Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[S:31][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:30])(=[O:29])[NH2:28])[CH:22]=4)[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl.O>>[S:27]([C:23]1[CH:22]=[C:21]([NH:20][C:17]2[N:16]=[CH:15][C:14]3[C:19](=[C:10]4[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[S:31][C:11]4=[CH:12][CH:13]=3)[N:18]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:30])(=[O:29])[NH2:28]
Reactant: CC(C)(C)OC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)c1cccc(Nc2ncc3ccc4sc(C(=O)O)cc4c3n2)c1
Reaction time: 2.5 h
Yield: 89.5 %

Procedure:
2-(3-Sulfamoyl-phenylamino)-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (1.84 g, 4.02 mmol) was placed in a 100 mL florentine and cooled in an ice-bath. Premixed TFA/dichloromethane/water (1:4:0.1, 9 mL TFA) was added in one portion and the resultant suspension was stirred at 0° C. for 10 minutes. After a further 2.5 hours at room temperature and 1.5 hours at 40° C. the reaction was concentrated under reduced pressure. The solid obtained was azeotroped with dry dichloromethane (3×10 mL), triturated with diethyl ether and isolated by filtration. The solid obtained was washed with diethyl ether (4×5 mL) and dried in a drying pistol at 40° C. overnight to afford the title compound as a yellow powder (1.44 g, 86% yield containing 1.24 eq. TFA). MS (ES+) 400. δH (d6 DMSO) 7.2-7.4 (2H, br s), 7.5 (1H, m), 7.6 (1H, m), 8.0 (3H, m), 8.7 (1H, s), 8.8-8.9 (1H, s), 9.4 (1H, s), 10.4-10.5 (1H, s), 13.4-13.8 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[H-].[Na+].[CH2:13](Cl)[C:14]#[CH:15].[Cl-].[Na+]>CN(C)C=O>[CH2:15]([N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:14]#[CH:13]
Reactant: COC(=O)CNC(=O)OC
Reactant: C#CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(CC(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 51.6 %

Procedure:
3.0 g of methyl N-methoxycarbonylglycinate were dissolved in 30 ml of N,N-dimethylformamide. Ice-cooling the mixture, 820 g of sodium hydride (60% oil dispersion) were added thereto under a nitrogen atmosphere and stirred for 20 minutes. Then 2.3 g of propargyl chloride were dropped thereto over 10 minutes and further stirred for 40 minutes. The reaction mixture was poured into ice-water and then sodium chloride was added thereto to saturate the same. Thereafter the aqueous layer was washed with hexane and it was subjected to two times of extraction with 100 ml of ether. The ether layers were combined together and dried over anhydrous magnesium sulfate and the solvent was evaporated off to obtain 1.95 g of methyl N-propargyl-N-methoxycarbonylglycinate.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:30])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: Cc1oc(-c2ccc(F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 81.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{cyclohexyl[5-(4-fluorophenyl)-2-methyl-3-furyl]methoxy}benzoic acid (163 mg) as well as ethyl 3-(methylamino)propanoate (63 mg) to give the title compound (161 mg, 82%) as an amorphous compound.
Reaction SMILES: [NH2:1][NH2:2].N.[Cl:4][C:5]1[N:6]=[N:7][C:8](Cl)=[CH:9][CH:10]=1>O>[Cl:4][C:5]1[N:6]=[N:7][C:8]([NH:1][NH2:2])=[CH:9][CH:10]=1
Reactant: NN
Reactant: Clc1ccc(Cl)nn1
Agent: N
Solvent: O
Product: NNc1ccc(Cl)nn1
Yield: 85.9 %

Procedure:
To a solution of 25% aqueous hydrazine (4.25 1) and 32% ammonia (7.5 1) in water (23.7 1) 3.6-dichloropyridazine (3 kg) was added, while maintaining a gentle stream of nitrogen. The mixture was headed at reflux for 2 hours and, after cooling, the precipitate was collected, washed with water and dried to afford 2.5 kg (85.9%) of 3-chloro-6-hydrazinopyridazine, m.p. 140°-141° C.
Reaction SMILES: [O:1]([CH:8]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[O:1]([CH:8]([O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Oc1ccccc1)Oc1ccc(N2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Oc1ccccc1)Oc1ccc(N2CCCCC2)cc1

Procedure:
3.55 g. of ethyl phenoxy-(4-piperidinophenoxy)-acetate is refluxed with 1 g. of NaOH in 40 ml. of methanol for 4 hours. The mixture is concentrated by evaporation, mixed with water, washed with ether, hydrochloric acid is added thereto to a pH of 5, and phenoxy-(4-piperidinophenoxy)-acetic acid is thus obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])[CH:2]([CH3:4])[CH3:3].[Cl:20]CCl.S(Cl)(Cl)=O>CN(C)C=O>[CH2:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]([Cl:20])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)COC(=O)NC(Cc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)COC(=O)NC(Cc1ccccc1)C(=O)Cl

Procedure:
A solution of 2-isobutoxycarbonylamino-3-phenyl-propionic acid (5 gm), dichloromethane (25 mL) and dimethylformamide (0.5 mL) was cooled to 0-5° C. To the resulting solution, thionyl chloride (1.5 mL) was added at same temperature. The solvent was distilled out completely to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[N:10]=[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[C:12]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=2[N:14]=1)[NH2:5].[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>>[CH2:27]([NH:29][C:30]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:12]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=3[N:14]=2)=[C:2]([F:1])[CH:3]=1)=[O:31])[CH3:28]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2F)nc2c1CCN(C)C2
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)c(F)c1
Yield: 6 %

Procedure:
Method as example 85 using (S)-3-fluoro-4-(7-methyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline and ethyl isocynate as starting materials. The solvent was removed in vacuo and purified by prep HPLC (low pH) yielding the title compound (4.3 mg, 0.01 mmol, 6%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:4].[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:18]1[CH2:17][C@H:16]([CH3:20])[NH:15][C@H:14]([CH3:13])[CH2:19]1
Reactant: O=C(CCl)Nc1ccccc1Cl
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1

Procedure:
The product of step (i) (5.9 g) was dissolved in ethanol (50 ml) and cis-2,6-dimethylpiperazine (3 g) and sodium hydrogencarbonate (6.63 g) were added at room temperature under a nitrogen atmosphere. The mixture was heated under reflux for 24 hours and the cooled solution was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in 1M HCl (22 ml) and washed with dichloromethane. The aqueous solution was then basified to pH13 with a solution of sodium hydroxide and the product was extracted with dichloromethane. The organic layer was washed with water, brine, collected, dried (MgSO4) and concentrated under reduced pressure to give the subtitle compound as a beige solid. Yield 4 g.
Reaction SMILES: Br[C:2]1[C:3]([F:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:6]=2[CH:17]=1.N1CCCCC1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>C1C=CC([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)=CC=1.[Cu]I>[NH2:16][C:12]1[N:11]=[C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:33]#[C:32][C:30]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)([OH:34])[CH3:31])[C:3]([F:18])=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][N:13]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: Nc1nccc(-n2cnc3cc(F)c(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1cc2c(cc1F)ncn2-c1ccnc(N)n1)c1nccs1
Temperature: 75 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a pressure tube was added 4-(6-Bromo-5-fluoro-benzoimidazol-1-yl)-pyrimidin-2-ylamine (66%, 250 mg, 0.54 mmol), piperidine (1.5 mL), tetrakis(triphenylphosphine)palladium (61.9 mg, 0.05 mmol), copper(I) iodide (10.2 mg, 0.05 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (164.09 mg, 1.07 mmol), degassed with N2 for 5 min and stirred at 75° C. for 3 hr before concentrating in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM: methanol gradient (98:2 to 90:10). The product obtained was triturated with methanol to obtain the title compound as an off-white solid (35 mg, 17.1% yield). 1H NMR (500 MHz, DMSO) delta 1.94 (3H, s), 7.08 (1H, s), 7.13 (1H, d, J=5.36 Hz), 7.18 (2H, br. s.), 7.65-7.73 (2H, m), 7.78 (1H, d, J=3.15 Hz), 8.39 (1H, br. s.), 8.64 (1 H, d, J=6.46 Hz), 9.17 (1H, s); LC-MS: m/z+381.40 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:14]([C:15]([NH:17][C:18]3([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH2:20][CH2:19]3)=[O:16])[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH2:9]2)=[CH:5][CH:4]=1.O[Li].O>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:14]([C:15]([NH:17][C:18]3([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)=[O:16])[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH2:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 78 %

Procedure:
The title compound (E23) (56 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1-(3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[4.1.0]heptane-4-carboxamido)cyclopropyl)benzoate (D140b) (74 mg). (LiOH H2O: 4 eq; reaction time: 10 hrs)
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:12])=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NC(=O)CN)cc1
Reaction time: 18 h

Procedure:
An ethyl acetate solution (45.5 ml) of 4N hydrogen chloride solution was added to 10 g of 2-(tert-butoxycarbonylamino)-N-(4-cyanophenyl)acetamide in a closed vessel and the mixture was stirred for 18 hours. The crystals formed were collected by filtration, washed with ethyl acetate and then dried under a reduced pressure to give 7.7 g of 2-amino-N-(4-cyanophenyl)acetamide hydrochloride. Then, 58.8 ml of an aqueous saturated sodium hydrogencarbonate solution and 20 ml of water were added to 3.7 g of the hydrochloride thus obtained, and the mixture was stirred for 1 hour. The crystals thus formed were collected by filtration and dried under a reduced pressure to give 2.5 g of 2-amino-N-(4-cyanophenyl)acetamide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[C:15]([CH3:17])[N:16]=[C:10]2[C:9]=1[I:18].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(Cl)Cl>[I:18][C:9]1[C:10]2[N:11]([CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1cn2ccc(N)c(I)c2n1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1ccn2cc(C)nc2c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A mixture of sodium carbonate (0.57 g, 5.38 mmol) and amine 23 (1.47 g, 5.38 mmol) in 50 mL of dry CH2Cl2 was treated, under argon, over a period of 15 min with ethyl chloroformate (2.34 g, 22.6 mmol). The reaction mixture was stirred at room temperature for 24 h. Then, water (50 mL) was added and organic layer was recovered, the aqueous layer was extracted with additional CH2Cl2 (3×50 mL). The organic extracts were dried (Na2SO4), filtered and evaporated under vacuum. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford in order of elution: Compound 24 (820 mg, yield: 44%); mp 148° C.; IR (KBr) 3380, 3124, 3049, 2988, 1738, 1642, 1541; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, 3H, J=7.1 Hz), 2.31 (s, 3H), 4.13 (q, 2H, J=7.1 Hz), 6.93 (d, 1H, J=7.1 Hz), 7.78 (s, 1H), 8.35 (d, 1H, J=7.1 Hz), 8.93 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 14.5, 60.7, 81.8, 110.1, 111.5, 125.7, 137.2, 142.7, 144.5, 153.9. Anal. Calcd for C11H12IN3O2: C, 38.28; H, 3.50; N, 12.18. Found: C, 38.04; H, 3.55; N, 12.08.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7](Br)[CH:6]=[N:5]1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC([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)=CC=1>[F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH:6]=[N:5]1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)Oc1c(Br)cnn(CC(F)(F)F)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OC(C)C)cc1
Yield: 80.8 %

Procedure:
A solution of 2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone (1.2 g, 3.8 mmol), 4-(methylthio)phenylboronic acid (704 mg, 4.19 mmol), tetrakis(triphenylphosphine)palladium(0) (220 mg, 5% mmol) and cesium carbonate (2.72 g, 8.3 mmol) in 20 mL of ethylene glycol dimethyl ether was heated to reflux for 5 hours. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (94:6 hexanes/ethyl acetate). The product was obtained as a greenish solid (yield: 1.1 g, 81%). 1H NMR (300 MHz, CDCl3) δ 1.19 (d, J=7.5 Hz, 6H), 2.55 (s, 3H), 4.83 (q, J=9 Hz, 2H), 5.28 (h, J=6 Hz, 1H), 7.32 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.85 (s, 1H). MS (DCI) m/z 359 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:32]/[O:33][CH3:34])/[C:12]([NH:14][C:15]2(SC)[CH2:19][O:18][N:17]([C:20]3([C:26]([O-:28])=[O:27])[CH2:24][CH2:23][C:22](=[O:25])[O:21]3)[C:16]2=[O:29])=[O:13])[N:10]=1)=[O:4].Cl[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42](OO)=O)[CH:37]=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:32]/[O:33][CH3:34])/[C:12]([NH:14][CH:15]2[CH2:19][O:18][N:17]([C:20]3([C:26]([O:28][CH:42]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:36][CH:37]=4)=[O:27])[CH2:24][CH2:23][C:22](=[O:25])[O:21]3)[C:16]2=[O:29])=[O:13])[N:10]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO/N=C(\C(=O)NC1(SC)CON(C2(C(=O)[O-])CCC(=O)O2)C1=O)c1csc(NC(=O)CCl)n1
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O)c1csc(NC(=O)CCl)n1
Reaction time: 20 h
Yield: 62.9 %

Procedure:
In 4 ml of dry methylene chloride was dissolved 210 mg of 2-{(4RS)-4-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2(methoxyimino)acetamido]-4-methylthio-3-oxo-2-isoxazolidinyl}-5-oxo-2-tetrahydrofuran carboxylate. To the solution was added 145 mg of m-chloroperbenzoic acid, and the reaction was allowed to proceed at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to a silica-gel column chromatography, eluting with ethyl acetate - n-hexane (1:1) to give 162 mg of the above-titled Compound (30a).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:23][CH3:24])=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:23][CH3:24])=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCC(NC(C)=O)c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCC(NC(C)=O)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)propyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as pale-brown crystals, m.p.=113-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([NH2:57])[CH:52]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([NH:57][C:22](=[O:23])[CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:26][CH:25]=2)[CH:54]=[CH:55][CH:56]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cc2ncnc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cccc(NC(=O)COc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.9 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenoxy}-acetic acid (150 mg), WSC.HCl (122 mg), and HOBT.H2O (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. m-Anisidine (63 mg) was then added to the solution, and the mixture was stirred at room temperature for 4 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1 N hydrochloric acid, water, and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (29 mg, yield 15%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][N:10]([C:12]([OH:14])=[O:13])[C:9]2[CH:15]=[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]3[NH:18][CH:19]=[C:20]([CH3:22])[C:21]=3[C:8]1=2)(=O)=O.S([O-])(=O)(=O)C.[Cl-:36].[Li+]>CN(C=O)C>[Cl:36][CH2:6][CH:7]1[CH2:11][N:10]([C:12]([OH:14])=[O:13])[C:9]2[CH:15]=[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]3[NH:18][CH:19]=[C:20]([CH3:22])[C:21]=3[C:8]1=2
Reactant: Cc1c[nH]c2c(OCc3ccccc3)cc3c(c12)C(COS(C)(=O)=O)CN3C(=O)O
Reactant: [Cl-]
Agent: CS(=O)(=O)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1c[nH]c2c(OCc3ccccc3)cc3c(c12)C(CCl)CN3C(=O)O
Temperature: 25 °C

Procedure:
200mg (0.29 mmol max) of the product of step 3A, 1,1-dimethylethyl ester of 1-(methanesulfonyloxymethyl) -1,6-dihydro-8-methyl-5-(phenylmethoxy)-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxylic acid, the crude mesylate, is stirred under nitrogen at 80° C. in 3 ml DMF and 40 mg lithium chloride for 25 minutes, when TLC shows the reaction to be complete. The reaction mixture is cooled to room temperature, and partitioned between methylene chloride and water. The layers are separated and the aqueous layer reextracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated under high vacuum. The crude product is chromatographed over 10 g silica gel, eluting with ethyl acetatehexane (20:80). Fraction of 5 ml are collected and the product found by TLC in fractions 7-17, which upon combining and evaporating yield compound 7, 1,1-dtmethylethyl ester of 1-(chloromethyl) -1,6-dihydro-8-methyl-5-(phenylmethoxy)-benzo[1,2-b:4,3-b']dipyrrole-3(2 H)-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]([NH2:21])[CH2:19][OH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:22](=O)(OCC)[O:23]CC.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]4[CH2:19][O:20][C:22](=[O:23])[NH:21]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)OCC
Reactant: CN1CCC(c2c[nH]c3ccc(CC(N)CO)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(CC4COC(=O)N4)cc23)CC1
Temperature: 130 °C

Procedure:
A mixture of the product from step (g) (1.6 g), diethyl carbonate (0.73 ml) and potassium carbonate (0.08 g) was heated at 130° C. for 5 hours. The mixture was cooled, taken up in methanol and the insoluble potassium carbonate filtered off. The filtrate was evaporated in vacuo and the residue eluted through a silica colum using DCM/EtOH/NH4OH (30:8:1) as eluant. The eluate was evaporated in vacuo and the residue recrystallised from isopropanol/ether to give the desired product as a colourless crystalline solid (1.1 g), mp 191°-192° C.