Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:21])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[CH:25][N:24]=1>CN(C)C=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:29][C:27]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=3)[C:14]2=[O:21])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCc1ccnc(Cl)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C(C)(C)C)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
To a suspension of 1.1 g of sodium hydride in 40 mL of dimethylformamide under argon are successively added 4.9 g of 3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage c) of Example 1 and 4.55 g of 2-chloro-4-(chloromethyl)pyridine. The reaction mixture is stirred for 48 hours at room temperature and then diluted with 260 mL of water. The solid formed is filtered off, rinsed with diisopropyl ether and dried to give 4.61 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[Cl:19])[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:12]([Cl:11])[CH:13]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: Clc1ccc(Nc2nc3ccccc3[nH]2)cc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,4-dichloroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp>270° C.). MS(ES+) m/z 278 (M+, 100).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>CCCCO>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: NCc1cccc(Cl)c1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1nc(NCc2cccc(Cl)c2)c2nc[nH]c2n1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (1 g, 1 eq, 5.9 mmol) in n-BuOH (50 ml) under an argon atmosphere, was added DIEA (2.6 ml, 2.5 eq, 14.75 mmol) followed by 3-chloro-benzylamine (1.25 g 1.5 eq, 8.85 mmol). The reaction mixture was heated at 100° C. for 3 hours after which the reaction was complete. The solvent was evaporated in vacuo and the residue purified by gradient column chromatography on silica gel, eluted with DCM:ether:MeOH (55:45:0→55:43:2), to afford the title compound as a white solid; Yield: 1.15 g (70%). δH (250 MHz, d6-DMSO) 4.78-4.6 (2 H, m, NHCH2Ar), 7.41-7.28 (4 H, m, ArH), 7.57 (1 H, s, br, ArH), 8.15 (1 H, s, br, NH), 8.88 (1 H, s, br, NH); δC (250 MHz, d6-DMSO) 142.3 (C), 133.02 (C), 132.92 (C), 130.25 (CH), 130.17 (C), 127.82 (CH), 127.27 (CH), 127.03 (CH), 126.76 (C), 125.92 (CH), 116.4 (C), 115 (C), 42.67 (CH2); m/z 278 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([O:23]CC)=[O:22])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([OH:23])=[O:22])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1c(Cl)ccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A mixture of ethyl 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.74 g), 4N aqueous sodium hydroxide solution (1.2 ml), tetrahydrofuran (6 ml) and methanol (4 ml) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, and acidified with 10% aqueous citric acid solution, and the resulting crystals were collected by filtration, washed with water, and dried to give the title compound (0.69 g, quantitative) as colorless crystals. melting point 286-288° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[NH2:11][CH2:10][CH:9]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: N#CC(=Cc1cccc(Cl)c1)c1cccc(O)c1
Agent: [Pd]
Solvent: CO
Product: NCC(Cc1ccccc1)c1cccc(O)c1

Procedure:
3-(3-Chlorophenyl)-2-(3-hydroxyphenyl)acrylonitrile (3.6 g, 14.08 mmol) was dissolved in 100 ml methanol, containing 0.02 eq Pd/C (0.3 g, 0.28 mmol) 10% on C. Hydrogenation was performed at room temperature over night. Reaction was filtered through celite and the solvent evaporated. The residue was suspended in ethyl acetate and the white precipitate was filtered and dried m=3.0 g (94%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:4]
Reactant: CCCCCCO
Reactant: CSCCC(O)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a 4 neck 1 L round bottom flask fitted with a reflux condenser, dean stark trap, thermocouple, and mechanical overhead stirrer was added 2-hydroxy-4-(methylthio)butanoic acid (100 g, 666 mmol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-hexanol (125.4 mL, 999 mmol), sodium hydrogen sulfate (1.60 g, 13.32 mmol), and toluene (500 mL). The reaction was heated to reflux with removal of water (20 mL) during the course of about 5.5 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and the organic layer was washed with saturated NaHCO3 (1×250 mL), DI water (1×250 mL) and brine (2×250 mL), dried over sodium sulfate, filtered and evaporated to give a brown oil (253.3 g). The oil was purified by kugelrohr distillation at 100° C. and 0.1 Torr vacuum to give a colorless oil (100.0 g, 64.1%). m/z 257 (MNa+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([I:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:15]([O:7][C:8]1[C:9]([I:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccnc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
152.6 g of potassium carbonate and 15.3 g of cesium carbonate are added to a solution of 122 g of 3-hydroxy-2-iodopyridine and 65.7 ml of benzyl bromide in 1.5 l of dimethylformamide, and the suspension is stirred under argon atmosphere for 20 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with dichloromethane, the filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel with hexane/10-20% ethyl acetate. 146.3 g of 3-benzyloxy-2-iodopyridine is obtained as oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:22]([O:24]CC)=[O:23])[C:5]2=[O:27].Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:27]
Reactant: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)cc1
Temperature: 120 °C
Yield: 87.6 %

Procedure:
A mixture of ethyl 6,7,8-trifluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.37 g), conc. hydrochloric acid (1 ml) and 90% acetic acid (4 ml) is heated at 120° C. for 1 hour. After cooling, the precipitated crystals are separated by filtration, washed with water and with a mixture of ethanol and ether to give 6,7,8-trifluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g).
Reaction SMILES: Br[C:2]1[S:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[C:3]=1[CH:19]1[CH2:21][CH2:20]1.[CH3:22]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].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.O>[CH:19]1([C:3]2[C:4]3[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]=3[S:18][C:2]=2[CH3:22])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(sc(Br)c2C2CC2)C1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1sc2c(c1C1CC1)OCCN(C(=O)OC(C)(C)C)C2
Yield: 76.1 %

Procedure:
A solution of tert-butyl 7-bromo-8-cyclopropyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (264 mg), methylboronic acid (169 mg), potassium phosphate (600 mg), tetrakis(triphenylphosphine)palladium (81.7 mg) and DME (3 mL) was stirred at 80° C. for 20 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2→10% ethyl acetate/hexane) to give the title compound (166 mg, 76%) as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([CH:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]2)=[O:7])[CH2:3]1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1.[H-].[Na+]>CS(C)=O.CCOC(C)=O>[CH3:32][C:28]1[N:29]=[CH:30][C:31]([O:1][CH:2]2[CH2:3][N:4]([C:6]([CH:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:10][CH2:9]3)=[O:7])[CH2:5]2)=[CH:26][CH:27]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: O=C(OCc1ccccc1)N1CCCC(C(=O)N2CC(O)C2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(OC2CN(C(=O)C3CCCN(C(=O)OCc4ccccc4)CC3)C2)cn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
To a solution of benzyl 4-[(3-hydroxyazetidin-1-yl)carbonyl]azepane-1-carboxylate (97 mg, 0.29 mmol) and 4-chloro-2-methylpyridine (52 μl, 0.46 mmol) in DMSO (2 ml) was added NaH (37 mg of a 60% dispersion in mineral oil, 0.93 mmol). The mixture was stirred at room temperature for 12 hours, 50° C. for 3 hours and a further 12 hours at room temperature. The reaction was then diluted with EtOAc (20 ml) and washed with water (3×10 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 99:1:1 to 95:5:1 DCM/MeOH/2M NH3 in MeOH) to give the title product as colourless oil (35 mg, 29%).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl.CO>[CH3:1][N:2]([CH3:28])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1
Reactant: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 2-{4-[(dimethylamino)carbonyl]phenyl}-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 41) (194 mg, 0.50 mmol) in dichloromethane (14 ml) was added trifluoroacetic acid (7 ml). The resulting mixture was stirred at room temperature, under argon, for 2 hours and then diluted with methanol. Reaction was purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Resulting crude product was purified further by column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol/dichloromethane (0-3%) to afford the title compound (D42). MS (ES+) m/e 285 [M+H]+.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][OH:12])=[N:8][CH:7]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:9]1[S:10][C:6]([CH2:5][O:4][CH3:3])=[CH:7][N:8]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1cnc(CO)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1cnc(COS(C)(=O)=O)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-(methoxymethyl)thiazol-2-yl)methanol (201 mg, 1.26 mmol) in dry CH2Cl2 (10.0 mL) was treated at 0° C. with Et3N (0.23 mL, 1.63 mmol) followed by DMAP (15.6 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.59 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (10 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 300 mg of crude (5-(methoxymethyl)thiazol-2-yl)methyl methanesulfonate as an orange oil. LC-MS-conditions 07: tR=0.59 min, [M+H]+=238.07. A solution of this crude material (300 mg) in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (1.50 g of a 9.6% solution in DMF, 1.26 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.43 mL, 2.53 mmol) and the reaction mixture was stirred for 24 h at 50° C. Water (10 mL), followed by EA (10 mL) was added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.29. LC-MS-conditions 07: tR=0.70 min, [M+H]+=255.85.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2ccc(N)cc2)CC1

Procedure:
10.0 g (45 mmol) 1-methyl-4-(4-nitro-phenyl)-piperazine are dissolved in 250 ml of ethanol, then combined with 2 g palladium/charcoal (10%) and hydrogenated at 5 bar hydrogen for 2 hours. Then the reaction mixture is suction filtered and the filtrate is concentrated by evaporation. The residue is recrystallised from cyclohexane. Yield: 7.7 g
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][C@H:9]1[O:24][C:22](=[O:23])[C@H:21]([CH3:25])[C@@H:20]([O:26][C@@H:27]2[O:32][C@@H:31]([CH3:33])[C@H:30]([OH:34])[C@@:29]([O:36][CH3:37])([CH3:35])[CH2:28]2)[C@H:19]([CH3:38])[C@@H:18]([O:39][C@@H:40]2[O:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([N:47]([CH3:49])[CH3:48])[C@H:41]2[OH:50])[C@:16]2([CH3:51])[O:17][C:13](=[C:14]([CH3:52])[CH2:15]2)[C@H:12]([CH3:53])[C@@H:11]([OH:54])[C@@:10]1([OH:56])[CH3:55]>CO>[CH3:53][CH2:12][C@@H:11]([OH:54])[C@@:10]([OH:56])([C@@H:9]1[O:24][C:22](=[O:23])[C@H:21]([CH3:25])[C@@H:20]([O:26][C@@H:27]2[O:32][C@@H:31]([CH3:33])[C@H:30]([OH:34])[C@@:29]([O:36][CH3:37])([CH3:35])[CH2:28]2)[C@H:19]([CH3:38])[C@@H:18]([O:39][C@@H:40]2[O:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([N:47]([CH3:49])[CH3:48])[C@H:41]2[OH:50])[C@:16]2([CH3:51])[O:17][C:13](=[C:14]([CH3:52])[CH2:15]2)[C@@H:8]1[CH3:7])[CH3:55]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC[C@@H](O)[C@@](C)(O)[C@@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@@H]1C

Procedure:
Synthesis of EM701 was disclosed in detail in WO 02/14338 A1. A glacial acetic acid solution of erythromycin was stirred at room temperature for 2 hours, and aqueous sodium hydrogencarbonate solution was slowly added and neutralized. The reaction mixture was extracted with chloroform. The organic layer was dehydrated by adding anhydrous sodium sulfate, which was removed off by filtration to obtain crude product. The crude product was purified by silica gel column chromatography with chloroform-methanol-aqueous ammonia (10:0.5:0.01→10:1:0.05) to obtain erythromycin A enol ether. Potassium carbonate was added to methanol solution of erythromycin A enol ether and refluxed for 2 hours. After solvent was removed, the residue was dissolved in aqueous sodium hydrogencarbonate and the mixture was extracted with chloroform. The extract was dehydrated with sodium sulfate, filtered and distilled off. The obtained crude product was purified by silica gel column chromatography with chloroform-methanol-aqueous ammonia (10:0.5:0.01→10:1:0.05) to obtain EM701 (white powder).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([OH:7])=O.[NH2:12][CH:13]1[C:43](=[O:44])[N:15]2[C:16]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:11])/[C:4](=[N:8]/[O:9][CH3:10])/[C:5]([NH:12][C@@H:13]1[C:43](=[O:44])[N:15]2[C:16]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:28])=[C:17]([CH2:20][S:21][C:22]3[S:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cnns3)CS[C@H]12
Reactant: CO/N=C(\C(=O)O)C(=O)CCl
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CO/N=C(/C(=O)CCl)C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cnns3)CS[C@H]12
Yield: 22.5 %

Procedure:
A solution of 4-chloro-2-(Z)-methoxyimino-3-oxo-butanoic acid (4.05 g, 22.6 mmol.), diphenylmethyl 7-amino-3-[(1,2,3-thiadiazol-5-yl)thiomethyl]ceph-3-em-4-carboxylate (11.2 g, 22.6 mmol.) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (5.58 g, 22.6 mmol.) in 200 ml of methylene chloride was stirred at room temperature for 3 hours. The solution was evaporated to dryness at reduced pressure and the residue was taken up in 150 ml of ethyl acetate which was extracted with 50 ml aliquots of 1N hydrochloric acid, water, saturated sodium bicarbonate, water and brine. The ethyl acetate was dried over magnesium sulfate, evaporated to dryness and the resulting product was purified by flash chromatography on silica gel 60 using ethyl acetate:hexane (1:2) as the eluent to afford 3.34 g of the desired compound:NMR (CDCl3) δ3.52 (pair of d, 2H, J=18 Hz, endocyclic --CH2S--), 4.05 (pair of d, 2 H, J=13 Hz, exocyclic --CH2S--), 4.15 (S, 3H, --OCH3) j, 4.59 (S, 2H, ClCH2 --), 5.04 (d, 1H, J=4.7 Hz, 6H of 7ACA), 5.88 (dd, 1H, J=4.7 and 8.6 Hz, 7H of 7ACA), 6.89 (S, 1H, --CH--), 7.33 (m, 10H, aromatic H), 8.37 (S, 1H, thiadiazole H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:22](O)=[O:23])[O:13][C:12]1([CH3:35])[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH:43][C:22](=[O:23])[C:21]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:20][C@@H:14]2[O:13][C:12]([CH3:35])([CH3:34])[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C@H:15]2[CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:38][CH:37]=1
Reactant: CC(C)C[C@H]1[C@H](C=C(CCOC2CCCCO2)C(=O)O)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: NCc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@H]1[C@H](C=C(CCOC2CCCCO2)C(=O)NCc2ccncc2)OC(C)(C)N1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
98 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl-2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid was dissolved in 0.4 ml of dry dichloromethane, and 21 μl of 4-picolylamine, 30 mg of 1-hydroxybenzotriazole and 45 mg of N,N'-dicyclohexylcarbodiimide were added thereto at 0° C. under stirring. The mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. Insolubles were filtered off, and 20 ml of ethyl acetate was added. The mixture was washed with a saturated sodium hydrogencarbonate aqueous solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (2 g of Kieselgel 60) by using chloroform/methanol (20/1) to obtain 121 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-4-isobutyl-2,2-dimethyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid 4-picolylamide as a colorless oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:42])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34]C(=O)OC(C)(C)C)[CH:29]=3)([CH3:27])[CH3:26])=[CH:15][CH:14]=2)[N:7]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[CH2:24][O:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([NH:12][C:11]([NH:10][C:8]3[N:7]([C:43]4[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:42])=[CH:14][CH:15]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCC(C)(C)c3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCC(C)(C)c3ccnc(N)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a suspension of the tert-butyl carbamate (62) (780 mg, 1.18 mmol) in DCM (10 mL) was added TFA (8.0 mL) and the resulting dark green solution stirred at RT for 2 hr. The mixture was evaporated in vacuo and the residue was taken up in MeOH (10 mL) and subjected to SCX capture and release to afford the title compound (Intermediate L) (690 mg, 100%): m/z 563 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:17]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[C:14]2[CH:15]=[CH:16][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:13]=2)=[CH:3]1
Reactant: Cn1ccc2ccccc21
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: Cn1cc(C(c2ccc(-c3ccccc3)cc2)c2cn(C)c3ccccc23)c2ccccc21

Procedure:
The compound Bis(1-methylindol-3-yl)-(1,1′-biphenyl-4-yl)methane was prepared following procedure A, starting from N-methyl indole and 4-biphenyl carboxaldehyde. LC: Tr 2.92 min, MS: 427 (M+H)+