Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([OH:19])=O)[S:11]3)=[CH:4][CH:3]=1.[Cl-].[NH4+].[B-](F)(F)(F)F.CCOC(C(C#N)=[N:33]OC(N(C)C)=[N+](C)C)=O.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([NH2:33])=[O:19])[S:11]3)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)sc2nc(-c3ccc(F)cc3)cn12
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(N)=O)sc2nc(-c3ccc(F)cc3)cn12
Yield: 28.3 %

Procedure:
6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid (example 7, 50 mg, 0.18 mmol), ammonium chloride (19.4 mg, 0.36 mmol), TOTU (63.32 mg, 0.2 mmol) and triethylamine (100.6 μl, 0.72 mmol) in 3 ml DMF were stirred at RT for 8 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 14 mg (28%) of the desired product. MS: M+H+=276.03.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=NO)[C:4]=2[N:3]=1.[OH2:14]>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[N:3]=1
Reactant: O
Reactant: ON=C1CCCc2cnc(Cl)nc21
Solvent: CC(C)=O
Product: O=C1CCCc2cnc(Cl)nc21
Temperature: 80 °C

Procedure:
2-Chloro-6,7-dihydro-5H-quinazolin-8-one oxime (Example 257a)(620 mg; 3.1 mmol) is dissolved in HClconc (12 ml), combined with water (50 ml) and acetone (12 ml) and heated to 80° C. for 20 minutes. The yellow solution is cooled and poured on Na2CO3/water (12 g/150 ml) and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to deliver the title compound as yellow crystals (480 mg; 84%).
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)CC.I[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[N:16]=2)[N:11]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:10]=1.[CH3:40][C:41]([CH3:47])([CH:45]=[O:46])[CH2:42][C:43]#[N:44]>O1CCCC1>[OH:46][CH:45]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[N:16]=2)[N:11]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:10]=1)[C:41]([CH3:47])([CH3:40])[CH2:42][C:43]#[N:44]
Reactant: CC(C)(C=O)CC#N
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Agent: CCC[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(n2)c(C(O)C(C)(C)CC#N)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
Propyl magnesium chloride lithium chloride (1.3 M solution in THF, 1.7 mL, 2.2 mmol) was added to 3 mL of tetrahydrofuran cooled to −78° C. A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (0.250 g, 0.440 mmol) in 2 mL of tetrahydrofuran was slowly added, and the mixture was stirred at −78° C. for 2 h. A solution of 3,3-dimethyl-4-oxo-butyronitrile (0.241 g, 2.17 mmol) in 2 mL of tetrahydrofuran was added dropwise, and the mixture was stirred, allowing to slowly warm to RT, for 19 h, then quenched with 100 mL of a sat. aq. NaHCO3 solution. The resulting mixture was extracted with 100 mL of ethyl acetate, and the organic layer was dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0→50% EtOAc/hexanes) afforded 0.152 g (62%) of 4-hydroxy-3,3-dimethyl-4-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyronitrile as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:19])=[C:9]([NH:11]C(=O)OC(C)(C)C)[N:10]=2)[CH:7]=1.CO>Cl.O1CCOCC1>[ClH:1].[NH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]2[C:8]=1[CH3:19]
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccc(Cl)cn12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(N)nc2ccc(Cl)cn12

Procedure:
Compound 15-B (0.500 g, 1.77 mmol) was dissolved in 4N HCl in dioxane (17.75 mL) and methanol (12 mL) and the reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated in vacuo to give compound 16-A as a light yellow solid; MS m/z (M+H+) 182.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]([C:17](=[O:19])[CH3:18])[CH2:10][CH2:11][N:12]([C:14](=[O:16])[CH3:15])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].O=O>>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][N:9]1[C:17](=[O:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1C=C(C(=O)NC(C)(C)C)N(C(C)=O)CC1
Agent: O=O
Agent: [Cl-]
Product: CC(=O)N1CCN(C(C)=O)[C@H](C(=O)NC(C)(C)C)C1
Reaction time: 20 h
Yield: 105.4 %

Procedure:
10 g (37 mmol) of 1,4-diacetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide, 20.3 mg (37 μmol) of 1-[1(R)-(di-tert-butylphosphino)ethyl]-2(S)-(diphenylphosphino)ferrocene and 9.2 mg (20 μmol) of bicyclo[2.2.1]hepta-2,5-dienerhodium(I) chloride dimer were placed in an autoclave, oxygen being excluded. After flushing with argon, 80 ml of oxygen-free methanol was added. Hydrogenation was carried out at an initial pressure of 50 bar and a temperature of 110° C. for 20 hours. The autoclave was depressurized and flushed with nitrogen. The solvent of the reaction mixture was completely distilled off to give 10.50 g (95%) of the title product. GC analysis showed a conversion of 85 percent. After cleavage of the protecting groups with hydrochloric acid, the enantioselectivity of the hydrogenation was determined by GC analysis, giving an ee of 90.5 percent.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[NH2:14]>C(Cl)(Cl)Cl>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:14][N:13]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:12])=[O:11])([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(N)c1nc2ccccc2o1
Solvent: ClC(Cl)Cl
Product: CN(NC(=O)c1ccccc1C(=O)O)c1nc2ccccc2o1
Reaction time: 8 h

Procedure:
A suspension of 5.2 g. of phthalic anhydride in 75 ml. of chloroform is stirred and treated with 5.7 g. of 2-(1-methylhydrazino)benzoxazole. A clear yellow solution results and the temperature drops several degrees, then rises to 33+ C. After about 15 min. precipitation of a solid begins. An additional 200 ml. of chloroform is added and the mixture is stirred overnight. The solid is filtered, washed with chloroform and dried to give 8.6 g. of product, m.p. 140°-142°.
Reaction SMILES: O=[C:2]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]>C(O)(=O)C>[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1)([OH:8])=[O:7]
Reactant: O=C(O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12
Solvent: CC(=O)O
Product: O=C(O)CCCCc1cn(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.5 g of 3-(1-oxo-4-carboxybutyl)-N-(3-pyridyl)-indole in 7.5 ml of glacial acetic acid is added 0.5 g of borane-tert-butylamine complex. The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated, the residue is dissolved in 10 ml of 1N sodium hydroxide, water is added to the residue, the pH is adjusted to 5.0 with hydrochloric acid and the product is filtered off and dried to yield 3-(4-carboxybutyl)-N-(3-pyridyl)-indole identical to the compound obtained in Example 3b.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][C:21]#[C:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][CH2:8]1)([OH:4])([OH:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[O-:46][P:47]([O:50][P:51]([O-])([O-:53])=[O:52])(=[O:49])[O-:48].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH2:20][C:21]#[C:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][CH2:8]1)([O:3][P:51]([O:50][P:47]([OH:49])([OH:48])=[O:46])([OH:53])=[O:52])(=[O:4])[OH:2]
Reactant: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O)C(F)(F)F
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Without being limiting in any way, monophosphate (6) can optionally be formed by treatment of 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′ dideoxyuridine (5) with, for example, POCl3. 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′-dideoxyuridine-5′-monophosphate (6) can then optionally be treated with, for example, carbonyldiimidazole (CDI) followed by tetrabutylammonium pyrophosphate (TBAPP) under appropriate conditions to form 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′ dideoxyuridine-5′-triphosphate (7). It will be recognized by one of skill in the art that conversion of 5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl)-2′,3′ dideoxyuridine (5) to triphosphate (7) can be accomplished by any method known in the art.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccn(C)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ccc(-c2ccc(C(=O)O)c(Cl)c2)n1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
To a solution of 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid, methyl ester (6.85 g) in methanol (32 ml) was added 2.5N sodium hydroxide solution (15.3 ml). The reaction was heated to 50° C. for one hour. The solvent was removed in vacuo, and the residue dissolved in water (250 ml), cooled in an ice bath, and acidified with 2N hydrochloric acid (24 ml). The resulting precipitate was filtered and dried to give a colorless solid (6.3 g) m.p. 232-233° C.; MS, (+FAB), m/z: 236 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])C.CO.Cl>[OH-].[Na+].CCOC(C)=O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[C:12]([Cl:18])[CH:13]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a 250 mL round bottom flask was added 1-(4-Bromo-2-chloro-phenyl)-2-(2-chlorophenyl)-1H-imidazole-4-carboxylic acid ethyl ester (3.60 g, 8.18 mmol), MeOH (65 mL), and IN aq NaOH (41 mL). The reaction solution was allowed to stir at 50° C. for 2 hr. The reaction solution was diluted with EtOAc (200 mL), neutralized by the addition of aq 1 N HCl, and poured into a separatory funnel. The organic phase was partitioned, and the aqueous phase was and extracted with EtOAc (150 mL×2). The combined organic phases were dried over Na2SO4, filtered into a round bottom flask and concentrated on the Rotavapor. The crude residue was reprecipitated in an EtOAc/hexane solution and the solid precipitate was filtered under vacuum to afford 2.98 g (88% yield) of title product. MS (ESI) 410.3, 412.3, 414.3 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:14][S:13][C@@H:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[S:11]1)(C(C)(C)C)(C)C>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([C@H:12]1[S:11][C@H:10]([CH2:9][OH:8])[CH2:14][S:13]1)=[O:16])[CH3:19]
Reactant: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)Cl
Product: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO)S1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of trans-4-(t-butyldimethylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-dithiolane (example 49) (9.84 g, 25.46 mmol) in anhydrous methanol (150 mL) was added acetyl chloride (12 drops) at 0° C. The solution was stirred at 0° C. for 30 min and then at room temperature for 3.5 hrs. A saturated solution of ammonium chloride (5 drops) was added and the solution was stirred for 15 min followed by evaporation of the solvents. The crude material was purified by flash chromatography with a mixture of dichloromethane and methanol (94:6) to give a white solid (5.97 g) in 86% yield.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[NH:32][C:33]2[CH2:38][CH2:37][NH:36][CH2:35][C:34]=2[N:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([N:36]3[CH2:37][CH2:38][C:33]4[NH:32][C:31]([CH3:30])=[N:39][C:34]=4[CH2:35]3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nc2c([nH]1)CCNC2
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCc4[nH]c(C)nc4C3)sc2c1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
A flask was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.20 mmol), 2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (85 mg, 0.40 mmol), Cs2CO3 (325 mg, 1.0 mmol), and then diluted with ACN (4 mL). The suspension was heated to 80° C. for 24 hours and then allowed to cool to room temperature. The resulting mixture was filtered and concentrated in vacuo. The crude residue was purified by reverse phase column chromatography (5-100% ACN/H2O+0.1% TFA)to afford the desired product. LCMS-ESI+: calc'd for C29H34ClN4O3S: 553.2 (M+H+); Found: 553.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[O:22][CH:23]([CH2:27][CH3:28])[C:24]([OH:26])=[O:25])=[CH:17][C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1.[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:35][C:20]1[C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:32])[F:33])=[CH:8][CH:7]=4)=[N:10][O:11][C:12]=3[CH:17]=2)=[CH:31][CH:30]=[CH:29][C:21]=1[O:22][CH:23]([CH2:27][CH3:28])[C:24]([OH:26])=[O:25]
Reactant: CCC(Oc1cccc(Oc2ccc3c(-c4ccc(C(F)(F)F)cc4)noc3c2)c1)C(=O)O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCC(Oc1cccc(Oc2ccc3c(-c4ccc(C(F)(F)F)cc4)noc3c2)c1F)C(=O)O

Procedure:
A solution of the title compound of example 10 (92 mg, 0.2 mmol) and SELECTFLUOR™ (Aldrich, 70 mg, 0.2 mmol) in acetonitrile (2.0 mL) was heated at 60° C. for 16 hrs. The reaction mixture was directly purified by preparative HPLC on a 100×20 mm YMC C-18 column using 0.1% TFA modified CH3CN—H2O solvent system as the eluent to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]([Br:17])[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[CH3:20][C:21]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:17][C:4]1[C:5]2[S:9][C:8]([NH:10][C:11](=[O:12])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:16]=[C:2]([C:30]2[CH:29]=[N:28][C:27]([N:24]3[CH2:25][CH2:26][C:21]([CH3:20])([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23]3)=[N:32][CH:31]=2)[C:3]=1[O:18][CH3:19]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCNC(=O)Nc1nc2cc(Br)c(OC)c(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)c(OC)c(Br)c2s1
Temperature: 110 °C

Procedure:
1-(5,7-Dibromo-6-methoxy-1,3-benzothiazol-2-yl)-3-ethyl-urea (Intermediate 14) (234 mg, 0.57 mmol), ethyl 4-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperidine-4-carboxylate (716 mg, 1.14 mmol, 60 mass %) and PdCl2(dppf).DCM (23 mg, 0.03 mmol) were dissolved in dioxane (7.5 mL) in a 10-20 mL microwave vial and a solution of cesium carbonate (559 mg, 1.72 mmol) in water (2.5 mL) was added. The vial was capped, the mixture degassed and heated in the microwave at 110° C. for 30 minutes. The mixture was poured into water and extracted into EtOAc (4×40 mL). The organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness in vacuo. The mixture was purified by chromatography, Biotage SP4, 40 g Si cartridge, 10-100% EtOAc in heptane. Two compounds were detected with the same mass ion (m/z) and retention time by LCMS but were distinct by TLC (60% EtOAc in heptane) so were assumed to be two regioisomers. The relevant fractions were combined to give the desired compound as a pale yellow oil, 47 mg (14%). MS: 577.04/579.07 [M+H]+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31]C)[O:11][C:10]1([CH2:52]O)[CH2:50][OH:51])C1C=CC=CC=1.O.[C:55]1([CH3:65])[CH:60]=[CH:59][C:58](S(O)(=O)=O)=[CH:57][CH:56]=1>ClCCl>[CH2:65]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:50][OH:51])[CH2:52][O:31]2)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 1i (2.49 g, 3.37 mmol) in dichloromethane (300 mL) was added p-toluenesulfonic acid monohydrate (0.32 g, 1.69 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour and quenched with 30 mL of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (20 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (20 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=7/1 to give the title compound 1j as pale yellow oil (1.06 g, 44.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.45 (d, 1H), 7.40 (m, 12H), 7.30 (m, 3H), 7.09 (m, 2H), 6.91 (m, 2H), 6.78 (m, 2H), 4.88 (m, 3H), 4.78 (d, 1H), 4.29 (m, 2H), 4.11-3.96 (m, 6H), 3.88 (d, 1H), 3.80 (m, 2H), 3.71 (m, 2H), 1.85 (t, 1H), 1.41 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O>O1CCCC1.O>[C:1]([O:5][C:6]([C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C2(C(=O)OC(C)(C)C)CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1(c2ccc(C(=O)O)cc2)CCCCC1
Yield: 88.2 %

Procedure:
To a solution of methyl 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoate (1) (0.273 g, 0.86 mmol) in tetrahydrofuran (5 ml) was added 0.63 N LiOH water solution (3 ml, 1.89 mmol) and the resultant suspension was stirred at ambient temperature for 5 days. The reaction mixture was diluted with water (20 ml) and saturated NaH2PO4 (5 ml), and the obtained suspension was extracted with ethyl acetate (2×30 ml). The extract was washed with brine (15 ml), dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica gel with toluene-ethyl acetate-acetic acid (8:2:01) as eluent to give the title compound (0.231 g, 88%) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.07-1.91 (8H, m); 1.35 (9H, s); 2.20-2.63 (2H, m); 7.52 (2H, d, J=8.5 Hz); 8.06 (2H, d, J=8.5 Hz); 11.20 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:16](=[O:18])[NH2:17])[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Br:19]Br>C(O)(=O)C>[Br:19][CH:11]1[CH2:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:16](=[O:18])[NH2:17])[CH2:14][CH2:13][C:12]1=[O:15]
Reactant: BrBr
Reactant: COc1cccc(C2(C(N)=O)CCC(=O)CC2)c1
Solvent: CC(=O)O
Product: COc1cccc(C2(C(N)=O)CCC(=O)C(Br)C2)c1
Temperature: 20 °C
Yield: 104.8 %

Procedure:
50.5 g of 4-(3-methoxyphenyl)-4-carbamoyl-cyclohexanone are dissolved in 500 ml of acetic acid, and a solution of 32.7 g of bromine in 500 ml of acetic acid is added dropwise thereto at 20°C. under stirring. Then, the mixture is poured into ice-water and extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. 69.8 g of 2-bromo-4-(3-methoxyphenyl)-4-carbamoyl-cyclohexanone are obtained as crude oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:26][CH3:27]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]([CH2:26][CH3:27])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1cccc(F)c1
Temperature: 50 °C
Yield: 95 %

Procedure:
A solution of 2F (3.0 g, 10.8 mmol) in DMF (15 mL) was added with an. K2CO3 (1.5 mol eq, 2.24 g) and, after few minutes, 2-iodoethane (1.2 mol eq, 1.33 mL) was added and the mixture heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (150 mL) and the aqueous phase extracted with EtOAc (4×50 mL). The recombined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 3F as a pale orange viscous oil (3.2 g, 95% yield). 1HNMR (DMSO, 200 MHz) δ 1.15 (m, 3H), 2.00 (s, 3H), 3.79 (q, 2H, J=8), 4.06 (t, 1H), 4.59 (t, 1H), 5.18 (m, 2H), 7.94 (m, 4H).