Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:25](=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24]
Reactant: O=C(O)c1ccccc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(N)c4)cc3CC[C@@H]12
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(NC(=O)c5ccccc5)c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (50 mg, 0.16 mmol), N,N-dimethylaminopyridine (3 mg, 0.024 mmol), benzoic acid (21 mg, 0.18 mmol), and 0.4 mL of dichloromethane. 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI) hydrochloride (120 mg, 0.64 mmol) was added in one portion, and the mixture was stirred at room temperature for 10 min. The mixture was diluted with dichloromethane, and the organic phase was washed with water followed by brine. The organic phase was dried over sodium sulfate, concentrated, and chromatographed on silica gel (0-50% methanol/ethyl acetate eluent gradient) to give 50 mg (76%) of the title compound as an amorphous foam. mp 257°-262° (decomp.) FDMS m/e=424. α[D]589 =+62.50 (c=0.61, chloroform).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:24])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Cc2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)NC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[2-(4-chloro-phenyl)-acetylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.54 mmol) in dichloromethane (8.0 mL) cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified on silica using gradient elution from ethyl acetate/methanol (2%) to ethyl acetate/methanol (20%). 1H-NMR (CDCL3) δ: 1.15-1.25 (2H, m), 1.80-1.90 (2H, m), 2.60-2.75 (2H, m), 2.90-3.10 (2H, m), 3.5 (2H, s), 3.85 (1H, m), 5.20 (1H, d), 7.15-7.35 (4H, m). ESI-MS m/z: 253 (M+1), UV retention time: 0.87 min.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](=[S:14])([NH2:13])[CH2:11][CH3:12].ClC1C=CC(CO)=CC=1CCO>C(O)C>[CH2:11]([C:10]1[S:14][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:13]=1)[CH3:12]
Reactant: CCC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Agent: OCCc1cc(CO)ccc1Cl
Solvent: CCO
Product: CCOC(=O)c1csc(CC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 3-bromo-2-oxopropanoate (24.7 mL) was added dropwise over 10 min to a solution of propanethioamide [Carboxylic Acid 1, step a] (15.8 g) in ethanol (150 mL) at 0-10° C. under nitrogen. When the addition was complete the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo, the residue diluted with water and extracted into ethyl acetate (×3). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, elution gradient 10, 15 and 20% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a pale green solid. Yield 16.0 g.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.CO[CH:17]([O:20]C)[CH2:18][NH2:19]>>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]1[CH:2]=[CH:11][N:19]=[C:18]1[C:17](=[O:20])[NH:10]2
Reactant: COC(CN)OC
Reactant: Clc1cc2nc(Cl)c(Cl)nc2cc1Cl
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n2ccnc12

Procedure:
By reacting 2,3,6,7-tetrachloroquinoxaline with aminoacetaldehyde dimethyl acetal, following a procedure that is similar to that described in example 1, there is obtained 7,8-dichloroimidazo[1,2-a]quinoxalin-4(5H)-one (m.p. >300° C.). By reacting this product with cyclopentylamine according to the method described in example 3, there is obtained 4-cyclopentylamino-7,8-dichloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=139.4° C.(onset); IR (KBr): 3247, 2961, 1589, 1556 cm-1 ; 1H-NMR (CDCl3): δ7.8 (2H,m), 7.7 (1H,s), 7.55 (1H,s), 6.2 (1H,d), 4.6 (1H,m), 2.4÷1.3 (8H,m); UV (EtOH): λmax =235, 274, 292, 304, 330, 345 nm. Elementary analysis for C15H14Cl2N4 (m.w. 321.21): calcd. C 56.09, H 4.39, N 17.44%; found C 56.13, H 4.41, N 17.52%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:14]([OH:18])[C:15]#[C:16][CH3:17].[H-].[Na+].O>O1CCCC1>[CH2:14]([O:18][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCO
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1cc(-c2ccccc2)ncn1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 186 mg of 4-chloro-6-phenylpyrimidine and 82 mg of 2-butyn-1-ol, to which 47 mg of sodium hydride (60% in oil) was added with stirring at room temperature, followed by further stirring for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-(2-butynyloxy)-6-phenylpyrimidine (the present compound (38)), m.p.: 59.6° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[N:19]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:18]4[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34]>CC1C=CC=CC=1>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:19]2[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:31]([O:32][CH2:33][CH3:34])=[O:35])[CH2:9][CH2:10]2)[CH:22]=1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4n3Cc3cccnc3)CC2)cc1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(Cc2nc3ccccc3n2Cc2cccnc2)CC1
Reaction time: 2 h
Yield: 50 %

Procedure:
To a stirred mixture of 76 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1-(3-pyridinylmethyl)-1H-benzimidazole and 360 parts of methylbenzene were added dropwise 41 parts of ethyl carbonochloridate. Upon completion, stirring was continued for 2 hours at reflux. Another portion of 5 parts of ethyl carbonochloridate was added dropwise. Upon completion, stirring was continued for 2 hours at reflux. After cooling, the organic layer was washed with a sodium carbonate solution, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 35.6 parts (50%) of ethyl 4-[[1-(3-pyridinylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinecarboxylate (57).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:21]([O-])=O)[N:3]=1>[Pd].CCOC(C)=O.CO>[NH2:21][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)C(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)C(C)C)c1
Yield: 82.3 %

Procedure:
A solution of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (0.55 g, 1.739 mmol) in 2:1 EtOAc/MeOH (30 mL) was treated with palladium on carbon (50% wet, 0.206 g, 0.174 mmol) and hydrogenated (1 atm) for 2 days. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate was concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (410 mg, 82%). 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 8.12 (d, J=5.7 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 6.58 (dd, J=5.7, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.95 (s, 2H), 2.69 (m, 1H), 2.04 (s, 3H), 1.02 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 287.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(N)CC>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:13][CH2:5][CH2:4][CH3:3])=[C:15]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCCN
Product: CCCNC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 129.9 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred in n-propylamine (1.0 ml) at 75° C. in a sealed flask for 19 h. Work up as described in Example 1, 2) gave 266 mg (65%) of the title compound as white crystals. Mp 196.5-198.5° C. 1H NMR (300 MHz, CDCl3): δ=0.9 (t, 3H), 1.55 (p, 2H), 2.88 (q, 2H), 7.40 (s, 2H), 7.48 (d, 2H), 7.68 (s, 1H), 7.81 (d, 2H); MA calc for C20H16ClF6N3O2S: C, 46.93%; H, 3.15%; N, 8.21%. Found: C, 46.82%; H, 3.19%; N, 8.10%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[CH2:16]([NH2:18])[CH3:17]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:18][CH2:16][CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: CCN
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCNCc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with ethylamine following procedure B. LC-MS showed the product had the expected M+H+ of 248.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][C@H:3]1[OH:15].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27](Cl)=[O:28]>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27]([NH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][C@H:3]1[OH:15])=[O:28]
Reactant: N[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1O)c1ccc(Cl)c(Cl)c1
Yield: 103.3 %

Procedure:
A solution of 112 (2.1 g) in warm THF (300 mL) was treated with triethylamine (5 mL) and the solution allowed to come to room temperature. A solution of 3,4-dichlorobenzoyl chloride (2.3 g) in THF (50 mL) was added dropwise over 20 min. After stirring over night, the solvent was evaporated to give a solid (3.97 g) that had the appropriate nmr spectrum.
Reaction SMILES: [NH3:1].[O:2]1[CH:8]2[CH:3]1[C:4]([CH3:27])([CH3:26])[O:5][C:6]1[CH:12]=[CH:11][C:10]([S:13]([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=[O:15])=[O:14])=[CH:9][C:7]=12.O>C(O)C>[NH2:1][C@@H:8]1[C:7]2[CH:9]=[C:10]([S:13]([C:16]([F:25])([F:24])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])(=[O:14])=[O:15])[CH:11]=[CH:12][C:6]=2[O:5][C:4]([CH3:26])([CH3:27])[C@H:3]1[OH:2]
Reactant: N
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)F)cc2C2OC21
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reaction time: 72 h

Procedure:
30 ml of 28% v/v aqueous ammonia were added to a solution of 1.086 g of 3,4-epoxy-6-heptafluoropropylsulfonyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (prepared as described in Preparation 3) in 30 ml of ethanol, and the resulting mixture was allowed to stand at room temperature for 3 days. At the end of this time, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and then the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent. The fractions containing the desired compound were then recrystallized from a mixture of ethyl acetate and hexane, to afford 0.796 g of the title compound, melting at 176°-177° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH:10](OCC)[O:11]CC.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH:10]=[O:11]
Reactant: CCOC(C#CCCCCCCCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=CC#CCCCCCCCl
Temperature: 62.5 °C
Yield: 97 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed 9-chloro-1,1-diethoxy-2-nonyne (246.8 g: 1.0 mol), para-toluenesulfonic acid (8.0 g: 0.05 mol), water (170.0 g) and tetrahydrofuran (42.0 g), and stirred at a reaction mixture temperature of from 60 to 65° C. During stirring, the pressure in the reactor was reduced gradually to 26.7 KPa to distill off refluxing ethanol. After stirring for 5 hours, completion of the reaction was confirmed by gas chromatography. The organic phase separated from the aqueous phase of the reaction mixture was washed with a solution of sodium chloride (5.0 g) in water (150.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 9-chloro-2-nonynal [bp: 82-88° C./0.13 KPa, 167.2 g, 0.97 mol]. [Yield: 96.9%]
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:37].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.O>[NH2:37][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (3.00 g, 9.22 mmol) in dichloromethane (60 mL) at rt was added m-CPBA (2.89 g, 9.22 mmol). After 1 h, concentrated ammonium hydroxide (60 mL) was added and the mixture was cooled in an ice bath. To the mixture was added TsCl (1.85 g, 9.68 mmol). The reaction was stirred rapidly overnight at rt. Additional TsCl (0.21 g) was added in the morning and the mixture was stirred 45 min. Water (75 mL) was added and the mixture was extracted with dichloromethane (3×100 mL). The combined organic phases were washed with brine and dried over MgSO4, filtered, and concentrated. The resulting foam was treated with acetonitrile and a white solid formed. The solid was recrystallized from acetonitrile and dried under vacuum to yield 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol as fine tan crystals (1.57 g, 50%), mp 156.5-158.0° C. 1H NMR (300 MHz, d6-DMSO) δ 8.27 (dm, J=8.4 Hz, 1H), 7.59 (dd, J=8.4, 1.2 Hz, 1H), 7.40 (m, 1H), 7.20 (m, 1H), 6.54 (br s, 2H), 4.89 (br s, 2H), 4.82 (br s, 2H), 4.78 (s, 1H), 3.52 (q, J=7.0 Hz, 2H), 1.75-1.43 (m, 8H), 1.14 (t, J=7.0 Hz, 3H). MS (APCI) m/z 341 (M+H+). Anal. calcd for C19H24N4O2: C, 67.04; H, 7.11; N, 16.46. Found: C, 67.12; H, 6.94; N, 16.36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=1
Reactant: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: Fc1cccc(CCl)c1
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Yield: 87 %

Procedure:
The procedure described in Example 3 was repeated using N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described for in Example 50, preparation of starting materials) and 3-fluorobenzyl chloride to give the title compound in 87% yield; NMR spectrum (DMSO-d6) 1.36 (d, 3H), 1.93 (s, 3H), 3.04 (s, 3H), 3.27 (1H obscured by H2O), 4.22 (dd, 1H), 5.07 (m, 1H), 5.25 (s, 2H), 7.16 (t, 1H), 7.29 (m, 5H), 7.45 (m, 1H), 7.65 (dd, 1H), 7.71 (t, 1H), 8.09 (d, 1H), 8.46 (s, 1H), 9.93 (s, 1H); Mass Spectrum MH+ 509.
Reaction SMILES: N[C@@H]1[C:8](=[O:9])[N:7]2[C@@H]1S[C@](C(O)=O)(N1CCN(N=CC3C=CC(C)=CC=3)C1=O)C2.[NH2:28][C@@H:29]1[C:35](=[O:36])[N:34]2[C@@H:30]1[S:31][C@@:32]([N:40]1[CH2:44][CH2:43][N:42]([N:45]=CC3C=CC=C(OC)C=3)[C:41]1=[O:55])([C:37]([OH:39])=[O:38])[CH2:33]2>>[NH2:28][C@@H:29]1[C:35](=[O:36])[N:34]2[C@@H:30]1[S:31][C@:32]([C:37]([OH:39])=[O:38])([N:40]1[CH2:44][CH2:43][N:42]([NH:45][C:8]([NH2:7])=[O:9])[C:41]1=[O:55])[CH2:33]2
Reactant: Cc1ccc(C=NN2CCN([C@]3(C(=O)O)CN4C(=O)[C@@H](N)[C@H]4S3)C2=O)cc1
Reactant: COc1cccc(C=NN2CCN([C@]3(C(=O)O)CN4C(=O)[C@@H](N)[C@H]4S3)C2=O)c1
Product: NC(=O)NN1CCN([C@]2(C(=O)O)CN3C(=O)[C@@H](N)[C@H]3S2)C1=O

Procedure:
(3R,5R,6R)-6-amino-3-carboxy-3-(3-p-methylbenzylideneamino-2-oxoimidazolidin-1-yl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane and (3R,5R,6R)-6-amino-3-(3-anisylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane were treated in the same manner to obtain (3R,5R,6R)-6-amino-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane. The physical property (IR) of this product were identical with that obtained above.
Reaction SMILES: [O-:1][S:2](S([O-])=O)=[O:3].[Na+].[Na+].O.[CH:10]([C:13]([C:16]([C:19]([C:22]([C:25]([CH2:28]I)([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11]>C(#N)C>[CH:10]([C:13]([C:16]([C:19]([C:22]([C:25]([CH2:28][S:2]([OH:1])=[O:3])([F:26])[F:27])([F:23])[F:24])([F:20])[F:21])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11]
Reactant: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CI
Reactant: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S(O)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 70 °C
Yield: 94 %

Procedure:
Na2S2O4 (260 mg, 3.0 mmol) was poured into a 20 ml flask and the inside of the flask was replaced with argon. Water (5.0 ml) was added thereto and then, H(CF2)6CH2I (442 mg, 1.0 mmol) was added dropwise using acetonitrile (5.0 ml). After ten-hour stirring at 70° C., purification was conducted by adding 3N—HCl to the reaction product, extracting with ether, extracting into water layer with an aqueous solution of saturated NaHCO3, again making the solution acidic with hydrochloric acid and then extracting into ether layer. After distilling off the solvent, drying was carried out under reduced pressure to obtain H(CF2)6CH2SO2H (359 mg, 0.94 mmol).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[Cl:23][CH2:24][CH2:25][NH2:26].CN1CCOCC1>CN(C=O)C>[Cl:23][CH2:24][CH2:25][NH:26][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCCl
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(NCCCl)nc3ccccc23)cc1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.671 g (2.0 mmol), 2-chloro-ethylamine hydrochloride 0.58 g (5.0 mmol) and N-methylmorpholine 1.0 mL in DMF 1.0 mL was stirred under microwave irradiation at 130° C. for 20 minutes. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.44-7.46 (m, 1H), 7.34-7.38 (m, 1H), 7.08-7.11 (m, 2H), 6.85-6.91 (m, 3H), 6.65-6.70 (m, 1H), 3.92-3.94 (m, 2H), 3.82-3.84 (m, 2H), 3.82 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[NH:18][C:17](=[O:26])[C@@H:16]2[CH2:27][CH3:28])(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.I[CH2:31][CH3:32].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>CS(C)=O>[CH2:31]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:15]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)(=[O:13])=[O:14])[C@@H:16]([CH2:27][CH3:28])[C:17]1=[O:26])[CH3:32]
Reactant: CCI
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(C)ccc3NC(=O)[C@@H]2CC)cc1
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Solvent: CS(C)=O
Product: CC[C@H]1C(=O)N(CC)c2ccc(C)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
Ethyl 4-{[(2S)-2-ethyl-7-methyl-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl carbonate was treated with iodoethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-1,3-diethyl-4-[(4-hydroxyphenyl)sulfonyl]-6-methyl-3,4-dihydroquinoxalin-2(1H)-one [α]D25=−118° (c=0.0054 G/ML, DMSO); MS (ESI) m/z 375 ([M+H]+); MS (ESI) m/z 373 ([M−H]−); Anal. Calcd for C19H22N2O4S: C, 60.94; H, 5.92; N, 7.48. Found: C, 61.50; H, 5.99; N, 6.89.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:25](=[O:32])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:25](=[O:32])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
To a stirred solution at 0° C. of 1-(2-tert-butylphenyl)piperazine (0.218 g, 1.00 mmol) and triethylamine (0.303 g, 3.00 mmol) in methylene chloride (5.0 mL) was added methyl 4-chloro-4-oxobutanoate (0.171 g, 1.10 mmol) and the resulting reaction mixture was warmed to room temperature. After 2 h the reaction mixture was diluted with methylene chloride (10.0 mL), washed with water (20.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate/heptanes) to provide methyl 4-(4-(2-tert-butylphenyl)-piperazin-1-yl)-4-oxobutanoate (0.245 g, 74%) as an off-white solid.