Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:25])[C@H:17]([NH2:24])[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:25])[C@@H:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:24][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)[C@H](N)C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)c1ccccc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a mixture of 2-nitrobenzoyl chloride (0.5 mL, 3.69 mmol) and (R)-amino-cyclohexyl-acetic acid methyl ester hydrochloride (1.0 g, 4.82 mmol), (prepared according to example A), in dichloromethane (10 mL) is added diisopropyl ethylamine (DIPEA) (1.5 mL, 8.61 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated and the resulting residue is purified by flash chromatography with 40% EtOAc in Hexane as the eluent to afford (R)-cyclohexyl-(2-nitro-benzoylamino)-acetic acid methyl ester (1.16 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][C:10]=1[F:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:38](OCC)(=[O:40])[CH3:39]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:38](=[O:40])[CH3:39])[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][C:10]=1[F:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (1.72 g) was added 4 M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (1.21 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].C([Mg]Cl)(C)C>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:29]=[CH:30][C:31]([S:34]([F:37])([F:35])([F:39])([F:36])[F:38])=[CH:32][CH:33]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FS(F)(F)(F)(F)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(S(F)(F)(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-iodo-4-pentafluorosulfanyl-benzene. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride-complex in tetrahydrofurane is used instead of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O.Cl.[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][NH:33][CH3:34])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:15]([F:37])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:9].[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][N:33]([CH3:34])[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[O:8])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:15]([F:37])[CH:14]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CNCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 144.7 %

Procedure:
Isonicotinoyl chloride (36 mg, 0.2 mmol) was added to a suspension of 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(methylamino)ethoxy)quinazoline hydrochloride hydrate (90 mg, 0.1 mmol), (prepared as described for the starting material in Example 54), in methylene chloride (3 ml) and triethylamine (80 mg, 0.8 mmol) was then added dropwise. The mixture was stirred for 30 minutes at ambient temperature and the solvent was then removed by evaporation. The residue was partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was dissolved in methylene chloride/methanol and 3M ethereal hydrogen chloride (0.5 ml) was added. The suspension was diluted with ether, the precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(4-pyridylcarbonyl)amino)ethoxy)quinazoline hydrochloride (75 mg, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH3:19])(=[N:12][C:13](=[O:18])[NH:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.Cl.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([CH3:19])(=[N:12][C:13](=[O:18])[NH:14][CH:15]([CH3:16])[CH3:17])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)NC(=O)N=S(C)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)NC(=O)N=S(C)(=O)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
18.61 g iron powder in 198 ml ethanol and 1.93 ml conc. hydrochloric acid were stirred for 30 minutes at room temperature. 7.8 g (27.34 mmol) (RS)—S-(3-nitrophenyl)-N-(isopropylcarbamoyl)-S-methylsulfoximide in 20 ml methanol were added. The mixture was stirred at 60° C. for 2 hours and filtered over a bed of silica gel. The residue was washed with hot ethanol. The combined filtrates were evaporated. The crude residue was purified by column chromatography (silica gel, dichloromethane:dichloromethane/ethanol 1:1) to give 4.53 g (65% yield) of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[C:10]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:9]=1.[CH:21]([N:24]=[C:25]=[S:26])([CH3:23])[CH3:22]>CN(C)C=O>[Cl:7][C:8]1[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[C:10]([S:17](=[O:19])(=[O:20])[NH:18][C:25](=[S:26])[NH:24][CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)N=C=S
Reactant: CC(=O)Nc1sc(Cl)cc1S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1sc(Cl)cc1S(=O)(=O)NC(=S)NC(C)C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
Potassium tert-butoxide (135 mg, 1.2 mmol) was added to a solution of N-(5-chloro-3-sulfamoylthiophen-2-yl)-acetamide(255 mg, 1.0 mmol) in dry N,N-dimethylformamide (5 ml) with stirring on an ice bath. After 5 min, isopropyl isothiocyanate (0.128 ml, 1.2 mmol) was added dropwise and the solution was stirred for 30 min at 0° C. and then at room temperature for 3 h. A further amount of potassium tert-butoxide (135 mg, 1.2 mmol) was added to the solution and stirring was continued at room temperature for 1 h. The solvent was evaporated at <50° C., and the residue was taken up in 10 ml of water and the aqueous solution was adjusted to pH 2 with 4 M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to give 274 mg (77%) of crude title compound; 1H-NMR (DMSO-d6): δ1.12 (d, 6H, 2×CH3), 2.28 (s, 3H, COCH3), 4.21 (m, 1H, NCH), 7.15 (s, 1H, H-4), 8.34 (br d, 1H, NH), 10.26 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 37.9 %

Procedure:
Prepared according to the method described in Example 65 from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), 4-chlorobenzeneboronic acid (0.180 g) and tetrakis(triphenylphosphine)palladium(0) (40 mg) in toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml) and ethanol (1 ml) with heating at reflux for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a white solid (0.104 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([C:9]2[O:10][CH:11]=[N:12][N:13]=2)[CH:8]=1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[O:10][CH:11]=[N:12][N:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2nnco2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(-c2nnco2)c(C)[nH]c1=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 21.3 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-[1,3,4]oxadiazol-2-yl-pyridine (10 mg, 0.0457 mmol) and sodium iodide (19 mg, 0.127 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (2 mL) followed by chlorotrimethylsilane (16.4 μL, 0.131 mmol). The reaction mixture is stirred at 50° C. under nitrogen for 2.5 hr. The reaction mixture is allowed to cool and then quenched with water (0.1 mL). After stirring for 30 min, the mixture is evaporated. The crude residue is purified by flash chromatography on a 2-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). The fraction containing the product is evaporated to give 3-ethyl-6-methyl-5-(1,3,4-oxadiazol-2-yl)-1H-pyridin-2-one (2 mg, 21% yield) as a white solid. LC/MS: RT: 1.98 min, MS: m/e=206 (M+H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([N:9]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[CH3:7]>C(Cl)Cl>[C:6]([N:9]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[CH:22]=[C:23]([O:26][CH3:27])[C:24]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:25][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)C(c1ccccc1)CN(C(C)=O)CC2
Solvent: ClCCl
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2c1ccccc1

Procedure:
Chlorosulfonic acid (2.3 g, 0.02 m) dissolved in methylene chloride (50 ml) was added slowly to a solution of 3-acetyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.95 g, 0.01 m) in methylene chloride (100 ml) stirred at -20°. The mixture was stirred at -20° for thirty minutes, and allowed to warm to 25°. The methylene chloride was decanted and the insoluble residue was treated with excess thionyl chloride in chloroform, heated to reflux, cooled and poured into ice water. The mixture was extracted with chloroform and the organic layer was washed, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl 7-chlorosulfonyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@:24]([CH2:27][OH:28])([CH3:26])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Si:42](Cl)([CH3:45])([CH3:44])[CH3:43].O>ClCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@@:24]([CH3:26])([CH2:27][O:28][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO)N2
Reactant: C[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO[Si](C)(C)C)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
To a solution of (2R,5S,7R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)-N,2-dimethyl-1,8-diazaspiro[4.5]decane-8-carboxamide (Example 18, 80 mg, 0.136 mmol) in Dichloromethane (DCM) (2 ml), TEA (0.021 ml, 0.149 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. TMS-Cl (0.026 ml, 0.204 mmol) was added dropwise and mixture was stirred at the same temperature overnight. Water (2 ml) was added and two phases were separated. The organic layer was dried and evaporated in vacuo affording the title compound (84 mg) that was used in the next step without further purifications. LC/MS (Basic gradient conditions): Rt=4.205 min, m/z 662 [M+H]+.
Reaction SMILES: [N:1]1([S:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](Cl)[C:13]([O:17][CH2:18][C:19]3([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][C:11]=2[F:28])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Cl>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1([S:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([CH:30]3[CH2:32][CH2:31]3)[C:13]([O:17][CH2:18][C:19]3([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][C:11]=2[F:28])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCC2)cc1F
Temperature: 100 °C
Yield: 60.7 %

Procedure:
To a mixture of N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide (0.18 g, 0.39 mmol), cyclopropylboronic acid (0.40 g, 4.65 mmol) and potassium phosphate (2.55 g, 12.00 mmol) in toluene (20 mL) and water (1.0 mL) was sparged with a nitrogen atmosphere for 10 minutes, tricyclohexylphosphine tetrafluoroborate (0.17 g, 0.48 mmol) and palladium acetate (0.05 g, 0.22 mmol) was added to this reaction mixture. The reaction mixture was heated to 100° C. for 96 hours under a nitrogen atmosphere and then cooled to ambient temperature. 5% aqueous hydrochloric acid (20 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3), the combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (10% to 30% gradient ethyl acetate in hexanes) afforded the title compound (0.11 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=16.2 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 6.57 (d, J=14.1 Hz, 1H), 4.23 (t, J=7.5 Hz, 4H), 3.99 (s, 2H), 2.31-2.20 (m, 2H), 2.08-1.94 (m, 3H), 1.89-1.70 (m, 6H), 0.95-0.88 (m, 2H), 0.67-0.60 (m, 2H); MS (ES+) m/z 465.1 (M+1), MS (ES−) m/z 463.1 (M−1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4].[CH2:21](I)[CH3:22].O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCI
Reactant: CCOC(=O)c1cnn(-c2ccc(O)cc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(OCC)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (234 mg) was added to a solution of 1-(4-hydroxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.2 g) in N,N-dimethylformamide (12 ml) at room temperature, stirred at the same temperature for 30 minutes, then ethyl iodide (0.8 ml) was added therein and the mixture was stirred at 80° C. for an hour. After completion of the reaction, the reaction solution was cooled to room temperature, water was added therein and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(4-ethoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.32 g) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.F[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCN(c4ccccn4)CC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Temperature: 100 °C
Reaction time: 24 h
Yield: 41.1 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-(piperidin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (150 mg, 0.29 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) and 2-fluoropyridine (114 mg, 1.17 mmol, 4.00 equiv). This was followed by the addition of potassium carbonate (81 mg, 0.59 mmol, 2.00 equiv). The resulting solution was stirred for 24 h at 100° C. The solids were filtered out. The resulting mixture was concentrated under reduced pressure. The residue was purified through a silica gel column with dichloromethane/methanol (50:1-20:1) to afford 70 mg of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-[1-(pyridin-2-yl)piperidin-4-yl]-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:27]=[CH:26][C:16]([CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)[S:11][CH:12]=1)=[O:7].[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[NH2:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[S:11][CH:12]=[C:8]([C:6]([C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[N:9]=2)=[CH:27][CH:26]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(=O)c2csc(-c3ccc(CN)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
At 0° C., to a solution of 68a (200 mg) in 10 mL CH2Cl2 was added a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT for 4 h. The precipitate (2r) was filtered and washed with diethyl ether. Yield: 81.3%. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.38 (br, 3H), 8.10 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.62 (s, 2H), 4.11 (s, 2H), 3.87 (s, 6H), 3.80 (s, 3H). MS (ESI) m/z 385.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][N:15]2[CH2:16][CH2:17][O:13][C:14]2=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(SCl)cc1
Reactant: O=C1NCCO1
Product: CC(C)(C)c1ccc(SN2CCOC2=O)cc1

Procedure:
Analogously to Example 4, 2.7 g of 3-(4-tert.-butylphenylthio)-oxazolidin-2-one were obtained as colourless crystals with a melting point of 76° to 81° C. from 4-tert.-butylphenylsulphenyl chloride and oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:9][CH2:10][C:11]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8])=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)c1cc(Cl)ccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(Ref: J. Org. Chem. 1955; 20; 813-818) A mixture of 4-chlorophenol (5 g; 39.0 mmol) and chloroacetyl chloride (3.41 mL; 42.8 mmol) was heated to 80° C. for 2.5 hours. Mixture cooled to 30° C. and aluminum chloride (5.2 g; 39.0 mmol) was added over 30 minutes. Mixture heated to 130° C. for 15 hours. Mixture cooled under N2 flow and reaction was quenched with 0.5 g of ice chuncks over 5 minutes. Mixture was treated with 12 mLs of 20% HCl and heated to 60° C. for 15 minutes (fumes generated). Mixture cooled back room temperature and after 30 minutes 2 phases observed. Aqueous phase was extracted, and oil organic layer was triturated with petroleum ether. Petroleum ether was decanted off. Mixture was then heated to 60° C. in 100 mL of benzene and charcoal. Mixture filtered and filtrate was concentrated to a third volume. Another 40 mLs of petroleum ether added and allowed to stand overnight. Mixture was decanted and mother liquor was evaporated to afford 2-chloro-1-(5-chloro-2-hydroxy-phenyl)-ethanone. (5 g; 63% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:56][C:57]([O:60][C:61]([NH:63][C:64]([N:73]1[CH2:78][CH2:77][CH:76]([C:79](O)=[O:80])[CH2:75][CH2:74]1)=[N:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[O:62])([CH3:59])[CH3:58].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:72][C:69]([O:68][C:66]([NH:65][C:64]([N:73]1[CH2:78][CH2:77][CH:76]([C:79]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:80])[CH2:75][CH2:74]1)=[N:63][C:61]([O:60][C:57]([CH3:56])([CH3:58])[CH3:59])=[O:62])=[O:67])([CH3:70])[CH3:71]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To a solution of the compound prepared in Example 6 (0.2 g, 0.7 mmol) in N,N-dimethylformamide (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.10 g, 0.26 mmol) at 0° C. After stirring for 20 minutes, the compound prepared in Example 7 (0.12 g, 0.26 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.8 mmol) were added and the reaction stirred at room temperature for 2 h. The reaction was quenched by adding ice cold water and the resulting precipitate was collected by filtration, dried and the crude product purified by flash chromatography to afford the title compound (0.11 g, 61%) as a white solid.