Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18](=[O:43])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH:27]([OH:42])[CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[N:37]=3)[N:32]=[CH:31][C:30]=2O)[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[C:13]([O:17][C:18](=[O:43])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH:27]2[CH2:28][C:29]3=[C:38]4[C:33](=[N:32][CH:31]=[C:30]3[O:42]2)[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[N:37]4)[CH2:22][CH2:21]1)([CH3:14])([CH3:16])[CH3:15]
Reactant: COc1ccc2ncc(O)c(CC(O)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc3c(c2n1)CC(C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)O3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl azodicarboxylate (650 μL, 4.13 mmol, 2.0 eq) is added at 0° C. to a stirred solution of {trans-4-[2-hydroxy-3-(3-hydroxy-6-methoxy-[1,5]naphthyridin-4-yl)-propyl]-cyclohexyl}-carbamic acid tert-butyl ester (890 mg, 2.06 mmol, 1.0 eq) in tetrahydrofuran (100 mL), followed by triphenylphosphine (1.08 g, 4.13 mmol, 2.0 eq). After 1 hour stirring at room temperature, solvent is removed and the crude is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford [trans-4-(8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalen-2-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid (420 mg, 49% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH2:9][O:10][CH3:11])[N:5]=[CH:6][C:7]=1Cl.[CH3:13][O-:14].[Na+]>CO>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH2:9][O:10][CH3:11])[N:5]=[CH:6][C:7]=1[O:14][CH3:13]
Reactant: COCn1ncc(Cl)c(Cl)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCn1ncc(OC)c(Cl)c1=O
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a stirred solution of 4,5-dichloro-2-methoxymethyl-2H-pyridazin-3one (500 mg, 2.39 mmol) in methanol (12 mL) at room temperature was added sodium methoxide (258 mg, 4.78 mmol). After stirred for 2 h, the reaction was concentrated. To this residue was added water (20 mL), then extracted with CH2Cl2 (2×50 mL). The combined organic layer was dried (Na2SO4) and concentrated to give 480 mg (98%) 4-chloro-5-methoxy-2-methoxymethyl-2H-pyridazin-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:31][C:13]2=[CH:14][C:15]3[C:16](=[O:30])[N:17]([CH:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)[C:18](=[O:22])[C:19]=3[C:20]([CH3:21])=[C:12]2[N:11]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:31][C:13]2=[CH:14][C:15]3[C:16](=[O:30])[N:17]([CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[C:18](=[O:22])[C:19]=3[C:20]([CH3:21])=[C:12]2[N:11]=1
Reactant: COc1nccc(Cl)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Temperature: 47.5 °C

Procedure:
A solution of 2-(4-chloro-2-methoxypyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione in a mixture of 1,4-dioxane and concentrated HCl was heated at 45-50° C. for 14 h. After the end of reaction was established by TLC, the reaction mixture was concentrated under vacuum to afford a crude product as a yellow solid, which was used for the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 12.60 (s, 1H, NH), 9.90 (s, 1H, NH), 7.90 (s, 1H, ArH), 7.70 (d, J=7.0 Hz, 1H, ArH), 6.58 (d, J=7.5 Hz, 1H, ArH), 4.34-4.29 (m, 1H, CH), 3.53-3.50 (m, 2H, CH2), 3.20-3.13 (m, 2H, CH2), 2.87 (s, 3H, CH3), 2.76 (d, J=4.5 Hz, 3H, CH3), 2.66-2.59 (m, 2H, CH2), 1.96-1.93 (m, 2H, CH2); Mass (ESI, positive) m/z 426.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:32]3[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([F:29])[CH:31]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: COc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1F
Yield: 51 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-fluoro-4-methoxyphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (51%).
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([F:28])[C:14]=1[OH:29])=[O:11])C1C=CC=CC=1>[C].[Pd].C(O)C>[C:19]([C:18]1[C:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])=[C:14]([OH:29])[C:15]([F:28])=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]=1[CH3:21])#[N:20]
Reactant: Cc1c(C#N)c(NC(=O)COCc2ccccc2)c(O)c(F)c1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C#N)c(NC(=O)CO)c(O)c(F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A catalyst 10%-palladium carbon (40.0 mg) was added to an ethanol (10 ml) solution of 2-(benzyloxy)-N-(5-cyano-2-fluoro-3-hydroxy-6-methylbiphenyl-4-yl)acetamide (I-89) (120 mg, 0.307 mmol), followed by stirring under hydrogen atmosphere at room temperature for 15 hours. After the reaction, the insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure to obtain the entitled compound. Not purified, this was used in the next reaction as such.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][N:3]1[CH:7]([CH3:11])[C:8]([OH:10])=O.[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH2:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH:15][C:8](=[O:10])[CH:7]([N:3]1[C:2](=[O:1])[CH2:6][S:5][CH2:4]1)[CH3:11]
Reactant: CC(C(=O)O)N1CSCC1=O
Reactant: Cc1cccc(C)c1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1NC(=O)C(C)N1CSCC1=O
Yield: 45.7 %

Procedure:
A mixture of 2-(4-oxo-3-thiazolidinyl)propionic acid (2.00 g), 2.6-dimethylaniline (1.38 g), and dicyclohexylcarbodiimide (2.35 g) in chloroform (15 ml) was refluxed for 48 hours. The resultant precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether and recrystallized from ethanol to give N-(2,6-dimethylphenyl)-2-(4-oxo-3-thiazolidinyl)propionamide (1.45 g) as colorless prisms.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][C:26]=1[Cl:37])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][CH:8]1[C:21]([O:23]C)=[O:22]>O1CCOCC1>[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][C:26]=1[Cl:37])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][CH:8]1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)C1CN(CCSc2cccs2)CCC1CCC(O)c1c(Cl)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2ncc(Cl)c(C(O)CCC3CCN(CCSc4cccs4)CC3C(=O)O)c2c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
Stereoisomer D 1.8 cm3 of a 1 N aqueous sodium hydroxide solution are added to 325 mg of methyl 4-[3-hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylsulfanyl)ethyl]piperidine-3-carboxylate (ester isomer D) solubilized in 10 cm3 of dioxane. The reaction medium is then heated at 70° C. for 5 h 30 min. The temperature is allowed to return to 19° C. for 12 hours and then heating is carried out again at 70° C. for 2 hours. Evaporation is then carried out under reduced pressure (20 kPa; 45° C.). The residue is taken up in 25 cm3 of distilled water and then extraction is carried out with 25 cm3 of diethyl ether. The aqueous phase is acidified with 1.6 cm3 of a 1 N aqueous hydrochloric acid solution (pH=6) and then this phase is extracted with 3 times 70 cm3 of ethyl acetate. The organic phase is dried under magnesium sulfate, filtered through a sintered glass funnel, and then evaporated under reduced pressure (20 kPa; 45° C.). After having dried under vacuum (50 kPa), the residue is taken up with 20 cm3 of acetone and then concentrated again under reduced pressure (20 kPa; 45° C.). Drying is carried out under reduced pressure (50 kPa; 20° C.) for 12 hours and 260 mg of 4-[3-hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylsulfanyl)ethyl]piperidine-3-carboxylic acid, in the form of a pale yellow solid (isomer D), are obtained.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C:9]1([C:28]#[N:29])[CH2:14][CH2:13][N:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1)(C)(C)C.[F-].C[N+](C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[OH:6][CH2:7][CH2:8][C:9]1([C:28]#[N:29])[CH2:14][CH2:13][N:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1(C#N)CCN(c2nc3ccc(C(F)(F)F)cc3s2)CC1
Agent: C[N+](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [F-]
Product: N#CC1(CCO)CCN(c2nc3ccc(C(F)(F)F)cc3s2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To 4-[2-(t-butyldimethyl silyloxy)ethyl]-1-(6-trifluoromethyl benzothiazole-2-yl)piperidine-4-carbonitrile (510 mg) was added tetramethylammonium fluoride (1 M tetrahydrofuran solution, 1.63 mL). The mixture was stirred at 0° C. for 0.5 hour. To the reaction solution was added aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (366 mg). Yield: 95%.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([C:18]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:24]=3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])C1C=CC=CC=1>C(O)C.[Pd]>[ClH:1].[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:12]([C:18]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:24]=3)[N:19]=2)=[CH:11][C:10]=1[OH:9]
Reactant: COc1ccc(-c2nc(-c3cccc(CN4CCCC4)c3)n[nH]2)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2nc(-c3cccc(CN4CCCC4)c3)n[nH]2)cc1O
Yield: 63 %

Procedure:
A solution of 5-(3-benzyloxy-4-methoxy-phenyl)-3-(3-pyrrolidin-1-ylmethyl-phenyl)-1H-[1,2,4]triazole hydrochloride (1:1) (300 mg, 0.63 mmol) in ethanol (80 ml) was hydrogenated (1 atm H2) with Pd/C (10%, 50 mg) at 20° C. overnight. The catalyst was filtered off, the solvent volume was reduced to ca. 5 ml and the resulting product recrystallized. After drying under high vaccum at 40° C. for 8 hrs. the title compound was obtained (152 mg, 63% yield) as a light yellow solid. MS: m/e=351.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[C:26]([F:46])[C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[C:26]([F:46])[C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Yield: 85 %

Procedure:
Prepared in 85% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S,24Z)-17,18-difluoro-4,5,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 690.4.
Reaction SMILES: [OH:1][C:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C(O)C>[OH:1][C:2]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(O)(c1ccccc1)c1ccc(OCOC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCOc1ccc(C(O)(CC(=O)O)c2ccccc2)cc1
Yield: 96 %

Procedure:
0.23 g of ethyl 3-hydroxy-3-[4-(methoxymethoxy)phenyl]-3-phenylpropionate was dissolved in 1 ml ethanol, and then stirred with 14 ml of 2 mol/l aqueous sodium hydroxide at room temperature for 16 hours. The reaction mixture was adjusted to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate three times, washed twice with water and once with brine, followed by drying over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was evaporated to give 3-hydroxy-3-[4-(methoxymethoxy)phenyl]-3-phenylpropionic acid (202 mg, yield: 95.7%) as a white solid.
Reaction SMILES: [Si](O[CH2:19][C@H:20]1[O:27][C@@H:24]([O:25][CH3:26])[C@H:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:22]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:21]1[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[S:67]([O:74]S(C(F)(F)F)(=O)=O)([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68]>ClCCl>[CH2:29]([O:28][C@@H:23]1[C@@H:22]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:21]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:20]([CH2:19][O:74][S:67]([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68])[O:27][C@H:24]1[O:25][CH3:26])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COS(=O)(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 6-O-tert-butyldiphenylsilyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside (800 mg, 1.71 mmol) in 8.55 mL of dry dichloromethane at −78° C. was added 2,6-di-tert-butyl-4-methyl pyridine (632 mg, 3.08 mmol) followed by triflic anhydride (345 μl, 2.05 mmol). After stirring 15 minutes at −78° C., the mixture was warmed to room temperature over 20 minutes, and then poured into a solution of saturated aqueous NaHCO, (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 (3×20 mL), saturated aqueous NaCl (1×20 mL), and dried over magnesium sulfate. Concentration provided crude target compound, which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[C:12]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=[CH:9][N:8]2[C:20]=1[CH3:21])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:2][CH2:3][C:5]1[N:6]=[C:7]2[C:12]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:11][CH:10]=[CH:9][N:8]2[C:20]=1[CH3:21]
Reactant: COC(=O)c1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)nc2c(NC(=O)C(C)(C)C)cccn12
Yield: 82.3 %

Procedure:
To a solution of 36.6 g of 2-methoxycarbonyl-3-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 400 ml of dry tetrahydrofuran are added 5.5 g of lithium aluminium hydride at ambient temperature over a period of 1 h. The reaction mixture is then carefully hydrolysed with 15 ml water and 16 ml 15% sodium hydroxide solution. The precipitate is removed by filtration and washed thoroughly with tetrahydrofuran. The filtrate is washed with 100 ml saturated ammonium chloride solution and concentrated in vacuo. The residue is dissolved in 400 ml tetrahydrofuran/toluene 1:1 (v/v) and the solvent distilled off at 80° C. The precipitate is filtered off and dried in vacuo to yield 27.2 g (83%) of the title compound (m.p. 186–187° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:21][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([CH3:14])[N:20]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Cc1nc(N)ccc1-c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)ccc1-c1ccccc1

Procedure:
2,6-Dichlorobenzoyl isocyanate (650 mg) was reacted with 6-methyl-5-phenyl-2-pyridylamine (500 mg) in 25 ml of ethyl acetate. A precipitate formed which was filtered and confirmed by NMR as the desired product, 219°-220° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](B3OC(C)(C)C(C)(C)O3)=[CH:7][N:8]2[S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:30]1[O:34][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[N:32][N:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:74]1[CH:79]=[N:78][CH:77]=[C:76]([CH:80]2[CH2:82][CH2:81]2)[N:75]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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]>[CH:80]1([C:76]2[N:75]=[C:74]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[C:3]([C:30]5[O:34][C:33]([NH:35][CH:36]([CH3:37])[CH3:38])=[N:32][N:31]=5)[CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=4)(=[O:13])=[O:12])[CH:7]=3)[CH:79]=[N:78][CH:77]=2)[CH2:82][CH2:81]1
Reactant: Brc1cncc(C2CC2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)c(F)cc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)c(F)cc32)cc1
Temperature: 130 °C
Yield: 36.3 %

Procedure:
A 20 mL microwave vial was charged with 5-(6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (185 mg, 0.342 mmol), Xphos (Strem Chemicals, Newburyport, Mass., 9.8 mg, 0.021 mmol), Pd2(dba)3 (Strem Chemicals, Newburyport, Mass., 9.4 mg, 10.27 μmol), 2-bromo-6-cyclopropylpyrazine (CombiPhos Catalyst Inc., Princeton, N.J., 82 mg, 0.411 mmol) and potassium phosphate (218 mg, 1.03 mmol) followed by purging with argon. The solids were then treated with dioxane (4.0 mL) and water (1.0 mL) and heated in the microwave at 130° C. for 20 min. The reaction mixture was treated with water and extracted with EtOAc, dried over MgSO4, filtered and concentrated. Purification of the crude residue on the ISCO Combiflash Rf (12 g Redisep column, using a gradient of 0-100% EtOAc in hexanes) afforded 5-(3-(6-cyclopropylpyrazin-2-yl)-6-fluoro-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (65.8 mg, 0.124 mmol, 36.1% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 533.0 (M+H)+. The material was used in the subsequent step without further purification.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][CH:9]([S:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]1[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=1.C(N(CC)CC)C>ClCCl.O>[S:18]1[C:19]2[NH:20][C:21]3[C:26]([C:27]=2[CH2:7][CH2:8][CH:9]1[CH2:10][C:11]1[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: CC1(C)COC(CC(CCO)Sc2cc3ccccc3[nH]2)=N1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)COC(CC2CCc3c([nH]c4ccccc34)S2)=N1
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
0.05 ml of methanesulfonyl chloride was added to a mixture of 165 mg of 2-[4-hydroxy-2-(indol-2-ylthio)butyl]-4,4-dimethyl-2-oxazoline (prepared as described in Example 79) and 0.10 ml of triethylamine in 5 ml of dichloromethane, with stirring and ice-cooling, and stirring was continued for 30 minutes. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was dissolved in a mixture of 5 ml of dichloromethane and 5 ml of benzene. 0.26 ml of a solution of 3M ethylmagnesium bromide in diethyl ether was then added to this mixture, with stirring, at room temperature, and stirring was continued at this temperature for 30 minutes. At the end of this time, the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a mixture of 30% v/v ethyl acetate in hexane as the eluent, to afford 73 mg of the title compound as a solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:42])=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH:23]=2)[CH:21]=1.CCN(CC)CC>C(Cl)Cl>[CH3:41][C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:24]2[CH:23]=[C:22]([C:20]3[C:19]([F:42])=[CH:18][CH:17]=[C:16]([CH2:15][NH:14][S:2]([C:5]4[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=4)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH:21]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31]1)=[O:36])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNS(=O)(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoic acid (0.0331 g, 0.15 mmol) in DCM (1.5 mL) was added 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.060 g, 0.15 mmol), and Et3N (0.0211 mL, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 h before it was concentrated and purified using a Gilson HPLC to afford the title compound 0.0374 g (43%). LC-MS m/z 584 (M+H)+.