Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH3:15])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[C:18]1([C:24]2[C:25]3[C:30]([C:31]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[C:32]4[C:37]=2[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33]4)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:18]1([C:24]2[C:37]3[C:32]([C:31]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[C:30]4[C:25]=2[CH:26]=[C:27]([C:2]2[CH:17]=[CH:16][C:5]5[N:6]([CH3:15])[C:7]([C:9]6[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=6)=[N:8][C:4]=5[CH:3]=2)[CH:28]=[CH:29]4)=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1c(-c2ccccc2)nc2cc(Br)ccc21
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1c(-c2ccccc2)nc2cc(-c3ccc4c(-c5ccccc5)c5ccccc5c(-c5ccccc5)c4c3)ccc21
Yield: 76.1 %

Procedure:
1.4 g (4.9 mmol) of 5-bromo-1-methyl-2-phenyl-1H-benzimidazole, 2.0 g (5.3 mmol) of 9,10-diphenylanthracene-2-boronic acid, and 0.11 g (0.097 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 2.0 g of a greenish white solid (76% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 536 with respect to a molecular weight of 536.23.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[CH2:18].[Na].FC(F)(F)C([O-])=O>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:18][CH2:17][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccncc1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [Cu+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccncc2)C1
Yield: 1.9 %

Procedure:
The title compound was prepared according to General Method 3. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 4-vinylpyridine (0.25 ml, 2.3 mmol), sodium (15 mg, 0.65 g atom) and CuSO4 (10 mg, catalytic) in ethanol (2 mL) at 120° C. for overnight (16 h) to obtain 6 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH2:16][CH3:17])(C)(C)C.[ClH:19].O1CCOCC1>C(Cl)Cl>[CH2:16]([C:11]1[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=[C:13]([I:15])[N:12]=1)[CH3:17].[ClH:19]
Reactant: CCc1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(2-ethyl-4-iodo-imidazol-1-yl)-ethyl]carbamic acid tert-butyl ester (5.720 g; 15.662 mmol) in DCM (125 ml) was added slowly 4N HCl in dioxane (78 ml; 312 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 1 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine was obtained as a pale beige solid (5.96 g; 100%; presence of 3 eq. of HCl). LC-MS: tR=0.14 min.; [M+H]+=266.24 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>O=S(Cl)Cl.C1COCC1.Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:7]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: C1COCCN1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-methoxy-4-nitro-benzoic acid Compound 127a (11.0 g, 55.8 mmol) was refluxed in SOCl2 (50 mL) for 1 hr, then cooled to ambient temperature and evaporated down. The oil was resuspended in DCM and evaporated down a second time. The residue was then taken up in THF (150 mL) and cooled to 0° C. A mixture of morpholine Compound 50b (4.85 mL, 55.8 mmol) and DIEA (29.2 mL, 167 mmol) in THF (50 mL) was added dropwise. The reaction was stirred for 2 hrs before diluting with 1N HCl and extracting with ethyl acetate. The combined organic layer was separated and dried (MgSO4), then filtered and concentrated to give (2-methoxy-4-nitro-phenyl)-morpholin-4-yl-methanone Compound 127b (13.1 g). MS 267 (MH+). Borane dimethylsulfide (9.3 mL, 97.7 mmol) was combined with Compound 127b (13 g, 48.9 mmol) in THF (260 mL) and refluxed for 2 hrs. The reaction was chilled in ice and MeOH (25 mL) was carefully added. The mixture was subsequently diluted with 1N HCl, then stirred for 1 hr before adjusting the pH to 10 with 1N NaOH and extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and evaporated down to give 4-(2-methoxy-4-nitro-benzyl)-morpholine Compound 127c (10 g). MS 253 (MH+). Using the procedure of Example 80, Compound 127c was used in place of 5-(2-chloro-4-nitro-phenoxy)-2-methyl-pyridine Compound 80c to give 3-methoxy-4-morpholin-4-ylmethyl-phenylamine Compound 127d. 1H NMR (400 MHz, CDCl3) δ 6.83 (1H, J=8.3 Hz, d), 6.19 (1H, J=2.0 Hz, d), 6.10 (1H, J=8.3 Hz, 2.0 Hz, dd), 3.66 (3H, s), 3.53 (4H, m), 3.28 (2H, s), 2.30 (4H, m). MS 223 (MH+). Using the procedure of Example 1, Compound 168 was used in place of Compound 1 and Compound 127d was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 176 as a HCl salt. 1H NMR (400 MHz, CDCl3) δ 10.65 (1H, br s), 10.24 (1H, s), 8.69 (1H, s), 7.62-7.39 (8H, m), 7.22 (1H, t), 7.13 (4H, d), 4.25 (2H, br s), 3.99-3.72 (7H, m), 3.32-3.21 (2H, m), 3.16-3.00 (2H, m). MS 609 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9](=[NH:11])[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1.[CH2:19]1[CH:26]2[C:22]3([C:28](O)=[O:29])[CH2:23][CH:24]([CH2:27][CH:20]1[CH2:21]3)[CH2:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9](=[N:11][C:28]([C:22]23[CH2:23][CH:24]4[CH2:27][CH:20]([CH2:19][CH:26]2[CH2:25]4)[CH2:21]3)=[O:29])[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: COCCn1cc(Cc2cccc(F)c2)sc1=N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1cc(Cc2cccc(F)c2)sc1=NC(=O)C12CC3CC(CC1C3)C2

Procedure:
A mixture of the product of Example 45A (342 mg, 1.29 mmol), hexahydro-2,5-methano-pentalene-3a-carboxylic acid (256 mg, 1.54 mmol), HATU (737 mg, 1.24 mmol) and triethylamine (1.08 mL, 7.74 mmol) in 20 mL of DMF was processed according to the method of Example 43B to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.50-1.61 (m, 4 H), 1.65-1.76 (m, 4 H), 2.03-2.11 (m, 2 H), 2.21-2.26 (m, 2 H), 2.48-2.55 (m, 1 H), 3.25 (s, 3 H), 3.68 (t, J=5.4 Hz, 2 H), 3.99 (s, 2 H), 4.25 (t, J=5.4 Hz, 2 H), 7.03-7.13 (m, 3 H), 7.26 (s, 1 H), 7.33-7.41 (m, 1 H); MS (DCI/NH3) m/z 415 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:10]([NH2:12])=[O:11])=[N:5][CH:6]=[CH:7][N+:8]=1[O-:9]>Br>[OH:2][C:3]1[C:4]([C:10]([NH2:12])=[O:11])=[N:5][CH:6]=[CH:7][N+:8]=1[O-:9]
Reactant: COc1c(C(N)=O)ncc[n+]1[O-]
Agent: Br
Product: NC(=O)c1ncc[n+]([O-])c1O
Temperature: 45 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
In 0.5 mL of 47% aqueous solution of hydrogen bromide is dissolved 0.05 g of 3-methoxy-2-pyrazinecarboxamide-4-oxide obtained according to the method described in literature [Eur. J. Med. Chem., 15(2), 157-163 (1980)]. The solution is stirred at 45° C. for 2 hours. The deposited crystals are collected by filtration and washed successively with ethanol and diethyl ether to obtain 0.03 g of 3-hydroxy-2-pyrazinecarboxamide-4-oxide.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.[CH2:19]([C:23]1[NH:24][C:25](=[O:32])[CH:26]=[C:27]([CH:31]=1)[C:28](O)=[O:29])[CH2:20][CH2:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>CN(C=O)C>[CH2:19]([C:23]1[NH:24][C:25](=[O:32])[CH:26]=[C:27]([C:28]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[CH:31]=1)[CH2:20][CH2:21][CH3:22]
Reactant: OCc1ccccc1
Reactant: CCCCc1cc(C(=O)O)cc(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1cc(C(=O)OCc2ccccc2)cc(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
13.3 g (123 mmol) of benzyl alcohol and 4.7 g (31 mmol) of hydroxybenzotriazole are added to a solution of 6.0 g (31 mmol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 100 ml of DMF. The resulting clear solution is cooled to 0° C. followed by the addition of 7.0 g (34 mmol) of dicyclohexylcarbodiimide and 4.2 ml (31 mmol) of triethylamine. The mixture is allowed to thaw at 20° C., stirred for a further 2 hours and subjected to aqueous work-up. 6.8 g (77%) of theory of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[N+:25]([CH:28]([CH3:31])[CH2:29]O)([O-:27])=[O:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([O:8][CH2:29][CH:28]([N+:25]([O-:27])=[O:26])[CH3:31])=[O:7]
Reactant: CC(CO)[N+](=O)[O-]
Reactant: Cc1nn(-c2cc(OC(C)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn(-c2cc(OC(C)C(=O)OCC(C)[N+](=O)[O-])c(Cl)cc2Cl)c(=O)n1C(F)F
Yield: 82 %

Procedure:
A stirred mixture of 0.5 g (0.0013 mole) of 2-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionic acid (Compound A1), 1.0 g (0.0095 mole) of 2-nitro-1-propanol and 0.05 g (0.0003 mole) of p-toluenesulfonic acid monohydrate in 60 mL of toluene was heated at reflux. The water generated in the reaction was removed by collection in a Dean-Stark trap. After refluxing for a total of two hours, the solvent was removed by distillation under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and washed first with water then with an aqueous 10% sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to yield 0.5 g of 2-nitropropyl 2-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound B1.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[N:12]1([C:17]2[CH:45]=[CH:44][C:20]([CH2:21][C:22]3[C:23]([O:42][CH3:43])=[N:24][C:25]4[C:30]([C:31]=3[Cl:32])=[CH:29][C:28]([C:33]([C:35]3[N:39]([CH3:40])[C:38]([CH3:41])=[N:37][CH:36]=3)=[O:34])=[CH:27][CH:26]=4)=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[N:13]1.O>O1CCCC1>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][C:22]3[C:23]([O:42][CH3:43])=[N:24][C:25]4[C:30]([C:31]=3[Cl:32])=[CH:29][C:28]([C:33]([C:35]3[N:39]([CH3:40])[C:38]([CH3:41])=[N:37][CH:36]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:34])=[CH:27][CH:26]=4)=[CH:44][CH:45]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.32 mL, 0.81 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (70.4 mg, 0.848 mmol, prepared according to PCT Int. Appl., 2008098104) in tetrahydrofuran (1 mL) at −50° C. After 20 minutes, a solution (gently warmed with a heat gun to dissolve the ketone starting material) of (3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (200 mg, 0.42 mmol, Intermediate 21: step b) in tetrahydrofuran (1 mL) was added dropwise. After 5 minutes, the flask was allowed to warm to 23° C. After 20 minutes, water (1 mL) was added. The biphasic mixture was partitioned between saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried with sodium sulfate. The dried solution was filtered. Silica gel (2 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound which was further purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.60-7.53 (m, 2H), 7.41-7.33 (m, 3H), 7.11 (d, J=1.4 Hz, 1H), 6.46-6.39 (m, 1H), 6.08-6.02 (m, 1H), 4.27 (s, 2H), 4.08 (s, 3H), 3.89 (s, 3H), 3.35 (s, 3H), 2.20 (s, 3H); MS (ESI): mass calcd. for C29H27ClN8O2, 554.2. m/z found, 555.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[C:11]([CH3:16])[CH:12]=2)[C:7]1=[O:18])[CH3:4].[C:19]1([N:25]2[C:29]3([CH2:34]CNC[CH2:30]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([N:25]2[C:29]3([CH2:30][CH2:2][N:3]([CH2:5][CH:6]4[CH2:15][CH2:14][C:13]5[C:8](=[CH:9][C:10]([CH3:17])=[C:11]([CH3:16])[CH:12]=5)[C:7]4=[O:18])[CH2:4][CH2:34]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc2c(cc1C)C(=O)C(CN(C)C)CC2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Reaction time: 14 h
Yield: 80.6 %

Procedure:
A mixture of 14.0 g of 2-[(dimethylamino)methyl]-3,4-dihydro-6,7-dimethyl-1(2H)-naphthalenone, hydrochloride, 13.1 g of 92% 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one and 250 ml of absolute ethanol is warmed on a steam bath for 1 hour and then stirred vigorously for 14 hours. The resulting precipitates are collected and washed with absolute ethanol to give 17.6 g of the title compound, melting point 182°-183° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>CCOCC>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][N:21]=[CH:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=CCCc1cccnc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(NN=CCCc2cccnc2)cc1

Procedure:
3-(3-Pyridyl)propanal (8.50 g) was added to a stirred suspension of 4-nitrophenylhydrazine (9.62 g) in ether 150 ml. After a minute an orange-brown oil formed which solidified on further stirring. The solid was filtered off to give the title compound pure enough for further reaction (14.05 g), m.p. 146°-147° C. (from ethyl acetate/methanol). Found: C,62.12; H,5.02; N,20.36. C14H14 N4O2 requires: C,62.21; H,5.22; N,20.73%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:16][CH2:17][CH:18]([O:21][C:22]2[N:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc(-c3ccc(C#N)cc3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cnc(OC3CCNCC3)nc2)cc1
Reaction time: 2.5 h
Yield: 100.3 %

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a methylene chloride solution (2.0 ml) of 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-(4-cyanophenyl)pyrimidine (122 mg, 0.32 mmol) at room temperature, and stirred for 2.5 hours at the temperature. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated saline solution in that order, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the entitled compound (90 mg, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.CS(C)=[O:19].C([O-])([O-])=O.[K+].[K+]>O>[CH3:15][C:6]([CH3:16])([CH2:5][CH2:4][CH:3]([OH:19])[CH3:2])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(C)(CCCCBr)COC1CCCCO1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(O)CCC(C)(C)COC1CCCCO1
Temperature: 25 °C
Yield: 85 %

Procedure:
In a 250 ml flask equipped with a magnetical stirrer and reflux condenser were placed 6-bromo-1(tetrahydropyranyloxy)-2,2-dimethylhexane (10 g, 0.034 mol) and DMSO (50 ml), then the mixture was treated with K2CO3 (10 g 0.068 mol) in water (100 ml). The reaction mixture was heated under reflux for two days, then was allowed to cool to room temperature and quenched with water (150 ml). The solution was adjusted to pH 7 with 1M HCl and extracted with ether (3×100 ml). The organic layers combined were then washed with saturated NH4Cl (150 ml) and brine (150 ml), dried (MgSO4), and the solvent was removed under reduced pressure, to provide 6.63 g of the above-titled compound as a colorless liquid (85% yield). 1H NMR CDCl3, δ (ppm): 4.40-4.50 (m, 1H), 3.90-3.75 (m, 1H), 3.38 (t, J=6.8 Hz, 1H), 2.97 (d, J=9.3 Hz, 1H), 2.50 (brs, 1H, OH), 1.90-1.20 (m, 12H), 0.84 (s, 3H), 0.86 (s, 3H); 13C NMR CDCl3, δ (ppm): 99.0, 76.2, 62.3, 61.8, 38.8, 34.0, 33.4, 30.5, 25.4, 24.4, 24.3, 19.9, 19.3.
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[C:23]1([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.C(O)(=O)C>CS(C)=O>[F:1][C:2]1[C:21]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:34]2)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: c1ccc(C2CNCCN2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccccc5)C4)cc3nc21
Temperature: 20 °C
Yield: 68.3 %

Procedure:
A suspension of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2 g) and (RS)-2-phenylpiperazine (2.1 g) in dimethyl sulphoxide (30 cc) is heated with stirring for 15 minutes to approximately 50° C. After cooling to approximately 20° C., the reaction mixture is poured into water (100 cc) and treated with acetic acid (1.2 cc). The insoluble matter is drained, washed with water (3×10 cc) and recrystallized in dimethylformamide (80 cc). (RS)-7-Fluoro-1-methoxy-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2 g) is obtained in the form of a yellow solid, decomposing at 284° C.
Reaction SMILES: N1C=CC=CC=1.[FH:7].[O:8]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:7][C:10]1([CH2:9][OH:8])[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(F)(CO)CC1
Reaction time: 0.42 h

Procedure:
A mixture of 5 ml hydrogen fluoride pyridine and 20 ml methylene chloride was cooled, and 10 ml solution of 4.95 g of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate in methylene chloride was added dropwise thereinto over 25 min such that the bulk temperature was 0° C. or less. The mixture was stirred for 35 min under ice-cooling. The reaction solution was poured into a mixture of saturated sodium bicarbonate and ice. The organic layer was recovered, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated, and then subjected to silica gel column chromatography to give 2.84 g of the title compound.
Reaction SMILES: [OH-].[Na+].O.[OH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8]>[Pd].C(Cl)Cl>[OH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OCc1ccccc1O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccccc1O

Procedure:
In substantially the same manner as in Example 1, 0.16 part of sodium hydroxide, 60 parts of water, 3.2 parts of 5 percent palladium-on-charcoal, 264 parts of methylene chloride and 5 parts of o-hydroxybenzyl alcohol are stirred in the presence of air and refluxed at 45° C.-48° C. for approximately three hours; VPC analysis of the reaction mixture at 160° C. reveals aldehyde formation. The crude reaction mixture is filtered and separated as in Example 1. 2.01 Parts of o-hydroxybenzaldehyde are isolated; 1.49 parts of unreacted o-hydroxybenzyl alcohol are also recovered indicating the reaction had not gone to completion.
Reaction SMILES: BrC1C=C2C(C=CC([C@H](N[C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:27])[C@@H:24]([NH2:26])[CH3:25])[NH:18]3)=[O:16])C)=N2)=CC=1.FC(F)(F)C(O)=[O:31]>ClCCl>[NH2:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([OH:16])=[O:31])[NH:18]1)=[O:27]
Reactant: C[C@H](N)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)N1CCC[C@@H](C(=O)O)N1
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (330 mg, 0.618 mmol) in dichloromethane (10 mL) at 0° C. was added trifluoroacetic acid (3.3 mL) and the reaction mixture stirred for 1 hour and then evaporated. The residue was dissolved in dichloromethane and washed with saturated bicarbonate solution (2×), the aqueous extracts washed with dichloromethane and the combined organic extracts passed through a hydrophobic frit and evaporated to give a yellow foam (232 mg) that was carried through to the next step directly.