Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.Cl[CH2:7][CH2:8][N:9]=[C:10]=[O:11].[H-].[Na+]>C1COCC1>[O:1]1[CH2:4][CH:3]([N:5]2[CH2:7][CH2:8][NH:9][C:10]2=[O:11])[CH2:2]1
Reactant: O=C=NCCCl
Reactant: NC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1C1COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A 0° C. solution of 3-oxetanamine (0.200 g, 2.74 mmol) in THF (15 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.257 mL, 3.01 mmol), allowed to warm to RT as the cooling bath expired, then concentrated to dryness. The residue was treated with toluene and concentrated to dryness (twice) to afford a white solid. The solid was dissolved in THF (15 mL), cooled to −20° C., under Ar, treated with NaH (60% in mineral oil, 0.274 g, 6.84 mmol), allowed to warm to RT and stirred overnight. The mixture was cooled to 0° C., quenched with satd. NH4Cl, warmed to RT, treated with brine and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to dryness. The aqueous layer was treated with solid NaCl until saturated, extracted with 1:1 EtOAc/THF (4×), then frozen and lyophilized. The lyophilized solid was stirred with EtOH for 1 h, the liquid decanted and the process repeated. The EtOH extracts were combined with the EtOAc/THF extracts, concentrated to dryness, then treated with 10% MeOH/DCM and the solids removed via filtration. The filtrate was combined with the initial EtOAc extracts and purified via silica gel chromatography (MeOH/DCM) to afford 1-(oxetan-3-yl)imidazolidin-2-one (270 mg, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.52 (s, 1 H), 4.86 (m, 1 H), 4.71 (t, J=6.6 Hz, 2 H), 4.62 (t, J=7.2 Hz, 2 H), 3.58 (m, 2 H), 3.29 (m, 2 H); MS (ESI) m/z: 143.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[S:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.CN1C(=O)CCC1>CO>[Cl:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:40][CH:37]4[CH2:38][CH2:39][S:34][CH2:35][CH2:36]4)[CH:3]=[C:4]([N:21]([CH:31]4[CH2:32][CH2:33]4)[CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:5]3=[N:10][CH:9]=2)=[O:12])[CH:19]=[CH:18][N:17]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Reactant: NC1CCSCC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2cc(NC3CCSCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Yield: 23.1 %

Procedure:
A microwave tube was charged with 6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.207 mmol), tetrahydro-2H-thiopyran-4-amine (121 mg, 1.034 mmol), and NMP (2 mL). The reaction mixture was irradiated at 120° C. (300 W) for 20 minutes. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 60 min gradient, monitored at 254 nm). The product (retention time=68.837 minutes) was isolated and lyophilized to dryness to afford N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-thiopyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (27 mg, 17.32%). HPLC Rt=4.816 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=563.9.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M50) (0.33 g, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (152 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:26])[C:14]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
0.50 g (1.3 mmol) of 3-(4-chloro-2-ethyl-6-fluorobenzofuran-7-yl)-6-trifluoromethyluracil and 0.30 g (2.3 mmol) of potassium carbonate, were suspended in 20 ml of N,N-dimethylformamide, and 0.23 g (1.6 mmol) of methyl iodide was dropwise added thereto under cooling with ice. After stirring at room temperature for 3 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.48 g (yield: 92%) of the desired product as white crystals. Melting point: 142-143° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]=[N:16][CH:15]=[C:14]2[CH2:23][C:24]1[NH:32][C:31]2[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[N:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[N:25]=1>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]=[N:16][CH:15]=[C:14]2[CH2:23][C:24]1[N:32]([CH3:1])[C:31]2[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[N:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[N:25]=1
Reactant: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2cncc(Cc3nc4c(c(=O)n(C)c(=O)n4CC(C)C)n3C)c2cc1OC
Reaction time: 8 h

Procedure:
Potassium carbonate (48 mg, 0.35 mmol) and iodomethane (0.018 ml, 0.295 mmol) are added to a solution of the product of Example 10, 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione (0.100 g, 0.24 mmol) in DMF (2 ml). The reaction is stirred overnight and purified by preparative HPLC to afford 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1,7-dimethyl-3,7-dihydro-purine-2,6-dione, [MH]+ 438.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:10][CH2:11][C:12]([O-:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[N+:40](=[CH2:42])=[N-:41]>O1CCCC1.C(O)(=O)C.C(OC)(C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH2:11][C:12](=[O:14])[CH:42]=[N+:40]=[N-:41])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)[O-])C(=O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)C=[N+]=[N-])C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
5.0 g (14.9 mmol) of 1-benzyl tert-butoxycarbonyl-(S)-glutamate is placed in 75 mL of tetrahydrofuran while cooling with ice, combined with 2.1 mL (16.5 mmol) of isobutylchloroformate and 2.5 mL (18 mmol) of triethylamine, and stirred for 60 minutes. Then 30 mL, (20 mmol) of diazomethane (0.7 molar in diethyl ether) and 200 mL of tert-butylmethylether are added and the mixture is stirred overnight at ambient temperature. After the addition of 1 mL glacial acetic acid, the phases are separated, and the organic phase is dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with dichloromethane/ethyl acetate (0%-20%). Yield: 2.2 g (41%); Rf value: 0.42 (silica gel: petroleum ether/ethyl acetate=6:4); C18H23N3O5 (361.40); mass spectrum: (M+H)+=362
Reaction SMILES: C(N1CCN([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)CC1)C1C=CC=CC=1.ClC(O[CH:28]=[CH2:29])=O>C(Cl)Cl>[N:15]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:22]=[CH:23][CH:14]=[N:15]3)[CH2:29][CH2:28][NH:22][CH2:23][CH2:14]1
Reactant: C=COC(=O)Cl
Reactant: c1ccc(CN2CCN(c3cnc4ccccc4n3)CC2)cc1
Solvent: ClCCl
Product: c1cc(N2CCNCC2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.3 %

Procedure:
To a room temperature solution of 1-benzyl-4-(quinoxalin-yl)-piperazine (1.0 g, 3.3 mmol) in anhydrous CH2Cl2 under nitrogen was added vinyl chloroformate (0.34 mL, 3.9 mmol) drop wise. The reaction mixture was heated at reflux 2 hours. The reaction was cooled, concentrated to dryness and concentrated HCl (25 mL) and 1,4-dioxane (25 mL) were added. The resulting solution was stirred at ambient temperature overnight. The solution was basified with 2.5 N NaOH (300 mL) and extracted into EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, concentrated and chromatographed (10% MeOH/CH2Cl2/NH4OH) to give 450 mg (64%) of an orange solid: mp 106-108° C.: MS (+) ESI m/e 215 [M+H]+.
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10](=[O:54])[NH:11][C@@H:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:41][C:42]([CH2:45][N:46]5[CH2:51][CH2:50][CH2:49][CH:48]([NH2:52])[C:47]5=[O:53])=[N:43][CH:44]=4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14].Cl[C:56]([O:58][CH3:59])=[O:57]>ClCCl>[CH3:59][O:58][C:56](=[O:57])[NH:52][C@@H:48]1[CH2:49][CH2:50][CH2:51][N:46]([CH2:45][C:42]2[NH:41][C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:31]4[CH:30]=[CH:29][C:28]([C:25]5[NH:24][C:23]([CH:19]6[CH2:20][CH2:21][CH2:22][N:18]6[C:16](=[O:17])[CH:12]([NH:11][C:10]([O:9][CH3:8])=[O:54])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:33][CH:32]=4)=[CH:35][CH:36]=3)=[CH:44][N:43]=2)[C:47]1=[O:53]
Reactant: COC(=O)Cl
Reactant: COC(=O)N[C@@H](C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCC[C@@H](NC(=O)OC)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Yield: 319 %

Procedure:
4-Methylmorpholine (71 μL, 0.64 mmol) was added to a suspension of (R)-{1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-yl methyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (137 mg, 0.21 mmol) in dichloromethane (5 mL). Methyl chloroformate (16.5 μL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed under reduced pressure. The residue was taken up in tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 2 hours the organic solvents were removed under reduced pressure and the aqueous phase was decanted. The residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide (R)-{1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester (46.7 mg, 0.67 mmol, 32%). C37H44N8O6 calculated 696.3 observed [M+1]+ 697.4; rt=1.58 min. 1H (DMSO-d6,): δ=8.05 (s, 1H), 7.87 (m, 8H) 7.30 (m, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.85 (d, J=15.6 Hz, 1H), 4.53 (d, J=16.0 Hz, 1H), 4.08 (m, 2H), 3.81 (m, 2H), 3.51 (s, 3H), 3.50 (s, 3H), 2.14 (m, 1H), 2.05-1.78 (series m, 8H), 0.78 (m, 6H).
Reaction SMILES: C[C:2](C)([NH2:11])[CH2:3][CH2:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].C([O-])(=O)C.C(N(CC)C(C)C)C.C(N(C(C)C)CC)(C)C>C(N(CC)CC)C.C1(C)C=CC=CC=1.C(OC)(C)(C)C.C(OCC)(=O)C.C(O)(C)C.C(O)C.CO.C(#N)C>[NH2:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2][NH2:11]
Reactant: CC(C)(N)CCC[C@H](N)C(=O)O
Agent: CC(=O)[O-]
Agent: CCN(CC)C(C)C
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: CC(C)O
Product: NCCCC[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
The 6,6-dimethyl lysine derivative of the formula (3) is dissolved in a suitable solvent and reacted with acetate derivative in the presence of a base. The solvent is exemplified by acetonitrile, methanol, ethanol, isopropyl alcohol, ethyl acetate, methyl t-butyl ether, toluene and the like. As the base, tertiary amine, such as triethylamine, diethylisopropylamine, diisopropylethylamine and the like, is used in an amount of generally 2–10 equivalents, preferably 3–4 equivalents relative to the 6,6-dimethyl lysine derivative. The acetate derivative is used in an amount of generally 1–2 equivalents, preferably about 1.2 equivalents. The mixture is stirred generally at 0° C.–40° C., preferably at room temperature, for generally about 12–48 h, preferably about 18–24 h. The reaction mixture is concentrated (or evaporated) by concentration under reduced pressure and the like, and extracted with an organic solvent such as ethyl acetate, toluene, dichloromethane and the like or a mixed solvent such as toluene-isopropyl alcohol and the like. Then, the organic solvent layer is evaporated under reduced pressure to give the optically active lysine derivative of the formula (5).
Reaction SMILES: CC(C)=[O:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH2:27][C:28]#[N:29])=[C:14]([CH2:25][OH:26])[CH:15]=[C:16]3[C:24]=2[C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=[CH:17]3)=[CH:8][CH:7]=1.[Mn]([O-])(=O)(=O)=O.[K+]>O>[C:28]([CH2:27][C:13]1[C:12]([C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[C:24]2[C:16]([CH:17]=[CH:18][C:19]3[O:23][CH2:22][O:21][C:20]=32)=[CH:15][C:14]=1[C:25]([OH:3])=[O:26])#[N:29]
Reactant: N#CCc1c(CO)cc2ccc3c(c2c1-c1ccc(F)cc1)OCO3
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: N#CCc1c(C(=O)O)cc2ccc3c(c2c1-c1ccc(F)cc1)OCO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of acetone (5 ml) and water (2 ml) was dissolved 9-(4-fluorophenyl)-7-hydroxymethylnaphtho[1,2-d]-1,3-dioxole-8-acetonitrile (200 mg), and potassium permanganate (400 mg) was gradually added thereto. The mixture was stirred for 1 hour at room temperature and potassium permanganate (200 mg) was gradually added thereto. The insoluble substances were filtered off and 1N hydrochloric acid was added to the filtrate. The resultant precipitates were collected by suction and recrystallized from methanol to give the entitled compound (23 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:25][CH2:24][C@:7]2([O:11][CH2:10][C:9]([C:12]3[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=3[O:20][CH:21]([CH3:23])[CH3:22])=[CH:8]2)[C@@H:6]1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:4].CO.[OH-].[Na+].Cl>C1COCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C@@H:6]2[C@@H:5]([C:3]([OH:4])=[O:2])[CH2:25][CH2:24][C@@:7]32[O:11][CH2:10][C:9]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=2[O:20][CH:21]([CH3:23])[CH3:22])=[CH:8]3)=[CH:31][CH:30]=1
Reactant: COC(=O)[C@H]1CC[C@@]2(C=C(c3cc(C#N)ccc3OC(C)C)CO2)[C@@H]1c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(C#N)cc1C1=C[C@@]2(CC[C@H](C(=O)O)[C@H]2c2ccc(F)cc2)OC1

Procedure:
(5R,6S,7S)-6-(4-Fluorophenyl)-3-(5-cyano-2-isopropoxyphenyl)-1-oxaspiro[4.4]non-3-ene-7-carboxylic acid methyl ester(128 mg, 0.294 mmol) was taken up in THF(2 mL) and methanol (2 mL) and treated with 2.5N NaOH (0.4 mL, 1.0 mmol) for 6 hours at room temperature. 2N Hydrochloric acid (5 mL) was then added, and the product extracted with ethyl acetate (2×30 mL). The combined extracts were washed with saturated brine solution, dried (MgSO4), and evaporated to afford the title compound; yield 124 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:15]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Product: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (4-3) (5.73 g, 20.01 mmol) in POCl3 (50 mL) was heated to 100° C. overnight. Cooled and concentrated in vacuo. The residue was basified with sat. aqueous Na2CO3 solution and then extracted with CH2Cl2. The combined organic layers was dried, filtered and concentrated to give 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (4-4) as a solid. LRMS m/z (M+H) Calcd: 305.1, found: 305.2.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:28][C:29]([F:32])([F:31])[F:30])[CH3:3].C1(C2C=C(C=CC=2OC(F)(F)F)COC2C=CC([C@@H](C3C=CON=3)CC(O)=O)=CC=2)CCCC1>>[CH:2]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C@@H:16]([C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)=[CH:6][C:5]=1[O:28][C:29]([F:32])([F:31])[F:30])([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)cc1OC(F)(F)F
Agent: O=C(O)C[C@@H](c1ccc(OCc2ccc(OC(F)(F)F)c(C3CCCC3)c2)cc1)c1ccon1
Product: CC(C)c1ccc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)cc1OC(F)(F)F

Procedure:
Compound 37 was synthesized from compound 35 using the procedure described above for the preparation of 23. 1H NMR (CD3CN) δ 1.25 (d, J=6.9 Hz, 6H), 2.96 (dd, J=7.4, 16.4 Hz, 1H), 3.20 (dd, J=7.4, 16.4 Hz, 1H), 3.34 (m, 1H), 4.56 (m, 1H), 5.09 (s, 2H), 6.27 (d, J=1.7 Hz, 1H), 6.97 (d, J=6.6 Hz, 2H), 7.25 (d, J=6.6 Hz, 2H), 7.37 (s, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 8.45 (d, J=1.7 Hz, 1H). MS ESI (pos.) m/e: 450 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C(#N)C>[F:1][C:2]1[C:3]([N:26]2[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CNCC1CCNC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC#N
Product: CNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OCC4C)C1
Yield: 226.4 %

Procedure:
0.75 g (2.7 mmole) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 40 ml acetonitrile, and 0.91 g (0.80 mmole) of N-methyl-3-pyrrolidinemethanamine were refluxed overnight. The solvent was removed at reduced pressure and the residue tititrated with 40 ml of methanol. The precipitate was filtered, washed repeatedly with 95% ethanol and finally with ether until dry to give 0.68 g of 9-fluoro-2,3-dihydro3-methyl-10-[3-[(methylamino)methyl]-1-pyrrolidinyl]-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 235°-237.5° C.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH3:31])[CH2:25]1>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH3:31])[CH2:25]1)=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: CCN1CCCC(N)C1
Product: CCN1CCCC(NC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C1
Yield: 89.1 %

Procedure:
The procedure of Example 9 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.8 g of 3-amino-1-ethylpiperidine were used as starting materials. 7.4 g (yield 90%) of the title compound was obtained as a pale yellow oil.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=2[CH:4]=[C:3]([C:18]([O:20][CH3:21])=[O:19])[CH:2]=1.[ClH:22]>>[ClH:22].[N:1]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:18]([O:20][CH3:21])=[O:19])[CH:2]=1
Reactant: COC(=O)c1cnc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: COC(=O)c1cnc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.2 %

Procedure:
To a flask was added 6-tert-butyl 3-methyl 7,8-dihydro-1,6-naphthyridine-3,6(5H)-dicarboxylate (1.79 g, 6.12 mmol) and hydrochloric acid (23.0 mL, 91.8 mmol, 4.0 M in 1,4-dioxane). The mixture was stirred at rt for 1 h. The solvent was completely evaporated to yield methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate hydrochloride (1.64 g, 100%). LC-MS: (FA) ES+ 193.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Sn].Cl.O1CCOCC1>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCc1cc(S(=O)(=O)Cl)ccc1OCC(=O)OCC
Agent: Cl
Agent: [Sn]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCc1cc(S)ccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
Compound 4.3 (43.27 g, 134.9 mmol) was dissolved in ethanol (168.6 mL). To the solution was added tin (80.1 g, 674.5mmol) and the reaction was stirred at room temperature for 15 min., then cooled to 0° C. To the reaction was added 4N HCl/dioxane solution (168.6 mL, 674.5 mmol) dropwise at 0° C. Then the reaction was refluxed for 3.5 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and filtered to remove insoluble materials and the filtrate was concentrated in vacuo to give the residue. The resulting residue was purified using silica gel column chromatography (hexane/EtOAc=10/1) to give 4.4 (27.2 g). 1H NMR (400 MHz) (CDCl3) δ 7.13 (1H, d, J=2.3 Hz); 7.09 (1H, dd, J=2.4, 8.4 Hz); 6.60 (1H, d, J=8.4 Hz); 4.59 (2H, s); 4.25 (2H, q, J=7.1 Hz); 3.32(1H, s); 2.63-2.55 (2H, m); 1.68-1.57 (2H, m); 1.28 (3H, t, J=7.1 Hz); 0.95 (3H, t, J=7.4 Hz).