Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([Cl:12])[C:3]=1[NH2:13].[F-].[Cs+].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH2:16]([NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([Cl:12])[C:3]=1[NH2:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1c(Br)cc(C(F)(F)F)nc1Cl
Reactant: NCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Temperature: 150 °C
Yield: 17.5 %

Procedure:
4-Bromo-2-chloro-6-trifluoromethyl-pyridin-3-ylamine (84 g, 300 mmol) was stirred in 500 ml DMSO in the presence of caesium fluoride (46.3 g, 305 mmol) and benzylamine (66.6 ml, 610 mmol). The resulting brown suspension was heated at 150° C. for 16 h. Added to the cooled suspension was 1500ml water and the mixture extracted with 2×500 ml diethyl ether. The combined organic extracts were dried (MgSO4), concentrated in vacuo and purified by column chromatography on silica, eluting with Hept:EtOAc, 4:1 to 2:1 to give the title compound (15.8 g, 17%) as a pale brown solid. The undesired isomer was similarly isolated as a brown oil (51.0 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=O.Cl.[NH2:12][OH:13]>C(O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[N:12][OH:13]
Reactant: O=Cc1cncc(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: ON=Cc1cncc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.5 %

Procedure:
A solution of 4,5-dichloropyridine-3-carbaldehyde (8.01 g, 45.51 mmol) in ethanol (50 ml) was added to a rapidly stirred solution of hydroxylamine hydrochloride (3.48 g, 50.06 mmol) in water (50 ml). The reaction was stirred at room temperature for 45 min then partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic layers were dried over magnesium sulfate before being concentrated in vacuo to afford the title compound as a white solid (8.3 g, 96%).
Reaction SMILES: [CH2:1]1[O:21][C:4]([CH3:20])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12]CC3C=CC=CC=3)=[CH:8][CH:7]=2)[O:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[CH2:2]1[O:3][C:4]([CH3:20])([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=2)[O:21][CH2:1]1
Reactant: CC1(Cc2ccc(OCc3ccccc3)cc2)OCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(Cc2ccc(O)cc2)OCCO1

Procedure:
A solution of 1-(4-benzyloxyphenyl) propan-2-one ethylene ketal (6 g) in ethanol (100 ml) was hydrogenated at 45 psi and ambient temperature in the presence of 10% Pd/C until hydrogen uptake had ceased. The solution was filtered and evaporated to give a light coloured oil which crystallised on standing m.p. 61°-64°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9]CC)=O)=[CH:3][CH:2]=1.[CH3:12][C:13]([CH3:15])=[O:14].C[O-].[Na+]>C1COCC1>[OH:14]/[C:13](/[CH3:15])=[CH:12]\[C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:9]
Reactant: CCOC(=O)c1ccncc1
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C(O)=C/C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-pyridinecarboxylate (30 g, 198 mmol) and acetone (34.58 g, 595 mmol) in THF (150 mL) was slowly added NaOMe (12.87 g, 238 mmol) at 35-40° C. The mixture was stirred at room temperature for 0.5 h, and then heated at reflux for 3 h. The mixture was cooled to room temperature and filtered to give a solid, which was washed with t-BuOMe, and dissolved in H2O. The solution was acidified with acetic acid and the resulting oily product was extracted with CHCl3. The solvent was removed in vacuo, and the crude product was obtained (12 g, 37%) and used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 2H), 7.76 (d, 2H), 6.63 (s, 1H), 2.21 (s, 3H); note: enolic OH does not appear.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12](=[O:17])[NH:13][CH2:14][C:15]#[N:16])=[O:5])[CH3:2].[S:18]([O-])(=[O:21])(=[O:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][S:18]([CH3:19])(=[O:21])=[O:20])[CH2:8][C@H:7]1[C:12](=[O:17])[NH:13][CH2:14][C:15]#[N:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)NCC#N
Reactant: CS(=O)(=O)[O-]
Product: CCOC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NCC#N

Procedure:
(1R,2R,4S)-2-(Cyanomethyl-carbamoyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester (second fraction from step 2) was converted to the corresponding mesylate according to the procedure from example 1, step 4 to give (1R,2R,4S)-2-(cyanomethyl-carbamoyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester as a colorless solid. MS: 319.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C@H:3]([NH2:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOCC>CC(C)=O>[C:24]([NH:13][C@@H:3]([CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C[C@H](NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-(-)-α-methyl-4-nitrobenzylamine hydrochloride (7.96 gm, 48 mmol) in acetone (20 mL) was added 5N sodium hydroxide (10 mL, 50 imol) and the solution was cooled in an ice bath. Solutions of benzylchloroformate (9.8 mL, 53 mmol) in acetone (10 mL) and 5N sodium hydroxide (11 mL, 55 mmol) were simultaneously added over 0.5 hr and the reaction was then allowed to warm to rt over 16 hrs. The reaction was poured into a mixture of ice water and ether and the layers were separated. The ether layer was washed with water and brine and the aqueous layers were consecutively extracted with a second portion of ether. The pooled ether layers were dried over sodium sulfate and evaporated to give 14.3 gm (quantitative) of clean title compound which was used without purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].Cl.[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15]>O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]([OH:4])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(c1ccccc1)C(F)(F)F
Reaction time: 4 h
Yield: 97 %

Procedure:
Under argon atmosphere, 20 mL (10.7 mmol, 2 equivalents) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise to a solution of 0.75 mL (5.35 mmol) of trifluoroacetophenone in 2.75 mL of THF at 7˜9° C. The mixture was stirred at 4˜5° C. for 4 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.54 g of the desired product (NMR yield 97%; internal standard dioxane).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[N:6][C:7]([O:10][C:11]2[N:16]=[C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C:14]([N+:27]([O-])=O)=[CH:13][N:12]=2)=[N:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CCOC(C)=O.CCO.[Pd]>[NH2:27][C:14]1[C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[N:16][C:11]([O:10][C:7]2[N:6]=[C:5]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:4]([NH2:1])=[CH:9][N:8]=2)=[N:12][CH:13]=1
Reactant: O=[N+]([O-])c1cnc(Oc2ncc([N+](=O)[O-])c(-c3cccc4ccccc34)n2)nc1-c1cccc2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnc(Oc2ncc(N)c(-c3cccc4ccccc34)n2)nc1-c1cccc2ccccc12
Temperature: 25 °C

Procedure:
The crude nitronaphthyl-pyrimidinyl ether from above (459 mg, 1.42 mmol, 1 equiv.) was taken up in 35 mL EtOAc and 35 mL EtOH. Ammonium formate was added (537 mg, 8.52 mmol, 6 equiv.) as well as 400 mg of 10% palladium-on-carbon. The reaction mixture was heated to a gentle reflux for one h, cooled back to room temperature, filtered through diatomaceous earth and the volatiles were removed in vacuo. The crude product was purified by chromatography on SiO2, eluting with 20-40% EtOAc in hexanes. The desired aminonaphthyl-pyrimidyl ether was isolated as a yellow foam (176 mg, 0.6 mmol, 42% for 2 steps).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:28][CH:22]5[NH:30][CH2:29][CH:26]4[CH2:25][CH2:24][CH2:23]5)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: C1CC2CNC(C1)CN2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2nc(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
A solution of 1.41 g (5.0 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1.10 (5.5 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 2.26 ml (15 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 30 ml of acetonitrile was heated under reflux for 4 hr. After cooling to room temperature, the precipitated solid was collected to give 0.97 g of the title compound, mp 255°-258° dec.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:44])[CH:21]([NH:25][CH2:26][CH:27]([NH:36]C(OC(C)(C)C)=O)[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:44])[CH:21]([NH:25][CH2:26][CH:27]([NH2:36])[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(NCC(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NCC(N)Cc1ccc(F)cc1)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 2-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)propyl]amino-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamide (A) (300 mg) in methylene chloride (5 ml), TFA (1 ml) was added under cooling with ice. The mixture was stirred at room temperature for 1 hour and evaporated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=15:1), giving the titled compound (180 mg, 71%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[CH3:36][N:37]1[C:41]([CH3:42])=[CH:40][C:39]([CH2:43]O)=[N:38]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:14](=[O:23])[N:13]([CH2:43][C:39]3[CH:40]=[C:41]([CH3:42])[N:37]([CH3:36])[N:38]=3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1cc(CO)nn1C
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NC(=O)N2c1ccccc1Cl
Product: Cc1cc(CN2C(=O)N(c3ccccc3Cl)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)nn1C

Procedure:
The title compound, MS: m/e=627.1 (M+), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 1,5 -dimethylpyrazole-3-methanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:18]([NH2:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]/[CH:27]=[CH:26]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH2:36])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCCC/C=C\CCCCCCCCN
Temperature: 120 °C
Yield: 83.3 %

Procedure:
1-bromohexadecane (15.27 g, 50 mmol) was rapidly added to oleylamine (26.75 g, 100 mmol) at 100° C. The reaction mixture was heated at 120° C. for 30 minutes and than cooled to room temperature. Chloroform(200 ml) was added followed by 1 N NaOH (50 ml). The mixture was then extracted with H2O (200 ml), the organic layer dried (Na2SO4) and concentrated to a syrup. Silica gel column chromatography using 5-20% gradient methanol in dichloromethane afforded 20.5 g of palmityloleylamine as a syrup (yield, 83%). The identity of the product was confirmed using NMR spectroscopy. 1H NMR (CDCl3) d 5.34 (m, 2H, CH═CH), 2.58 (m, 4H), 2.00 (m, 4H), 1.47 (m, 4H), 1.25 (m, 48H), 0.86 (m, 6H). FAB-MS: 493 [M+H]+. (Other reagents could include oleyl-bromide and hexadecane amine)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([O:14][C:15](=O)[O:16]C(C)(C)C)([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[N:1]1([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCN2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
Indoline (10 g, 84 mmol) was dissolved in tetrahydrofuran (100 mL) and di-tert-butylcarbonate (22 g, 0.1 mol) was added. The mixture was left stirring for 16 hours at room temperature under an inert nitrogen atmosphere. The tetrahydrofuran was removed in vacuo and the crude product purified by vacuum distillation to give the title compound (15.1 g) as a clear pale pink oil that crystallised upon standing (temperature: 160-162° C., pressure 1-0.1 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[O:30])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccncc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 62 h
Yield: 30.6 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) and commercially available isonicotinic acid (45 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (98 mg) was added, and the admixture was stirred at room temperature for 62 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 22 mg of the title compound (yield: 31%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[OH:11][CH2:12][C:13]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][O:11][CH2:12][C:13]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: Fc1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(F)cc(Br)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-fluorobenzene (0.8 g, 3.0 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.72 g, 2.5 mmol) were combined in dimethylformamide (8 mL) and cooled to 0° C. The reaction was treated with sodium hydride (120 mg, 4.98 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.2 g (84%). 1H-NMR (CDCl3, 500 MHz) δ 7.34-7.38 (m, 4H), 7.24-7.25 (m, 1H), 7.08-7.10 (m, 1H), 7.01 (s, 1H), 6.70-6.72 (m, 1H), 4.29 (s, 2H), 3.74-3.77 (m, 2H), 3.38 (s, 2H), 3.00-3.06 (m, 2H), 2.17-2.20 (m, 2H), 1.84-1.90 (m, 2H), 1.44 (s, 9H). Mass spec.: 501.32 (MNa)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[CH:8]=1.C1C=CC(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:39][C:5]1[C:4](=[O:24])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(C(=O)O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(N)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)-1,4-dihydropyridazine-3-carboxylic acid (1.18 g, 3.42 mmol), DPPA (1.10 mL, 5.13 mmol) and Et3N (0.715 mL, 5.13 mmol) in toluene (12 mL) was heated to 100° C. for 1 h. To the mixture was added 8 M NaOH aqueous solution (4.3 mL) at 0° C. The mixture was stirred at room temperature for 1 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and recrystallized with EtOAc/hexane to yield the title compound (704 mg, 65% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 173 (3H, s), 6.21 (2H, s), 7.85 (1H, d, J=9.4 Hz), 7.90 (1H, d, J=6.4 Hz), 8.33 (1H, s).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:17][C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22].ClC(OCC(C)C)=O>>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC[C@H](N)C(N)=O
Agent: CC(C)COC(=O)Cl
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(N)=O
Yield: 75 %

Procedure:
Condensation of BocLeuOH (2.0 g.) and HNleNH2 (1.0 g.) by the mixed anhydride method using isobutyl chloroformate gave BocLeu-NleNH2 in 75% yield. De-t-butoxycarbonylation of BocLeu-NleNH2 (1.42 g.) using hydrogen chloride in dioxane gave HLeu-NleNH2 in 88% yield. Condensation of ZGlyOSu (1.91 g.) and HLeu-NleNH2 (0.95 g.) by the activated ester method gave ZGly-Leu-NleNH2 in 79% yield. Debenzyloxycarbonylation of ZGly-Leu-NleNH2 (1.40 g.) by hydrogenation with palladium catalyst gave HGly-Leu-NleNH2 in 67% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2(O)[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:5][CH:6]=[CH:7][N:8]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][C:9]1([C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=2)[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: COc1nccnc1C1(O)CN2CCC1CC2
Solvent: ClCCl
Product: COc1nccnc1C1(Cl)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.4 g of (8) (0.010 mol) in 100 ml of CH2Cl2 was cooled to 0° C. as 2 ml of thionyl chloride in 5 ml of CH2Cl2 was added dropwise. The cooling was removed, the reaction stirred for 1.5 h, then heated to reflux for 45 min. Upon cooling to ambient temperature, ice-water was added to the reaction, followed by enough saturated aqueous K2CO3 to make the reaction basic. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 2.5% ethanol-0.25% NH4OH-CHCl3 to give 1.74 g of (12). Recrystallization from hexane gave colorless crystals, mp 59°-60° C. NMR ppm (CDCl3) 1.5 (1H, bs), 1.65 (2H, m), 2.35 (1H, m), 2.7 (2H, m) 2.97 (1H, m), 3.15 (2H, m), 3.65 (1H, m), 4.03 (1H, bm), 4.07 (3H, s), 8.1 (2H, m). Anal. C12H16ClN3O requires C: 56.81; H: 6.36; N: 16.56%. Found C: 56.63; H: 6.41; N: 16.48%. Further elution with 5% ethanol-0.5%NH4OH-CHC13 gave 0.13 g of (11), identical to the material produced previously.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1)=O>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[O:23][CH:22]=[N:21][CH:20]=4)=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Cl)cn1
Product: Clc1ccc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 27 %

Procedure:
The procedure of Referential Example 1 was repeated, except that 2-amino-5-chloropyridine (49 mg) and 2-bromo-1-[4-(1,3-oxazol-5-yl)phenyl]-1-ethanone (100 mg), which had been produced in Referential Example 10 were used, to thereby yield the title compound (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11]([NH:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1
Reactant: COc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Reactant: Nc1cccc(C(=O)O)c1
Product: COc1ccc2sc(S(=O)(=O)Nc3cccc(C(=O)O)c3)c(C)c2c1
Yield: 33 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 5-methoxy-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 8) (85 mg, 0.31 mmol) and 3-aminobenzoic acid (42 mg, 0.31 mmol). The title compound was obtained in 33% yield (38.2 mg). MS (ESI+) calcd mass for C17H15NO5S2 377.039164, found 377.039474.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](S(C)(=O)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:30]=[CH:31][C:32](B2OC(C)(C)C(C)(C)O2)=[N:33][CH:34]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[N:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Product: Nc1cnc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-methanesulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine (75 mg) was reacted with 5-aminopyrazine-2-boronic acid pinacol ester following General Procedure A to give 20 mg of 187 following reversed phase HPLC purification. MS (Q1) 491 (M)+