Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([NH:16][NH2:17])=[N:7][CH:6]=1
Reactant: Clc1ncc(-c2ccccc2Cl)nn1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1ncc(-c2ccccc2Cl)nn1

Procedure:
A solution of 19.8 g. of 3-chloro-6-(o-chlorophenyl)-1,2,4-triazine in 120 ml. of pyridine is treated with 15 g. of hydrazine hydrate as described in Example 12, giving 6-(o-chlorophenyl)-3-hydrazino-1,2,4-triazine as yellow needles.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[N:21][CH:22]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[N:21][CH:22]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1cnc[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(Nc1ccc(O)cc1)c1cnc[nH]1
Yield: 100 %

Procedure:
A solution of 3-H-imidazole-4-carboxylic acid (4-benzyloxyphenyl)amide. (3.3 g, 11.2 mmol) in glacial acetic acid (70 mL) was hydrogenated (60 psi) over g of 10% palladium on carbon (0.3 g) at 25° C. for 18 hours. The catalyst was removed by filtration, and the solvent was evaporated in vacuo. The residue was stirred with NaHCO3 solution and the solid collected. There was obtained 2.4 g (100% yield) of the title compound as a yellow solid. MS m/z 204 (MH+). 1H NMR (DMSO-d6) δ 6.7 (dd, 2H), 7.5 (dd, 2H), 7.7 (s, 1H), 7.8 (s, 1H), 9.1 (s, 1H), 9.6 (s, 1H) and 12.5 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[C:16](Cl)(=[O:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1>C1COCC1>[CH2:21]1[O:22][C:23]2[CH:24]=[CH:25][C:17]([C:16]([C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[O:26])=[CH:18][C:19]=2[O:20]1
Reactant: O=C(O)c1ccccc1Br
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)c1ccc2c(c1)OCO2
Temperature: -100 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a solution of 2-bromobenzoic acid (12 g, 0.06 mol) in THF (200 ml) at -100° C. under an argon atmosphere was added dropwise n-butyl lithium (50 ml of 2.5M solution in hexanes, 0.125 mol), maintaining the temperature below -90° C. Upon completion of the addition, the resulting solution was stirred at -100° C. for 1 h, at which time was added slowly a solution of piperonylic acid chloride (11 g, 0.06 mol) in THF (50 ml), maintaining the temperature below -90° C. The resulting mixture was allowed to warm to -80° C. and stirred for 1 h, then was allowed to slowly warm to room temperature and left to stand for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between Et2O and 1M HCl. The organic phase was extracted with 10% aqueous NaOH. The NaOH extract was acidified with concentrated HCl, and the combined aqueous material was extracted with Et2O. The Et2O extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of 10-30% EtOAc/0.1% HOAc/hexanes to afford the title compound as an off-white solid (4.5 g, 28%).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[O:3][C:2]2=[O:10].C(N(CC)CC)C.Cl.[CH2:19]([NH:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:29]1([CH2:28][O:27][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([C@@H:5]2[CH2:6][CH2:7][C@H:1]([C:2]([OH:3])=[O:10])[CH2:8]2)=[O:9])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(CNOCc2ccccc2)cc1
Reactant: O=C1OC(=O)C2CCC1C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@H]1CC[C@@H](C(=O)N(Cc2ccccc2)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
552 mg of 3-Oxabicyclo[3.2.1]octane-2,4-dione (3.94 mmol, prepared according to the procedure described in Chem. Lett., p 93, (1994)) is added to a rapidly stirring solution of triethylamine (0.55 mL, 3.94 mmol) and N-benzyl-O-benzylhydroxylamine hydrochloride (983 mg, 3.94 mmol) in CH2Cl2 in a flame dried flask under nitrogen. After stirring at ambient temperature for 3 days, the reaction is quenched with aqueous citric acid (1M). Extraction into CH2Cl2 (3×50 mL), followed by drying over MgSO4, yielded a pale yellow oil, 1.51 g. Recrystallization in ethyl acetate/hexane provided the product as a white crystalline solid, 1.32 g (95%). mp. 118°-120° C.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[CH3:20][O:21][C:22](=[O:44])[C@H:23]([CH2:25][C:26]1[CH:33]=[C:31]([I:32])[C:30]([O:34][C:35]2[CH:42]=[C:40]([I:41])[C:39]([OH:43])=[C:37]([I:38])[CH:36]=2)=[C:28]([I:29])[CH:27]=1)[NH2:24]>O>[CH3:20][O:21][C:22](=[O:44])[C@H:23]([CH2:25][C:26]1[CH:27]=[C:28]([I:29])[C:30]([O:34][C:35]2[CH:36]=[C:37]([I:38])[C:39]([OH:43])=[C:40]([I:41])[CH:42]=2)=[C:31]([I:32])[CH:33]=1)[NH:24][C:3](=[O:5])[CH2:2][NH:1][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: O
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 82.5 %

Procedure:
To the Boc-Gly-OSu solution was added under ice-cooling the thyroxine methyl ester solution. The resulting mixture was allowed to stand to reach room temperature, and then stirred for 1.5 hrs. The reaction liquid was allowed to stand overnight, and to this were added 25 ml. of distilled water and 50 ml. of ethyl acetate for extraction with the ethyl acetate. The extraction with 25 ml. of ethyl acetate was repeated three times. The ethyl acetate extracts were combined and dried over anhydrous magnesium sulfate. The dry extract was concentrated in a rotary evaporator and subjected to gel chromatography using a column filled with Sephadex LH-20 (tradename of Pharmacia Corp.). In this procedure, a mixture of acetone and methanol in a volume ratio of 4:1 was employed as the developing solvent. Under confirmation by TLC, the fractions containing the desired product were collected and concentrated under reduced pressure to obtain a crystalline product. There was obtained 950 mg. (yield 82.5%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:18]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:18][CH:17]([CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:26])[C:16]([O:15][CH3:14])=[O:27])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)[C@@H](N)C(C)c1ccccc1
Product: COC(=O)C(NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(C)c1ccccc1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and DL-β-methylphenylalanine methyl ester.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:19]([Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])([CH3:22])([CH3:21])[CH3:20].[Br:34]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:33])[CH3:32]
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
A catalytic amount of benzoylperoxide (0.5 g) was added to a refluxing solution of an equimolar mixture of Example 1d (30 g, 0.134 mol) and N-bromosuccinamide (24 g, 0.134 mol) in dry CCl4 (175 mL) for 1.5 h. The reaction mixture was filtered, concentrated and purified using flash chromatography (silica gel, PE60-80° C.) to obtain the title compound as an oil. Yield: 36 g, (90%); 1H NMR (CDCl3): δ 0.30 (s, 6H, 2CH3), 1.10 (s, 9H, 3CH3), 4.5 (s, 2H, CH2), 6.8-7.5 (m, 4H, Ar).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of tert-butyl(3-hydroxyphenyl)carbamate (3.02 g, 14.4 mmol) and potassium carbonate (2.99 g, 21.7 mmol) in N,N-dimethylformamide (35 mL) was added 2-chloro-5-nitropyridine (2.52 g, 15.9 mmol), and the mixture was stirred at 70° C. for 2 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 50 mL). The organic layer was washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl{3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate as a yellow solid. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]2([CH2:11][C:12]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:13]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[C:21](=[O:22])[O:20][CH2:19]4)=[O:14])[CH2:10][CH2:9]2)[CH:7]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]2([CH2:11][C:12]([OH:30])([C:26]([F:28])([F:27])[F:29])[C:13]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[C:21](=[O:22])[O:20][CH2:19]4)=[O:14])[CH2:9][CH2:10]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(C(=O)Nc2ccc3c(c2)COC3=O)C(F)(F)F)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1OCc2cc(NC(=O)C(O)(CC3(c4cc(F)ccc4O)CC3)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
225 mg of 5-{3-[1-(5-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylamino}-phthalide is mixed in 4.5 ml of dichloromethane at 0° C. with 2.48 ml of a 1 molar solution of boron tribromide in dichloromethane. After 3 hours of stirring at 0° C., the mixture is added to water, extracted with ethyl acetate, the organic phase is dried (Na2SO4) and concentrated by evaporation. After the residue is triturated with hexane, the title compound is obtained in crystalline form, flash point 196-199° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([O:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Reactant: COS(=O)(=O)c1ccc(N)cc1
Product: COc1ccc2sc(C(=O)Nc3ccc(S(=O)(=O)OC)cc3)c(OC(C)C)c2c1
Yield: 56 %

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (300 mg, 1.1 mmol) and 402 mg, 1.8 mmol) methyl 4-aminobenzenesulfonate [obtained by catalytic hydrogenation of methyl 4-nitrobenzenesulfonate (Aldrich) followed by salt formation] provides 295 mg (56%) of product; mp 176.5°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.I[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[S:22]1(=[O:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[S:22]1(=[O:32])=[O:31])[CH2:9][CH2:8]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCN(CCCN1C(=O)c2ccccc2S1(=O)=O)C1CCc2cccc(OC)c2C1

Procedure:
8-Methoxy-N-propyl-2-aminotetralin (Arvidsson L.-E. et al., J. Med. Chem., 27, 45 (1984) (2 g, 10 mmol), N-(3-iodopropyl)-2,3-dihydro-1,1-dioxo-3-benzisothiazolone (7.5 g), sodium carbonate (2.5 g), and acetonitrile (25 ml) were heated to reflux for 24 hours. After cooling, the solvent was removed in vacuo and the residue placed on a flash silica gel column (3 cm×35 cm) and eluted with ethyl acetate/hexane (5:95, 10:90, 15:85, 20:80, successively). Solvent removal in vacuo afforded the title compound as a white powder (m.p. 131° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11](O)([CH3:14])([CH3:13])[CH3:12].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.6 %

Procedure:
A mixture of 11.3 g of 6-methylnicotinic acid, 5.0 g of 4-dimethylaminopyridine, 18.3 g of t-butyl alcohol, 22.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 280 ml of dichloromethane is stirred at room temperature for 2 days. The reaction mixture is washed with water, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel with chloroform to give 7.1 g of t-butyl 6-methylnicotinate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:18]([OH:29])[C@@H:17]([CH3:30])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:31][S:32]([O:29][C@@H:18]1[C@@H:17]([CH3:30])[CH2:16][C@@H:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:20][C@H:19]1[NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,2R,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-hydroxy-3-methylcyclohexyl)carbamate (1.0 equiv.) in pyridine (0.17 M) was added MsCl (5.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, 10% CuSO4, H2O, Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 59% yield. LC/MS (m/z)=500.3 (MH+), Rt=0.74 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[OH:31].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:32]([O:31][C@@H:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C@H:17]([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1c2cccnc2[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 250 mL round-bottom flask was dissolved (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (1.004 g, 2.243 mmol) in methylene chloride (20 mL) to give a colorless solution. Acetic anhydride (0.423 mL, 4.49 mmol) and triethylamine (0.938 mL, 6.73 mmol) were added, followed by DMAP (0.055 g, 0.449 mmol). The mixture was stirred at room temperature under nitrogen. 2 h: LCMS showed complete conversion. It was quenched with Sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated to give a colorless oil (100%), which was directly carried onto next reaction without further purification and characterization. MS(ESI)[M+H+]=490.26.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)N4CCOCC4)cc3)cc2)CC1
Yield: 39.7 %

Procedure:
The title compound (37 mg, 32%) was prepared from [4-(4-morpholinylcarbonyl)phenyl]boronic acid (47 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.58 (m, 2H) 7.51 (d, 2H, J=8.8 Hz), 7.46 (d, 2H, J=8.2 Hz), 6.96 (d, 2H, J=8.8 Hz), 4.97-4.86 (m, 1H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.2 Hz), 3.72 (bs, 6H), 3.53 (bs, 2H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.36-1.26 (m, 2H), 1.24 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 467 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12](O)=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12]([Cl:19])=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2scc(C(=O)Cl)c2c1

Procedure:
5-Acetoxybenzo[b]thiophene-3-carboxylic acid (12) (1,349 mg) prepared above was refluxed for 1.5 hours with dimethylformamide (1 drop), thionyl chloride (1.22 ml) and toluene (25 ml). The solvent was removed under reduced pressure to provide 1,454 mg of the title compound (13).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(=O)CC1
Reactant: C1CCNC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN1CC=C(N2CCCC2)CC1

Procedure:
A mixture of 1-butyl4-piperidone (10.5 g, 67.6 mmol), pyrrolidine (6.73 g, 94.7 mmol), amberlyst-15 (200 mg) and toluene (100 ml) was stirred at reflux overnight, with a Dean and Stark water collector connected. The crude mixture was co-evaporated with toluene twice (100 ml). The product was isolated as an oil in quantitative yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 67.8 %

Procedure:
A mixture of 2-bromo-1-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (4.90 g, 14.0 mmol) and thiourea (1.07 g, 14.1 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 100 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (3.10 g) as yellow solids in 68% yield: 1H NMR (500 MHz, CDCl3) δ 6.98 (m, 2 H), 6.88 (m, 2 H), 6.64 (s, 2 H), 6.27 (s, 1 H), 5.40 (bs, 2 H), 3.81 (s, 3 H), 2.13 (s, 6 H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].N1C=CC=CC=1.[CH2:14]([OH:17])[CH2:15][OH:16]>C(Cl)Cl>[C:2](=[O:3])([O:4][CH:5]([CH3:7])[CH3:6])[O:16][CH2:15][CH2:14][OH:17]
Reactant: CC(C)OC(=O)Cl
Reactant: OCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)OCCO
Temperature: 25 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
To a stirred solution of isopropyl chloroformate (2 g, 0.016 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added pyridine (3.8 mL, 0.048 mol) and then ethylene glycol (2.7 mL, 3 eq). The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 15 hrs at room temperature. After removing the solvent under reduce pressure, the residue was purified by silica gel column chromatography to give 2-hydroxyethyl isopropyl carbonate as a colorless oil (0.5 g, 42% yield). 1HNMR (400 MHz, CDCl3): δ 1.22 (t, J=7.2 Hz, 3H); 2.94 (sbroad, 1H); 3.78 (t, J=4.4 Hz, 2H); 4.18 (t, J=4.4 Hz, 2H); 4.07 (q, J=7.2H, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[S:11]([Cl:15])(=O)(=[O:13])[OH:12]>[OH-].[Na+]>[Cl:15][S:11]([C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: O=C(O)c1ccccc1F
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 200 °C

Procedure:
5-(Chlorosulfonyl)-2-fluorobenzoic acid was prepared from 2-fluorobenzoic acid using a Biotage Initiator 8 microwave set to high absorbance as follows. Using conditions described, the reaction typically reached a pressure of 12 barr. The pressure was reduced to 3 barr after cooling and was vented prior to decapping the reaction vessel. To a 5 ml Biotage microwave reaction tube was added 2-fluorobenzoic acid (0.5 g, 3.57 mmol) and a Teflon covered magnetic stir-bar. To this was added 2 ml of chlorosulfuric acid. The vessel was capped and heated to 200° C. for 3.25 min. After cooling to room temperature, the remaining pressure was vented into a 50 ml syringe and discharged into 30 ml 1M NaOH. Reaction was quenched by adding dropwise to 30 ml of crushed ice. The solid product was collected by vacuum filtration, washed with water (5 ml, 3×) and air-dried under vacuum for 2 h, yielding 5-(chlorosulfonyl)-2-fluorobenzoic acid as a light yellow solid.