Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17](=[O:25])[CH2:18][CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[C:4]=2[CH:3]=1.[OH:26]O>C(O)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:26])(=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17](=[O:25])[CH2:18][CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[C:4]=2[CH:3]=1
Reactant: OO
Reactant: O=C(CCn1ccnc1)N1c2ccccc2S(=O)c2ccc(Cl)cc21
Solvent: CC(=O)O
Product: O=C(CCn1ccnc1)N1c2ccccc2S(=O)(=O)c2ccc(Cl)cc21
Reaction time: 3 h

Procedure:
A mixture of 1 g of 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5-oxide, 4 ml of 30% H2O2 and 40 ml of acetic acid is stirred for 3 hours at 45° and is worked up in the customary manner to give 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5,5-dioxide, melting point 134°-135° (decomposition). Hydrochloride, melting point 200°-201°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1NC(C)=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1NC(C)=O
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of methyl 2-acetylamino-4-nitrobenzoate (1.31 g, 5.50 mmol) in MeOH (30 mL) was added 5% Pd on carbon (195 mg), and the stirring under H2 gas (3 atm) was continued for 18 hours at rt. The catalyst was filtered off and the mixture was evaporated. The resulting crude solid was recrystallized with CHCl3-MeOH-hexane to give methyl 2-acetylamino-4-aminobenzoate (1.03 g, 90%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 2.23 (s, 3 H), 3.82 (s, 3H), 4.20 (s, 2 H), 6.30 (dd, J=2.5 Hz, 8.8 Hz, 1 H), 7.80 (d, J=8.8 Hz, 1 H), 8.06 (s, 1 H), 11.26 (s, 1 H); MS (FAB), m/z 208 (M+).
Reaction SMILES: FC1C=C(C2OC3(CCN([C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH3:30])[CH:21]=4)=[O:19])CC3)CC(O)C=2)C=NC=1.[H-].[Na+].C(I)C>C(O)C.[Pd]>[CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][C:22]=1[CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(O)C=C(c2cncc(F)c2)O3)ccc1OC(C)C
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCI
Product: Cc1cc(C=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 293.5 %

Procedure:
A solution of [10-(5-fluoro-3-pyridyl)-8-hydroxy-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (56 mg, 0.13 mmol) in ethanol (4.4 mL) was purged with nitrogen for 5 min and treated with 10% palladium on carbon (13 mg, 0.012 mmol). The mixture was evacuated and put under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 12 h at 25° C. The reaction mixture was evacuated and put under an inert atmosphere and re-charged with 10% palladium on carbon (54 mg, 0.05 mmol). The mixture was evacuated and put under a hydrogen atmosphere (balloon) and stirred for 4 h. The reaction mixture was evacuated and put under an inert atmosphere. The Pd-catalyst was removed via filtration and was washed with ethyl acetate. The filtrate was concentrated to dryness and dissolved in DMF (2.4 mL). The mixture was cooled to 0° C. and treated with 60% NaH (28 mg, 1.19 mmol) and ethyl iodide (95 μL, 1.2 mmol). The reaction mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was quenched by the addition of methanol and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by reverse phase HPLC (1-100% acetonitrile in water, no modifier) afforded cis-4-ethoxy-2-(5-fluoropyridin-3-yl)-1-oxa-9-azaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone (68 mg) ESI-MS m/z calc. 470.26, found 471.2 (M+1)+; Retention time: 1.453 minutes (3 min run).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][C:26](Cl)=[N:27][OH:28].C(N(CC)CC)C>O1CCCC1>[F:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][C:26]1[CH:2]=[C:1]([C:3]2[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=2)[O:28][N:27]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2F)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of the 3-ethynyl-pyridin-2-ylamine (38.4 mg, 0.325 mmol) described in Manufacturing Example 1-2-3 and (2-fluoro-4-(pyridin-2-yloxymethyl)-phenyl)acetohydroximoyl chloride (150 mg, 0.509 mmol) described in Manufacturing Example 204-1-8 was added triethylamine (97.2 μL, 0.697 mmol), which was stirred for 2 hours at 60° C. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (46 mg, 24%).
Reaction SMILES: [Br-].[CH2:2]([Li])[CH2:3][CH2:4][CH3:5].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:24](OCC)C>CCCCCC.C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([CH:18]=[C:2]2[CH2:24][CH2:5][CH2:4][CH2:3]2)[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOCC
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: [Li]CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCCCCC
Solvent: ClCCl
Product: C(=C1CCCC1)c1cccc(OCc2ccccc2)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
5.66 g of cyclopentyltriphenylphosphonim bromide was suspended in 25 mL of diethyl ether, to which 8.8 mL of a solution of n-butyllithium in n-hexane (1.56 M) was added dropwise at −30° C. After the reaction mixture was stirred for one hour at 5° C., 2.67 g of 3-(benzyloxy)benzaldehyde dissolved in 5 mL of diethyl ether was added to the reaction mixture, which was then stirred another one hour at room temperature. The reaction mixture was added to a mixture of methylene chloride and dilute hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to yield 1.06 g of 1-(benzyloxy)-3-(cyclopentylidenemethyl)benzene as light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1>CC#N.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(Br)ccc1O)C(=O)OC(C)(C)C
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CN(Cc1cc(Br)ccc1OCc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 98 %

Procedure:
A mixture of (5-bromo-2-hydroxy-benzyl)-methyl-carbamic acid tert-butyl ester (1.0 g, 3.2 mmol), K2CO3 (655 mg, 4.74 mmol), and 4-bromomethyl-1,2-dichloro-benzene (1.14 g, 4.74 mmol) in CH3CN (6.3 mL) was heated at 90° C. overnight. The mixture was then cooled to rt, diluted with EtOAc and water, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Purification by FCC (EtOAc/hexanes) gave the desired product (1.49 g, 99%). 1H NMR (CDCl3, mixture of rotamers): 7.49 (d, J=1.9, 1H), 7.46 (d, J=7.8, 1H), 7.31 (dd, J=8.7, 2.0, 1H), 7.28-7.22 (m, 2H), 6.73 (d, J=8.6, 1H), 5.00 (s, 2H), 4.52-4.38 (m, 2H), 2.90-2.80 (m, 3H), 1.52-1.39 (m, 9H).
Reaction SMILES: [CH3:1][S-:2].[Na+].CS(O[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[C:11]=1[O:23][CH3:24])(=O)=O>O1CCOCC1>[C:16]([C:14]1[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[C:11]([O:23][CH3:24])=[C:10]([CH2:9][S:2][CH3:1])[CH:15]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: COc1c(COS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(CSC)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
At ambient temperature 1.50 g sodium thiomethoxide are added to a solution of 4.64 g 5-tert-butyl-2-methoxy-3-nitro-benzyl methanesulphonate in 50 ml of 1,4-dioxane. The solution is stirred overnight at 40° C. Then the solvent is removed and the residue is chromatographed on silica gel with cyclohexane/ethyl acetate (98:2→60:40) as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19](Br)C2C=CC=CC=2)[CH:14]=1.[CH3:27][C:28]1[O:32][C:31]([CH2:33][NH2:34])=[CH:30][CH:29]=1>>[CH3:27][C:28]1[O:32][C:31]([CH2:33][NH:34][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[O:1][CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[N:7]=2)=[CH:30][CH:29]=1
Reactant: Oc1cccc2nc(Cl)ccc12
Reactant: BrC(c1ccccc1)c1cccnc1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(OCc4cccnc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=346.3 (M+H+), was prepared in accordance with the general method of example 63 from 5-hydroxy-2-chloroquinoline (CAS 124467-35-2), 3-pyridyl benzyl bromide and 5-methyl-2-furanmethanamine.
Reaction SMILES: C(OC(N1C(C(=O)N[C@H](C(OC)=O)CC2C=CC(C3C=CC(C#N)=CC=3)=CC=2)CC2C=C3C([O:13][C@@H:14]([C:46]4[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=4)C(=O)N3)=CC=2C1)=O)(C)(C)C.Cl.C[O:55][C:56](=[O:110])[C@@H:57]([NH:73][C:74]([CH:76]1[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:96]=[CH:95][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([Cl:105])=[C:101]([C:106]([F:109])([F:108])[F:107])[CH:100]=5)=[CH:93][CH:92]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78][NH:77]1)=[O:75])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=2)=[CH:61][CH:60]=1>>[C:14]([N:77]1[CH:76]([C:74]([NH:73][C@@H:57]([CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=3)=[CH:63][CH:64]=2)[C:56]([OH:55])=[O:110])=[O:75])[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:96]=[CH:95][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([Cl:105])=[C:101]([C:106]([F:109])([F:107])[F:108])[CH:100]=5)=[CH:93][CH:92]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78]1)(=[O:13])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)C(=O)N3
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=O)N3
Agent: Cl
Product: N#Cc1ccc(-c2ccc(C[C@H](NC(=O)C3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCc4ccc(Cl)c(C(F)(F)F)c4)cc3)C(=O)N5)C(=O)O)cc2)cc1

Procedure:
(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester was converted to (S)-2-({(S)-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure L. and C. Title compound was prepared from (S)-2-({(S)-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.05 mmol) following the general procedure F and B. LC-MS (m/z): 886.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([CH3:14])[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>CC(C)=O.C(OCC)(=O)C>[C:34]([O:33][C:31](=[O:32])[NH:30][CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[C:8]([CH3:14])[C:9]2=[O:13])[CH2:25][CH2:26]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COc1ccc2nc(C)c(=O)[nH]c2c1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc2nc(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 10.2 %

Procedure:
7-Methoxy-3-methylquinoxalin-2(1H)-one (Intermediate 161, 500 mg, 2.60 mmol) was deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.9 mmol) as described for Intermediate 2. Chromatography on silica gel with 70% ethyl acetate in hexanes, followed by a second chromatography on silica gel with 20% acetone in hexanes gave 110 mg (10%) of the product as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl[CH2:15][C:16](Cl)=[O:17].Cl.[NH2:20][CH2:21][CH2:22][OH:23]>O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:17][CH2:16][CH2:15][NH:20][CH2:21][C:22]([N:11]1[CH2:10][CH2:9][S:8][C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2)=[O:23]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCS2
Reactant: O=C(Cl)CCl
Reactant: NCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNCCO)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (500 mg, 2.55 mmol) in tetrahydrofuran (10 mL) was added 2-chloroacetyl chloride (302 mg, 2.68 mmol). The resulting mixture was stirred at 60° C. for 5 minutes. The reaction first turns cloudy then clarifies. At this time, the reaction was cooled to 0° C., and hydrogen chloride (4 M in dioxane; 5.10 mL, 20.38 mmol) and 2-aminoethanol (1.868 g, 30.6 mmol) were added to the reaction simultaneously in a dropwise fashion. The resulting mixture was warmed to room temperature, and water (5 mL) was added to aid dissolution. The mixture was then stirred at 60° C. for 3 hours. The mixture was then diluted with water and saturated sodium carbonate and then extracted with dichloromethane (5×). The combined organic layers were dried, filtered, concentrated, and then chromatographed in 1:4:5 (2M NH3 in methanol):ethyl acetate:dichloromethane giving the desired product (473 mg, 62.4%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 8.36 (d, J=2.1 Hz, 1H), 7.93 (dd, J=8.7, 2.1 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 4.50 (t, J=5.1 Hz, 1H), 3.96-3.90 (m, 2H), 3.56 (s, 2H), 3.48-3.40 (m, 2H), 3.32-3.26 (m, 2H), 2.58 (t, J=5.0 Hz, 2H), 2.18-2.08 (brs, 1H); ESI-MS (m/z, %): 298 (MH+, 100).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.[NH2:34][NH2:35].O>CN(C=O)C>[CH2:25]([C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:35][N:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cc1ccccc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-3-phenylacetyl-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (220 mg, 0.50 mmol) produced in Synthesis Example 1 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 80 μL), and the mixture was stirred at 100 to 110° C. for 3 hours. To the reaction solution was added water. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-benzyl-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (204 mg, yield 94%).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>>[CH3:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: CCCn1c(C)cc(=O)n(CCC)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCn1c(C)c([N+](=O)[O-])c(=O)n(CCC)c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 g, 6 mmol, of 6-methyl-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione, as prepared in Example 1, was added in small portions to a cooled (0° C.) solution of concentrated sulfuric acid (3.0 ml) and nitric acid (2.0 ml). The reaction stirred at 0° C. for 2 hours. The reaction mixture was poured over ice and a green amorphous solid formed. The solid was removed by filtration and washed copiously with water. The solid was dissolved in dichloromethane and concentrated. The residue was purified using column chromatography (1:1.2 EtOAc:Hexanes) to yield 6-methyl-5-nitro-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione(0.430 g, HNMR)
Reaction SMILES: [C:1]([O-])(=O)[C:2]1C=CC=CC=1.[OH:10][C:11]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[K+].[K+].S(OCC)(O[CH2:31][CH3:32])(=O)=O>CC(C)=O>[CH2:1]([O:10][C:11]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:31][CH3:32])=[O:14])[CH3:2]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C([O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(C)cc1OCC

Procedure:
The ethyl 2-ethoxy-4-(2-<2-chloro-pyridine-3-carboxamido>ethyl)benzoate used as the starting material was prepared in the following manner: 2-hydroxy-4-methylbenzoic acid was reacted with K2CO3 and diethyl sulfate in acetone to give ethyl 2-ethoxy-4-methylbenzoate (boiling point at 1 mm=107°-108° C.), which was hydrolyzed to give the corresponding carboxylic acid (melting point 72°-74° C., from acetone). Subsequent bromination provided the 4-bromomethyl compound (melting point 98°-100° C.), which gave the 4-cyanomethyl compound (melting point 114°-117° C.) with sodium cyanide. Ethyl 2-ethoxy-4-(2-aminoethyl)benzoate hydrochloride was obtained by catalytic hydrogenation with Raney nickel and reaction with ethanolic hydrochloric acid, and this was reacted with 2-chloronicotinic acid, methyl chloroformate and triethylamine to give ethyl 2-ethoxy-4-(2-<2-chloro-pyridine-3-carboxamido>ethyl)benzoate (melting point 83°-85° C. after column purification).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([O:29][C:30](=[O:41])[CH:31]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32][NH2:33])[CH3:28]>ClCCl>[CH2:27]([O:29][C:30](=[O:41])[CH:31]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32][NH:33][C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:28]
Reactant: CCOC(=O)C(CN)Cc1ccccc1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C(CNC(=O)Cc1cccc2ccccc12)Cc1ccccc1
Yield: 41.1 %

Procedure:
A solution of 173 g of 1-naphthylacetic acid and 151 mg of 1,1'-carbonyldiimidazole in dry dichloromethane was stirred for 1 hour at room temperature. To the mixture was added 227 mg of 3-amino-2-benzylpropionic acid ethyl ester obtained, and the mixture was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and then the organic layer was washed successively with a 1N-hydrochloric acid, a 5% aqueous sodium bicarbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/ethanol=5/1 by volume) to obtain 169 mg of 2-benzyl-3-(1-naphthylacetamido)propionic acid ethyl ester as colorless crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[N:11]([O-])=[O:12].[Na+]>O>[N:11]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1)=[O:12]
Reactant: O=N[O-]
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.2 %

Procedure:
Aqueous hydrochloric acid (2N, 20 mL) was added to piperidine-3-carboxylic acid (5.02 g, 38.87 mmol). The mixture was cooled with an ice bath and a solution of sodium nitrite (2.78 g, 40.29 mmol) in water (4 mL) was added. The reaction mixture was stirred at room temperature for 15 h. The mixture was extracted with dichloromethane (20 mL×3). The combined organics were washed with brine (2×), solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 1-nitrosopiperidine-3-carboxylic acid (4.5 g). MS (EI+) (M+) 158.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2].C(N([CH2:39][CH3:40])CC)C.C(O)C.[C:44]([O-])([OH:46])=[O:45].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:44]([O:46][CH2:39][CH3:40])=[O:45])[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=C([O-])O
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc2c(c(C(F)(F)F)c1)C(O)(c1ccc3ccccc3c1)C(=O)N2CCN(CC)CC
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A mixture of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole of Example 48 (300 mg, 0.527 mmol), triethylamine (0.15 mL, 1.08 mmol), and (PPh3)2PdCl2 (40 mg, 0.087 mmol) in a mixed solvent of ethanol (1.5 mL) and toluene (1.5 mL) was stirred for 7 h at 60° C. under CO atmosphere. Sat. aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 50:1 chloroform/methanol to give the title compound (273 mg, quant.).