Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C>C1COCC1>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([B:29]([OH:30])[OH:28])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)Oc1ccc(Oc2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 1-bromo-4-(4-(trifluoromethoxy)phenoxy)benzene (5.07 g, 15.2 mmol) in THF (76 ml) at −78° C. was added n-butyl lithium (7.6 ml, 2.5 M in hexanes, 19.0 mmol) dropwise. The reaction mixture was stirred 0.5 hours at −78° C., and triisopropylborate (7.0 ml, 30.4 mmol) was added. The reaction was stirred 4 hours at room temperature, quenched with 1 N HCl and stirred 0.5 hours at 0° C. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with brine and dried over magnesium sulfate. Purification by silica gel chromatography (0-10% methanol in dichloromethane) provided 4.38 g (4-(4-(trifluoromethoxy)phenoxy)phenyl)boronic acid (97% yield) as a light brown viscous oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.9 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.07-7.14 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]([O:32]C2CCCCO2)[C:12]2[CH:31]=[CH:30][C:15]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[C:20]([OH:28])[C:19]=3[CH3:29])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH2:39][C:40]([NH2:42])=[S:41].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:42][C:40]1[S:41][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:11]([OH:32])[C:12]3[CH:31]=[CH:30][C:15]([CH2:16][O:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[C:20]([OH:28])[C:19]=4[CH3:29])=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[N:39]=1
Reactant: NC(N)=S
Reactant: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)CCl)c3)cc2)c(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4csc(N)n4)c3)cc2)c(C)c1O
Yield: 52.1 %

Procedure:
Heat a solution of 1-(4-{4-[[3-(2-chloro-acetyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-methyl-phenyl)-propan-1-one (0.250 mg, 0.466 mmol) and thiourea (71 mg, 0.931 mmol) in ethanol (0.20 M) overnight at 70° C. Add p-toluenesulfonic acid (10 mg) and stir overnight. Evaporate solvents and chromatograph residue. Major fraction isolated was the title compound (0.115 g, 0.243 mmol, 52%): 1H NMR (400 MHz, DMSO-d6) δ 1.09 (t, J=10.5 Hz, 3H), 2.02 (s, 3H), 3.03 (q, J=14.4 Hz, 2H), 5.20 (s, 2H), 5.75 (s, 1H), 6.70 (d, J=9.0 Hz, 1H), 7.14 (s, 1H), 7.37 (d, J=6.43 Hz, 1H), 7.42 (m, 6H), 7.60 (m, 1H), 7.80 (m, 2H), 12.89 (s, 1H). MS (m/z): 473 (M−H).
Reaction SMILES: C[Mg]I.[Br:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Br:19])[CH:13]=3)[C:8](=O)[C:7]=2[CH:6]=1.[CH3:21]C(O)=O>C1COCC1.CCOC(C)=O>[Br:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Br:19])[CH:13]=3)[C:8](=[CH2:21])[C:7]=2[CH:6]=1
Reactant: CC(=O)O
Reactant: O=c1c2ccc(Br)cc2oc2ccc(Br)cc12
Agent: C[Mg]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1c2ccc(Br)cc2Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Referring to Scheme 10, methylmagnesium iodide (14.12 mL, 3 M in Et2O, 42.4 mmol) was added to a stirred solution of 2,6-dibromo-9H-xanthen-9-one (7-2) (10 g, 28.2 mmol) in THF (30 mL) at 0° C. The reaction mixture was allowed to warm up to rt and stirred for 2 h. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (250 mL) and stirred for 30 min. The volatiles were removed in vacuo. The residue was taken up in CHCl3 (200 mL), and the organic layer was separated and the aqueous phase was extracted with CHCl3 (2×200 mL) and combined organics was dried over MgSO4, filtered and solvents removed in vacuo to crude product (9.46 g). The crude reaction was taken up in EtOAc (200 mL) and AcOH was added (20 mL) and the reaction mixture was stirred at room temperature for 3 hrs, the volatiles removed in vacuo and the residue was precipitated from isohexanes to give 2,6-dibromo-9-methylene-9H-xanthene (9-1) (6.43 g, 64.7% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[C:14]([S@:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6](/[C:8](=[N:20]\[S@@:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19])/[CH:9]([F:11])[F:10])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Product: CC(C)(C)[S@@](=O)/N=C(\c1cc(Br)ccc1F)C(F)F
Yield: 77 %

Procedure:
In a manner analogous to that described for the preparation of sulfinyl imine A2.1 the reaction of 1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone (CAS 1262858-97-8; WO2011009943) with (R)-tert-butylsulfinamide yielded the (R)-2-methyl-propane-2-sulfinic acid [1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-eth-(E)-ylidene]-amide (77% of theory) as a yellow oil. MS (ISP): m/z=356.1 [M+H]+and 358.0 [M+2+H]+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:39]=[CH:38][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:37])([CH3:36])[O:17][Si:18]([CH3:35])([CH3:34])[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1)([O:5]C)=[O:4]>O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:36])([CH3:37])[O:17][Si:18]([CH3:35])([CH3:34])[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=2)=[CH:38][CH:39]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc(OCCCC[Si](C)(C)O[Si](C)(C)CCCCOc2ccc(C(=O)OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[Si](C)(CCCCOc1ccc(C(=O)O)cc1)O[Si](C)(C)CCCCOc1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
A reaction mixture consisting of 8 parts NaOH in 200 parts H2O and 54.6 parts of 1,3-bis(p-carbomethoxyphenoxybutyl)tetramethyldisiloxane (see Example XII) were combined and heated to reflux. The mixture was initially heterogeneous but became homogeneous after three hours, at which time the reaction was terminated, extracted two times with 100 ml. toluene and acidified with excess HCl. A white precipitate formed, which was filtered and recrystallized from pentane. The structure was confirmed by I.R. and N.M.R.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12][C:13]1[C:14]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1>ClCCl>[Br:12][C:13]1[C:14]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:15][C:16]([NH:19][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])=[N:17][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Oc2c(F)cccc2F)c(Br)cn1
Solvent: ClCCl
Product: O=C(NC(=S)Nc1cc(Oc2c(F)cccc2F)c(Br)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl isothiocyanate (1.63 g, 10.0 mmol) is added to a solution of 5-bromo-4-(2,6-difluorophenoxy)pyridin-2-amine (3.01 g, 10 mmol) in dichloromethane (20 mL) at 0° C. The reaction mixture is warmed to room temperature and stirred for one hour. The reaction mixture is diluted with hexanes and filtered to afford N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-ylcarbamothioyl)benzamide.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:2].C([Li])CCC.[I:20]CCI.C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[N:6][N:7]2[C:12]([I:20])=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:14]
Reactant: CCN(CC)c1cnn2ccccc12
Reactant: ICCI
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)c1cnn2c(I)cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-diethylaminopyrazolo[1,5-a]pyridine (0.57 g, 3.00 mmol) in THF (5.00 mL) was cooled to −78° C. and treated with a solution of n-butyl lithium (1.20 M in hexanes, 3.25 mL, 3.90 mmol). The reaction was stirred for 30 minutes then treated with a solution of 1,2-diiodoethane (1.01 g, 3.60 mmol) in THF (10 mL). The reaction was stirred at −78° C. for 3 hours then quenched with saturated NaHCO3 at −78° C. and warmed to room temperature. The reaction was diluted with water and extracted twice with methylene chloride, dried over MgSO4 and concentrated in vacuo to give a dark green oil which was subjected to column chromatography (5% ethyl acetate/hexane) to give 0.59 g (63%) of a yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.58 (dd, J=8.8, 1.2 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.81–6.76 (m, 1H), 3.13 (q, J=7.1 Hz, 4H), 1.06 (t, J=7.1 Hz, 6H); MS (EI) m/z 316.14 (M++H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:17][C:18]1[CH:19]=[C:20]([S:24][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(S)c1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (500 mg, 1.52 mmol), 3-aminobenzenethiol (381 mg, 3.04 mmol), potassium carbonate (630 mg, 4.56 mmol) and N,N-dimethylformamide (5.0 mL) was stirred at 80° C. for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and precipitated from ethyl acetate to give the title compound (396 mg, 80%).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]2[NH:28][C:29](=[O:31])[NH:30][C:26]=2[CH:25]=1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[NH:28][C:29](=[O:31])[NH:30][C:26]=5[CH:25]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nn23)cc1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.22 mmol) was coupled with 5-amino-1,3-dihydro-benzimidazol-2-one (57 mg, 0.38 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 79 mg (67%) of brown powder. LC/MS: 421 (M+H); HPLC: 97% pure, RT=2.32 min; 1H NMR: (DMSO, δ) 10.65 (s, 1H), 10.48 (s, 1H), 9.38 (s, 1H), 9.02 (s, 1H), 8.49 (d, J=8.6, 2H), 8.04 (d, J=8.6, 2H), 7.35 (m, 2H), 7.29 (s, 1H), 6.98 (d, J=4.8, 1H), 6.91 (d, J=8.6, 1H), 3.27 (s, 3H).
Reaction SMILES: C[Si]([I:5])(C)C.C[Si](N[Si](C)(C)C)(C)C.[CH2:15]1[N:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1>C(#N)C>[CH2:15]1[N:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1.[IH:5]
Reactant: C[Si](C)(C)I
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-carboxylic acid (8c), as produced in Example 13a, was converted to the carbacephem (9a) through reaction with trimethylsilyl iodide (TMSI). Specifically, the carboxylic acid (8c) (0.726 g, 2 mM), was combined with 5 ml acetonitrile (ACN), HMDS (1.06 ml, 5 mM), and TMSI (0.72 ml, 5 mM), and the mixture was stirred for 4 hours at room temperature. DABCO (0.56 g, 5 mM) in 5 ml ACN was added and the solution stirred overnight at room temperature, yielding a DABCO-HI precipitate. Both reactions appeared normal and the DABCO reaction (elimination) gave an HPLC ratio of product to starting material of 39.1/12.0 for a conversion of about 77%. 5 ml of 1N HCl was added and the mixture stirred for 30 min. at room temperature. The pH was at 3.55. The DABCO-HI precipitate dissolved and the desired carbacephem product (9a) appeared as a precipitate. The product was filtered and washed successively with 10 ml of ACN/H2O (2/1), 5 ml of H2O, and 5 ml of ACN. Vacuum drying at 50° C. yielded 0.275 g of a nearly white solid. Yield was about 63.5%. NMR was excellent in DMSO (d-6) with trifluoroacetic acid (TFA) to dissolve.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:30])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29].Cl>O.CO>[CH3:28][C:27]1[C:20]2[C:19]([CH2:18][N:11]3[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:9]([CH2:8][CH2:7][C:6]([OH:30])=[O:5])[C:10]3=[O:29])=[CH:23][S:22][C:21]=2[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc2scc(Cn3c(=O)n(CCC(=O)O)c4ccccc43)c12
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Lithium hydroxide monohydrate (99 mg, 2.4 mmol) is dissolved in water (12 mL) and this solution is added into 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester (600 mg, 1.6 mmol) in methanol (12 mL) at room temperature. The mixture is stirred for 2 hr and then 1.0 M HCl aqueous solution (3 mL) is added along with water (100 mL). Then the mixture is extracted with EtOAc (3×100 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give about 560 mg (97%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([NH:18][C:19]2[CH:23]=[CH:22][S:21][C:20]=2[C:24]([O:26]C)=[O:25])(=[O:17])=[O:16])[CH:10]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([NH:18][C:19]2[CH:23]=[CH:22][S:21][C:20]=2[C:24]([OH:26])=[O:25])(=[O:17])=[O:16])[CH:10]=1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1cccc(-c2c(C)cccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(S(=O)(=O)Nc2ccsc2C(=O)O)c1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
A solution of 154 (172 mg; 0.43 mmol) in tetrahydrofuran (2.1 mL) was placed in a 2.5-5.0 mL microwave reactor tube. Aqueous sodium hydroxide (2.1 mL; 2N) was added and the reaction vessel was subjected to the following microwave conditions: Temperature=140° C.; Time=30 minutes; Power=250 W; Cooling on; Absorption=High. After cooling to room temperature, the reaction mixture was acidified with aqueous hydrochloric acid (25 mL; 6N) and extracted with ethyl acetate (40 mL×2). The organic layers were combined and successively washed with aqueous sodium hydroxide (20 mL; 2N), aqueous hydrochloric acid (25 mL; 6N), and aqueous saturated sodium chloride (25 mL). The dichloromethane extracts were dried over magnesium sulfate, filtered, and concentrated under reduced. The resulting white solid was purified by silica gel chromatography (2 columns; 1st column gradient: 16% ethyl acetate in hexanes to 5% methanol in dichloromethane; 2nd column gradient: dichloromethane to 5% methanol in dichloromethane) to yield the title compound as a white solid (61 mg).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@@H]([C@@H](CO)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
3.0%, D-lyxose: 2.3%, D-ribose: 3.0%,
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])(O)=O.[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][C:20]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)=[CH:19][CH:18]=2)[C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: OB(O)c1ccsc1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 2-methyl 5-[4-(methylsulfonyl)phenyl]-1-(4-bromophenyl)-1H-pyrrole (0.2 g, 0.51 mmol) in DME (6 mL) was added thiophene-3-boronic acid (0.079 g, 0.61 mmol), bis(triphenylphosphine)palladium(II)chloride (0.04 g, 0.06 mmol) and saturated NaHCO3 solution (2 mL) at room temperature under nitrogen. The mixture was heated at reflux temperature for 6 hours, and cooled down to room temperature. The reaction mixture was filtered through celite, the filtrate was poured into water and the whole was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4/1). The resulting solid was recrystallized from ethyl acetate/hexane to give the title compound (0.15 g, 75.0% yield).
Reaction SMILES: [C:1]([CH:3]1[CH2:9][CH2:8][CH2:7][N:6]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:5]2[C:4]1=O)#[N:2].O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[C:3]2[CH2:9][CH2:8][CH2:7][N:6]3[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:5]3[C:4]=2[NH:21][N:20]=1
Reactant: NN
Reactant: CCOC(=O)c1cc2n(c1)CCCC(C#N)C2=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2n(c1)CCCc1c(N)n[nH]c1-2
Yield: 78.4 %

Procedure:
To ethyl 8-cyano-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2-carboxylate (12 g, 49 mmol) in ethanol a solution of hydrazine monohydrate (6.5 g, 130 mmol) and acetic acid (9 g, 150 mmol) was added. The reaction was refluxed for 62 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and NH3. The organic phase was dried on Na2SO4. 10 g of a pale yellow solid were obtained (yield 78%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][S:25](Br)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][S:25]([O:23][CH2:22][CH2:21][CH2:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:12]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Br
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(CCCO)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1cc(CCCOS(C)(=O)=O)c2ccccc21
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
To a solution of 3-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-indol-3-yl]propan-1-ol (Intermediate 41; 3.2 g, 0.009 mol) in CH2Cl2 (25 mL) was added at −40° C. methanesulfonyl bromide (0.93 mL, 0.011 mol) and triethylamine (1.74 mL, 0.012 mol). The reaction mixture was stirred for 5 minutes. More CH2Cl2 was added into the mixture and the organic layer was washed with water. The solvent was removed under reduced pressure giving the title compound (3.5 g, 88%), which was used in the next step without further purification.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:21][C:22]([C:25]2[NH:26][C:27]([CH:30]([C:38]3[CH:43]=[CH:42][C:41]([S:44]([CH:47]4[CH2:49][CH2:48]4)(=[O:46])=[O:45])=[CH:40][CH:39]=3)[CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][CH:29]=2)=[N:23][N:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:47]1([S:44]([C:41]2[CH:42]=[CH:43][C:38]([CH:30]([C:27]3[NH:26][C:25]([C:22]4[S:21][C:20]([CH2:19][OH:18])=[N:24][N:23]=4)=[CH:29][CH:28]=3)[CH2:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:39][CH:40]=2)(=[O:45])=[O:46])[CH2:49][CH2:48]1
Reactant: CC(C)(C)[Si](OCc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CO)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a solution of 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole (122 mg) in tetrahydrofuran (1.2 mL) was added tetrabutylammonium fluoride (0.44 mL: 1M tetrahydrofuran solution), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (51.3 mg, yield 63%) was obtained as white crystals from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio). melting point 208.5-208.6° C. MS: 474 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][S:5]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1)=[O:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)CCSCc1ccc2sc(S(N)(=O)=O)cc2c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)CCS(=O)Cc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a partial solution of 5-[2-(dimethylamino) ethylthiomethyl]-2-sulfamoylbenzo[b]thiophene (1.32 g, 0.004 mol) in 20 ml of ethanol and 40 ml of water was added sodium metaperiodate (0.94 g, 0.0044 mol) and the mixture was stirred at room temperature for 16 hours over night. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The white solid residue was recrystallized twice from 4/1 (V/V) water/ethanol and chromatographed on silica gel eluting with 7.5% (V/V) methanol/CHCl3. There was recovered 0.88 g of white solid, m.p. 180-183° C., dec. (Yield 64%).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([OH:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>CN(C=O)C>[CH2:1]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([O:17][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 82 %

Procedure:
3-Butyl-6-(methyloxy)-2-phenyl-1-naphthalenol (81) (0.25 g, 0.82 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.27 g (82%) of 82 as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, J=7.3 Hz, 3H), 1.10-1.25 (m, 2H), 1.40-1.50 (m, 2H), 2.55-2.60 (m, 2H), 3.94 (s, 3H), 6.68 (d, J=8.6 Hz, 2H), 7.05 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.13 (m, 2H), 7.17 (d, J=2.6 Hz, 1H), 7.18-7.25 (m, 3H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 411 (M+H)+.