Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=3[Cl:29])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[O:5][C:4]([CH3:31])([CH3:30])[CH2:3]1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].CCN(CC)CC>C(Cl)Cl>[Cl:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[C:8]1[N:7]=[C:6]2[O:5][C:4]([CH3:31])([CH3:30])[CH2:3][CH:2]([NH:1][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]2=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(N)CC(C)(C)O3)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)C(C)(C)C)CC(C)(C)O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Step A (100 mg, 0.22 mmol) in 5.0 mL of CH2Cl2 was added pivaloyl chloride (32 μL, 0.26 mmol) and NEt3 (46 μL, 0.33 mmol). After stirring at rt for 16 h, the reaction mixture was concentrated. Chromatography on a Biotage 25+M cartridge using 1:1 v/v EtOAc/hexanes as the eluant afforded the product as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:14]([CH2:21][CH2:22][CH3:23])[CH2:15][C:16]([O:18]CC)=[O:17].C[O-].[Na+].[OH-].[Na+]>CO>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([N:1]2[C:14]([CH2:21][CH2:22][CH3:23])=[C:15]([C:16]([OH:18])=[O:17])[N:3]=[N:2]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)O)nnn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 1-azido-4-nitrobenzene (16.4 g) obtained in Example 1a) and ethyl 3-keto-n-hexanoate (17.0 ml) in methanol (200 ml) was added 28% sodium methoxide in methanol solution (21 ml) under ice-cooling, and the mixture was stirred for 30 min and then at 50° C. overnight. Then, 1N aqueous sodium hydroxide solution (100 ml) was added, and the mixture was stirred at 50° C. for 1.5 hr, and cooled to room temperature. The solvent was evaporated under reduced pressure, and the residual aqueous solution was diluted with water and washed with ethyl acetate. Then, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (13.4 g, 49%). The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].[CH3:13][C:14]1([CH3:28])[O:19][CH2:18][C:17]([CH3:27])([C:20](=[O:26])[CH2:21][C:22](OC)=[O:23])[CH2:16][O:15]1.C1(C)C=CC=C(C)C=1.CO>CCCCCCCC>[N+:10]([C:7]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[C:4]([NH:5][C:22](=[O:23])[CH2:21][C:20](=[O:26])[C:17]2([CH3:27])[CH2:16][O:15][C:14]([CH3:13])([CH3:28])[O:19][CH2:18]2)[CH:6]=1)([O-:12])=[O:11]
Reactant: COC(=O)CC(=O)C1(C)COC(C)(C)OC1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: Cc1cccc(C)c1
Solvent: CO
Solvent: CCCCCCCC
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)CC(=O)C1(C)COC(C)(C)OC1

Procedure:
2Methoxy-5-nitroaniline (63.06 g, 0.375 mol) and methyl 2,2,5-trimethyl-b-oxo-1,3-dioxane-5-propanoate (90.0 g, 0.391 mol) were dispersed in n-octane (500 mL) and m-xylene (100 mL) in a 2-liter three-necked flask. The mixture was heated at the boiling point while methanol was continuously removed by a very slow nitrogen sweep. After 2 hr of heating the solution was allowed to cool slowly with good stirring; the yellow-orange precipitate which formed was filtered and allowed to air dry. The crude precipitate was dissolved in ethyl ether and extracted with dilute hydrochloric acid, after which the ethereal solution was washed once with dilute sodium bicarbonate, once with water, the organic and aqueous layers separated, and the organic layer dried over magnesium sulfate. The mixture was filtered and the excess solvent removed in vacuo. The residue was recrystallized from ethyl alcohol, m.p. 113-5° C.; H-NMR was consistent. Elemental analysis calculated for C17H22N5O7: C, 55.73; H, 6.05; N, 7.65. Found: C, 55.64; H. 6.14; N, 7.53.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1cnccn1
Product: O=C(NC(=S)NCCSCc1cnccn1)c1ccccc1

Procedure:
By the procedure of Example 18, 2-[(2-aminoethyl)-thiomethyl]pyrazine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-pyrazinylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(2-pyrazinylmethylthio)ethyl]thiourea.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[C:15]([CH2:39][OH:40])=[C:16]([O:31]CC4C=CC=CC=4)[C:17]([C:20]([NH:22][O:23]CC4C=CC=CC=4)=[O:21])=[N:18][CH:19]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[C:15]([CH2:39][OH:40])=[C:16]([OH:31])[C:17]([C:20]([NH:22][OH:23])=[O:21])=[N:18][CH:19]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cnc(C(=O)NOCc2ccccc2)c(OCc2ccccc2)c1CO
Agent: [Pd]
Solvent: CO
Product: O=C(NCc1ccc2c(c1)OCO2)c1cnc(C(=O)NO)c(O)c1CO
Yield: 90 %

Procedure:
The final product of Example 3 above (0.170 g, 0.330 mmol, 1 eq) and 10% Pd/C (5 mg) catalyst were mixed in methanol (4.0 mL) under an atmosphere of hydrogen 1 hour. The catalyst was filtered and reaction mixture was concentrated under vacuum yielding 0.029 g of N5-(benzo[d][1,3]dioxol-5-ylmethyl)-N2,3-dihydroxy-4-(hydroxymethyl)pyridine-2,5-dicarboxamide (90% yield) as a white solid; 1H-NMR (400 MHz, MeOD): δ=8.176 (s, 1H), 6.93 (m, 3H), 5.95 (s, 2H), 4.77 (s, 2H), 4.50 (s, 2H); MS-ESI m/z 362 [MH]+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[O:1][N:2]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1cccnc1
Agent: N
Product: c1cncc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 3-ethynylpyridine (Aldrich, 0.52 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.77 (dd, J=7.9, 5.2 Hz, 1H), 7.92 (s, 1H), 8.55 (dt, J=7.9, 1.8 Hz, 2H), 8.76-8.98 (m, 3 H), 9.32 (d, J=1.2 Hz, 2H) ppm; MS (DCI/NH3) m/z 225 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([N+:17]([O-])=O)=[CH:7][C:8]2[O:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[C:9]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:17][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][C:9]2[C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: CC(C)(C)c1cc2c(cc1[N+](=O)[O-])OC(=O)C2(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc2c(cc1N)OC(=O)C2(C)C

Procedure:
Palladium on carbon (wet; 5 wt %) was placed into a round bottomed flask under nitrogen flow. 5-tert-butyl-3,3-dimethyl-6-nitro-benzofuran-2-one (4.7 g, 17.85 mmol) was then added to the vessel. Methanol (120 mL) was then carefully charged to the vessel under nitrogen atmosphere. The vessel was then purged with N2, evacuated, then charged with hydrogen gas. The vessel was evacuated and re-charged with hydrogen gas, and then a continuous hydrogen gas stream was introduced. After completion, the reaction was filtered through Celite® and the cake was washed with MeOH (300 ml). The solvent was removed in vacuo and the product dried under high vacuum to give a white crystalline solid. 1H-NMR (400 MHZ, DMSO-d6) δ 7.05 (s, 1H); 6.48 (s, 1H); 5.02 (s, 2H, NH2); 1.34 (s, 6H); 1.30 (s, 9H)
Reaction SMILES: [CH2:1]([CH:4]([CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6])[CH2:2][CH3:3].[CH2:16]1[O:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][CH2:18][CH:17]1O.C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([O:7][CH2:8][CH2:9][C:10](=[O:12])[O:11][CH:17]1[CH2:18][O:19][CH:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:21][CH2:16]1)=[O:6])[CH2:14][CH3:15]
Reactant: CCCC(CCC)C(=O)OCCC(=O)O
Reactant: OC1COC(c2ccccc2)OC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)C(=O)OCCC(=O)OC1COC(c2ccccc2)OC1
Reaction time: 72 h
Yield: 83 %

Procedure:
3-(2-propylpentanoyloxy)propanoic acid (2.05 g, 9.5 mmol) was dissolved in anhydrous CH2Cl2 (200 ml) under argon. 1,3-O-benzylideneglycerol (2.50 g, 13.67 mmol triethylamine (4.04 g, 40.0 mmol) and O-benzotriazol-1-yl-N,N, N′,N′-trimethyluronium hexafluorophosphate (4.2 g, 11.0 mmol) were added successively. The reaction mixture was stirred under argon for 72 h. The reaction mixture was washed with saturated NaHCO3 solution (1×90 ml), water (1×90 ml) and dried over Na2SO4. The organic solvent was removed under reduced pressure giving a pale, pink solid (2.99 g, 7.9 mmol, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][NH:14][CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:18]([BH3-])#N.[Na+]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([CH3:18])[CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CNC[C@@H]21
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C[C@H]2CCN(C(=O)OC(C)(C)C)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3aR,6aR)-hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butyl ester (18.31 g, 0.86 mol) in MeOH (450 ml) was added paraformaldehyde (52 g, 1.72 mole), and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride was then added, and the mixture was stirred at room temperature for 10 hours, diluted with 1N NaOH (450 ml), extracted with dichloromethane (5×200 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.18 (m, 1 H) 3.47-3.59 (m, 1 H) 3.34-3.46 (m, 2 H) 2.75-2.90 (m, 1 H) 2.71 (m, 1 H) 2.44-2.60 (m, 2 H) 2.29 (s, 3 H) 1.89-2.06 (m, 1 H) 1.65-1.81 (m, 1 H) 1.42-1.49 (m, 9 H). MS: (M+H)+=226.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][C:8]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:9][CH:10]=3)[C:5]([CH3:35])([CH3:34])[C:4]=2[CH:3]=1.[CH2:36](O)[CH3:37].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CO>[C:8]1([C:37]2[CH:36]=[CH:33][CH:28]=[CH:29][CH:30]=2)[CH:9]=[CH:10][C:11]([N:12]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:12]([C:11]5[CH:10]=[CH:9][C:8]([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)=[CH:7][CH:6]=5)[C:13]5[C:4](=[CH:3][C:2]([C:15]6[CH:2]=[CH:3][CH:4]=[CH:13][CH:14]=6)=[CH:15][CH:14]=5)[C:5]([CH3:34])([CH3:35])[C:17]=4[CH:18]=3)=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)c2cc(Br)ccc2N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc21
Reactant: CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)c2cc(-c3ccccc3)ccc2N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccc(N(c4ccc(-c5ccccc5)cc4)c4ccc(-c5ccccc5)cc4)cc3)cc21
Temperature: 72 °C
Reaction time: 8.5 h
Yield: 75 %

Procedure:
2-Bromo-10-(biphenyl-4-yl)-9,9-dimethyl-7-phenylacridan (2.5 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)phenyl]amine (3.0 g), toluene (37 ml), ethanol (9.3 ml), and a 2M potassium carbonate aqueous solution (7.2 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.11 g) and stirred at 72° C. for 8.5 hours. The mixture was allowed to cool to a room temperature, and methanol (40 ml) was added. A precipitated solid was collected by filtration and washed with water to obtain an orange crude product. The crude product was dissolved by adding toluene (360 ml), purified by adsorption using silica gel (3.6 g), and crystallized with toluene/methanol three times. Further, methanol (60 ml) was added to the product, and the product was washed and purified by heating under reflux to obtain a white powder of bis(biphenyl-4-yl)-[4-{10-(biphenyl-4-yl)-9,9-dimethyl-7-phenylacridan-2-yl}phenyl]amine (3.04 g; yield 75%).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21]C(=O)C)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2].[ClH:25]>>[ClH:25].[NH2:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([NH:9][C:7]2[S:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CC(=O)NCCc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Agent: Cl
Product: CC(C)c1nnc(NS(=O)(=O)c2ccc(CCN)cc2)s1

Procedure:
16.8 g N-{2-[4-(5-Isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-ethyl}-acetamide was suspended in 120 ml one molar hydrochloric acid and heated under reflux for six hours. The cooled reaction mixture was evaporated in vacuo. The resulting residue was dissolved in 300 ml ethanol and dried over MgSO4. The ethanol was removed in vacuo to obtain 21.0 g 4-(2-Amino-ethyl)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide hydrochloride as an amorphous solid, impurified with salts. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=O)[NH:7][C:6]=2[CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.N>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1
Reactant: O=C1COc2ccc(F)cc2N1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)NCCO2
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 6-fluoro-2H-1,4-benzoxazin-3(4H)-one (1.5 g) in tetrahydrofuran (30 ml), lithium aluminum hydride (683 mg) was added under ice cooling and heated under reflux for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with 28% aqueous ammonia under ice cooling, and then filtered to remove insoluble materials. The filtrate was evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 5:1) to give the titled compound, i.e., 6-fluoro-3,4-dihydro-2H-1,4-benzoxazine (1.35 g) as a red oil.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[CH3:21])[NH:17][C:16]([C:22]([OH:24])=O)=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[CH:25]1([C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([CH:2]([CH3:3])[CH3:4])[CH2:6][CH2:7]3)=[C:20]([CH3:21])[CH:19]=4)=[O:24])[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH2:27]1
Reactant: Cc1cc2[nH]c(C(=O)O)cc2cc1OC1CCN(C(C)C)CC1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: Cl
Product: Cc1cc2[nH]c(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2cc1OC1CCN(C(C)C)CC1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(1-isopropyl-piperidin-4-yloxy)-6-methyl-1H-indole-2-carboxylic acid hydrochloride and 1-(cyclopropanecarbonyl)piperazine to afford the title compound as a light-yellow foam (56%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([N:18]=[C:19]=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[N+:8]([C:7]1[C:2]([NH:1][C:19]([NH:18][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: CCCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1ncccc1[N+](=O)[O-]
Yield: 36.8 %

Procedure:
A mixture of 2-amino-3-nitropyridine (1.39 g), heptyl isocyanate (1.41 g) and 4-dimethylaminopyridine (0.37 g) was stirred in toluene (5 ml) at 100°-110° C. for 5 hrs. The solvent was distilled off and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1-(3-nitro-2-pyridyl)-3-heptylurea (1.03 g, 37%) as crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:47][C@@H:48]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:49][OH:50].C(N(CC)CC)C>C(Cl)Cl>[OH:50][CH2:49][C@@H:48]([NH:47][C:17]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=1)=[O:19])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: N[C@H](CO)Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](CO)Cc1ccccc1)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.3 %

Procedure:
To a solution of 2-phenyl-4-quinoline-carboxylic acid (0.33 g, 1.3 mmol, Aldrich Chemical Company) in methylene chloride (5 mL) was added benzotriazol-1-yloxytris-(dimethyamino)phosphoniumhexafluorophosphate (BOP) (0.63 g, 1.43 mmol). The resulting mixture was shaken at room temperature for 5 min. (S)-(-)-2-arnino-3-phenyl-1-propanol (0.2 g, 1.3 mmol) was added along with triethylamine (0.2 mL, 1.43 mmol). The resulting mixture was shaken at room temperature for 24 h. Methylene chloride (10 mL) was added and the organic layer was washed with NaHCO3, H2O, brine, dried (MgSO4), filtered, and concentrated in vacuo to give an oil. The oil was purified by flash chromatography (silica gel, 30-80% EtOAc/hexane) to yield the title compound as a white solid (0.3 g, 60%). MS (ES+) m/e 383.5 [M+H]+, 405 [M+Na]+, 787 [2M+Na]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].S(Cl)([Cl:26])=O>C1C=CC=CC=1>[Cl:26][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CCl)c1

Procedure:
2.5 g of N-[3-[3-(hydroxymethyl)phenoxy]propyl]phthalimide was dissolved in 12 ml of benzene, and 3 ml of thionyl chloride was added. The mixture was refluxed for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in ether. The solution was washed twice with a 5% aqueous solution of potassium carbonate, and then rinsed with water. The product was dried over anhydrous sodium sulfate, and the solvent was distilled off to afford 2.8 g of N-[3-[3-(chloromethyl)phenoxy]propyl]phthalimide as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.[CH3:21][NH:22][C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][N:22]([CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)[C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21

Procedure:
A mixture of 1-(1,1-dimethylethyl) 4-(4-chloromethyl-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step C) (0.15 g, 0.47 mmol), (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (0.076 g, 0.47 mmol) and potassium carbonate (0.072 g, 0.52 mmol) in dry acetonitrile (5 mL) was heated at reflux for two days. Then the reaction mixture was filtered, concentrated under reduced pressure, diluted with dichloromethane, and washed with 1 N aqueous hydrochloric acid and water. The organic layers were dried (MgSO4) and concentrated under reduced pressure to give 0.19 g of the title compound as a tan foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:14]=[C:13]([NH:15][C:16]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[N:17][C:18]([C:20]2[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][N:23]([CH3:25])[CH:24]=2)=[O:19])[NH:12][N:11]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:14]=[C:13]([NH:15][C:16]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[N:17][C:18]([C:20]2[C:21]([C:26]([F:29])([F:27])[F:28])=[N:22][N:23]([CH3:25])[CH:24]=2)=[O:19])[NH:12][N:11]=1
Reactant: COc1ccc(-c2cc(NC(=NC(=O)c3cn(C)nc3C(F)(F)F)Nc3ccccc3F)[nH]n2)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cc(C(=O)N=C(Nc2cc(-c3ccc(O)cc3F)n[nH]2)Nc2ccccc2F)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
N-(((3-(2-Fluoro-4-methoxyphenyl)-1H-pyrazol-5-yl)amino)((2-fluorophenyl)amino)methylene)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (0.168 g, 0.323 mmol) was dissolved in dichloromethane (DCM) (5 mL) and cooled to 0° C. in an ice bath. To the cooled solution was added 1 M BBr3 in DCM (0.485 mL, 0.485 mmol). The reaction mixture was brought to room temperature after 1 hour and the reaction was allowed to continue for 16 hours. Next, the reaction was quenched by the addition of MeOH and then volatiles were evaporated in vacuo. The resulting residue was purified by column chromatography (0-10%, DCM:MeOH) to provide the title compound (32% yield). LCMS (ESI): calc.=505; obs. M+H=506.2. HPLC (Method D): retention time was 2.16 minutes.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[H-].[Na+]>[Cu]Br.C1(C)C=CC=CC=1>[C:4]([C:3]1[C:2]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])=[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([O:17][CH3:18])=[CH:8][CH:7]=1)([OH:6])=[O:5]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCOc1c(OC)ccc(C(=O)O)c1Br
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCOc1c(OC)ccc(C(=O)O)c1C(C(=O)OCC)C(=O)OCC
Reaction time: 1 h

Procedure:
2-bromo4-methoxy-3-pentyloxybenzoic acid (80.1 g, 253 mmol), toluene (480 ml), copper (I) bromide (3.62 g, 25.3 mmol) and diethyl malonate (153.4 ml, 1.01 mol) were mixed, and sodium hydride (60% dispersion, 30.3 g, 758 mmol) was added to this suspension. The mixture was stirred at 78° C.-83° C. for 1 hour. Said reaction mixture was combined with a reaction mixture in which 2-bromo-4-methoxy-3-pentyloxybenzoic acid (49.43 g, 156 mmol) had been reacted in the same manner, and the resulting reaction mixture was extracted with water (1000 ml, 500 ml). The aqueous layer was washed with hexane (500 ml). Concentrated hydrochloric acid was added to make the aqueous layer acidic. The aqueous layer was extracted with ethyl acetate (1000 ml, 500 ml). The organic layers were combined, and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of diethyl 2-(6-carboxy-3-methoxy-2-pentyloxyphenyl)-malonate.