, 0.64 mmol) is added and the mixture is stirred at room temperature for 10 min. 5-Methyl-3-aminoisoxazole (62 mg, 0.64 mmol) is added and the reaction is stirred at 60° C. for 16 h and is cooled to room temperature. The mixture is diluted with methanol, filtered and evaporated. The residue is purified via flash column chromatography using a gradient elution of 0-10% CH2Cl2/methanol and is triturated with CH2Cl2 (3 mL), filtered and dried to afford the title compound (25 mg, 36%).
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:17][CH:18]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[N:10]=2.C(N(CC)CC)C.Cl[C:27]1[N:36]=[C:35]([NH:37][CH3:38])[C:34]2[C:29](=[CH:30][C:31]([O:41][CH3:42])=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1>C(O)CCC>[N:8]1[C:7]2=[CH:17][CH:18]=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][C:9]=1[N:11]1[CH2:16][CH2:15][N:14]([C:27]2[N:36]=[C:35]([NH:37][CH3:38])[C:34]3[C:29](=[CH:30][C:31]([O:41][CH3:42])=[C:32]([O:39][CH3:40])[CH:33]=3)[N:28]=2)[CH2:13][CH2:12]1
Reactant: CNc1nc(Cl)nc2cc(OC)c(OC)cc12
Reactant: Clc1ccc2nc(N3CCNCC3)nc-2cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CNc1nc(N2CCN(c3nc4cccccc-4n3)CC2)nc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A mixture of 2-(1-piperazinyl)cycloheptimidazole hydrochloride (1.5 g, described in Example 1) and triethylamine (1.0 g) in butanol (150 ml) was stirred at room temperature for 15 min and 2-chloro-4-methylamino-6,7-dimethoxyquinazoline (1.53 g) was added. The mixture was refluxed for 22 hr, cooled and filtered. The precipitate was washed and dried to give 2.18 g of the title compound. This compound was dissolved in methanol and the solution was acidified with hydrogen chloride. The precipitate was collected, washed with diethyl ether and crystallized from water-methanol to obtain the dihydrochloride salt of the title compound: mp>250° C.; ir (nujol mull) 3000 cm-1 ; uv max (MeOH) 345 (ε=22,000), 257 nm (ε=54,500) and 245 nm (ε=55,200); nmr (DMSO-d6) δ 3.07 (d, 3H), 3.88 (s, 6H), 4.18 (s, 8H) and 8.0 (s, 7); and Anal. Calcd for C23H25N7O2.2HCl. H2O: C, 53.90% H, 5.46% N, 19.14% Cl, 13.86% and Found: C, 53.82% H, 5.68% N, 19.47% Cl, 13.1%.
Reaction SMILES: [C:1]1([CH:11]=[CH:12]C(=O)C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>CO>[C:5]1([CH:4]=[CH:3][CH:2]=[CH:1][C:11](=[N:17][OH:18])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)C=Cc1cccc2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=CC=Cc1ccccc1)=NO
Yield: 60.6 %

Procedure:
In a 250 ml single neck flask was charged 5.28 g (30 mmoles, 1.0 eq.) of 4-(1-naphthyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.4 of 4-(2-phenylethenyl)-3-buten-2one 2-oxime (E/Z mixture of isomers) as an oil in 60.6% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH:19][C@@H:20]([CH2:33][NH2:34])[CH2:21][O:22][C:23]1[C:31]2[NH:30][C:29](=[O:32])[NH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.C(O)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:34][CH2:33][C@H:20]([OH:19])[CH2:21][O:22][C:23]3[C:31]4[NH:30][C:29](=[O:32])[NH:28][C:27]=4[CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1
Yield: 48.4 %

Procedure:
A mixture of 1-(4-ethoxycarbonylphenyl)-4-piperidone (0.25 g, 1 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.22g, 1 mmol) (U.S. Pat. No. 5,786,356/1998) in 100 mL of ethanol and 0.5 mL of acetic acid was hydrogenated in the presence of 400 mg of 10% palladium on carbon under hydrogen (5˜20 psi) for overnight. The catalyst was then removed by filtering through a short pad of silica gel. The filtrate was concentrated and purified by thin layer chromatography (12% methanol/methylene chloride) to give the title compound as a white solid (0.22 g, 48%); mp >170° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.28 (t, J=7.0 Hz, 3H), 1.30-1.55 (m, 2H), 1.80-2.10 (m, 2H), 2.80-3.10 (m, 5H), 3.80-4.10 (m, 5H), 4.23 (q, J=7.0 Hz, 2H), 6.58 (d, J=7.8 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.86 (dd, J=8.4, 7.8 Hz, 1H), 6.98 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 10.60 (s, 1H), 10.75 (s, 1H); MS (ES) m/z: 455.1 (MH+); HRMS Calcd. for C24H30N4O5 (MH+): 454.2216. Found: 454.2211.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=O)=[CH:24][CH:23]=2)=[O:21])=[N:4][N:3]=[N:2]1.Cl.C[N:35](C)C=O>N.O>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:35])=[O:30])=[CH:24][CH:23]=2)=[O:21])=[N:1][N:2]=[N:3]1
Reactant: CN(C)C=O
Reactant: O=C(O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: NC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 6 ml of N,N-dimethylformamide was dissolved 0.63 g of 4-[2-[2-(1H-tetrazol-5-yl)phenylthio]phenylcarbamoyl]phenoxyacetic acid (prepared in Example 6) followed by addition of 0.24 g of N,N'-carbonyldiimidazole. The mixture was stirred at room temperature for 1 hour, and then it was poured in 28% aqueous ammonia and stirred for 1 hour. The reaction mixture was diluted with water and, then, acidified with concentrated hydrochloric acid, and the crystals separated out therefrom were collected by filtration and washed with water. The crude crystals thus obtained were recrystallized from N,N-dimethyl-formamide-ethanol to give 0.52 g of the title compound as white crystals.