Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[N:18]1([CH2:24][CH2:25][C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[CH:28][N:27]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>ClCCCl>[N:18]1([CH2:24][CH2:25][C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[C:28]([C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:12])[N:27]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: c1ccn2c(CCN3CCOCC3)ncc2c1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1cccc2ccccc12)c1nc(CCN2CCOCC2)n2ccccc12
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a solution of naphthoylchloride (0.28 mL, 1.85 mmol) in 1,2-dichloroethane (20 mL) was added aluminum trichloride (300 mg, 2.25 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine (200 mg, 0.87 mmol) in 1,2-dichloroethane (5 mL) was added. The mixture was stirred at ambient temperature for 30 min. then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (160 mg, 48%). 1H NMR (DMSO-d6 δ 8.56 (1H), 8.27 (1H), 8.07 (1H), 8.02 (2H), 7.76 (1H), 7.51 (4H), 7.11 (1H), 3.52 (4H), 3.18 (2H), 2.67 (2H), 2.40 (4H); m/z (M+H)=386.2.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:30])[N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[Cl:30][C:4]1[N:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:33]=2[O:32][CH3:31])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:9][CH:10]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)nc(Cl)cc3c2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nc(Cl)cc3c2)cc1
Temperature: 90 °C
Yield: 741.3 %

Procedure:
This reaction was conducted in two separate vials. For the first reaction, a vial was charged with 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (57.11 mg, 0.109 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (25.1 mg, 0.114 mmol), Pd(AmPhos)2Cl2 (3.85 mg, 5.44 μmol), potassium phosphate (69.3 mg, 0.326 mmol), 1,4-dioxane (408 μl), and water (136 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 15 min at 90° C. A second vial was charged with 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (422 mg, 0.804 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (186 mg, 0.844 mmol), Pd(AmPhos)2Cl2 (28.5 mg, 0.040 mmol), potassium phosphate (512 mg, 2.412 mmol), 1,4-dioxane (3015 μl), and water (1005 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 15 min at 90° C. The reaction mixtures from each vial were combined, and the combined mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated, and the residue was purified by chromatography on silica gel (40-g column, 20 to 60% EtOAc/Heptane) to give 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate RRR; 500.9 mg, 0.808 mmol, 89% yield) as an off-white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.15 (t, J=1.1 Hz, 1H), 7.77 (s, 1H), 7.68-7.65 (m, 2H), 7.50 (s, 1H), 7.44-7.38 (m, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.27 (s, 1H), 7.04 (d, J=3.6 Hz, 1H), 6.73 (d, J=8.8 Hz, 2H), 5.11 (s, 2H), 3.76 (s, 3H), 3.73 (s, 3H); m/z (ESI) 620.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH3:19][NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>>[CH3:19][N:20]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:15](=[O:16])[CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:1])([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Product: COC(=O)c1ccc(N(C)C(=O)Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 53.4 %

Procedure:
In a manner similar to Example 4(c), by reaction of 2.46 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylacetic acid with 1.65 g (10 mmol) of methyl 4-methylaminobenzoate, 2.1 g (54%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][Si:2]1([CH3:12])[CH2:11]OC2C(=CSC=2)O[CH2:3]1.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([OH:23])[C:21]=1[OH:22])=[O:16].S1C=CC=C1.OC([SiH](C)C)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH3:27][O:26][C:24]([C:19]1[S:18][C:17]([C:15]([O:14][CH3:13])=[O:16])=[C:21]2[C:20]=1[O:23][CH2:3][Si:2]([CH3:12])([CH3:11])[CH2:1][O:22]2)=[O:25]
Reactant: COC(=O)c1sc(C(=O)OC)c(O)c1O
Reactant: C[Si]1(C)COc2cscc2OC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: C[SiH](C)C(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(C(=O)OC)c2c1OC[Si](C)(C)CO2

Procedure:
A synthesis for 6,6-dimethyl-6,7-dihydro-5H-4,8-dioxa-2-thia-6-sila-azulene, a silicon-containing EC monomer generally related to 3,4-alkylenedioxythiophene, is shown in FIG. 7. First, 3,4-Dihydroxy-thiophene-2,5-dicarboxylic acid dimethyl ester, the thiophene derivative labeled A7 in FIG. 7 (hereinafter referred to as compound A7) is synthesized from commercially available chemicals according to prior art techniques (see K. Zong, L. Madrigal, L. B. Groenendaal, R. Reynolds, Chem. Comm., 2498, 2002). Note that the same initial step is employed in the synthesis of FIG. 5. Then, a solution of compound A5, dihydroxylmethyldimethylsilane (labeled B7 in FIG. 7), PPh3 (labeled C7 in FIG. 7), and DEAD (labeled D7 in FIG. 7) is refluxed in THF for about 15-24 hours (preferably under an inert atmosphere). A small amount of water is then added to quench the reaction. The reaction mixture is evaporated to dryness. The resulting material is loaded into a silica gel column and eluded by hexane and dichloromethane (2:1, 1:1, volume ratio) to yield 6,6-Dimethyl-6,7-dihydro-5H-4,8-dioxa-2-thia-6-sila-azulene-1,3-dicarboxylic acid dimethyl ester, the silicon-containing thiophene derivative labeled E7 in FIG. 7 (hereinafter referred to as compound E7).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2)[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][NH:3]1.[Li+].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH3:27][N:3]1[CH2:4][CH:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6]2([CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)C(=O)NCC2c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A diastereomeric mixture. of tert-butyl 1-oxo-4-phenyl-2,8-diazaspiro[4.6]undecane-8-carboxylate (step 4) (669.5 mg; 1.944 mmol) in THF (19.5 ml) under nitrogen was cooled in an ice/brine bath. 1M LHMDS (2.5 ml, 2.53 mmol) was added and the mixture was stirred at 0° C. for 40 minutes. Iodomethane (182 ul, 2.92 mmol) was added and the mixture was allowed to warm slowly to RT overnight. The reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with EtOAc afforded the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[Br:18]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl.CC#N>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[C:15]([Br:18])[CH:16]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(N)cc2)CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(N)c(Br)c2)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 4-(4-amino-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 1.65 g, 7.01 mmol) in 100 mL of 1:1 DCM/CH3CN at 0° C. was slowly added N-bromosuccinimide (NBS) (1.25 g, 7.01 mmol) in 25 mL of 1:1 DCM/CH3CN under Ar. After stirring at 0° C. for 0.5 h, the mixture was treated with 50 mL of EtOAc and washed with H2O (2×30 mL) and brine H2O (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1-4% EtOAc/DCM) to give 1.85 g (84%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C13H16BrNO3, 314.0 (M+H). found 314.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34].N>N1C=CC=CC=1.CN(C=O)C>[NH2:30][C:31]1[C:32]([C:33]([NH2:35])=[O:34])=[CH:36][CH:37]=[CH:38][C:39]=1[NH:40][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)c1cccc(N)c1N
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-{[(Benzyloxy)carbonyl]amino}-2-methylpropanoic acid (5.18 g, 21.83 mmol) in a mixture of pyridine (25 mL) and DMF (25 mL) was treated with 1,1′-carbonyldiimidazole (3.72 g, 22.92 mmol) and heated at 40° C. for 2 hours. 2,3-Diaminobenzamide dihydrochlolide (4.89 g, 21.83 mmol), prepared as described in WO0026192, was added and the mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The formed slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1A. MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: NCC1CCCCN1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-aminomethylpiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.93 minutes; C23H25Cl2N5O2 (474.39); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: CO[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>CO.O1CCCC1>[OH:28][CH2:27][CH2:29][NH:30][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: NCCO
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 53.6 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (40 mL) and tetrahydrofuran (10 mL) was treated with ethanolamine (0.094 g) and the mixture was refluxed for 48 hours. The solvents were removed by evaporation and the residue was purified by HPLC (ethyl acetate-methanoltriethylamine; 95:5:2) followed by crystallization from tetrahydrofuran-ethyl alcohol to give 0.29 g of N-(2-hydroxyethyl)-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 138°-140° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[O:14][C:15]([CH2:18][CH3:19])=[CH:16][N:17]=1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[CH2:18]([C:15]1[O:14][C:13]([CH2:12][CH2:11][NH2:10])=[N:17][CH:16]=1)[CH3:19]
Reactant: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCc1cnc(CCN)o1

Procedure:
A solution of [2-(5-ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester (step 3) (0.41 g, 1.49 mmol), 2M HCl (0.75 ml) in ethanol (40 ml) is stirred under hydrogen in the presence of 10% Pd on carbon (0.041 g) for 5 hours. The reaction mixture is filtered and concentrated in vacuo to yield the titled compound.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:17]([C:15]1[CH:16]=[C:11]([C:10]2[O:21][C:2]3[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=3[N:9]=2)[C:12]([F:20])=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: O=C(Nc1cc(Br)ccc1O)c1cc([N+](=O)[O-])ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Br)ccc3o2)c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-5-bromophenyl)-2-fluoro-5-nitrobenzamide (1.42 g, 4.0 mmol) and p-toluenesulfonic acid monohydrate (1.67 g, 8.8 mmol) the subtitle compound was obtained (654 mg, 48%). MS 339.0 m/z (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:7]2[C:8](=[O:32])[CH:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:6]2[S:5][CH:4]=1.[H-].[Na+].[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)[CH2:37][CH2:36]1>CS(C)=O>[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2/[CH:42]=[CH:12]/[C:10]2[N:11]=[C:6]3[S:5][CH:4]=[C:3]([CH3:2])[N:7]3[C:8](=[O:32])[CH:9]=2)[CH2:36][CH2:37]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1csc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc(=O)n12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3c(C)csc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.096 mmol) in dry DMSO (12 ml) was treated with NaH (92 mg, 2.306 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (475 mg, 2.306 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford 260 mg of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.31-0.32 (m, 2H), 0.53-0.55 (m, 2H), 1.18-1.22 (m, 1H), 2.66 (s, 3H), 3.73-3.76 (m, 2H), 3.79 (s, 3H), 6.15 (s, 1H), 6.97-7.13 (m, 4H), 7.30-7.33 (m, 1H), 8.07 (d, J=16.2 Hz 1H); ESI-MS (m/z) 369.26 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]([CH3:24])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20][C:19](=O)[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:27][O:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>C(O)(=O)C>[CH3:32][N:31]([CH3:33])[C:29]([O:28]/[N:27]=[C:19]1/[CH2:20][CH2:21][CH2:22][C:15]2[C:14]([S:11]([N:10]([CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:25])[CH3:24])(=[O:12])=[O:13])=[CH:18][S:17][C:16]/1=2)=[O:30]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Reactant: CN(C)C(=O)ON
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)C(=O)O/N=C1/CCCc2c(S(=O)(=O)N(C)CC(O)c3ccc(F)cc3)csc21

Procedure:
7-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 48) (60 mg) and [[(aminooxy)carbonyl](methyl)amino]methane hydrochloride (the compound of Preparation Example 122) (24 mg) were stirred in acetic acid at 50° C. for 3 hours. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate). Among the two spots that were identifeid by developing the reaction solution by TLC (solvent system was hexane:ethyl acetate=1:3), the fraction of the compound with a high polarity (low Rf value) was collected, and the title compound (9 mg) was obtained as a colorless amorphous substance.
Reaction SMILES: CC([CH:5]1[C:14]2[C:9](=[C:10]([C:15]([NH:17][OH:18])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]1[C:19]([O-:21])=[O:20])(C)C.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[C:28](OC)=O>O1CCCC1>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[O:18][N:17]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[C:9]=3[CH2:8][CH2:7][N:6]([C:19]([O:21][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:20])[CH2:5]4)[N:16]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)(C)C1c2cccc(C(=N)NO)c2CCN1C(=O)[O-]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Yield: 159.5 %

Procedure:
1,1-dimethylethyl5-[(hydroxyamino)(imino)methyl]-3,4-dihydro-2(1H)-isoquinoline carboxylate (Preparation 1) (2 g, 6.86 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) and stirred with sodium hydride (60% dispersion, 0.302 g, 7.55 mmol) under argon at room temperature for 30 minutes. Then methyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (Preparation 2, 2.355 g, 10.30 mmol) was added and the reaction heated at reflux temperature for 1.5 hours. The cooled reaction was evaporated and partitioned between DCM (100 mL) and water (100 mL). The water layer was washed with DCM (50 mL) and the combined DCM layers dried (hydrophobic frit) and evaporated. The crude product was purified by chromatography through a small silica pad, eluting with DCM to yield 1,1-dimethylethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinoline carboxylate (2.57 g, 5.47 mmol, 80% yield). 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, s), 8.05 (1H, d), 7.95 (1H, d), 7.34 (1H, t), 7.27 (1H, d), 7.06 (1H, d), 4.76-4.63 (1H, m), 4.66 (2H, br.s), 3.67 (2H, br.t), 3.25 (2H, br.t), 1.51 (9H, s), 1.45 (6H, d); m/z (API-ES) 414, 416 [M+H-56]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][S:28]([C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([C:34]3[S:35][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=3)=[O:37])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)s1

Procedure:
The title compound, yellow solid (101 mg, 78%), MS (ISP) m/z=515.3 [(M+H)+], mp 214° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 5-methanesulfonyl-thiophene-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56]1[CH:63]=[CH:62][C:59]([NH:60][CH3:61])=[CH:58][CH:57]=1>CN(C=O)C.CCOC(C)=O>[I:20][C:16]1[CH:15]=[C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:60]([C:59]2[CH:62]=[CH:63][C:56]([O:55][CH3:54])=[CH:57][CH:58]=2)[CH3:61])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)O
Reactant: CNc1ccc(OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(I)c2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(3-iodophenyl)propanoic acid (3.8 g, 9.65 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 4.4 g, 11.6 mmol) and DIPEA (2.5 ml, 14.5 mmol) were dissolved in DMF (10 ml) and treated with 4-methoxy-N-methylaniline (1.59 g, 11.6 mmol). The mixture was stirred vigorously overnight at room temperature. The mixture was diluted with EtOAc (100 ml) and washed with brine (2×50 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The oily crude product was introduced to a silica gel loading column and purified by column chromatography (15-38% EtOAc/hexanes) to provide the desired product (4.63 g, 9.07 mmol), 94%. MS (m/z) 511 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23]O)=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:25])=[O:4].[N:28]1C=CC=C[CH:29]=1.C(N(C(C)C)CC)(C)C.CN.Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][CH:2]([F:27])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH2:23][NH:28][CH3:29])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:25])[CH3:26])=[O:4]
Reactant: c1ccncc1
Reactant: CC1(C)O[C@H](c2ccc(-c3cnc(CO)s3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
Mesyl anhydride (860 mg, 4.9 mmol) is added to 2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-5-(4-(2-(hydroxymethyl)thiazol-5-yl)phenyl)-2,2-dimethyl-oxazolidin-3-yl)ethanone (1.4 g, 3.5 mmol) in CH2Cl2 (35 mL). Pyridine (0.5 mL, 5.9 mmol) is added and stirred at room temperature for 1 hour. The reaction is diluted with CH2Cl2 (35 mL) and washed with water and brine. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude mesylate is dissolved in acetonitrile (10 mL) and transferred to a scintillation vial. Diisopropylethylamine (0.65 mL, 3.7 mmol) and methylamine.HCl (130 mg, 1.9 mmol) are added and the reaction mixture is heated to 55° C. for 18 hours. The reaction mixture is cooled and diluted with saturated NaHCO3 (75 mL). The reaction mixture is extracted with CH2Cl2 (2×75 mL) and the combined organic phase is dried (Na2SO4) and concentrated under vacuum to afford the title compound (475 mg): m/z (CI) M+H 414.