Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([CH2:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:17][O:18][C:19](=[O:28])[CH:20]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:21][CH3:22].C(N(CC)CC)C.Cl.[Cl-].[Na+]>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:28])[CH:20]([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[N:21]([S:2]([NH:5][C:6]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3])[CH3:22]
Reactant: OCc1ccccc1
Reactant: CNC(CCC(C)C)C(=O)OC
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CCC(C)C)N(C)S(=O)(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a stirred solution of 5.77 ml (66.78 mmol) of chlorosulfonyl isocyanate in methylene chloride was added, under nitrogen, phenylmethanol (6.89 ml, 66.57 mmol) at 0°-5° C. After stirring the above solution for 1 hour, a solution of 13.166 g (62.78 mmol) of 2-(3-methylbutyl)sarcosine methyl ester hydrochloride in methylene chloride containing triethylamine (27.33 ml, 194.62 mmol) was added at 0°-5° C., and the resulting mixture was stirred overnight allowing the mixture to warm to room temperature. The reaction mixture was poured into 600 ml of 10% aq. HCl solution, saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with methylene chloride and the combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 21.22 g (87.2%) of N-(carbobenzyloxyaminosulfonyl)-2-(3-methylbutyl)-sarcosine methyl ester (Formula XII: R=CH3 ; R1 =(CH2)2CH(CH3)2 ; R2 =H; R3 =CH3) which was purified by silica column chromatography (20% ethyl acetate in hexane) to afford an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>CC(C)=O>[CH2:22]([O:21][C:19]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:20])[CH3:23]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21

Procedure:
The title compound was prepared from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one (2.35 g, 0.0102 molel), ethyl chloroformate (1.1 ml, 0.0102 mole) and triethylamine (1 ml, 0.0102 mole) by reaction in 150 ml of acetone solvent according to the general method of Example 17. The yellowish, crude product was chromatographed on a Waters LC 500 instrument to give 1.62 g of a clear oil which crystallized to a solid, mp 84°-86° C. The confirmatory elemental analysis for the product is shown in Table III.
Reaction SMILES: C[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][NH2:9].[CH2:10]1[O:18][CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19](#N)C>>[OH:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][N:9]([CH3:19])[CH2:8][CH2:7][C:6]1[CH:5]=[CH:4][S:3][CH:2]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: CC#N
Reactant: Cc1sccc1CCN
Product: CN(CCc1ccsc1)CC(O)c1ccccc1

Procedure:
A solution of methyl thiophene-3-ethylamine (3.3 g) and styrene oxide (1.8 ml) in acetonitrile (17 ml) was heated under reflux for 24 hours. The mixture was evaporated and the residual oil chromatographed on silica eluting with 2% methanol in dichloromethane to give the title product as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:46][C:47]([OH:49])=O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.[NH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:75])[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>CN(C=O)C>[CH2:68]([O:67][C:66](=[O:75])[NH:65][CH2:64][CH2:63][NH:62][C:47](=[O:49])[CH2:46][C@@H:45]([NH:44][C:42]([O:41][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:43])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
549.7 mg (1.446 mmol) of HATU and 339.7 mg (2.629 mmol) of N,N-diisopropylethylamine are added to a solution of 500 mg (1.31 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid in 25 ml of anhydrous DMF. After stirring at RT for 15 min, 333.5 mg (1.446 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[N:3]=1.C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH:10][C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CC(=O)OC(=O)C(F)(F)F
Reactant: COc1ccc(N)nc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)C(F)(F)F)nc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
2-Bromo-3-methoxy-6-aminopyridine (Desc. 6; 1.0 g, 4.9 mmol) in dichloromethane (25 ml) was treated with N,N-diisopropylethylamine (2.2 ml, 12.3 mmol) and the solution cooled to 0° C. Trifluoroacetic acetic anhydride (770 μl, 5.4 mmol) was then added dropwise and the solution stirred to 22° C. over 2 hours. The mixture was then poured into saturated sodium bicarbonate solution (25 ml) and extracted with dichloromethane (25 ml). The extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash silica chromatography to give the product as a white solid (890 mg, 3.0 mmol, 61% yield).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])=[C:17]([CH:20]=[O:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[CH:16]([C:22]([O:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C:17]([CH:20]=[O:21])=[CH:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=O)CS[C@H]12)c1csc(NC=O)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=O)=CS[C@H]12)c1csc(NC=O)n1
Yield: 82.7 %

Procedure:
A solution of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-formyl-3-cephem-4-carboxylate (syn isomer) (3 g) and triethylamine (0.45 g) in tetrahydrofuran (30 ml) was stirred at ambient temperature for 40 minutes. To the reaction mixture was added ethyl acetate (50 ml) and washed with 3% hydrochloric acid and brine. The organic solution was dried over magnesium sulfate and evaporated. The residue was pulverized in diisopropyl ether to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-formyl-2-cephem-4-carboxylate (syn isomer) (2.48 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH:22]([CH2:24]O)[CH2:21][C:20]2=[O:26])=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH:22]2[CH2:21][C:20](=[O:26])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[CH2:23]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C1CC(CO)CN1c1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(F)cc3)C2)cc1
Temperature: 0 °C
Yield: 73.1 %

Procedure:
4-Hydroxybenzoic acid methyl ester (0.20 g, 1.314 mmol), 1-(4-fluoro-phenyl)-4-hydroxymethyl-pyrrolidin-2-one (0.33 g, 1.577 mmol), Ph3P (0.345 g, 1.314 mmol) and triethyl amine (0.20 ml, 1.577 mmol) were mixed under argon atmosphere followed by the addition of the dry toluene (10 mL). The reaction mixture was cooled to 0° C. followed by addition of DIAD (0.3 mL, 0.788 mmol) drop wise. The reaction mixture was allowed to warm to room temperature and heated at 80° C. for 24 h. The reaction was quenched with 5% HCl (10 mL), extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash column chromatography to obtain 4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid methyl ester (0.33 g, 73%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][C:28]([CH3:42])([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:42][C:28]1([O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of Intermediate A (111 mg, 0.680 mmol) in DMF (2 mL) was added NaH (60% in oil, 68 mg, 1.70 mmol) and the mixture stirred at RT for 20 min, before Intermediate 79d (230 mg, 0.566 mmol) was added. This mixture was stirred at 60° C. for 1 h. The cooled reaction mixture was diluted with EtOAc (100 mL), washed with water (2×), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (160 mg, 51%). LCMS (Method 1): Rt 3.06 min, m/z 550 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N:13]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cc2ccc(F)cc2)cc1
Reactant: ClCCNCCCl
Agent: Cl
Product: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 500 mg of 4-(4-fluorophenyl)methylaniline and 445 mg of bis(2-chloroethyl)amine hydrochloride was stirred at 100° C. for two hours, then gradually raised in temperature and stirred at 200° C. for a further two hours. This was cooled to room temperature, then the product was purified by silica gel column chromatography (chloroform:methanol:water (2% acetic acid)=65:35:5) to obtain the above-referenced compound (10) in an amount of 503 mg (yield 75%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH3:40])[CH:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[O:24])=[CH:16][C:15]=3[CH:41]=2)=[CH:7][CH:6]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1COCC1.CC(C)=O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH3:40])[CH:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[O:24])=[CH:16][C:15]=3[CH:41]=2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 65 °C
Reaction time: 14 h
Yield: 88.3 %

Procedure:
In THF/acetone (1/1, 60 ml) was dissolved 7-(4-methoxymethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (650 mg). To the mixture was added 1N sulfuric acid (4.4 ml), and the mixture was stirred at 65° C. for 14 hours, cooled to room temperature and neutralized with saturated sodium bicarbonate solution. Under reduced pressure, the solvent was evaporated, and the residue was added to water. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(4-hydroxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 89) (530 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:16]=[CH:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:24][CH:23]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a mixture of 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentan-1-ol (1.1 g), triethylamine (0.333 g) and dichloromethane (40 ml) was added dropwise, under ice-cooling, methanesulfonyl chloride (0.345 g). The mixture was stirred for 2 hours at room temperature, which was washed with water and dried (MgSO4). The solvent was distilled off to leave 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate (1.21 g, 92%). Recrystallization from dichloromethane-ether gave colorless prisms, m.p.132°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([OH:33])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1.[CH2:38]1CCN2C(=NCCC2)CC1.IC>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33][CH3:38])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)O)C2c1ccc2c(c1)OCO2
Solvent: CC#N
Solvent: CI
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.9 %

Procedure:
To a solution of (1RS,2SR,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (1.98 g, 3.91 mmol) in acetonitrile (15 ml) was added DBU (0.655 g, 4.3 mmol) followed by iodomethane (2.77 g, 19.5 mmol). The reaction mixture was stirred at room temperature 3.5 h then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to provide the title compound (1.79 g, 88%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:5]([N:7]([CH3:24])[C@H:8]([C:21]([OH:23])=[O:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Cl.[CH3:30][O:31][C:32](=[O:45])[C@H:33]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH2:34].OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:30][O:31][C:32](=[O:45])[C@H:33]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH:34][C:21](=[O:23])[C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[N:7]([C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:27]=[C:26]([CH3:28])[CH:25]=1)[CH3:24].[CH3:30][O:31][C:32](=[O:45])[C@H:33]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH:34][C:21](=[O:22])[C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[N:7]([C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:27]=[C:26]([CH3:28])[CH:25]=1)[CH3:24]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@@H](Cc2ccc(-c3ccno3)cc2)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1

Procedure:
At 0° C., N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine (445 mg) is stirred in N,N-dimethylformamide (24 ml) together with (L)-tryptophane methyl ester hydrochloride (400 mg), hydroxybenztriazol (330 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.32 ml) for 1 hour and at ambient temperature over night. After extraction with ethyl acetate and 10% aqueous citric acid the organic phase is washed with 4% aqueous sodium bicarbonate, and with brine, dried and evaporated. Flash chromatography on silica gel (hexane/ethyl acetate 2:1) gives the product as a mixture of diastereoisomer. Separation by medium pressure chromatography on a silica gel column, using ether/dichloromethane (1:1) as solvent gives both [N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanyl]-(L)-tryptophane methyl ester, and [N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(L)-alanyl]-(L)-tryptophane methyl ester.
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=O)[CH2:13][CH2:14][C:15]=3[C:16]([Cl:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[CH2:22]([Mg]Br)[CH3:23]>>[Cl:18][C:16]1[C:15]2[CH2:14][CH2:13][CH:12]([CH2:22][CH3:23])[C:11]=2[C:10]2[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=2[CH:17]=1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)N1CCc2cc(Cl)c3c(c2CC1)C(=O)CC3
Product: CCC1CCc2c(Cl)cc3c(c21)CCNCC3

Procedure:
Example 6 was prepared in a similar fashion to Example 4, except Intermediate 4 was used as the starting material and ethylmagnesium bromide (3M in diethyl ether) was used instead of cyclopropylmagnesium bromide (Example 4, step (a)). 1H NMR (300 MHz, CDCl3) δ 6.92 (s, 1H); 3.16-3.09 (m, 1H); 2.98-2.84 (m, 10H); 2.37-2.32 (br s, 1H); 2.17-1.94 (m, 2H); 1.47-1.25 (m, 2H); 0.95 (t, J=7.5 Hz, 3H); MS: ESI (positive): 250, (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].O1CCCC1.B.CO>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(F)cc(Br)c1
Temperature: 0 °C

Procedure:
3-Bromo-5-fluorobenzoic acid (1.0 g, 4.52 mmol) was suspended in tetrahydrofuran (8 mL) and cooled to 0° C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 9 mL, 9.0 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 0.88 g (95%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.29 (s, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 4.66 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:32]([C:27]3[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:34])=[O:33])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
To a solution of [4-(4-Amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and 2-Methyl-benzenesulfonyl chloride (113 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 ml, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum. The residue was diluted with water (10 mL) and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (40 g) column, eluting with 5-30% ethyl acetate in hexanes, to afford {6-chloro-3-methyl-4-[4-(toluene-2-sulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (90 mg, 62.1%) as a white foam. HRMS calcd. for C27H23ClFNO4S [(M−H)−] 492.1042, obsd. 492.1042.