Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:26](Br)[CH:27]=[CH2:28].C(OCC)(=O)C>CN(C)C=O>[CH2:28]([O:19][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 6.5 h
Yield: 14 %

Procedure:
46 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in N,N-dimethylformamide (0.5 mL), and 21 mg of sodium hydrogen carbonate and 30 μL of allyl bromide were added, followed by stirring for 6.5 hours. Ethyl acetate was added to the reaction solution, followed by sequential washing with water and saturated brine and drying over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to afford 7.5 mg of the title compound as a colorless solid (yield 14%). The resulting solid was recrystallized from ethyl acetate-hexane, the generated precipitate was filtered off, the wet crystal was washed with hexane, and subsequently dried under reduced pressure at room temperature to afford the title compound as a colorless crystalline powder. Enantiomeric excess: 999% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 8.0 minutes).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 100 °C
Yield: 95.5 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 5.0 g of 3-cyanophenol and 5.93 g of 2-fluoronitrobenzene followed by addition of 8.71 g of potassium carbonate, and the mixture was stirred with heating at 100° C. for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water 3 times, dried and concentrated. The residue was crystallized from diisopropyl ether to give 9.63 g of the title compound as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C>>[N:20]1([CH2:19][CH2:18][CH2:17][NH:16][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1Cl
Yield: 74.5 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), 4-(3-aminopropyl)morpholine (993 mg, 6.88 mmol) and triethylamine(1.92 mL, 13.76 mmol) were reacted to form the desired product (2.04 g, 74%). LC-MS (m/z) 398.0 (M+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.ClCCl>C(#N)C>[CH2:1]([N:8]1[C:9]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[N:25][N:24]=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1nnnn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolution of the white solid isolated in Step A (8.02 g, 27.2 mmol) in acetonitrile (100 mL) was achieved by heating to reflux. After the solution was cooled to 0° C., NaN3 (2.30 g, 35.4 mmol) and trifluoromethanesulfonic anhydride (10 g, 35.4 mmol) were added. The resulting solution was then stirred at room temperature overnight. Dichloromethane (200 mL) was added. The resulting solution was washed with saturated sodium bicarbonate solution three times and brine one time and then dried over MgSO4. The solution was filtered and concentrated to yield 2-(1-benzyl-1H-tetrazol-5-ylmethyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[S:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C)c(N2CCCCC2=O)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(N2CCCCC2=S)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 161 %

Procedure:
1-(2-Chloro-4,6-dimethylphenyl)piperidin-2-one (18.8 g) and Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (19.2 g) were combined in 150 mL toluene and the mixture was stirred in an 80° C. oil bath for 3 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated on the rotary evaporator and the residue was chromatographed on silica gel, eluting with 9:1 hexane/acetone, to provide 19.4 g of 1-(2-chloro-4,6-dimethylphenyl)piperidine-2-thione, mp 146.8-148.0° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:20](=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH:5]1([C:11]2[C:12]([CH3:19])=[C:13]([C:14]([CH3:18])=[C:15]([CH3:17])[CH:16]=2)[C:20]([OH:22])=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Cc1cc(C)c(C2CCCCC2)cc1C
Reactant: O=C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1cc(C2CCCCC2)c(C)c(C(=O)O)c1C

Procedure:
A 350 ml flask is charged with 44.0 g (0.33 mol) of aluminium chloride and 80.9 g (0.40 mol) of 1-cyclohexyl-2,4,5-trimethylbenzene (97.7%; of Example E). With stirring, CO2 gas is passed over the reaction mixture over c. 17 hours at room temperature. The dark brown solution is then diluted with 200 ml of toluene and poured onto ice. The two phases are separated and the organic phase is extracted with 10% sodium hydroxide solution. The basic aqueous phase is acidified with hydrochloric acid and extracted with toluene. The toluene phase is concentrated, giving 12.3 g of crystals. These crystals are recrystallised repeatedly from petroleum ether and then from hexane ethyl acetate. The purified crystals have a melting point of 170°-172° C. 1H-NMR analysis confirms this structure.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=[N+:14]=[N-:15]>>[ClH:1].[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][N:13]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]2[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=2)[N:15]=[N:14]1
Reactant: [N-]=[N+]=NCc1ccco1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccco3)nn2)c[nH]1
Yield: 50 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.093 g, 0.500 mmol) was reacted with 2-azidomethyl-furan (0.074 g, 0.601 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1Himidazol-2-ylamine hydrochloride (0.075, 50%) as a pale yellow solid. 1H NMR (300 MHz, DMSO) δ 7.85 (s, 1H), δ 7.65 (s, 1H), δ 6.70 (s, 2H), δ 6.64 (s, 1H), δ 6.52 (t, 1H), δ 6.46 (s, 1H), δ 5.58 (s, 2H), δ 2.61 (t, 2H), δ 2.41 (t, 2H), δ 1.82 (m, 2H) ppm; 13C NMR (75 MHz, DMSO) δ 163.6, 149.4, 147.9, 147.4, 144.3, 128.5, 122.6, 111.5, 110.3, 109.9, 46.3, 28.4, 24.9 ppm; HRMS (ESI) calcd for C13H16N6O (M+) 272.1458. found 272.1460.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24]O>>[CH3:24][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCNC(=O)OCc1ccccc1
Yield: 58 %

Procedure:
To a solution of 6-benzyloxycarbonylamino-hexanoic acid (10 g, 38 mmol) in methanol (200 mL) at room temperature was added thionyl chloride (11 g, 95 mmol). The reaction mixture was then refluxed for 16 h. The solvent was concentrated in vacuo, the residue was dissolved in ethyl acetate (200 mL) and washed with brine (3×150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was- purified by flash column chromatography (silica, 14% ethyl acetate in hexane) to afford the titled compound (6.2 g, 58%), a colorless liquid.
Reaction SMILES: C(Cl)Cl.[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)#[N:5].BrN1C(=[O:27])CCC1=O>O>[C:4]([N:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH:9]([OH:27])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2)#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CN1c2ccccc2CCc2ccccc21
Solvent: O
Solvent: ClCCl
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
150 ml of CH2Cl2, 25 g of (I) and 21 g of N-bromosuccinimide are loaded under nitrogen in a 500 ml pyrex round-bottom flask, and irradiated from the outside with a 300 watt halogen lamp, refluxing for 2 hours. 150 ml of water are added. 80 ml of CH2Cl2 are distilled off, 150 ml of toluene and 5 g of PEG 6000 are added while distilling off CH2Cl2 at inner temperature of 85-90° C. The mixture is left for 3 hours at said temperature, water is removed at 60° C., the mixture is washed with 2×50 ml of water and 30-40 ml of toluene are distilled off at 40 mm/Hg. The mixture is cooled at 0° C. for 2-3 hours, filtered, washed with 20 ml of toluene at 0° C. and air-dried at 60° C., to obtain 20.4 g of (VI) m.p. 110-111° C., with good purity. From mother liquors a further 1.8 g are recovered (overall yield 82%).
Reaction SMILES: C(N[C:4]([NH:9][CH2:10][C:11]#C)=[N:5][CH2:6][CH2:7]S)#N.[C:13]([NH:15][C:16]([NH:21][C:22]([CH3:26])([C:24]#[CH:25])[CH3:23])=[N:17][CH2:18][CH2:19][SH:20])#[N:14]>>[C:13]([NH:15][C:16]([NH:17][CH2:18][CH2:19][S:20][CH2:11][C:10]1[NH:9][CH:4]=[N:5][C:6]=1[CH3:7])=[N:21][C:22]([CH3:26])([C:24]#[CH:25])[CH3:23])#[N:14]
Reactant: C#CC(C)(C)NC(=NCCS)NC#N
Reactant: C#CCNC(=NCCS)NC#N
Product: C#CC(C)(C)N=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The general procedure of Example 1C is repeated except that the N-cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N-cyano-N'-(2-methyl-3-butyn-2-yl)-N"-(2-mercaptoethyl)guanidine, and the title product is thereby produced.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14]CC)=[O:13])=[CH:8][NH:9]2)=[N:4][CH:3]=1.[OH-].[Na+].C>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c2cc(Br)cnc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2cc(Br)cnc2c1O
Reaction time: 0.03 h

Procedure:
Ethyl 7-bromo-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (1 g, 3 mmol) and 2.5 M NaOH (10 mL) were refluxed for 1 h in a RBF fitted with a reflux condenser. The hot, heterogeneous mixture was diluted with boiling water at which point a tan precipitate dissolved. Charcoal was added to the solution, which was swirled for 2 min and then the mixture was filtered. Glacial acetic acid was added to the filtrate and a white precipitate started to form (pH adjusted to 4). The precipitate was filtered off upon cooling, washed with water and dried to provide the desired product as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][NH:6][N:5]=[CH:4]1)[CH3:2].[CH2:8]([N:10]=[C:11]=[S:12])[CH3:9]>C(O)C>[CH2:8]([NH:10][C:11]([N:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[CH:7]=[N:6]1)=[S:12])[CH3:9]
Reactant: CCC1C=NNC1
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)N1CC(CC)C=N1
Yield: 1 %

Procedure:
2.68 g (1 mol equiv.) 4-Ethyl-4,5-dihydro-1H-pyrazole (synthesized as described in WO 2008/034863) and 3.11 mL (1.3 mol equiv.) ethyl isothiocyanate were added to 20 mL ethanol. The reaction mixture was refluxed overnight, silica gel was added and volatiles were removed under reduced pressure. Purification by flash chromatography on silica gel (Et2O:PA=1:3) afforded 1.80 g (36%) 4-ethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J=7.5 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.47-1.71 (m, 2H), 3.08-3.18 (m, 1H), 3.63-3.72 (m, 2H), 3.86 (dd, J=11.5, 7.1 Hz, 1H), 4.25 (t, J=11.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 7.12 (br.s., 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:13]=1)=[O:11])[CH3:8]>C(#N)C>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([C:25]([CH3:26])([CH3:28])[CH3:27])[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: CC#N
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 61.8 %

Procedure:
To a refluxed solution of 487 mg (5.65 mmoles) piperazine in 30 mL acetonitrile was gradually added 612 mg (1.87 mmole) of 1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-7-chloro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester over a 10 mn period. The solution was refluxed 30 minutes and evaporated to dryness. The residue was taken up in water and filtered to give 435 mg of 7-piperazinyl-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])([P:3]([O:8][CH2:9][CH3:10])(=[O:7])[O:4][CH2:5][CH3:6])[CH3:2].CCCCCC.C([Li])CCC.CSC1C=CC(S[Cl:39])=CC=1>O1CCCC1>[Cl:39][C:1]([P:3]([O:4][CH2:5][CH3:6])(=[O:7])[O:8][CH2:9][CH3:10])([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C)P(=O)(OCC)OCC
Reactant: CSc1ccc(SCl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(OCC)C(C)(Cl)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 13.29 g (40 mmol) of tetraethyl ethane-1,1-diphosphonate in 120 ml of dry tetrahydrofuran was cooled to -78° C. in an argon atmosphere followed by the addition of 24.24 ml (40 mmol) of a n-butyllithium hexane solution (1.65 mmol/ml) and stirring for 30 minutes. After adding a solution of 7.63 g (40 mmol) of 4-methylthiobenzenesulfenyl chloride in 50 ml of dry tetrahydrofuran to this mixture, the reaction mixture was allowed to warm up to room temperature followed by stirring for 3 hours. After pouring the resulting mixture into icewater, the mixture was extracted with ethyl acetate (3×150 ml). The solvent was distilled off under reduced pressure after the combined organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. A mixture of tetraethyl 1-methylthiophenyl)thio]ethane-1,1-diphosphonate and tetraethyl 1-chloroethane-1,1-diphosphonate was obtained as the residue. This mixture was then carefully purified with column chromatography (developing solvent: ethanol: ethyl acetate=5:95) to obtain 7.12 g of the target compound in the form of a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]1[CH:33]=[CH:32][C:25]2[CH:26]=[C:27]([C:29](O)=[O:30])[O:28][C:24]=2[CH:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:27]1[O:28][C:24]2[CH:23]=[C:22]([O:21][CH3:20])[CH:33]=[CH:32][C:25]=2[CH:26]=1)=[O:30]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: COc1ccc2cc(C(=O)O)oc2c1
Product: COc1ccc2cc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)oc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-methoxy-benzofuran-2-carboxylic acid. MS: 434.2 (M+H).
Reaction SMILES: C[Li].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:10].O1CCC[CH2:29]1>C1C=CC=CC=1.CCCCCC>[OH:10][C:9]([C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH3:29]
Reactant: COc1ccc(C(=O)Nc2ccccc2C(=O)c2ccccn2)cc1
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Nc2ccccc2C(C)(O)c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
Methyl lithium (0.24 mole, 142 ml. of 1.7 molar in ether) is added to 2'-(2-pyridinecarbonyl)-p-anisanilide (36.6 g., 0.11 mole) in 400 ml. of tetrahydrofuran in 15 min. with stirring at 10° -20° C. Stirring is continued for another 30 min., the reaction mixture hydrolyzed by addition of 300 ml. of water, concentrated under reduced pressure until the tetrahydrofuran solvent is substantially removed, and the mixture extracted with ethyl acetate. The ethyl acetate extract washed with water, brine, dried over sodium sulfate and concentrated affords a residual dark brown oil. The residue taken up in benzene and diluted with hexane affords 2'-[1-hydroxy-1-(2-pyridyl)ethyl] -p-anisanilide, m.p. 127° -128° C., from aqueous-methanol.
Reaction SMILES: C(N(CC)CC)C.C([NH:11][CH:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13]([OH:15])=[O:14])(=O)C>C(OCC)(=O)C>[NH2:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: CC(=O)NC(C(=O)O)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC(C(=O)O)c1ccccc1

Procedure:
Triethylamine (8.39 ml) was added to a suspension of DL-N-acetyl-2-cyclohexylglycine (10.00 g) obtained from α-aminophenylacetic acid according to a known method [Collect. Czeck. Chem. Commun., 31: 4563 (1996)] in ethyl acetate (50 ml). Ethyl chlorocarbonate (5.28 ml) was dropwise added to the mixture under ice-cooling. The mixture was stirred under ice-cooling for one hour, added with ethyl acetate (150 ml), and washed successively with water and saturated brine. The ethyl acetate solution was concentrated under reduced pressure to give 9.86 g of the title compound as an oil.
Reaction SMILES: [OH:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][O:23][C:17]=4[CH:16]=3)=[CH:13][C:5]=2[S:4][C@H:3]1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][N:7]1[C:6]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][O:23][C:17]=4[CH:16]=3)=[CH:13][C:5]=2[S:4][C@@H:3]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:2]([OH:1])[C:8]1=[O:9]
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccc5c(c4)OCO5)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccc5c(c4)OCO5)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1

Procedure:
Following a procedure similar to that described in Example 11(d). 0.68 g of (2S, 3S)-2,3-dihydro-3-hydroxy- 2-(4-methoxyphenyl)-8-(3,4-methylenedioxyphenoxy)-1,5- benzothiazepin-4(5H)-one [prepared as described in step (c) above] was alkylated with 2-dimethylaminoethyl chloride hydrochloride to afford 0.72 g of the title compound as a gum.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C.O>[Cl:1][C:2]1[N:11]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1COCCN1
Solvent: O
Solvent: CCO
Product: Clc1nc(N2CCOCC2)c2ccccc2n1
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
Twenty grams of 2,4-dichloroquinazoline was suspended in 200 ml of ethanol. To this suspension was added 17.4 g of morpholine. A mildly exothermic reaction ensued with the concomitant dissolution of the suspended dichloroquinazoline. When the reaction subsided, after about 10 minutes, the mixture was heated at reflux for 15 minutes, and then was allowed to cool. The reaction mixture then was diluted with 800 ml of water. The solid which precipitated was collected by filtration and was washed with water. After drying, the solid was recrystallized from 1:2 benzene:hexane, to give 18.5 g of 2-chloro-4-morpholinoquinazoline; m.p. 103°-105°. The following analytical data were obtained:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][OH:48].[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>N1C=CC=CC=1>[C:49]([O:48][CH2:47][C:3]1[CH:4]=[C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
To a solution of alcohol 103 (9.9 g, 14.88 mmol) in pyridine (36 mL) was added benzoyl chloride (1.9 mL, 16.37 mmol) at room temperature. The mixture was stirred at room temperature for 6 hours. The mixture was washed with aq. saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the mixture of anomers of the title compound (10.5 g). The anomeric mixture of 104 was recrystallized with IPA (150 mL). The precipitate was collected by filtration and washed with cold IPA (50 mL) and dried under high vacuum to obtain β-anomer of the title compound 104 (6.13 g, 54%).