Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([C:29]([OH:31])=[O:30])=[C:23]([CH3:28])[NH:24][C:25]=1[CH:26]=O>>[CH3:32][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([C:29]([OH:31])=[O:30])=[C:23]([CH3:28])[NH:24][C:25]=1[CH:26]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=2)[NH:11][C:10]1=[O:15]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(CCCN(C)C)c1C(=O)O
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c(C)c(C(=O)O)c1CCCN(C)C)C(=O)N2
Yield: 22.4 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (113 mg) was condensed with 4-(3-dimethylaminopropyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid (119 mg) to give 50 mg 4-(3-dimethylaminopropyl)-2-methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[NH3:20]>>[S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](=[O:13])[NH2:20])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Reactant: N
Product: CC(C)OC(=O)C(C(N)=O)=C1SCS1

Procedure:
A solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate (10 g) in methanolic ammonia (60 ml) was stirred at room temperature for 4 hrs. The mixture was concentrated and purified with n-hexane and ethyl ether to give the titled compound as a white solid. (5.2 g, 68%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1.C1CCCCC1>[C:25]([O:24][C:22](=[O:23])[CH2:21][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Brc1ccc(C2c3ccccc3-c3nccn32)cc1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Temperature: 25 °C

Procedure:
To a solution of 5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindole (3.17 g) in THF (60 mL) at −78° C. was added LAD solution (10.19 mL, 1.5 M in cyclohexane) drop wise. After stirring for 5 minutes tert-butyl bromoacetate was added, cooling bath was removed and the reaction mixture was stirred at room temperature. After 1.5 h the reaction was quenched with aqueous saturated NH4Cl and layers were separated. Aqueous layer was extracted with EtOAc (2×). Combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography using a linear gradient of 1-50% EtOAc in hexanes afforded title compound as a white solid. Mass. found (M+H)+, 427.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](O)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B.CSC.Cl.C1C[O:22]CC1>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([OH:22])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Product: CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 g of 3-nitrophenylacetic acid was added to a solution of 26 ml of 10 M borane-methyl sulfide in 200 ml of THF, and the mixture was stirred at 25° C. for 3 hr. The solution was then acidified with HCl in methanol, followed by evaporation of the solvent. The product 3-nitrophenylethanol (IV, A=H) was partitioned between diethyl ether (Et2O) and aqueous sodium carbonate, and the Et2O layer dried over sodium sulfate. Evaporation of the Et2O afforded 34.8 g of 3-nitrophenylethanol (IV, A=H) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:4]([F:25])[CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: CC(=O)N1CCN(c2cc(F)c(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(F)c2)C1=O
Yield: 66.5 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.23 g) described in Preparation Example 111 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (912 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH:26][CH:25]=1.[Cl-].[Li+]>O1CCOCC1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[N:29]=3)[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cccc(-c2cccc3c2C(=O)OC(C)(C)O3)n1
Temperature: 140 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
10.9 g of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)-benzodioxin-4-one, 16.0 g of 6-methoxy-2-tributylstannylpyridine, 4.25 g of lithium chloride, 0.78 g of tetrakistriphenylphosphine-palladium0 and 40 mg of 2,6-di-t-butyl-4-methylphenol are dissolved in 120 ml of dioxane and the mixture is stirred for 4 h at 140° C. in an autoclave. It is concentrated under reduced pressure and the product is chromatographed on silica gel 60 using ethyl acetate/toluene. 9.1 g (95%) of a solid of m.p. 130-132° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C:7]=2[CH:20]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8][C:7]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C#N)cc2C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C(=N)NO)cc2C1
Temperature: 60 °C
Yield: 78.4 %

Procedure:
A suspension of 1,1-dimethylethyl 7-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 74) (2.016 g, 7.35 mmol), hydroxylamine hydrochloride (1.021 g, 14.70 mmol) and sodium bicarbonate (3.09 g, 36.7 mmol) in ethanol (30 ml) was heated at 60° C. overnight. The grey solid was removed by filtration and the filtrate evaporated. The resulting residue was dissolved in EtOAc, washed with water (3×20 ml), dried (MgSO4) and evaporated to give the title compound (1.77 g) as a white solid. MS (ES): C15H21N3O4 requires 307; found 308 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CN(C)C=O.[H-].[Na+].Br[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Reactant: Brc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Sc2ccsc2)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
3.4 G. of 2-amino-4-mercapto-1-nitrobenzene is dissolved in 40 ml. of dimethylformamide under nitrogen and treated at 20°-25° C with 0.5 g. of 100% sodium hydride. After 1 hour, 2.8 g. of cuprous oxide and 4.0 g. of 3-bromothiophene are added. The mixture is heated in an oil bath for 5 hours at 140°-150° C, cooled, diluted with water, and extracted with chloroform. The chloroform solution is passed through a silica gel column and the eluate evaporated to yield 2-amino-4-(3-thienylthio)-1-nitrobenzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:9][C:10]1([CH3:22])[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([OH:21])=[CH:15][CH:16]=2)[O:11]1.[Cl-].[NH4+]>O1CCCC1>[CH3:9][C:10]1([CH3:22])[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[C:12](=[CH:13][C:14]([OH:21])=[CH:15][CH:16]=2)[O:11]1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccccc2)c2ccc(O)cc2O1
Yield: 57.4 %

Procedure:
Bromobenzene (141.3 g) in dry tethydrofuran (300 ml) was added to magnesium (23.7 g) in dry tetrahydrofuran (100 ml). 2,2-Dimethylchroman-4-one-7-ol (34.5 g) in dry tetrahydrofuran (250 ml) was then added and the solution refluxed for 48 hours. The mixture was poured into ammonium chloride solution, the tetrahydrofuran layer was separated and evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate and the organic layer and the residue from the tetrahydrofuran layer was shaken with 10% sodium hydroxide solution. The basic layer was acidified and re-extracted with ethyl acetate. The organic layers were dried (MgSO4). Removal of the solvent under reduced pressure gave an oil (26 g) which was chromatographed on silica. Elution with ether - petrol (1:1) gave the title compound (14 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:26]2[CH2:27][CH2:28][C:23]([OH:22])([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH2:24][CH2:25]2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCl)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(CC2(O)CCN(CCCNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Yield: 28.4 %

Procedure:
A mixture of 4-benzyloxy-N-(3-chloro-propyl)-benzamide (0.5 g, 1.64 mmol), ), 4-hydroxy-4-(4-methyl-benzyl)-piperidine (0.34 g, 1.65 mmol), potassium carbonate (0.45 g, 3.29 mmol) and 2-butanone (10 ml) was stirred at 60° C. for 48 h. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride methanol from 95:5 to 9:1) to give 4-benzyloxy-N-[3-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-propyl]-benzamide (220 mg, 28%) as light yellow solid. MS: me/e =473 (M+H)+.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>ClCCl>[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(F)cc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(F)cc3c(Cl)n2)cc1
Yield: 88.4 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.12 g), 4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenol (1.70 g), anhydrous potassium carbonate (0.86 g) and methyl ethyl ketone (20 ml) was heated under reflux for a period of 3 hours. The mixture was cooled, diluted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oil which was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (2.00 g) as a yellow oil. The assigned structure was confirmed by proton magnetic spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.29 (3H, t); 1.65 (3H, d); 3.47 (3H, s); 4.27 (2H, q); 4.75 (1H, q); 6.47 (1H, s) 6.85-7.20 (6H, m); 7.30 (1H, d).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][C@H:13]1[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14]1.C([O-])(O)=O.[Na+].O>CCOCC>[CH2:5]([O:4][C:2]([N:16]1[CH2:17][C@H:13]([OH:12])[CH2:14][C@H:15]1[C:18]([OH:20])=[O:19])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
A solution of benzyl chloroformate (50 mL, 0.35 mol) in Et2O (160 mL) was added dropwise, during 10 min, to a rapidly stirred mixture of trans-4-hydroxy-L-proline (39.8 g, 0.308 mol), NaHCO3 (63.7 g, 0.758 mol) and H2O (660 mL). The reaction mixture was stirred at room temperature for 20 h. The layers were separated, and the aqueous layer was washed with Et2O (4×200 mL), cooled, and then acidified to pH 1-2 with concentrated hydrochloric acid The resulting emulsion was extracted with EtOAc (5×200 mL). Combined EtOAc extracts were washed in succession with H2O (3×500 mL) and brine (3×500 mL), dried over MgSO4, and then concentrated in vacuo to give intermediate (4) as a colorless foam (62.7 g, 78%). Additional reactions were carried out to give a total of 284 g of product suitable for further transformation.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[C:19]([CH3:29])[CH:18]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[C:27]([CH3:28])[C:17]([O:16][CH3:15])=[CH:18][C:19]=3[CH3:29])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1cc(C)c(C=CC(=O)O)cc1C
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(C)c(OC)cc3C)nc2n(CC)c1=O
Yield: 52.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.9 g (13.9 mmol) of 4-methoxy-2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.43 g (yield 52%) of Compound 74 as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccc(C(C)C)cc2)oc1C)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
0.28 g (1.0 mmol) rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) and 0.30 g (1.2 mmol) 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole were dissolved under argon in 5.0 ml N,N-dimethylformamide; 0.048 g (1.1 mmol) sodium hydride (55% in mineral oil) were added and the reaction mixture then stirred for 48 hours at ambient temperature. It was then diluted with water and extracted with ether. The combined organic phases were dried over MgSO4 and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of hexane and ethyl acetate) to give 0.32 g (67%) of rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-methyl-1H-indol-5-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[N:28]1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:32]([C:29]3[CH:30]=[CH:31][N:27]([CH3:26])[N:28]=3)(=[O:34])=[O:33])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NCc3ccccc3)ccc2C1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)n1
Temperature: 25 °C

Procedure:
A solution of 6-Benzylamino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (320 mg, 0.95 mmol), methyl-1-H-pyrazole-3-sulfonyl chloride (303 mg, 1.68 mmol) and pyridine (229 μl, 2.84 mmol) in dry dichloromethane (10 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by column chromatography (1% methanol in dichloromethane) to afford the title compound as an off yellow solid (393 mg, 86% yield). HPLC retention time 4.72 min. Mass spectrum (ES+) m/z 505 (M+23, sodium salt).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[CH:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([O:17][S:33]([CH3:32])(=[O:35])=[O:34])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)O)[C@H]2C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e10) (80 mg) was treated with methanesulphonyl chloride and triethylamine in dichloromethane as described in Example 1. After work-up, evaporation of the dichloromethane solution afforded p-nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e11) as a pale-yellow foam (67 mg); νmax (CH2Cl2) 1780, 1700, 1675, 1425, 1245 and 1175 cm-1.
Reaction SMILES: [N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:40][O:41][CH2:42][CH2:43][OH:44].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])[CH:18]=2)[N:13]=[C:12]([O:44][CH2:43][CH2:42][O:41][CH3:40])[C:11]=1[CH2:10][C:9]1[CH:38]=[CH:39][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.174 mmol, Intermediate 64), 2-methoxyethanol (13.7 μL, 0.174 mmol), toluene (2 mL) and sodium hydride (60% dispersion in mineral oil, 17.4 mg, 0.435 mmol) were combined in a round bottom flask under an N2 atmosphere. The contents were heated to reflux and refluxed overnight. The reaction solution turned from a heterogeneous white mixture to slightly yellowish with a moderate amount of precipitate. The contents were cooled to 0° C. in an ice water bath then transferred to a separatory funnel with EtOAc dilution and extracted with saturated, aqueous NH4Cl and saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) then further purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H29Cl2N5O3, 613.2. m/z found, 614.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 8.14 (d, J=2.5 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.64 (dd, J=8.8, 2.1 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.41-7.32 (m, 4H), 6.50-6.46 (m, 1H), 6.36 (s, 1H), 4.66-4.59 (m, 2H), 4.35 (s, 2H), 3.81-3.74 (m, 2H), 3.49 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: [Br-].[N:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N+:3]=[N-:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]([O:41][C:42](=[O:60])[NH:43][CH2:44][CH2:45][CH2:46][O:47][C:48]1[C:57]2[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=2[C:51]([CH:58]=O)=[CH:50][CH:49]=1)([CH3:40])([CH3:39])[CH3:38].O>C1COCC1>[C:37]([O:41][C:42](=[O:60])[NH:43][CH2:44][CH2:45][CH2:46][O:47][C:48]1[C:57]2[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=2[C:51]([CH:58]=[CH:7][CH2:6][CH2:5][N:2]=[N+:3]=[N-:4])=[CH:50][CH:49]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2c1CCCC2
Reactant: [N-]=[N+]=NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=CCCN=[N+]=[N-])c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
(3-Azido-propyl)-triphenylphosphonium bromide (112, 11.5 g, 27 mmol) was stirred with 100 mL of dry THF at −76° C. LiHMDS (0.5 M in toluene, 27 mL) was added and the mixture was stirred for 30 minutes. [3-(4-Formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester (111, 6 g, 18 mmol) in 12 mL dry THF solution was introduced. The reaction mixture was stirred at this temperature for another 30 minutes, and slowly warmed to room temperature. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, concentrated, and purified by flash chromatography (0-25% EtOAc/Hexane) to give 3.5 g 113 {3-[4-(4-azido-but-1-enyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-propyl}-carbamic acid tert-butyl ester.