Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[N+:19]([O-])=O.O.O.[Sn]Cl.[Cl-].[NH4+].O>CN(C)C=O.C(OCC)(=O)C>[NH2:19][C:3]1[CH:4]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[C:2]=1[NH2:1]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(N)c(N)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.4 %

Procedure:
To a solution of methy 6-amino-4′-fluoro-5-nitrobiphenyl-3-carboxylate (0.42 g, 1.44 mmol) in N,N-dimethylformamide (4.8 mL) was added tin(1) chloride dihydrate (1.3 g, 5.8 mmol). The mixture was stirred at ambient temperature for 4 h and stored in the refrigerator for 18 h. Saturated ammonium chloride, water, and ethyl acetate were added. The mixture was extracted with ethyl acetate (3×). The combined organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (0.17 g): LC-MS [M+1]=261.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[C:18]([F:21])([F:20])[F:19])=[CH:5][C:4]=1[Cl:22].[NH2:23][C:24]1[CH:25]=[C:26]([C:30]([NH:32][C@@:33]2([C:38](O)=[O:39])[CH2:37][CH2:36][O:35][CH2:34]2)=[O:31])[CH:27]=[N:28][CH:29]=1>>[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[C:26]([CH:25]=1)[C:30]([NH:32][C@@:33]1([C:38](=[O:39])[NH:1][CH2:2][C:3]2[C:4]([Cl:22])=[CH:5][C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=3[C:18]([F:21])([F:19])[F:20])=[CH:7][N:8]=2)[CH2:37][CH2:36][O:35][CH2:34]1)=[O:31]
Reactant: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Reactant: COc1ccc(Nc2cnc(CN)c(Cl)c2)c(C(F)(F)F)c1
Product: COc1ccc(Nc2cnc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)c(Cl)c2)c(C(F)(F)F)c1

Procedure:
Analogously to Example 1e), (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine (1.3 mmol) was reacted with (S)-3-[(5-amino-pyridin-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (product from Example 2b, 1.3 mmol).
Reaction SMILES: [CH:1]1([N:7]2[CH:15]([OH:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]1([C:24]([CH:26]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[CH:8]([CH2:26][C:24]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:25])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]2=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(O)N1C1CCCCC1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(CC1c2ccccc2C(=O)N1C1CCCCC1)N1CCCCC1
Yield: 73.6 %

Procedure:
A solution of 1.2 g of 2-cyclohexyl-3-hydroxyisoindolin-1-one and 2.2 g of piperidinocarbonylmethylenetriphenylphosphorane in toluene (30 ml) was refluxed for 3 hours. After cooling, the toluene was distilled off and ether was added whereupon triphenylphosphine oxide separated out. After filtration, the filtrate was allowed to stand to giving crude crystals. Recrystallization from ether gave 1.3 g of 2-cyclohexyl-3-piperidinocarbonylmethylisoindolin-1-one.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:23]([O:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCCl.ClCCl>[CH2:1]([NH:8][C@H:36]1[CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][C@H:31]1[O:30][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(OCc2ccccc2)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87.6 %

Procedure:
Benzylamine (1.47 g, 13.7 mmol) and sodium (triacetoxy)borohydride (5.30 g, 25 mmol) were added to a solution of tert-butyl 3-(benzyloxy)-4-oxopiperidine-1-carboxylate obtained in Example (90b) (3.81 g, 12.5 mmol) in 1,2-dichloroethane (40 mL), and the mixture was stirred at room temperature for 40 minutes. The reaction solution was diluted with dichloromethane, washed with a 1 N aqueous sodium hydroxide solution and brine, and dried over magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 4.34 g of the title compound as a colorless solid (91%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:20]1([CH3:28])[CH:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[O:21]1>C(OCC)(=O)C.[Pt]=O>[CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:20]1([CH3:28])[CH:22]([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[O:21]1
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCC(C)C
Yield: 80.6 %

Procedure:
A solution of 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-morpholinocarbonyloxy-1-oxaspiro[2,5]octane (1.23 g) in ethyl acetate (12 ml) was hydrogenated under hydrogen (1 atom) in the presence of platinum oxide (120 mg) for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with a mixture of diethyl ether and n-hexane (1:1, V/V) to give 5-methoxy-4-[2-methyl-3-(3-methylbutyl)oxiranyl]-6-morpholinocarbonyloxy-1-oxaspiro[2,5]octane (996 mg) as an oil, which was standing on to give crystals of the same compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]1[N:11]([C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[C:10]2[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=2[N:8]=1.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([CH:29]=[CH:30][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]1[N:11]([C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[C:10]2[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=2[N:8]=1)([OH:32])=[O:31]
Reactant: C=CC(=O)O
Reactant: OC[C@H]1O[C@@H](n2c(NCc3cccc(Br)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 26.5 %

Procedure:
2-(3-Bromobenzylamino)-1-(β-D-ribofuranosyl)-1H-benzimidazole (200 mg), acrylic acid (112 mg), palladium acetate (10 mg) and tri-o-tolylphosphine (28 mg) were suspended in acetonitrile (2 mL). To the mixture was added triethylamine (0.3 mL), and the mixture was stirred at 100° C. for 10 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (52 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.C(Cl)(Cl)Cl>[CH2:12]([C:9]1[N:7]2[N:8]=[C:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=3)[C:6]2=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCCCc1c(CNS(C)(=O)=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 mL) in dichloromethane (2 mL) was added methanesulfonyl chloride (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (62.8 mg)
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20](Br)[S:21][C:22]=3[CH3:23])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[CH3:26][CH2:27]O.[Li+].[OH-]>C1COCC1.O>[CH:9]([C:26]1[CH:27]=[CH:7][C:6]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:3])=[O:25])[CH2:7][CH2:8]4)[N:19]=2)=[CH:5][CH:4]=1)([CH3:10])[CH3:8]
Reactant: CCO
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(Br)sc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of Example 174 (305 mg, 0.657 mmol) in a mixture of THF (8 mL), water (8 mL), and EtOH (4 mL), was added LiOH (63 mg, 2.63 mmol). The reaction mixture was vigorously stirred for 24 hours, diluted with water (20 mL), and washed with Et2O (10 mL). The aqueous phase was then acidified to pH ˜1 using 1 N HCl, and then extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to afford product (189 mg, 66%) as a white solid. (C26H29NO3S): LC-MS, RT 3.95 min., M+H 436.4; 1H NMR (CDCl3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (AB quartet, 4H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[CH2:7][CH2:8][CH3:9].CO.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].C[O-].[Na+]>O.C(O)(=O)C>[C:14]([C:16]1[C:17](=[O:18])[NH:19][C:6]([CH2:7][CH2:8][CH3:9])=[CH:5][C:4]=1[CH2:3][CH2:2][CH3:1])#[N:15]
Reactant: CCCC(=O)CC(=O)CCC
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCCc1cc(CCC)c(C#N)c(=O)[nH]1
Reaction time: 22 h
Yield: 81.9 %

Procedure:
3-Cyano-4,6-di-n-propyl-2(1H)-pyridinone was prepared as follows: A mixture containing 15.6 g of 4,6-nonanedione, 200 ml of methanol, 10 g of cyanoacetamide and 6 g of sodium methoxide was refluxed with stirring for 22 hours and then stripped to dryness in vacuo. The residue was dissolved in 100 ml of water and the solution acidified with acetic acid. The white precipitate was collected, washed with water, air-dried, recrystallized from isopropyl alcohol-n-hexane and dried in vacuo at 80°-85° C. to produce 16.7 g of 3-cyano-4,6-di-n-propyl-2(1H)-pyridinone, m.p. 151°-152° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][NH:37][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: CNC(=O)c1ccc2cc(-c3nc(Cl)ncc3C)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCN(C(=O)OC(C)(C)C)CC4)ncc3C)sc2c1
Temperature: 95 °C
Yield: 43.2 %

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methylamide (400 mg, 1.20 mmol), 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (688 mg, 3.01 mmol) and diisopropylethylamine (467 mg, 3.61 mmol) in 1,4-dioxane (4 mL) is heated at 95° C. under nitrogen for 3 days. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with EtOAc in dichloromethane 0-35%, to give 4-{2-[5-methyl-4-(6-methylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid (264 mg, 43% yield). The intermediate is subjected to deprotection by dissolving this material (264 mg, 0.518 mmol) in MeOH (12 mL) and bubbling anhydrous HCl gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (246 mg, 98% yield). ES+(m/z) 410 [M(free base)+H].
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)N1OCCOCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOCCON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
To 1 mL of DMF/H2O (v/v=9/1) was added 2-(2-(2-bromoethoxy)ethoxy)isoindoline-1,3-dione (50 mg, 0.17 mmol) and sodium azide (16.6 mg, 0.26 mmol). The mixture was heated to 80° C. overnight. Then it was allowed to cool down to room temperature and was extracted with ethyl acetate for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, the crude product was purified by silica gel column chromatography (hexanes: ethyl acetate 2:1) to afford 2-(2-(2-azidoethoxy)ethoxy)isoindoline-1,3-dione (44 mg, 0.17 mmol, 100%) as colorless oil. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.28 (t, J=4.7 Hz, 2H), 3.64 (t, J=4.8 Hz, 2H), 3.84 (t, J=3.8 Hz, 2H), 4.34 (t, J=3.9 Hz, 2H), 7.71 (dd, J=2.6, 4.7 Hz, 2H), 7.79 (dd, J=3.2, 5.0 Hz, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[Cl:1][CH2:2][C:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccccc1
Reactant: Brc1ccccn1
Product: O=C(CCl)N(c1ccccc1)c1ccccn1
Yield: 93 %

Procedure:
Using 2-chloro-acetanilide (5.1 g) and 2-bromopyridine (9.5 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:2 to 1:1) produced 2-chloro-N-(2-pyridyl)acetanilide (6.9 g, crude product) as a red oil.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]([CH2:13][C:14](=[O:28])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>CO>[O:28]=[C:14]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH2:13][N:6]([CH2:5][C:4]([OH:29])=[O:3])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CN(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a mixture of ethyl[(2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl)(phenyl)amino]acetate (40.8 mg) in methanol (0.60 mL) was added 1N sodium hydroxide aqueous solution (0.157 mL) at ambient temperature and the mixture was stirred at ambient temperature overnight. The mixture was neutralized with 1N hydrochloric acid and the precipitate was collected by filtration. The solid was washed with n-hexane/ethyl acetate (1:1, 1.0 mL) to afford [(2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl) (phenyl)amino]acetic acid (24.8 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:16]=[C:15]([NH:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]([NH:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[N:14]=3)=[CH:11][CH:12]=2)=[CH:33][CH:34]=1.[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]([NH:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[N:14]=3)=[CH:11][CH:12]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H](C)Nc1cc(C(=O)OC(C)(C)C)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](C)Nc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 72 h

Procedure:
To a solution of the (S)-tert-butyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate (0.312 g, 0.667 mmol) in DCM (10 mL) was added TFA (5 mL, 67 mmol). After stirring for 3 days the reaction was evaporated in vacuo and the residue triturated with hexanes, filtered and dried under a stream of nitrogen to give (S)-2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylic acid as the trifluoroacetic acid salt as a cream-colored powder (0.326 g, 0.620 mmol, 93%). 1H NMR (400 MHz, DMSO-d6): 8.36-8.26 (3H, m), 7.32-7.24 (2H, m), 7.20-7.13 (2H, m), 7.10-7.03 (3H, m), 4.60-4.52 (1H, m), 3.64 (3H, s), 1.45 (3H, d, J=7.2 Hz). LC/MS: m/z=412.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C([O-])(=O)C.[NH4+]>C(O)C>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[CH:29]=[CH:30][C:23]([N:22]([CH3:31])[CH3:21])=[CH:24][CH:25]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)cc1
Yield: 47.1 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1.30 mg, 0.386 mmol), 4-(dimethylamino)benzaldehyde (63.3 mg, 0.424 mmol) and ammonium acetate (59.4 mg, 0.771 mmol) were heated in ethanol (5 mL) at 70° C. for 18 hours. The desired product precipitated from the reaction mixture. The mixture was diluted with ethyl ether (5 mL) and filtered. The remaining solid was dried under high vacuum to afford 85 mg (47%) of the title compound. mp: 264-265° C., 1H NMR (300 MHz, DMSO-d6): 12.73 (s, 1H), 7.96 (d, J=8 Hz, 2H), 7.84 (d, J=4 Hz, 1H), 7.65 (s, 1H), 7.15 (s, 1H), 6.81 (d, J=8 Hz, 2H), 6.70 (d, J=8 Hz, 1H), 6.37 (d, J=8 Hz, 1H), 6.32 (s, 2H), 3.89 (br s, 1H), 2.99 (s, 6H), 2.87 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=7 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 467, 469 (M+H), HPLC: 2.43 min (G method).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CO.[OH-].[K+].Cl>C1COCC1.O>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc2nc(C)oc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ccc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 110.2 %

Procedure:
A solution of compound 138 (920 mg, 4.815 mmol) in THF:MeOH (30 mL of a 1:1 solution) was treated with a solution of potassium hydroxide (0.698 g, 17.86 mmol) in H2O (15 mL). The reaction mixture was stirred for 65 min at room temperature then quenched with 1N HCl (18 mL, 18.6 mmol) (final pH of 2.5), THF was removed under reduced pressure and the remaining aqueous solution was cooled to −78° C. and lyophilized to give compound 139 (940 mg, quantitative).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([NH:10][C:11]1[S:12][CH:13]=[N:14][N:15]=1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28]>O1CCCC1>[Cl:23][CH2:24][CH2:25][NH:26][C:27]([NH:2][CH:3]([C:8]([NH:10][C:11]1[S:12][CH:13]=[N:14][N:15]=1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:28]
Reactant: O=C=NCCCl
Reactant: CC(C)CC(N)C(=O)Nc1nncs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)NCCCl)C(=O)Nc1nncs1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
7.5 g of 2-DL-leucylamino-1,3,4-thiadiazole hydrochloride and 3.1 g of triethylamine were suspended in 100 ml of tetrahydrofuran, and 3.2 g of 2-chloroethyl isocyanate was added thereto and stirred for 2 hours. The reaction solution was concentrated, and the resulting crystals were washed with water and n-hexane to obtain 7.9 g (Yield 83%) of 2-[N-{(2-chloroethyl)carbamoyl}-DL-leucyl]amino-1,3,4-thiadiazole was obtained as slightly yellow crystals having a melting point of from 162° to 166° C. (dec.).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10].[CH3:22][O:23][CH:24]([C:26]([O:28][CH3:29])=[O:27])[NH2:25]>C(Cl)Cl>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([NH:25][CH:24]([O:23][CH3:22])[C:26]([O:28][CH3:29])=[O:27])=[O:10])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C(N)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.06 g, 0.05 mole) and p-nitrobenzyl chloroformate (10.78 g, 0.05 mole) are added to an ice-cold solution of methyl α-methoxyglycinate (6.10 g, 0.05 mole) in dry CH2Cl2 (100 ml). The resulting mixture is stirred in the cold and under N2 for 2 hours, and then washed with 3 portions of water. The CH2Cl2 phase is dried over MgSO4, filtered, and evaporated in vacuo. Recrystallization of the residue affords pure methyl N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycinate.