Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:19])[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[CH3:20][C@H:21]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:31]3[CH2:33][O:32]3)[CH:28]=2)[C:23](=[O:34])[O:22]1>CCO>[OH:32][CH:31]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:34])[O:22][C@@H:21]([CH3:20])[CH2:30]2)[CH2:33][N:8]1[CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4][C:3]1([CH2:2][OH:1])[CH3:19]
Reactant: CC1(CO)CN(C(=O)OCc2ccccc2)CCN1
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Solvent: CCO
Product: C[C@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)CC3(C)CO)ccc2C(=O)O1
Temperature: 80 °C

Procedure:
To a solution of racemic benzyl 3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate (1.0 g, 3.8 mmol) (prepared as described in US Patent Application Publication No. US2007/0088039A1, Example 10) in EtOH (13 mL) was added (3S)-3-methyl-6-(oxiran-2-yl) isochroman-1-one (773 mg, 3.80 mmol), the resulting mixture was heated at 80° C. for 16 h, the reaction mixture was concentrated to dryness and purified on silica gel to afford the title compound: LC/MS: m/e 469.2 (M+H)+.
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[C:6]([Cl:15])[N:5]=1.Cl>C(O)(C)(C)C>[Cl:10][C:9]1[C:4](=[O:1])[NH:5][C:6]([Cl:15])=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:8]=1.[Cl:10][C:9]1[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6](=[O:1])[NH:5][C:4]=1[Cl:3]
Reactant: [OH-]
Reactant: FC(F)(F)c1cc(Cl)c(Cl)nc1Cl
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]c(Cl)c(C(F)(F)F)cc1Cl
Product: O=c1[nH]c(Cl)c(Cl)cc1C(F)(F)F

Procedure:
To a solution of 2.7 g of potassium hydroxide dissolved in 37 ml of t-butanol was added 6.0 g of 2,3,6-trichloro-5-trifluoromethylpyridine, and the solution was reacted at 80° C. for 3 hours while stirring. After completion of the reaction, the reaction product was allowed to cool and made acidic with concentrated hydrochloric acid. The solvent was distilled off under reduced pressure, and the residue was extracted with methylene chloride. The methylene chloride solution was washed with water and dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure, and the resulting residue was passed through a silica gel column (eluent: an n-hexane-ethyl acetate (3:1 by weight) mixture) to obtain 1.5 g of 3,6-dichloro-5-trifluoromethyl-2-pyridone having a melting point of 129° to 131° C. and 0.8 g of 5,6-dichloro-3-trifluoromethyl-2-pyridone having a melting point of 163° to 165° C., respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[NH:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of tert-butyl 2-amino-4-(thiophen-2yl)phenylcarbamate (0.12 g, 0.41 mmol, 1.0 equiv.) in pyridine (2 mL) was added a solution of dimethylcarbamic chloride (0.07 g, 0.62 mmol, 1.5 equiv.) in toluene (0.3 mL). The resulting solution was stirred at room temperature overnight. The crude residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with water (10 mL), dried, filtered and concentrated. The crude residue was washed with petroleum ether (5 mL) to afford tert-butyl (2-(3,3-dimethylureido)-4-(thiophen-2-yl)phenyl)carbamate (0.12 g, 80% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])C=1>>[CH3:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:3][CH:4]=2)[O:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Reactant: Cc1c(-c2ccccc2)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(-c2ccccc2)c(=O)oc2cc(OC(=O)N3CCOCC3)ccc12
Yield: 41.1 %

Procedure:
The title compound (75 mg, 41% yield, crystals) was prepared from 7-hydroxy-4-methyl-3-phenyl-chromen-2-one (126 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[CH2:14]([O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH2:29][C@@H:30]([OH:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=1[CH3:36])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]2[C:44](=[O:53])[NH:45][C:46]3[C:51]([CH:52]=2)=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:39][CH2:38]1>C1COCC1.N1C=CC=CC=1>[O:53]=[C:44]1[C:43]([CH:40]2[CH2:39][CH2:38][N:37]([C:2]([O:35][C@@H:30]([C:31]([O:33][CH3:34])=[O:32])[CH2:29][C:25]3[CH:24]=[C:23]([CH3:36])[C:22]([O:21][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:27]([CH3:28])[CH:26]=3)=[O:3])[CH2:42][CH2:41]2)=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: COC(=O)[C@H](O)Cc1cc(C)c(OCc2ccccc2)c(C)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere 0.91 g (4.38 mmol) 4-nitrophenyl chloroformate in 10 mL THF were metered into 20 mL pyridine within 10 min at a bath temperature of 60° C., the mixture was stirred for 10 min, then 1.38 g (4.38 mmol) methyl (R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate in 40 mL pyridine were added and the reaction mixture was stirred for 2 h at 60° C. The reaction solution was combined with 1.00 g (4.38 mmol) 3-piperidin-4-yl-1H-quinoline-2-one and stirred for 4 h at 100° C. The reaction mixture was evaporated down i.vac. and the residue was purified by HPLC. The fractions containing the product were combined, evaporated down i.vac., the residue was made alkaline with 15% K2CO3 solution, the precipitate was suction filtered, washed with 20 mL water and dried at 50° C.
Reaction SMILES: C([C:3]1([C:33]([O-:35])=O)[C:8]2[C:9]3[CH:15]=[C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:13]=[C:12]([Cl:25])[C:10]=3[O:11][C:7]=2[CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O)C.Cl.[C:37](=[O:40])(O)[O-].[Na+].Cl[CH2:43]Cl>O1CCOCC1>[Cl:25][C:12]1[C:10]2[O:11][C:7]3[CH2:6][CH2:5][NH:4][CH:3]([C:33]([O:40][CH2:37][CH3:43])=[O:35])[C:8]=3[C:9]=2[CH:15]=[C:14]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:13]=1
Reactant: O=C([O-])O
Reactant: CCC1(C(=O)[O-])c2c(oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc23)CCN1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1NCCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of the product of step C (60 mg, 0.12 mmol) in dichloromethane (2 mL) was added 4M HCl in dioxane (2 mL). The resulting solution was stirred at ambient temperature for 3 h. The solvents were removed in vacuo to afford a brown residue which was treated with saturated aqueous sodium bicarbonate (15 mL). The resulting solution was extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 4:2 to 3:7, hexanes/ethyl acetate) to afford ethyl 6-chloro-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-1-carboxylate (51 mg, 99%) as a brown oil: 1H NMR (CDCl3, 300 MHz) δ 8.23 (d, J=1.8 Hz, 1H), 7.97-7.85 (m, 2H), 7.70-7.57 (m, 4H), 4.76 (s, 1H), 4.27-4.17 (m, 2H), 3.77-3.63 (m, 2H), 3.42-3.22 (m, 1H), 2.98-2.76 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([S:7][CH2:8][CH:9]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][CH2:13][C@@H:12]([C:22]([OH:24])=[O:23])[NH:11][C:10]1=[O:25])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:1]([S:7][CH2:8][CH:9]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][CH2:13][C@@H:12]([C:22]([O:24][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:23])[NH:11][C:10]1=[O:25])(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)C(=O)SCC1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)SCC1CCCCCCCSC[C@@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R)-6-(Pivaloylthiomethyl)-5-oxo-1thia-4-azacyclotridecane-3-carboxylic acid (0.25 g, 0.64 mmol) is dissolved in dimethylformamide (5 ml) and cesium carbonate (0.23 g, 0.71 mmol) is added, followed by benzyl bromide (0.11 g, 0.64 mmol). The mixture is stirred overnight at room temperature, poured into water (300 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers are washed with water (2×100 ml), brine (1×200 ml), dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (3% ethyl acetate/hexane) gives benzyl (3R)-6-(pivaloylthiomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylate, m.p. 135°-137° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#N)=[CH:22][C:21]=1[O:28][CH3:29])(=O)C.FC(F)(F)C(O)=[O:33]>>[CH3:29][O:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[OH:19])[C:24]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C#N)ccc1OC(C)=O
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Product: COc1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)ccc1O
Reaction time: 2 h

Procedure:
A mixture of 19.4 g. (0.1 mol.) of 2-phenylbenzofuran and 19.1 g. (0.1 mol.) of 4-acetoxy-3-methoxybenzonitrile in 20 ml. of trifluoroacetic acid is refluxed for 3 hours. The reaction mixture is cooled, diluted with 200 ml. of water and the resulting aqueous solution is extracted with ether. The extracts are concentrated to dryness and the residue is dissolved in 100 ml. of ethanol and heated with 20 ml. of 10% aqueous sodium carbonate for 2 hours. The mixture is concentrated, the residue extracted with ether and the extracts are dried and concentrated to give 3-(3-methoxy-4-hydroxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25]O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58].O>C(Cl)Cl>[Br:58][CH2:25][C:22]1[N:21]=[CH:20][C:19]([C:17]2[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14]([CH3:36])=[C:13]([CH:18]=2)[C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:37])=[CH:24][CH:23]=1
Reactant: CCN(c1cc(-c2ccc(CO)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CBr)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-(hydroxymethyl)pyridin-3-yl)-2-methylbenzamide (0.35 g, 0.694 mmol) in DCM (5 mL), triphenyl phosphine (0.361 g, 1.38 mmol) was added and stirred it at room temperature for 10 min. Finally CBr4 (0.318 g, 1.38 mmol) was added portion wise to it and resulting solution was stirred at room temperature for 18 h. On completion, water was added to the reaction mass and extraction was carried out using DCM. Combined organic layers were dried over sodium sulphate, concentrated under reduced pressure to give crude material which then column purification gave desired compound (0.35 g, 89%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Yield: 98.1 %

Procedure:
(S)-4-benzyl-2-oxazolidinone (2.26 g, 15.0 mmol) and 30 ml of dehydrated tetrahydrofuran were mixed, which was cooled to −78° C. under an atmosphere of argon. Under stirring, 1.6 mol/l solution of n-butyl lithium in hexane (10.3 ml, 16.5 mmol) was added dropwise for over 10 minutes and the mixture was stirred for 30 minutes as it was. Next, butyryl chloride (1.56 ml, 15.0 mmol) dissolved into 30 ml of dehydrated tetrahydrofuran was added dropwise for over 10 minutes and the mixture was stirred for 30 minutes, followed by stirring for 3 hours at room temperature. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and concentrated. Water was added to the residue, which was extracted with ethyl acetate. The extract was washed with water and with brine, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:1 v/v) to obtain 3.64 g (98%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:28]2[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:27]2=[N:26][CH:25]=1)CCC>CO.ClCCl>[N:14]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]3[N:28]4[CH:29]=[CH:30][C:31]([C:33]([F:34])([F:35])[F:36])=[N:32][C:27]4=[N:26][CH:25]=3)[CH:3]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Brc1cccc(-c2ccccc2-n2cncn2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccccc4-n4cncn4)c3)cnc2n1

Procedure:
1-(3′-Bromobiphenyl-2-yl)-1H-[1,2,4]triazole (91 mg, 0.30 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.25 mmol) by the method of Example 32. The product was obtained by preparative thin-layer chromatography on silica gel with 3% methanol in dichloromethane as eluent followed by high performance liquid chromatography to give 3-[2′-([1,2,4]triazol-1-yl)biphenyl-3-yl]-7-trifluoromethylimidazo[1,2-a]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 8.57 (1H, d, J 7), 7.95-8.11 (3H, m), 7.48-7.66 (7H, m), 7.35 (1H, J 8), 7.27 (1H, m); m/z (ES+) 407 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5](/[CH:21]=[N:22]/[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:4]=1.C([BH3-])#N.[Na+].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([CH2:21][NH:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:4]=1
Reactant: COCn1c(=O)c2c(c3c(OC)cc(/C=N/N4CCOCC4)cc31)NCCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCn1c(=O)c2c(c3c(OC)cc(CNN4CCOCC4)cc31)NCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
The compound (50 mg, 0.12 mmol) prepared in step 2 was dissolved in tetrahydrofuran (2 ml), added with sodium cyanoborohydride (4 mg, 0.06 mmol) and 1.25 N hydrochloric acid methanol solution (5 ml) slowly. The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to remove the solvent. The residue was basified with 1 N sodium hydroxide aqueous solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated to dryness. The residue was then purified by flash column chromatography (dichloromethane:methanol=20:1) to obtain the title compound (18 mg, yield: 38%, yellow solid).
Reaction SMILES: COC([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:19]3[O:18][C:17]([C:20](=[O:23])[NH:21][CH3:22])=[C:16]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:15]=3[CH:14]=[C:13]([CH3:31])[CH:12]=2)[CH2:7][CH2:6]1)=O.C(OC([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[C:52]3[O:51][C:50]([C:53](=[O:57])[N:54]([CH3:56])[CH3:55])=[C:49]([CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:48]=3[CH:47]=[C:46]([CH3:65])[CH:45]=2)[CH2:40][CH2:39]1)=O)(C)C.Cl>>[CH3:22][NH:21][C:20]([C:17]1[O:18][C:19]2[C:11]([N:8]3[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]3)=[CH:12][C:13]([CH3:31])=[CH:14][C:15]=2[C:16]=1[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:23].[CH3:56][N:54]([CH3:55])[C:53]([C:50]1[O:51][C:52]2[C:44]([N:41]3[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]3)=[CH:45][C:46]([CH3:65])=[CH:47][C:48]=2[C:49]=1[CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:57]
Reactant: CNC(=O)c1oc2c(N3CCN(C(=O)OC)CC3)cc(C)cc2c1Cc1ccccc1
Reactant: Cc1cc(N2CCN(C(=O)OC(C)C)CC2)c2oc(C(=O)N(C)C)c(Cc3ccccc3)c2c1
Agent: Cl
Product: CNC(=O)c1oc2c(N3CCNCC3)cc(C)cc2c1Cc1ccccc1
Product: Cc1cc(N2CCNCC2)c2oc(C(=O)N(C)C)c(Cc3ccccc3)c2c1

Procedure:
4-(3-Benzyl-5-methyl-2-methylcarbamoyl-benzofuran-7-yl)-piperazine-1-carboxylic acid methyl ester and 4-(3-Benzyl-2-dimethylcarbamoyl-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid isopropyl ester were each separately treated with ethanolic HCl, following the procedure of step 4 of Example 2, to provide 3-benzyl-5-methyl-7-piperazin-1-yl-benzofuran-2-carboxylic acid methylamide ((M+H)+ 364) and 3-benzyl-5-methyl-7-piperazin-1-yl-benzofuran-2-carboxylic acid dimethylamide ((M+H)+ 378) respectively.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)[N:24]=2)=[C:19]([Cl:33])[CH:18]=1>O1CCOCC1>[Cl:33][C:19]1[CH:18]=[C:17]([NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[CH:22]=[CH:21][C:20]=1[C:23]1[O:27][N:26]=[C:25]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[N:24]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1)OCC(Cl)(Cl)Cl
Yield: 55.3 %

Procedure:
2,2,2-Trichloroethyl chloroformate (1.56 g) is added to a mixture of 1.05 g of potassium carbonate and 1.3 g of 5-(4-amino-2-chlorophenyl)-3-(2-furanyl)-1,2,4-oxadiazole in 30 ml of dioxane. The mixture is heated at reflux for 2 hours and concentrated to dryness. The residue is partitioned between water and chloroform and the aqueous layer is extracted twice with chloroform. The combined chloroform extract is dried, filtered and concentrated to yield the crude product. Recrystallization from benzene/dioxane yields 1.2 g of the title compound, melting point 219°-220°C.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@@:26]2([CH3:27])[C:10](=[CH:11][CH:12]=[C:13]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH:18]([CH:20]=[O:21])[CH3:19])[CH2:9][C@@H:8]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:7]1)=[O:4].CC(C)=[O:36].OS(O)(=O)=O.O=[Cr](=O)=O.[Cr](O)(O)(=O)=O.S(=O)(=O)(O)O>CC(C)=O.O.C(O)(C)C>[CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@@:26]2([CH3:27])[C:10](=[CH:11][CH:12]=[C:13]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH:18]([C:20]([OH:36])=[O:21])[CH3:19])[CH2:9][C@@H:8]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:7]1)=[O:4]
Reactant: CC(C)=O
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1

Procedure:
In 5 ml of acetone was dissolved 120 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde and the solution was stirred with ice-cooling. Then, Jones' reagent prepared by mixing chromic acid with concentrated sulfuric acid and diluting the mixture with water in accordance with the method of K. Bowden et al. (J. Chem. Soc., p. 39, (1946)) was added dropwise to the above solution until the red color of the reagent would be persistent. After the excess reagent was decomposed with isopropyl alcohol, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated to give 85 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].Cl>CC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH:20]([CH3:22])[CH3:21])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 60 °C
Yield: 91.3 %

Procedure:
To a stirred solution of 15.8 g (0.083 mole) of 2-chloro-4-fluoro-5-nitrophenol in 90 mL of acetone was added 17.1 g (0.12 mole) of potassium carbonate followed by a solution of 21.0 g (0.12 mole) of 2-iodopropane in 10 mL of acetone. After complete addition, the reaction mixture was heated at 60° C. for approximately 18 hours. The mixture was cooled and poured into a mixture of ice and concentrated hydrochloric acid. The resultant mixture was extracted with ethyl acetate, and the extract was washed with a 1N sodium hydroxide solution. The washed extract was dried over anhydrous magnesium sulfate and was filtered. The solvent was evaporated under reduced pressure to leave 17.7 g of 4-chloro-2-fluoro-5-(1-methylethoxy)nitrobenzene as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.[OH:32][C@@H:33]([CH2:46][NH2:47])[CH2:34][O:35][C:36]1[C:44]2[NH:43][C:42](=[O:45])[NH:41][C:40]=2[CH:39]=[CH:38][CH:37]=1>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH:28]([NH:47][CH2:46][C@H:33]([OH:32])[CH2:34][O:35][C:36]5[C:44]6[NH:43][C:42](=[O:45])[NH:41][C:40]=6[CH:39]=[CH:38][CH:37]=5)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)[S:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(CC4SC(=O)NC4=O)cc3)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Nc3ccc(N4CCC(NC[C@H](O)COc5cccc6[nH]c(=O)[nH]c56)CC4)cc3)cc2)S1

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 231) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.10 (m, 2H), 2.50-2.70 (m, 2H), 2.70-3.50 (m, 5H), 3.60 (brd, J=11.6 Hz, 2H), 4.00 (brs, 3H), 4.60 (dd, J=9.4, 4.2 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 6.70-6.90 (m, 5H), 7.35 (d, J=8.4 Hz, 2H), 7.55 (d, J 8.4 Hz, 2H), 9.70 (brs, 1H), 10.61 (brs, 1H), 10.72 (brs, 1H); MS (ES) m/z: 667.0 (MH+); HRMS Calcd. for C31H35N6O7S2 (MH+): 677.2009. Found: 677.1999.