Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:25][C:24]([F:27])([F:26])[C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C(F)(F)F)c2)cc1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.81) (0.20 g, 0.45 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.109 g, 0.49 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.160 g, 77%). MS (ISP) 461.2 [(M+H)+]; mp 260° C.
Reaction SMILES: [CH3:1][S:2][CH:3]([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Br:15])=[C:10]([CH3:16])[CH:9]=1)[C:4]([OH:6])=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[Br:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([O:7][CH:3]([S:2][CH3:1])[C:4]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:6])=[CH:9][C:10]=1[CH3:16]
Reactant: CSC(Oc1cc(C)c(Br)c(C)c1)C(=O)O
Reactant: CC(C)(C)N
Product: CSC(Oc1cc(C)c(Br)c(C)c1)C(=O)NC(C)(C)C

Procedure:
In a similar procedure to Stage 2 of Example 1, 2-methylthio-2(4-bromo-3,5-dimethylphenoxy)acetic acid was condensed with tert-butylamine to give 2-(4-bromo-3,5-dimethylphenoxy)-2-methylthio-N-(2-methyl-prop-2-yl)acetamide as a colourless solid, m.p. 123-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=O)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O>C(O)C>[N:15]1([C:13]2[C:8]([CH3:7])=[C:9]([NH2:10])[C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Solvent: CCO
Product: Cc1c(N2CCOCC2)ccc(N)c1N
Temperature: 20 °C
Yield: 98.6 %

Procedure:
4-(3,4-Dinitro-benzyl)-morρholine (0.800 Kg, 2.99 mol, 1.O wt), and ethanol (11.20 L, 14.0 vol) were charged to a suitable flask and stirred at 15 to 25° C. and a vacuum/nitrogen purge cycle was performed three times. 10% Palladium on carbon (10% Pd/C, 50% wet paste, 0.040 Kg, 0.05 wt wet weight) was slurried in ethanol (0.80 L, 1.O vol) and added to the reaction. The mixture was cooled to 10 to 2O° C. and a vacuum/nitrogen purge cycle was performed three times. A vacuum/hydrogen purge cycle was performed three times and the reaction was stirred under a hydrogen atmosphere at 10 to 2O° C. Reaction completion was determined by 1H NMR analysis (d6-DMSO), typically 14 to 20 hours. A vacuum/nitrogen purge cycle was performed three times and the reaction mixture was filtered through glass microfibre paper under nitrogen. The filter-cake was washed with ethanol (3×0.80 L, 3×1.O vol) and the combined filtrate and washes were concentrated to dryness under vacuum at 35 to 45° C. to give 4-morpholin-4-yl-methyl-benzene-1,2-diamine (0.61 IKg 98.6%) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:10][C:4]1([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CC(C)(C)OO
Product: CC1(C)CC(=O)CC(C)(OOC(C)(C)C)C1

Procedure:
A reaction mixture of 62.2 g. (0.45 mole) of isophorone, 104 g. (0.9 mole) of 78% t-butyl hydroperoxide and 32.4 g. of Amberlyst 15® sulfonic acid type ion-exchange resin was stirred at 40° C. for 48 hours and at 50° C. for one hour. The ion-exchange resin was separated by filtration, the filtrate diluted with pentane and the pentane solution washed with water and sodium bisulfite solution. After drying over anhydrous magnesium sulfate, the pentane was removed under reduced pressure. The recovered product weighed 74.7 g. (72.8% of the calculated amount). The infrared spectrum had a strong absorption band in the 880 cm-1 region usually associated with t-butylperoxy groups. Iodometric assay showed the presence of active oxygen.
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH2:44][CH3:45])[CH2:3][C:4]1[N:5]=[C:6]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[C:32]([O:42]C)[CH:31]=2)[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1>Br.C(O)(=O)C>[CH3:1][C:2]([CH3:46])([CH2:44][CH3:45])[CH2:3][C:4]1[N:5]=[C:6]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[C:32]([OH:42])[CH:31]=2)[NH:7][CH:8]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CCc2ccc(-c3ccccn3)c(OC)c2)n1
Agent: Br
Solvent: CC(=O)O
Product: CCC(C)(C)Cc1c[nH]c(CCc2ccc(-c3ccccn3)c(O)c2)n1

Procedure:
A solution of 2-(4-{2-[4-(2,2-Dimethylbutyl)-1-trityl-1H-imidazol-2-yl]ethyl}-2-methoxyphenyl)pyridine (110 mg, 0.19 mmol) in 30% HBr in acetic acid (5 mL) was heated at reflux in a sealed tube for 6 hours. Upon cooling, the volatiles were removed, and the resulting residue was purified by flash column chromatography on silica gel eluting with 0-5% methanol/ammonium hydroxide mixture in methylene chloride to give the title compound, which was converted to the HCl salt with 1M HCl in diethyl ether. 1H NMR (500 MHz, CD3OD) δ 8.75-8.73 (δ, J=5.8 Hz, 1H) 8.57-8.54 (t, J=7.6 Hz, 1H), 8.35-8.32 (d, J=8.3 Hz, 1H), 7.92-7.88 (t, J=6.6 Hz, 1H), 7.75-7.72 (d, J=8.4 Hz, 1H), 7.17 (s, 1H), 6.92-6.90 (m, 2H), 3.40-3.30 (t, 2H, masked by solvent), 3.17-3.12 (t, J=7.0 Hz, 2H), 2.52 (s, 2H), 1.28-1.21 (q, J=7.7 Hz, 2H), 0.89-0.82 (m, 9H); LC-MS: m/e 350 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:16]1[CH:18]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:17]1>CN(C)C=O>[F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[N:6]([CH2:17][CH:18]([OH:16])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Reactant: Nc1nc(=O)[nH]cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(O)Cn1cc(F)c(N)nc1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
A mixture of 5-fluorocytosine (0.80 g, 6.20 mmol), anhydrous potassium carbonate (40 mg) and anhydrous dimethyl formamide (15 mL) is heated to 70° C. under a nitrogen atmosphere. Then rac-1,2-epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) is added to this mixture with stirring over a period of 1 hour. The resultant reaction mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure (0.5 mm Hg) to afford the crude product as a cream solid. This crude material is purified by chromatography and dried in vacuo to give 0.6 g (22%) 5-fluoro-1-[2'-hydroxy-3'-octadecyloxypropyl]-cytosine (CPR 1152): Thin-layer Chromatography (TLC; 4×8 cm silica gel 60, 0.25 mm thickness): 8:2 (v/v) CHCl3 -CH3OH (Rf value=0.75); mp 118°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([NH2:19])[C:15]([CH3:20])=[N:14]1.[CH3:21][N:22]=[C:23]=[O:24]>O1CCCC1.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([NH:19][C:23]([NH:22][CH3:21])=[O:24])[C:15]([CH3:20])=[N:14]1
Reactant: CN=C=O
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)Nc1c(C)nn(-c2cc(OC(C)C)c(Cl)cc2F)c1C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 1-(2-fluoro-4-chloro-5-isopropoxyphenyl)-3,5-dimethyl-4-aminopyrazole (29.8 g) in tetrahydrofuran (100 ml) was added one drop of triethylamine and then added dropwise a solution of methyl isocyanate (6.0 g) in tetrahydrofuran (50 ml). After the completion of addition, the reaction mixture was left to stand at room temperature for one hour. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (34.7 g) as a white crystalline solid. Recrystallization of the solid from a mixture of cyclohexane/acetone provided a white crystalline solid. m.p. 184°-185° C.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:10]=[CH:9][C:8]=1[OH:21])=CC>C(O)(=O)C.C(OCC)(=O)C>[OH:21][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][C:7]=1[CH:4]=[O:1]
Reactant: CC=Cc1cc(Oc2ccccc2Cl)ccc1O
Reactant: O=[O+][O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Oc2ccccc2Cl)ccc1O

Procedure:
Ozone gas was introduced into a solution of 2-(1-propenyl)-4-(2-chlorophenoxy)phenol (14.5 g) in a mixture of acetic acid (10 ml) and ethyl acetate (150 ml) with stirring at 2°-7° C. for an hour. After removing of the excess of ozone gas and addition of aqueous solution of sodium dithionite, the organic layer was separated, washed with saturated aqueous sodium bicarbonate and water, dried and evaporated. The residue was purified by column chromatography (silical gel, benzene) to give oily 2-hydroxy-5-(2-chlorophenoxy)benzaldehyde (10.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1.[H][H]>CN(C)C=O.O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1
Reactant: O=C1CC(Nc2cc([N+](=O)[O-])ccc2Cl)=NN1c1c(Cl)cc(Cl)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1

Procedure:
A solution of 50 g (0.115 mol) 3-(2-chloro-5-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one in dimethylformamide and tetrahydrofuran was reduced with 35 psi hydrogen and Raney nickel catalyst. Removal of the catalyst by filtration and concentration of the filtrate gave 21 g (0.052 mol) light yellow solid 3-(2-chloro-5-aminoanilino-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one. To an acetic acid solution containing 6.9 g (0.017 mol) of this amine and 9.5 g potassium acetate was added, in small portions, 9.5 g (0.019 mol) of the acid chloride B2Cl prepared in Example 2. After stirring overnight, the mixture was concentrated to a third of its volume, poured into a large volume of water and extracted with diethyl ether. The organic layers were washed, dried, concentrated, and crystallized from methanol to give 14 g (0.016 mol) buff-colored solid acetate ester of the desired coupler, mp 115°-116° C. To a solution of this product in dimethylformamide stirred under nitrogen was added an aqueous solution containing 2 g potassium hydroxide. After 15 minutes the mixture was acidified with hydrochloric acid, poured into dilute hydrochloric acid, extracted with diethyl ether, washed, dried, concentrated, and crystallized from methanol to give 9.2 g white crystalline coupler M-28, mp 127°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](/B(O)O)=[CH:27]\[CH3:28].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:26]=[CH:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: C/C=C/B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 61.6 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (600 mg, 1.34 mmol) and trans-1-propen-1-ylboronic acid (460 mg, 5.36 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0), (4.84% Pd, 285 mg, 0.13 mmol) and 2M aqueous solution of K2SO4 (2.68 mL, 5.36 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC and gave the pure product (142) as white solid (300 mg, 63%).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:11]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Yield: 43.4 %

Procedure:
8-(2-Chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (0.86 g, 1.92 mmol) was added to a solution of ethanol (32 mL) and sodium hydroxide (0.53 g, 13.4 mmol) in water (10.4 mL). The mixture was heated to reflux for 6.5 hours. The solution was concentrated under reduced pressure and water (43 mL) was added to the residue. Any starting material was extracted with ethyl acetate/heptane (1/10, 43 mL). The heptane extract was discarded. The remaining aqueous solution was adjusted with 10 N hydrochloric acid solution to pH=6. The product was extracted with CH2Cl2 (3×40 mL), dried over Na2SO4, concentrated and purified by column chromatography (silica gel, ethyl acetate/heptane=1/10 to 1/3) to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid (Compound Im, 0.35 g, 43.8% yield, 99.6% purity by HPLC) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 10.43 (br, 1H), 7.52 (d, 1H, J=7.50 Hz), 7.39 (d, 1H, J=8.10 Hz), 7.28-7.15 (m, 2H), 7.03 (d, 1H, J=5.0 Hz), 6.69 (d, 1H, J=5.0 Hz), 4.24 dd, 1H, J=9.3, 4.2 Hz), 3.83 (d, 1H, J=14.40 Hz), 3.51 (d, 1H, J=14.40 Hz), 2.92-2.73 (m, 4H), 1.99-1.81 (m, 2H), 1.46-1.41 (m, 2H), 1.28-1.15 (m, 6H), 1.13 (s, 6H). (t, 3H, J=7.2 Hz), 1.15-1.08 (m, 2H), 1.07 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 184.02, 138.85, 135.16, 133.87, 133.42, 129.60, 129.17, 128.17, 126.92, 125.52, 122.74, 63.53, 50.54, 47.90, 42.29, 40.70, 32.95, 30.52, 25.75, 25.64, 25.26, 24.96. HRMS (FIA-ESI): Calculated for C23H30ClNO2S (M+H)+: 420.1759. found 420.1779. CHN analysis: Calculated; 65.77; C, 7.20; H, 3.33; N. found; 60.77; C, 6.68; H, 3.11; N. Best fit for CHN: C23H30ClNO2S+HCl
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[OH:12])([CH3:4])[CH3:3].[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[C:13]([Si:17]([O:12][C:6]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:20])[CH3:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc(F)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(F)c1O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 95.3 %

Procedure:
To a 100 mL round-bottomed flask were added a stir bar, 2-(1,1-dimethylethyl)-6-fluorophenol (2.62 g, 15.6 mmol), tert-butyldimethylchlorosilane (4.84 g, 31.1 mmol), imidazole (1.46 g, 21.5 mmol) and dry DMF (48 mL). The flask was purged with nitrogen and heated at 60° Celsius for 24 hours. The mixture was cooled to room temperature and then partitioned between EtOAc and water. The EtOAc layer was washed with water followed by brine. The organic layer was dried over Na2SO4 and concentrated. Purification by FCC yielded tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (4.2 g, 96%). 1H NMR (600 MHz, CDCl3) δ 7.04 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 1.56 (s, 6H), 1.39 (s, 9H), 1.01 (d, J=0.7, 9H).
Reaction SMILES: N[C@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[BrH:10].N([O-])=O.[Na+]>O>[Br:10][C@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: Br
Reactant: CC[C@H](C)[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC[C@H](C)[C@@H](Br)C(=O)O
Reaction time: 2 h
Yield: 87.5 %

Procedure:
The (2R,3S)-2-amino-3-methylpentanoic acid (D-allo-isoleucine, 1g, 7.62 mmol) was dissolved in a mixture of HBr 48% (6.95 mL, 61 mmol) and H2O (10.5 mL). At 0° C., a solution of NaNO2 (1.68 g, 24.4 mmol) in H2O (5 mL) was added over a period of 30 min. The reaction was stirred for two hours. The reaction mixture was degassed in vacuo and extracted with EtOAc (2×20mL). The extracts were washed with water (15 mL), dried (Na2SO4), filtered and evaporated to give 1.3 g (87% yield) of the (2R, 3S)-2-bromo-3-methylpentanoic acid as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[S:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=2[CH:16]=1.C(=O)(O)[O-].[Na+:21]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[S:10][C:9]([C:13]([O-:15])=[O:14])=[CH:8][C:7]=2[CH:16]=1.[Na+:21]
Reactant: COc1ccc2c(=O)sc(C(=O)O)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(=O)sc(C(=O)[O-])cc2c1
Reaction time: 2 h

Procedure:
To a stirred suspension of 1.6345 g. (6.915 mM) of the carboxylic acid of Example 5 in 50 ml. of distilled water is added 0.5809 g. (6.915 mM) of sodium bicarbonate. After stirring at 25° for 2 hours, the solution is filtered and freeze-dried to give sodium 6-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylate as a white solid, m.p. >360°.
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.CN(C)C=[O:23].C([O-])=O.[Na+].Cl>O>[OH:23][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(O)cccc21
Reaction time: 1 h

Procedure:
1-Nitroanthraquinone (96.4%, 3.4%-dinitroanthraquinones), (7.6 g; 0.03 mole), dimethylformamide (50 ml), and sodium formate (4.1 g; 0.06 mole) were stirred at 130° C. for 17 hours. There was a slow evolution of gas during the reaction period. The reaction mass was cooled, mixed with water (300 ml) and acidified with 32% hydrochloric acid. The resulting suspension was stirred for one hour and filtered. The cake obtained was washed with water, then dried to give 1-hydroxyanthraquinone (6.6 g; 0.03 mole) which by gas chromatographic analysis contained 96.4% 1-hydroxyanthraquinone; 1.8% 1-nitroanthraquinone and 1.8% anthraquinone.
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]([NH2:14])[CH3:13].[C:15]([NH:22][CH2:23][CH2:24][C:25](O)=[O:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:18]([O:17][C:15](=[O:16])[NH:22][CH2:23][CH2:24][C:25](=[O:26])[NH:14][CH:12]([C:4]1[NH:3][C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)[CH3:13])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(N)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)CCNC(=O)OC(C)(C)C)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.9 %

Procedure:
A mixture of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethylamine dihydrochloride (Example 75) (108 mg, 0.46 mmol), N-Boc-β-alanine (71 mg, 0.37 mmol), diisopropylethylamine (0.31 mL, 1.85 mmol), EDCI (78 mg, 0.41 mmol) and HOBt (catalytic amount) in methylene chloride (2.2 mL) was stirred at room temperature under a nitrogen atmosphere overnight (22 h). The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in CH2Cl2, washed with water and saturated NaHCO3, and dried over Na2SO4. Filtration and concentration provided tert-butyl[2-[N-[1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl]carbamoyl]ethyl]carbamate (70 mg, 58%) as a tan solid: 1H NMR (500 MHz, CD3OD) δ1.45 (9H, s), 1.63 (3H, d), 2.37-2.51 (2H, m), 3.30-3.42 (2H, m), 5.26-5.35 (1H, m), 6.43 (1H, s), 7.48-7.51 (1H, m), 7.99-8.05 (1H, m), 8.60 (1H, s); ESI MS m/z 333 [C17H24N4O3+H]+; HPLC (Method A) 95.9% (AUC), tR=14.39 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH2:30]C=C)[C:15](=[O:29])[C@H:16]([NH:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[CH2:17][CH:18]=[CH2:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CCOC(C)=O>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C@@H:16]2[CH2:17][CH:18]=[CH:19][CH2:30][N:14]([C@@H:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]3)[C:15]2=[O:29])[CH:26]=[C:25]([F:27])[CH:24]=1
Reactant: C=CC[C@@H](Nc1cc(F)cc(Cl)c1)C(=O)N(CC=C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CC=CC[C@@H](Nc3cc(F)cc(Cl)c3)C2=O)C1
Temperature: 25 °C

Procedure:
A solution of (R)-3-{allyl-[(R)-2-(3-chloro-5-fluoro-phenylamino)-pent-4-enoyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.4 mmol) in DCM (50 mL) was degassed and purged with argon. To the solution was added Grubb's 2nd generation catalyst (0.12 g, 0.13 mmol) and the mixture was refluxed for 90 minutes. After the solution was cooled to rt, the solvent was removed under reduced pressure to afford a solid which was dissolved in EtOAc. The organic phase was washed with brine, a solution of NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford a residue which was purified by silica gel chromatography (gradient hexanes:EtOAc 0-70%). LCMS, m/z 381.9 [M−tBu]+.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH2:34]>>[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH:34][C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: NCC1CCCO1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCC2CCCO2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and C-(tetrahydro-furan-2-yl)methylamine. The crude product was used without further purification (86%, oil). HPLC-MS: m/z=(M+1); Rt: min.