Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:34])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[C:22]([NH2:24])=[O:23])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[NH:24][C:22](=[O:23])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[N:20]=2)=[CH:11][CH:10]=1)([CH3:34])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2cccc(OC)c2)C(N)=O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3cccc(OC)c3)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
1-[4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)phenyl]butyryl]-2-(3-methoxyphenylmethyl)semicarbazide (4.08 g, 8.65 mmol) was dissolved in ethyl acetate (7.5 mL). Camphorsulfonic acid (2.21 g, 9.51 mmol) was added in one portion and the solution was heated to reflux overnight. The solution was cooled to rt and washed with sat'd aq. NaHCO3 (2×40 mL) followed by 1N HCl (2×40 mL). The organic was concentrated to an oil, which was redissolved in ethyl acetate (40 mL). Amberlyst-15 resin (4.41 g) was added and the mixture was heated to 50° C. and stirred for 4 h. The mixture was then cooled to rt, filtered, concentrated, and purified by column chromatography (SiO2, 9:1 ethyl acetate:hexanes) to afford the title compound as an oil (1.93 g, 49.2%). 1H NMR (DMSO-d6) δ 11.47 (s, 1 H), 7.22 (t, 1 H, J=8 Hz), 7.04 (d, 2 H, J=8 Hz), 6.82 (d, 1 H, J=2 Hz), 6.76 (m, 2 H), 6.68 (d, 2 H, J=2 Hz), 4.73 (s, 2 H), 4.13 (q, 2 H, J=7 Hz), 3.69 (s, 3 H), 2.48 (t, 2 H,. J=8 Hz), 2.36 (t, 2 H, J=8 Hz), 1.80 (quint, 2 H, J=7 Hz), 1.47 (s, 6 H), 1.14 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 160.0, 155.0, 153.8, 146.7, 139.8, 135.5, 130.2, 129.8, 120.1, 119.5, 113.8, 113.2, 79.2, 61.6, 55.6, 47.8, 34.0, 28.4, 26.2, 25.7, 14.6; IR (CHCl3) 2940, 1692, 1508, 1467 cm−1; Anal. Calcd. for C25H31N3O5: C, 66.21.; H, 6.89; N, 9.26. Found: C, 66.29; H, 6.75; N, 9.19.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[CH:14]=[N:15][O:16][CH3:17])(=[O:8])=[O:7])(C)C.[C:18](O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:17][O:16][N:15]=[CH:14][C:10]1[N:11]([CH3:18])[CH:12]=[CH:13][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8]
Reactant: CON=Cc1[nH]ccc1S(=O)(=O)NC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=Cc1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.74 g (21.9 mmol) of N-(1,1-dimethylethyl)-2-[(methoxyimino)-methyl]-1H-pyrrole-3-sulfonamide in 75 mL methylene chloride under a nitrogen atmosphere was add 75 mL, of TFA. The clear orange reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The orange reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the residue and removed by evaporation to remove residual TFA, affording 3.49 g of the title compound as a gray solid, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH2:21][O:22][CH3:23])[O:17][C:16]=3[CH:24]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36](F)=[C:37]([CH:40]=1)[C:38]#[N:39].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:20]2[CH2:19][CH:18]([CH2:21][O:22][CH3:23])[O:17][C:16]3[CH:24]=[C:12]([S:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=4)[C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]2=3)=[C:37]([C:38]#[N:39])[CH:40]=1
Reactant: COCC1CNc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1CN(c2ccc(Cl)cc2C#N)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (150 mg, 0.324 mmol) and 5-chloro-2-fluorobenzonitrile (50.55 mg, 0.324 mmol, Aldrich) in DMF (5.0 mL) was added Cs2CO3 (210 mg, 7.95 mmol) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel 100-200 mesh and 0-30% ethyl acetate in hexane) to obtain 4-(4-chloro-2-cyanophenyl)-N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (170 mg, 87.6%) as an off white solid. m/z (ESI) 596.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(N(C(C)C)C(C)C)C.O>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[N:5]=[C:6]([CH:13]=[CH:12][C:11]([O:15][CH3:16])=[O:14])[CH:7]=1
Reactant: C=CC(=O)OC
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cc(Cl)nc(OC)n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 33.1 %

Procedure:
To a solution of 4,6-dichloro-2-methoxypyrimidine (780 mg) in DMF (10 mL) were added methyl acrylate (760 mg), tris(dibenzylideneacetone)dipalladium (200 mg), N-ethyldiisopropylamine (1.14 g) and tetrabutylammonium chloride (61 mg), and the mixture was stirred at 90° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (330 mg) as a white solid.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].Cl.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9].C1COCC1>CCOC(C)=O>[NH2:3][C:2]([N:15]1[CH2:14][CH2:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:8]([O:7][CH3:6])=[O:9])[CH:11]=2)[CH2:16]1)=[S:1]
Reactant: N#C[S-]
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCN(C(N)=S)C2
Temperature: 100 °C
Yield: 100.1 %

Procedure:
A mixture of ammonium thiocyanate (0.105 g, 1.384 mmol), 6-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g, 1.3176 mmol) and THF (2 mL) was heated in a CEM microwave reactor for 1 h at 100° C. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, and washed with H2O, 1 N HCl, saturated aqueous NaHCO3 and brine respectively, dried over anhydrous MgSO4, and concentrated under reduced pressure to afford methyl 2-(aminocarbonothioyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (0.33 g, 47%) as a white solid. LCMS: (FA) ES+ 251.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]1[C:21]([F:22])=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([F:23])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:23][C:14]1[CH:13]=[C:12]([CH2:11][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:21]([F:22])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(F)c(CBr)cc1F
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(F)c(COc2cccc(OC)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-methoxyphenol (221 mg, 1.8 mmol) in DMSO (5 mL) was added methyl 4-(bromomethyl)-2,5-difluorobenzoate (Preparation 27, 491 mg, 1.8 mmol) followed by potassium carbonate (491 mg, 3.5 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 18 hours. The mixture was poured into water and extracted with EtOAc (3×20 mL), washed with 1 M aqueous NaOH and water, dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound as a solid, which was taken to the next step without further purification (441 mg, 81%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:21])([F:20])[CH:10]([C:16]([F:19])([F:18])[F:17])[C:11](OCCl)=O>>[F:8][C:9]([F:21])([F:20])[C:10]([C:16]([F:19])([F:18])[F:17])=[CH2:11]
Reactant: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: C=C(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Yield: 71.9 %

Procedure:
In a four necked 100 ml flask equipped with a condenser, a dropping funnel and a thermometer, triethylamine (20.0 g, 198 mmol) was charged and warmed to 60° C. Monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (4.88 g, 20 mmol) was dropwise added thereto while stirring. The reaction was continued at the same temperature as above for 2.5 hours while stirring. The gas evolved from a top of the condenser was washed with an alkaline solution, dried with alumina and cooled. The resultant liquid was distilled to give 2-trifluoromethyl-3,3,3-trifluoropropene (2.36 g). Yield, 72 %.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=2)[C:10]([CH2:25][C:26]([NH:31][C:32](=[O:34])[CH3:33])([CH2:29][OH:30])[CH2:27][OH:28])=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:28][CH2:27][C:26]([NH:31][C:32](=[O:34])[CH3:33])([CH2:29][OH:30])[CH2:25][C:10]1[C:11]2[C:16](=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[NH:8][CH:9]=1
Reactant: CCCCCCCCc1ccc2c(CC(CO)(CO)NC(C)=O)cn(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc2c(CC(CO)(CO)NC(C)=O)c[nH]c2c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Compound 29 (200 mg, 0.46 mmol) is added to methylene chloride (10 mL) and the solution is cooled to −40° C. Trifluoroacetic acid (3.0 mL) is added and the reaction is stirred for 1 hour maintaining the temperature. The reaction is quenched with methanol (10 mL) at −40° C. and then partitioned between methylene chloride (25 mL) and aqueous sodium hydroxide (1.0 N, 25 mL). The aqueous layer is back extracted with methylene chloride (2×10 mL) and the combined organic layers are washed with aqueous sodium hydroxide (1.0 N, 3×10 mL), then brine and dried over MgSO4. The organic layer is evaporated to dryness and the residue purified using silica gel chromatography with methanol (10%)-methylene chloride (90%) to give compound 30.
Reaction SMILES: B1([C:7]2[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=2)OCCCO1.[Cl:13][C:14]1[CH:15]=[C:16]([C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C@@H:29]([NH:31][C:32]([C:34]3[N:35]=[CH:36][NH:37][CH:38]=3)=[O:33])[CH3:30])[N:24]=2)[CH:17]=[C:18]([F:22])[C:19]=1[C:20]#[N:21].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C@@H:29]([NH:31][C:32]([C:34]3[N:35]=[CH:36][N:37]([C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[CH:38]=3)=[O:33])[CH3:30])[N:24]=2)[CH:17]=[C:18]([F:22])[C:19]=1[C:20]#[N:21]
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(-c2cccnc2)cn1
Temperature: 25 °C
Reaction time: 47 h
Yield: 16.57 %

Procedure:
3-Pyridineboronic acid 1,3-propanediol ester (43.7 mg, 0.268 mmol), (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-imidazole-4-carboxamide (50 mg, 0.134 mmol), anhydrous copper(II) acetate (36.5 mg, 0.201 mmol), pyridine (0.022 ml, 0.268 mmol) and DCM (1 ml) were added into a flask and stirred at RT for 47 h. The reaction mixture was extracted with ethyl acetate, dried, filtered and evaporated. The product was purified by column chromatography. Yield 16.57%. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 4.28 (dd, 1H), 4.47 (dd, 1H), 4.57-4.67 (m, 1H), 6.64 (d, 1H), 7.48-7.55 (m, 2H), 7.74-7.78 (m, 1H), 7.81 (d, 1H), 7.88 (d, 1H), 7.91-7.94 (m, 2H), 8.27 (d, 1H), 8.72 (d, 1H), 8.79 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[C:28]3[O:30][CH2:31][O:32][C:27]3=[CH:26][C:25]=2[N+:33]([O-])=O)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:33][C:25]1[CH:26]=[C:27]2[O:32][CH2:31][O:30][C:28]2=[CH:29][C:24]=1[CH2:23][N:20]1[CH2:21][CH2:22][C@@H:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:36]=[C:37]([C:40]([F:43])([F:41])[F:42])[CH:38]=[CH:39][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2cc3c(cc2[N+](=O)[O-])OCO3)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2cc3c(cc2N)OCO3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine prepared above, 10% Pd-activated carbone (22 mg), and methanol (3.0 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The Pd catalyst was filtered off, and the filtrate was concentrated to afford (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (87.1 mg, quant.): Any remarkable by-products were not detected in TLC.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:17][C:16](=S)[NH:15][C:14](=[O:19])[CH:13]=1.N>CCO.[Ni]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][NH:15][C:14](=[O:19])[CH:13]=1
Reactant: COCCOc1ccccc1-c1cc(=O)[nH]c(=S)[nH]1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COCCOc1ccccc1-c1cc(=O)[nH]cn1

Procedure:
6-[2-(2-methoxy-ethoxy)-phenyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.3 g, 1.08 mmol) is dissolved in EtOH (10 mL) and aqueous solution of ammonia (25%, 3 mL). After addition of Raney-Nickel (0.3 g) the reaction mixture is stirred under reflux for 1 h, filtered from the solid material, which is washed with a mixture of ammonia and EtOH. The combined solutions were evaporated, dissolved in water (5 mL), neutralized with 10% HCl and extracted with ethyl acetate (3×10 mL). Organic layers were combined, washed with water (5 mL) then dried over anhydrous sodium sulfate and concentrated. The residue was triturated with diethyl ether yielding 0.2 g (75%) 6-[2-(2-methoxy-ethoxy)-phenyl]-3H-pyrimidin-4-one as white powder.
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21]>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: COc1ccc2c(c1)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)O)=C2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A mixture of 1,1-dimethylethyl N-((4-hydroxy-7-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (0.36 g, 0.9 mmol) in 2 mL TFA was stirred at room temperature for 30 minutes, M+1=362, M−1=360. The mixture was concentrated and then triturated in DCM/hexane (5:10). The solid was filtered, washed with 10 mL DCM/hexane (5:10), and dried under high vacuum to give 0.3 g of the product as an off-white solid. MS (m/z)=362 (M+H)+. Calculated for C18H19NO7 361.12.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([Cl:24])[C:11]3[CH:15]([CH2:16][C:17]([O:19]CC)=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([Cl:24])[C:11]3[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(Cl)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nnc(Oc2cc(Cl)c3c(c2)B(O)OC3CC(=O)O)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 4.9 %

Procedure:
To a solution of ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-4-chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)acetate (330 mg, 0.89 mmol) in THF (10 mL) and H2O (3 mL) was added LiOH (100 mg, 4.16 mmol). The reaction mixture was stirred at 0° C. for 3 h and acidified with 1N HCl to pH=2-4. The resulting mixture was extracted with EtOAc (2×10 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (15 mg, yield 5%). 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.57 (s, 1H), 7.56 (m, 2H), 7.20 (s, 2H), 5.51 (m, 1H), 3.22 (m, 1H), 2.32 (s, 3H), 2.36 (m, 1H). MS (ESI) m/z=342 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][C:12]([O:14]C)=[O:13])=[O:4].Br[CH2:25][C:26]1[C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:30]([O:39]C(OC(C)(C)C)=O)[C:29]([C:47]([F:50])([F:49])[F:48])=[CH:28][CH:27]=1>>[C:35]([O:34][C:32]([C:31]1[C:30]([OH:39])=[C:29]([C:47]([F:48])([F:49])[F:50])[CH:28]=[CH:27][C:26]=1[CH2:25][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][C:12]([OH:14])=[O:13])=[C:5]([C:3]([N:2]([CH3:23])[CH3:1])=[O:4])[CH:6]=2)=[CH:21][CH:20]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1C(=O)N(C)C
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CN(C)C(=O)c1cc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)ccc1CC(=O)O
Yield: 67 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl {3-[(dimethylamino)carbonyl]-4′-hydroxy-1,1′-biphenyl-4-yl}acetate (82 mg, 0.262 mmol) obtained in Example (89-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (131 mg, 0.288 mmol) obtained in Example (28-5), the title compound was obtained (100 mg, three-step total yield: 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[N:17]([CH:18]2[CH2:24][C@H:23]3[N:25]([CH2:26][CH2:27][C:28]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[C@H:20]([CH2:21][CH2:22]3)[CH2:19]2)[C:16]2[CH:40]=[CH:41][CH:42]=[CH:43][C:15]=2[N:14]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:31]2[CH2:30][CH2:29][C:28]([CH2:27][CH2:26][N:25]3[C@H:20]4[CH2:21][CH2:22][C@@H:23]3[CH2:24][CH:18]([N:17]3[C:16]5[CH:40]=[CH:41][CH:42]=[CH:43][C:15]=5[N:14]=[C:13]3[CH3:12])[CH2:19]4)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:33][CH2:32]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCNCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(S(=O)(=O)c2cccc(Cl)c2)CC1
Yield: 20.8 %

Procedure:
3-Chlorobenzenesulfonyl chloride (31.6 mg, 0.122 mmol) was added to a solution of 2-methyl-1-{(1R,5S)-8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (50.0 mg, 0.117 mmol) and diisopropyletheylamine (44.9 mg, 0.348 mmol) in DCM. The reactions were quenched with sat. NaHCO3 and separated with a hydrophobic frit. Flash chromatography on silica 0 to 10% MeOH in EtOAc afforded 1-[(1R,5S)-8-(2-{1-[(3-chlorophenyl)sulfonyl]-4-phenyl-4-piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole 14.7 mg (20% yield). MS ES+ 603 (M+H). 1H NMR (300 MHz, chloroform-d) δ ppm 1.6 (m, 2H), 1.7 (m, 4H), 1.9 (m, 8H), 2.4 (m, 4H), 2.6 (s, 3H), 2.8 (m, 2H), 3.4 (m, 2H), 4.6 (m, 1H), 7.2 (m, 5H), 7.3 (m, 3H), 7.4 (t, J=7.9 Hz, 1H), 7.5 (m, 1H), 7.6 (d, J=7.8 Hz, 1H), 7.7 (m, 1H), 7.7 (m, J=1.8, 1.8 Hz, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1([CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:12]([C:13]1([CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:17][CH2:18]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CCO[Si](C)(C)C(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C=O)(CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To a solution of oxalyl chloride (3.3 mL, 38 mmol) in methylene chloride (500 mL) at −70° C. was added DMSO (5.4 mL, 76 mmol) over 5 min. After 15 min, a solution of tert-butyl 4-hydroxymethyl-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (7.1 g, 19 mmol) in methylene chloride (125 mL) was slowly added over 15 min. After 1 h, triethylamine (21.2 mL, 152 mmol) was added and the reaction was allowed to warm to room temperature for 1 h. The mixture was poured into water and extracted three times with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (40% ethyl acetate in hexanes) to afford the title product (6.3 g).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[Cl:23])([OH:16])[CH2:12]2)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[C:11]1([OH:16])[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccncc1Cl)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2ccncc2Cl)CC2CCC(C1)N2
Reaction time: 1 h
Yield: 100 %

Procedure:
3-(3-Chloro-pyridin-4-yl)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.34 g, 1.0 mmol) was dissolved in TFA (1 mL) and DCM (2 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum and the residues were passed through an SCX cartridge, eluting with 2 M ammonia in methanol to give the title compound (0.24 g, 1.0 mmol). 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.46 (d, 1H), 7.66 (d, 1H), 3.74 (m, broad, 2H), 2.79-2.71 (m, broad, 2H), 2.25-2.17 (m, broad, 3H), 1.98-1.85 (m, broad, 3H), 1.70-1.62 (m, broad, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>N1C=CC=CC=1>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:1][C@H:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: Fc1nc2ccccc2s1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)Nc1nc2ccccc2s1
Yield: 62.1 %

Procedure:
A mixture constituted by (1,1-dimethyl ethyl) L-tyrosinate 4-1 (120 mg, 0.5 mmole) and fluorobenzothiazole (75 mg; 0.5 mmole) in 3 ml of pyridine is heated under reflux for 2 hours. The reaction medium is then evaporated under reduced pressure until a dry extracted is obtained which is purified by chromatography eluting with a heptane/ethyl acetate mixture (100/0→0/100). 115 mg of expected product is obtained.