Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and methyl 4-(bromomethyl)benzoate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, methyl 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (95%) as a colorless solid: mp 136-140° C.; 1H NMR (300 MHz, CDCl3) δ8.01 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.17 (d, J=7.4 Hz, 2H), 7.02 (dd, J=7.4, 7.4 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 4.99 (ABq, 2H), 4.84 (ABq, 2H), 4.54 (t, J=8.6 Hz, 2H), 3.89 (s, 3H), 3.06-2.92 (m, 2H); MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(OCC(O)CBr)ccc2N1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CBr)COc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 6-(3-bromo-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one (0.2 g, 0.666 mmol) in DCM was added 4 Å molecular sieves powder (0.2 g) and pyridinium chlorochromate (0.287 g, 1.333 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered through celite and washed with DCM (50 mL). The filtrate was concentrated and the crude product purified by flash chromatography on silica gel using 60% ethyl acetate in hexane to give 6-(3-bromo-2-oxopropoxy)-3,4-dihydroquinolin-2(1H)-one as an off white solid (0.15 g, 76%). LCMS: RT 0.67 min; LCMS (ES-API), m/z 298.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[NH:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[NH:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCCOc1ccccc1-c1nc2cc([N+](=O)[O-])ccc2c(=O)[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCOc1ccccc1-c1nc2cc(N)ccc2c(=O)[nH]1

Procedure:
A stirred solution of 7-nitro-2-(2-propoxyphenyl)-4(3H)-quinazolinone (3.0 g) in dry methanol (450 ml) was treated sequentially under a carbon dioxide atmosphere with 5% Pd/C(1.5 g) and anhydrous ammonium formate (2.8 g). After 60 minutes solids were removed by filtration and the filtrate evaporated to dryness. The residue was partitioned between water and dichloromethane, the organic layer separated, dried (magnesium sulphate) and evaporated. The residue was recrystallized from diethyl ether-petroleum ether to give 7-amino-2-(2-propoxyphenyl)-4(3H)-quinazolinone, 2.7 g, m.p. 185° C.
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH2:7].[OH-].[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C@H:6]1[O:1][CH2:7]1
Reactant: O
Reactant: C=Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc([C@@H]2CO2)c1
Temperature: 0 °C
Yield: 92 %

Procedure:
A 2-necked round-bottom flask equipped with a water-cooled overhead stirrer was charged with 3-chlorostyrene (5.01 g, 3.61×10−2 mol), CH2Cl2 (45 mL), (R,R)-3 (0.578 g, 9.10×10−4 mol), and 4-PPNO (0.924 g, 5.40×10−3 mol). The solution was cooled to 0° C., and precooled buffered bleach (0.6 M, 75 mL, 4.50×10−2 mol, Clorox®, buffered to pH=11.3 with 0.05 M Na2HPO4 and 1M NaOH) was added. The two phase system was stirred vigorously, and the course of the reaction was monitored by GC. Upon complete consumption of starting olefin (<6 h), the reaction mixture was filtered through a plug of Celite on a coarse glass frit and washed with CH2Cl2 (75 mL). The organic layer of the filtrate was washed with distilled water (2×25 mL), and the aqueous layers were extracted with CH2Cl2 (2×25 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Removal of the catalyst was effected by elution through a pad of SiO2 (30 g) using pentane and CH2Cl2 (1:1). The eluent was concentrated in vacuo, and subsequent bulb-to-bulb distillation (70° C., 0.6 mm Hg) from CaH2 afforded (R)-3-chlorostyrene oxide (5.15 g, 92%) as a pale yellow liquid in 32% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C([O-])(=[O:18])C.[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:18])[CH:7]=1
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1O
Temperature: 80 °C
Yield: 81.3 %

Procedure:
A mixture of 10 g of 2,4-dichloro-5-nitrobenzotrifluoride, 4.15 g of potassium acetate and 60 ml of DMF was stirred while heating at 60° C. for one hour and at 80° C. for three hours. To the reaction mixture, 4.15 g of potassium acetate was added. The reaction mixture was stirred while heating at 80° C. for further one hour. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 7.55 g of 5-chloro-2-nitro-4-trifluoromethylphenol.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:29]=[CH:28][C:6]2[O:7][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:27]=[CH:26][C:20]4[CH:21]=[CH:22][C:23](=[O:25])[O:24][C:19]=4[CH:18]=3)[CH2:9][O:10][C:5]=2[CH:4]=1.[C:30](Cl)(=[O:32])[CH3:31]>C(O)(=O)C>[C:30]([O:2][C:3]1[CH:29]=[CH:28][C:6]2[O:7][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:27]=[CH:26][C:20]4[CH:21]=[CH:22][C:23](=[O:25])[O:24][C:19]=4[CH:18]=3)[CH2:9][O:10][C:5]=2[CH:4]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: O=c1ccc2ccc(OCCCNCC3COc4cc(O)ccc4O3)cc2o1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2c(c1)OCC(CNCCCOc1ccc3ccc(=O)oc3c1)O2
Reaction time: 8 h

Procedure:
7-[3-[[(2,3-Dihydro-6-hydroxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (0.10 g, 0.24 mmole), prepared as in example 5 above, was dissolved in 50 ml of glacial acetic acid and 3.05 ml (43 mmole) of acetyl chloride added in portions over a 30 minute period, during which the reaction mixture was gently warmed with a heat gun. The solvent and excess reagent were then removed in vacuum and diethyl ether added. Upon standing overnight, 0.030 g of the title compound as a monohydrochloride, m.p. 175° C., crystallized.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].[NH2:15][NH2:16]>CO>[CH3:1][C:2]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:16]=[N:15][C:3]=1[OH:4]
Reactant: C=C(CC(=O)c1ccccc1)C(=O)O
Reactant: NN
Solvent: CO
Product: Cc1cc(-c2ccccc2)nnc1O
Yield: 60.5 %

Procedure:
To a stirred solution of compound 5A, (4.48 g, 23.6 mmol) in 50 mL of methanol at 35° C. under argon was added hydrazine (0.75 mL, 35.3 mmol) over 5 min The reaction mixture was then heated to reflux under argon for 2 h, as a precipitate formed. The reaction mixture was then cooled and evaporated under reduced pressure. The solid residue was slurried in isopropanol, filtered and air-dried to give 4-methyl-6-phenylpyridazin-3-ol (2.66 gm, 61%) as a yellow solid. MS [M+H]+: found 187.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([Br:14])=[N:10][NH:9][C:8]2=[O:15])=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].N1C=CC=CC=1.CC#N>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([Br:14])=[N:10][N:9]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)[C:8]2=[O:15])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=c1[nH]nc(Br)c(=O)n1Cc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
According to Scheme 2 Step 3: To a stirred solution of 4-(4-chlorobenzyl)-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (0.400 g) and 2(B) (411 mg, 1.3 mmol) in DMF (5 mL) were successively added of the 3-acetamidophenylboronic acid (0.34 g, 1.9 mmol), copper(II) acetate (0.23 g, 1.3 mmol) and 0.20 g of pyridine (2.5 mmol). The mixture was stirred overnight at 60° C. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by C18 reverse phase column, 65 g column: 20% CH3CN gradient 20 to 60% to afford 0.350 g (yield=62%) of N-(3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 2(C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[C:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C([O-])=O.[NH4+].F[P-](F)(F)(F)(F)F.[N:33]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH2:33])=[O:13])[CH:8]=[C:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)c2cccc(F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2cccc(F)c2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 9 %

Procedure:
8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid (7-4, 100.0 mg, 0.351 mmol), ammonium formate (88.0 mg, 1.40 mmol), BOP (202.0 mg, 0.456 mmol), and triethylamine (0.147 ml, 1.052 mmol) were dissolved into DMF (1.0 mL), and the resulting mixture was stirred at 60° C. for 5 hours. The mixture was cooled and diluted with Methylene Chloride, washed with water, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide (7-5, 9.00 mg, 9.0%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.209 (s, 1H); 8.138 (br s, 1H); 8.658 (d, J=8.62 Hz, 1H); 7.379-7.493 (m, 4H); 7.145-7.214 (m, 2H); 6.004 (br s, 1H). LRMS m/z (M+H) 285.1 found, 285.1 required.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[N:2]1.[ClH:18].[CH3:19][NH:20][CH3:21].[BH4-].[Na+]>CO.C(OCC)(=O)C>[ClH:18].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][N:20]([CH3:21])[CH3:19])=[N:2]1
Reactant: O=Cc1ccccc1-c1noc2ccccc12
Reactant: CNC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
In one portion, a total of 2.0 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde was added to a solution of 8.0 g of dimethylamine hydrochloride in 70 ml of methanol. The reaction mixture was stirred at room temperature for 16 h, after which 2.0 g of sodium borohydride were added. After stirring at room temperature for another 24 h, the solids were filtered off, and the residue was washed with dichloromethane. The combined filtrate was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The resulting solid was purified by chromatography on silica gel, eluting with ethyl acetate, affording 0.89 g. This solid was dissolved in ethyl acetate, and triturated with a solution of hydrogen chloride in methanol. This solution was evaporated to dryness under reduced pressure and the residue was crystallised from ethanol/diethyl ether/hexane, yielding 0.54 g of pure 2-(1,2-benzisoxazol-3-yl)-N, N-dimethyl-benzenemethanamine hydrochloride, melting at 190° C.
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH:3](O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]([F:15])([C:11]([F:12])([F:13])[F:14])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(O)C(F)(F)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)/C=C/C(F)(F)C(F)(F)F
Temperature: 140 °C

Procedure:
Ethyl 4,4,5,5,5-pentafluoro-3-hydroxy-pentanoate (11.9 g from step C) was placed in a 25 ml round-bottom flask and phosphorpentoxid was added in small portions until the educt was almost completely absorbed. The temperature was raised slowly to 140° C. until a brown syrup was obtained. The flask was connected to a distilling apparatus and the product isolated by distillation at reduced pressure (50 mbar, 50° C.). 5.5 g (25.2 mmol, 50% over 2 steps) were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([NH:18][C:19](=[O:27])OC3C=CC=CC=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[CH2:3][CH2:2]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([NH:46][C:19]([NH:18][C:10]2[CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=[C:8]([CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:9]=2)=[O:27])[CH:47]=[CH:48][CH:49]=1
Reactant: O=C(Nc1cc(CN2CCOCC2)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(CN5CCOCC5)cc(C(F)(F)F)c4)c3)c2cc1OC
Yield: 32.2 %

Procedure:
The procedure described in Example 138B was used to react phenyl 3-(morpholinomethyl)-5-(trifluoromethyl)phenylcarbamate (140 mg, 0.37 mmol) with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (78 mg, 0.25 mmol). To this solution was added diisopropylethyl amine (64 μL, 0.37 mmol) and DMAP (3.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with methanol to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)urea (47 mg, 32% yield). 1H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.97 (s, 1H), 8.57 (s, 1H), 7.92 (s, 1H), 7.60 (m, 3H), 7.40 (m, 2H), 7.28 (m, 2H), 6.96 (m, 1H), 4.00 (s, 6H), 3.51 (s, 4H), 3.38 (s, 2H), 2.35 (s, 4H). LCMS (ESI) m/z 584 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>C(O)C.Cl.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: COc1ccc(-c2ccncc2)c(OC)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1ccc(C2CCNCC2)c(OC)c1
Reaction time: 8 h

Procedure:
4-(2,4-Dimethoxy-phenyl)-pyridine (6.9 g) is dissolved in a mixture of Ethanol (140 ml) and conc hydrochloric acid (3.5 ml). PtO2 (0.7 g) is added and the mixture is stirred under hydrogen atmosphere for 8 hours. The catalyst is filtered off and the solution is evaporated to dryness. MS-APCI+ (M+H)+=222
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:28][CH2:29][S:30][CH3:31])=[O:27])=[C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(OCc2cccnc2)cc1-c1ccccc1
Agent: N
Product: CSCC[C@H](NC(=O)c1ccc(OCc2cccnc2)cc1-c1ccccc1)C(=O)O

Procedure:
The desired compound was prepared by saponification of the compound of Example 240F using the procedure of Example 159. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (bs, 1H), 8.55 (bd, 1H), 8.39 (d, 1H), 7.88 (dt, 1H), 7.40 (m, 6H), 7.07 (dd, 1H), 7.03 (d, 1H), 5.17 (s, 2H), 4.28 (ddd, 1H), 2.25 (m, 2H), 2.00 (s, 3H), 1.84 (m, 2H). MS (CI, NH3) m/e 454 (M+NH4)+, 437 (M+H)+, 419, 320, 288. Anal calcd for C24H24N2O4S (+0.23 H2O): C, 65.42; H, 5.59; N, 5.99. Found: C, 65.41; H, 5.42; N, 5.99.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][N:6]([CH2:36][C:37]([O:39]CC)=[O:38])[C:7](=[O:35])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][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][CH3:34])=[CH:12][CH:11]=1)=[O:9])C.[OH-].[Na+]>CO>[C:4]([CH2:5][N:6]([C:7](=[O:35])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][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][CH3:34])=[CH:14][CH:15]=1)=[O:9])[CH2:36][C:37]([OH:39])=[O:38])([OH:42])=[O:3]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)N(CC(=O)OCC)CC(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)N(CC(=O)O)CC(=O)O)cc1
Yield: 94.5 %

Procedure:
A mixture of 0.7 g (1.19 mmol) of N-(2-ethoxy-2-oxoethyl)-N-[2-[4-(octadecyloxy)phenyl]-1,2-dioxoethyl]glycine ethyl ester and 1.0 ml (6.0 mmol) of 6.0 N NaOH in 75 ml of methanol was stirred at reflux under an argon atmosphere for 4 hours. After removal of the solvent at reduced pressure, the residue was acidified with dilute HCl and the product was extracted with ethyl acetate. The dried extract was concentrated at reduced pressure to a solid which was recrystallized from acetone-hexane to give 0.6 g (95% yield, mp 130°-132°) of N-(carboxymethyl)-N-[2-[4-(octadecyloxy)phenyl]-1,2-dioxoethyl]glycine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Na].CN(C)[CH:14]=[O:15]>CO.[Cu]Br>[CH3:14][O:15][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu]Br
Agent: [Na]
Solvent: CO
Product: COc1cnc2[nH]ccc2c1
Yield: 77.3 %

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 10 g, 50.8 mmol) in N,N-dimethylformamide (200 mL) and methanol (150 mL) at 25° C. was added sodium (100 g, 185.1 mmol) and copper(I) bromide (14.56 g, 101.5 mmol) under a nitrogen atmosphere. The mixture was then heated at reflux for 5 h. After cooling, the solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3×300 mL), and washed with a saturated aqueous ammonium chloride solution, brine, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford 5-methoxy-1H-pyrrolo[2,3-b]pyridine (5.8 g, 77.3%) as a light yellow solid: LC/MS m/e calcd for C8H8N2O [M+H]+ 149.17, observed 149.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1>>[NH2:21][CH2:20][CH2:19][C@H:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:10][C:7]2[CH:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH2:13][CH2:14]1)[CH3:22]
Reactant: CCOc1ccc(N)cn1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: CCOc1ccc(NC2CCN([C@H](C)CCN)CC2)cn1

Procedure:
Using general procedure A with 6-ethoxy-pyridin-3-ylamine (Nishikawa, Yoshinori; et al., J. Med. Chem., 32, 3, 1989, 583-593) (210 mg, 1.52 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (278 mg, 1.67 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-ethoxy-pyridin-3-yl)-amine as a white solid (365 mg, 83% over 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH3:16])[CH2:9][N:10]2[C:14]([SH:15])=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(C1C=CC=[C:29]2[C:30](NC(=O)[C:28]=12)=[S:31])CC>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH3:16])[CH2:9][N:10]2[C:14]([S:15][S:31][CH2:30][CH2:29][CH3:28])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: CCCc1cccc2c1C(=O)NC2=S
Reactant: C[Si](Cn1ncnc1S)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CCCSSc1ncnn1C[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of 1.4 g (0.004 mol) of bis(4-fluorophenyl)methyl(5-mercapto-1H-1,2,4-triazol-1-ylmethyl)silane in 10 mL of chloroform at 25° was added 1.1 g (0.005 mol) of propylthiophthalimide. The mixture was stirred two hours, filtered, and evaporated. The residue was flash chromatographed using 0-10% ether/methylene chloride to give 1.5 g of the title disulfide as a thick oil: ir (neat) 2950, 1585, 1495, 1230, 1160, 1104, 820 cm-1 ; nmr (CDCl3) δ 0.7 (3H, s), 1.0 (3H, t), 1.7 (2H, m), 2.8 (2H, t), 4.2 (2H, s), 7.1 (4H, m), 7.5 (4H, m), 7.8 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[C:4]([N+:11]([O-])=O)[CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:11][C:4]1[CH:3]=[CH:2][C:7]([OH:8])=[C:6]([F:9])[C:5]=1[CH3:10]
Reactant: Cc1c([N+](=O)[O-])cc(Cl)c(O)c1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(N)ccc(O)c1F
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methyl-4-nitrophenol (4.11 g, 19.9 mmol) in ethanol (200 ml) were added 10%-palladium/carbon (containing 50% water, 410 mg) and ammonium formate (15.1 g, 240 mmol), and the resulting mixture was stirred for 3 hours with heating under reflux while maintaining the temperature. The mixture was filtered by the use of Celite and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was partitioned by the use of water and ethyl acetate (the aqueous layer was adjusted to pH 6 to 7 with a 5% aqueous sodium hydrogencarbonate solution and re-extracted), and the organic phase was washed with a 5% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 4-amino-2-fluoro-3-methylphenol (2.89 g, 100%).