Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[F:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[CH3:23]>>[F:13][C:14]1[N:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:16][C:15]=1[CH3:23]
Reactant: Cc1cc(B(O)O)cnc1F
Reactant: O=Cc1cnc2ccc(Br)cn12
Product: Cc1cc(-c2ccc3ncc(C=O)n3c2)cnc1F
Yield: 44 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 6-fluoro-5-methylpyridin-3-ylboronic acid. Yield: 44%; 1H NMR (DMSO-d6; 300 MHz): δ10.0 (s, 1H), 9.59 (s, 1H), 8.58-8.00 (m, 5H), 2.24 (s, 3H), MS: m/z 256(M+1)+.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].P(=O)(O)(O)O>CN(C)C=O>[C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Sodium hydride (5.0 g, 0.114 mole) and 4-phenylphenol (15.3 g, 0.09 mol) were stirred at 0° C. in 75 mL of dimethyl formamide (hereinafter “DMF”) for 2 h. Ethyl 4-chloroacetoacetate (5.0 g, 0.03 mol) in DMF (75 mL) was added. The mixture was stirred for 1 h at 0° C. and for 12 h at room temperature, then neutralized with 50% phosphoric acid and extracted with dichloromethane. The product was purified by silica gel chromatography using (8:2) toluene:ethanol as the mobile phase.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28](Cl)(=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>ClCCl>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH:19][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCNCCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{[4-(3-Aminopropyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.16 g) synthesized in Example 33 and triethylamine (1.68 mL) were dissolved in dichloromethane (50 mL), heptanoyl chloride (1.62 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (10 mL), 1 M-borane/tetrahydrofuran complex (26.6 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (30 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (30 mL) was added, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound (2.86 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH3:13])[C:9]([F:12])=[CH:10][CH:11]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([C:9]([F:12])=[CH:10][CH:11]=1)[CH2:13][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Oc2cccc(F)c2)ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(Oc2ccc(F)c(CBr)c2)c1
Temperature: 10 °C
Yield: 51 %

Procedure:
48.4 g (0.22 mol) of 3-(3-fluorophenoxy)-6-fluorotoluene were dissolved in 300 ml of anhydrous carbon tetrachloride and heated under reflux with 41 g of N-bromosuccinimide. After 70° C. was reached, 3 g of azo-diisobutyronitrile were added; after about 10-20 minutes the reaction commenced, with evolution of heat, and after the exothermic reaction had subsided the mixture was heated under reflux for a further 4 hours. The reaction batch was then cooled to 10° C., the succinimide was filtered off and the carbon tetrachloride was distilled off in vacuo. The oil which remained was distilled at 142°-150° C./2 mm Hg. 3-(3-Fluorophenoxy)-6-fluorobenzyl bromide was obtained in 51% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19](O)[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27](=[O:29])[CH3:28].CS(Cl)(=O)=O.Cl>CN(C)C=O.N1C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27](=[O:29])[CH3:28]
Reactant: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
A solution of 21 -chloro-11β,17-dihydroxy-16α-(2-oxopropoxy)pregna-1,4-diene-3,20-dione (10 mmoles) in 40 ml of dimethylformamide and 20 ml of pyridine is stirred at 0°C for 75 minutes with 10 ml of methanesulfonyl chloride. The mixture is poured into cold, dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated to give the title compound.
Reaction SMILES: [C:1]1([N:7]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([CH3:31])[C:15]([CH2:17][N:18]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=4)[CH2:19][CH2:20][CH2:21][CH3:22])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[ClH:41].[C:1]1([N:7]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([CH3:31])[C:15]([CH2:17][N:18]([C:23]4[CH:24]=[CH:25][C:26]([C:29](=[NH:46])[NH2:30])=[CH:27][CH:28]=4)[CH2:19][CH2:20][CH2:21][CH3:22])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCCCN(Cc1nc2cc(C(=O)N(CCC(=O)OCC)c3ccccc3)ccc2n1C)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCCCN(Cc1nc2cc(C(=O)N(CCC(=O)OCC)c3ccccc3)ccc2n1C)c1ccc(C(=N)N)cc1
Yield: 62 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 62% of theory, C32H38N6O3 (554.7) ##EQU100##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([CH3:28])([S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O)[CH3:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[S:18][C:16]([CH3:28])([CH3:17])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]([OH:15])=[O:14]
Reactant: CC(C)(Sc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(Sc1ccccc1N)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Yield: 99.9 %

Procedure:
A mixture of (R)-2-(benzyloxycarbonylamino)-3-methyl-3-(2-nitrophenylthio)butanoic acid (18.3 g, 45.2 mmol, Eq: 1.00), NH4Cl (4.84 g, 90.5 mmol, Eq: 2) and Zn (45.9 g, 701 mmol, Eq: 15.5) in MeOH (500 mL) was heated at reflux for 6 h and the mixture was filtered through Celite. The filter cake was washed with hot MeOH. The filtrate was concentrated, the residue was tritrurated with H2O, 1:3 Et2O/Hexane and azeotroped with toluene. The resulting material was dried under vacuum to give (R)-3-(2-aminophenylthio)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (16.9 g, 100%) which was used without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1O.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][O:14][C:17]2[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=2[Br:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1=CCN(Cc2ccccc2)C1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(OCC2=CCN(Cc3ccccc3)C2)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
(1-Benzyl-2,5-dihydro-1H-pyrrol-3-yl)methanol (14.0 g) obtained in Example 50(2), 2-bromo-4-trifluoromethylphenol (19.0 g), DEAD (13.5 g) and triphenylphosphine (23.3 g) were dissolved in tetrahydrofuran (450 mL). The reaction solution was stirred under a nitrogen atmosphere at 50° C. overnight. Tetrahydrofuran was evaporated under reduced pressure, and the residue was purified by silica gel column (20% diethyl ether/petroleum ether to 33% diethyl ether/petroleum ether) to give the object product as a pale-yellow oil (10 g, 33%).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[C:9]([N+:12]([O-])=O)[C:8](=[O:15])[N:7]([CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]>CCOC(C)=O.[Pd]>[NH2:12][C:9]1[C:8](=[O:15])[N:7]([CH3:16])[C:6](=[O:17])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=1[CH3:11]
Reactant: CCCCn1c(C)c([N+](=O)[O-])c(=O)n(C)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCn1c(C)c(N)c(=O)n(C)c1=O
Reaction time: 67 h
Yield: 96 %

Procedure:
To 1.48 g (6.14 mmol) of 1-butyl-3,6-dimethyl-5-nitro-1H-pyrimidine-2,4-dione in 60 mL EtOAc was added 500 mg of 10% Pd/C. The resulting mixture was hydrogenated under 1 atm of H2 for 67 h at 23° C. The reaction mixture was then poured through Celite and the solvent evaporated to give 1.24 g (5.87 mmol, a 96% yield) of the title compound as a white solid. mp: 74-75° C.; 1H NMR (300 MHz, CDCl3): δ 0.99 (t, J=7.3 Hz, 3H), 1.40 (hex, J=7.4 Hz, 2H), 1.56-1.67 (m, 2H), 2.22 (s, 3H), 3.39 (s, 3H), 3.84 (t, J=7.3 Hz, 2H), NH2 not visible; IR (KBr, cm-1): 3142w, 2965w, 1719s, 1679s, 1627s, 1380m, 1296m, 1166s, 1063m; MS (ES) m/z (relative intensity): 363 (M+ +H, 100). Anal. Calcd for C10H17N3O2 : C, 43.03; H, 5.28; N, 15.44. Found: C, 43.11; H, 5.33; N, 15.26.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(Cl)Cl>[CH:24]([CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:23]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dess-Martin Reagent (0.011 mol) was added neat over 1 minutes to intermediate (11) (0.010 mol) dissolved in DCM (35 ml). After 15 minutes, the ice bath was removed, and the mixture was allowed to warm to room temperature. More Dess-Martin Reagent (0.33 g) was added, and the mixture was stirred for 30 minutes more. The mixture was re-cooled to 0° C. and treated slowly with a partial suspension/solution of Na2S2O3 (25 g) which had attempted to dissolve in a saturated aqueous NaHCO3 (100 ml) solution. After 10 minutes, the mixture was removed from ice, and the layers were separated. More DCM was added, and the mixture was filtered. The organic was separated from the filtrate, and the combined organic phases were dried, filtered, concentrated and purified through flash column chromatography (eluent: 10% ethyl acetate:hexane, dissolving the sample in 3:1 ethyl acetate:hexane (5 ml)), yielding 1,1-dimethylethyl 2-formyl-2,3-dihydro-1H-indole-1-carboxylate (intermediate 12, mp. 85-87° C.).
Reaction SMILES: C([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:42](O)[C:41]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=3[C:35]2=[O:44])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[C:35](=[O:44])[C:36]3[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=3[CH:42]2[CH2:6][C:4]([OH:5])=[O:3])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(N2C(=O)C3=C(CCCC3)C2O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)C3=C(CCCC3)C2CC(=O)O)cc1
Yield: 948 %

Procedure:
Ethoxycarbonylmethylenetriphenylphosphorane (3.0 g) was added to a solution of 2-(4-methoxyphenyl)-3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one (2.59 g) in toluene (30 ml) and the solution was refluxed gently for 48 hours. After cooling, the solvent was distilled off and the residue was dissolved in 30 ml of methanol. Potassium carbonate (3 g) and water (10 ml) were added and the mixture was refluxed for an hour. After cooling, the methanol was distilled off, 100 ml of water and 100 ml of dichloromethane were added and the mixture was stirred well. The aqueous layer was separated and acidified with 5% hydrochloric acid to give crystals, which were washed with water, dried and recrystallized from methanol-ether (1:3) to give 24.6 g of 2-(4-methoxyphenyl)-3-oxo-4,5,6,7-tetrahydroisoindoline-1-acetic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.CO[CH:15](OC)[CH2:16][NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:4]=1[CH:5]=[N:17][CH:16]=[CH:15]2
Reactant: COC(CN)OC
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc2ccncc12
Reaction time: 0.5 h
Yield: 7 %

Procedure:
A mixture of 2-trifluoromethylbenzaldehyde (15 g; 86 mmol) and aminoacetaldehyde dimethylacetal (9.37 ml; 86 mmol) in toluene (75 ml) was heated at reflux under Dean/Stark conditions for 2 hours. The cooled reaction mixture was evaporated to dryness and the residue added dropwise to conc. sulfuric acid (200 ml) at 140° C.; after complete addition the heating was continued for 30 mins then the warm mixture was poured over ice. The mixture was filtered and the filtrate basified by the addition of 4N NaOH with cooling. The basic solution was extracted with Et2O (×3), the combined Et2O layers were dried over Na2SO4, filtered and evaporated. The residue was dissolved in DCM and filtered through a short plug of silica and evaporated to give 1.2 g (Yield 7%).
Reaction SMILES: C(O[CH:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C[Si]([N:32]=[N+:33]=[N-:34])(C)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@H:5]1[N:32]=[N+:33]=[N-:34])(=[O:10])[CH3:9]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
1,2,3,4,6-penta-O-acetyl-galactopyranose (1.17 g, 3 mmol) was dissolved in dry CH2Cl2 (15 ml), then trimethylsilyl azide (416 mg, 3.6 mmol) and SnCl4 (0.18 ml) were added under nitrogen. The mixture was stirred at room temperature for 24 hours. The reaction mixture was subsequently diluted with CH2Cl2 (40 ml), dried over MgSo4 and evaporated. The residue was purified by chromatography using hexane/EtOAc 8:7 v/v as the mobile phase to give 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl azide (1.05 g, 94%).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[C:4]([N:6]([CH2:14][CH3:15])[CH:7]([O:12][CH3:13])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5].[CH3:24][N:25](CCN(C)C)[CH3:26].[Li]C(C)(C)C.CCCCC.BrCCBr>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:24][N:25]([CH3:26])[C:19]1[CH:18]=[CH:17][C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:3]([CH:2]=1)[C:4]([N:6]([CH2:14][CH3:15])[CH:7]([O:12][CH3:13])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5]
Reactant: CN(C)CCN(C)C
Reactant: CCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(OC)C(C)(C)C
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCN(C(=O)c1cc(N(C)C)ccc1[Si](C)(C)C)C(OC)C(C)(C)C
Temperature: -20 °C

Procedure:
A solution of the compound of Example 201 (0.72 g, 2.0 mmol) and TMEDA (1.20 mL, 8.0 mmol) in THF (30 mL) at -78° C. was treated with a solution of 1.7 M t-BuLi in pentane (5.6 mL, 9.6 mmol) and allowed to slowly warm to -20° C. over 4 h. The reaction was quenched with 1,2-dibromoethane (0.86 mL, 10 mmol), was diluted with sat NaHCO3, extracted with ether, the organic layers washed with brine, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallization from pentane (-78° C.) to afford the title compound as a white solid (0.14 g, 20%). m.p. 96-98° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C@@H:17]([NH:24]C(=O)OC(C)(C)C)[CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:11]1.[ClH:33]>O1CCOCC1>[ClH:33].[NH2:24][C@@H:17]([CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:11][CH2:12]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccccc3o2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-tert-butyl 1-(4-(benzo[d]oxazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (367.5 mg, 0.805 mmol) was dissolved in 1,4-dioxane (5 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (5 mL, 12.0 mmol). The resulting mixture was stirred at room temperature for 3 h, then additional 4N HCl in 1,4-dioxane (1 mL) was added and the resulting mixture stirred for 18 h. The resulting solid was collected by decantation, washed with 1,4-dioxane, and purified by recrystallization from an isopropanol-diethyl ether mixture to yield the title compound as an off-white solid.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]2[C:28]([O:30]CC)=[O:29])=[CH:9][C:8]1=[O:33].[OH-].[Li+]>CO>[CH3:27][C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][C@@H:15]([C:10]2[C:11]([CH3:14])=[C:12]([CH3:13])[N:7]([CH3:6])[C:8](=[O:33])[CH:9]=2)[C@H:16]([C:28]([OH:30])=[O:29])[CH2:17]1)=[O:22])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc(=O)n(C)c(C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)cc(=O)n(C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 3:2 (v/v) THF:MeOH solution (0.07 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(1,5,6-trimethyl-2-oxo-1,2-dihydro-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added lithium hydroxide (1 M aq. solution, 3.1 eq.). The resulting cloudy solution was stirred vigorously at RT for 18 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and 10% aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: N[C:2]1[C:7](OC)=[C:6]([Cl:10])[CH:5]=[C:4](F)[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].[CH3:25][O:26]C(OC)N(C)C>>[Cl:10][C:6]1[CH:5]=[CH:4][C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([O:26][CH3:25])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Product: COc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Yield: 47 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.5 g, 1.4 mmol) and dimethylformamide dimethylacetal (0.8 g, 7 mmol) was refluxed for 4 hr under a blanket of nitrogen. Excess reagent was removed in vacuo and product extracted with ether. Solvent was removed to afford a residue which was chromatographed on silica gel. Elution of the column with hexane-ethyl acetate (6:4) afforded the title compound (0.22 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.C([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C.Cl.N>S1(CCCC1)(=O)=O.CO>[CH3:10][C:4]1[CH:3]=[C:2]([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1c[n+]([O-])c(C)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Agent: N
Solvent: O=S1(=O)CCCC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCC(N)CC2)c(C)cn1
Temperature: 220 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
A mixture 4-chloro-2,5-dimethyl-pyridine 1-oxide (200 mg, 1.41 mmol), Boc-4-aminopiperidine (311 mg, 1.55 mmol) and N,N-diisopropyl ethyl amine (484 μL, 2.82 mmol) in sulfolane (1 mL) was heated to 160° C. for 30 minutes in a microwave oven followed by heating to 220° C. for 30 minutes. After the addition of aqueous hydrochloric acid (25% in water, 0.5 mL) the mixture was stirred for 18 h at ambient temperature. It was treated with ammonia in methanol and concentrated. Purification by chromatography (SiO2, dichloromethane/methanol/ammonia=95:4.5:0.5 to 90:9:1) afforded the title compound (99 mg, 40%) as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[OH:10]O>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:9])[C:4]([CH3:8])=[CH:5][C:6](=[O:10])[CH:7]=1
Reactant: OO
Reactant: Cc1cccc(C)c1O
Solvent: CC(=O)O
Product: CC1=CC(=O)C=C(C)C1=O
Temperature: 55 °C

Procedure:
A mixture of 2,6-dimethylphenol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 50-60° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 1 h. The catalyst was recovered by simple filtration and 2,6-dimethyl-1,4-benzoquinone formed (97%) was separated by chromatographic purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCc1ccccc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2)ccc1OCCc1ccccc1
Yield: 75 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxy-phenylamine (0.029 g, 0.08 mmol) was treated with 4-fluorophenyl isocyanate (0.013 g, 11.0 μL, 0.09 mmol, 1.2 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 65 (0.030 g, 0.06 mmol, 74%) as a solid film. LCMS m/z (%)=509 (M+H79Br, 100), 511 (M+H81Br, 97). 1H NMR (400 MHz, acetone-d6) δ: 8.22 (s, 2H), 7.63 (d, J=8.9 Hz, 1H), 7.48-7.56 (m, 3H), 7.41 (s, 1H), 7.15-7.28 (m, 3H), 7.08-7.16 (m, 3H), 7.03 (t, J=8.7 Hz, 2H), 4.08-4.30 (m, 2H), 3.50 (s, 3H), 2.86-3.06 (m, 2H).