Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[N:6](CCCCC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)C=N[NH:3]1.[CH3:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]=3)=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[CH2:31][CH2:32][C:33]#[N:34].[Na].[Cl-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:29][CH:30]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]=3)=[CH:46][CH:45]=2)=[CH:40][CH:41]=1)[CH2:31][CH2:32][C:33]1[NH:6][N:2]=[N:3][N:34]=1
Reactant: CC(CCC#N)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: CN1NN=CN1CCCCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(CCc1nnn[nH]1)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 135 °C

Procedure:
5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)phenyl)butyl)tetrazole. A mixture of 4-methyl-5-(4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl) valeronitrile (1.5 g.), sodium aside (3 g), ammonium chloride (1.9 g) in dimethylformamide (20 ml) is stirred and heated at 135° C. for 18 hours. After cooling, the reaction mixture is poured into ice water and the insoluble material is taken up by chloroform. The residue from the evaporation of chloroform is purified by silica gel dry column (5% methanol in chloroform as eluant) to yield 5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)benzyloxy)-phenyl)butyl)tetrazole.
Reaction SMILES: [C:1]1([CH2:7][S:8][CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][C:19]=1[CH3:27].[K+].[Br-]>CCOCC>[OH:15][C:13]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[C:19]([CH3:27])[CH:20]=2)[O:12][C:10](=[O:11])[C:9]=1[S:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: COc1ccc(C(C)=O)cc1C
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1C
Yield: 68 %

Procedure:
This compound is prepared by the condensation of diethyl ester of [(phenylmethyl)thio]propanedioic acid (1 g, mmol) with the corresponding trimethylsilylenol ether of 4'-methoxy-3'-methylacetophenone as described in general procedure A. Isolated Yield: 68%. m. p. 159°-106° C. 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, 1 H), 7.61 (s, 1 H), 7.2 (m, 5 H), 6.8 (d, 1 H), 6.38 (s, 1 H), 3.96 (s, 2 H), 3.89 (s, 3 H), 2.25 (s, 3 H); IR (KBr) 3432, 2945, 1613, 1507, 1402, 1262, 1142, 1030, 812, 704 cm-1; MS (CI) m/e 355 (78.3), 263 (19.6), 235 (11.8), 149 (12.7), 91 (100); Analysis calc'd for : C, 67.78; H, 5.12; found: C, 67.35; H, 5.17.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:31][C:32]1[C:33]([O:40][CH3:41])=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH3:41][O:40][C:33]1[C:32]([CH2:31][N:21]([C:22]2[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=2)[C:19]([CH:14]2[C:15]3[C:10](=[C:9]([OH:8])[CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12][CH2:13]2)=[O:20])=[CH:37][CH:36]=[C:35]([O:38][CH3:39])[N:34]=1
Reactant: COc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)c(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(C(=O)C2CCCc3c(O)cccc32)c2ccc(C(C)C)nc2)c(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
To a solution of 5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) in trifluoroacetic acid (2.4 mL) was added thioanisole (0.49 mL), and the mixture was stirred at room temperature for one day. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate and partitioned with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(Br)cc4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 4-bromophenyl boronic acid. Mass spectrum (ESI) 472.2 (M+1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:2]=1.Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:2]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3cccnc3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3cccnc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [N+:1]([C:4]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)O1)([O-])=O.[NH3:19]>>[C:13]1([C:4]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:19][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: O=[N+]([O-])C1(c2ccccc2)OC1c1ccccc1
Product: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)nc2-c2ccccc2)cc1

Procedure:
12 parts of 2-nitro-2,3-diphenyl-oxirane melting at from 109° to 110° C and 100 parts by volume of liquid ammonia are shaken for 6 hours in an autoclave at 100° and 65 atmospheres. After evaporation of the ammonia, the solid residue is treated with water and the constituent left undissolved is filtered off and recrystallized from glacial acetic acid. 5.2 parts of 2,3,5,6-tetraphenylpyrazine (54% of theory) melting at from 253° to 254° C are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:9][O:10]C)[C:3]=1[CH3:15].S(=O)(=O)(O)O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:12]2[CH2:14][CH2:13]2)[CH:9]=[O:10])[C:3]=1[CH3:15]
Reactant: COC=C(c1nccc(Cl)c1C)C1CC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Cc1c(Cl)ccnc1C(C=O)C1CC1
Yield: 84.2 %

Procedure:
1.66 g of 2-(4-chloro-3-methyl-2-pyridyl)-2-cyclopropyl-1-methoxyethene (XI) was dissolved in 16 ml of THF and 16 ml of dilute sulfuric acid was added to the resulting mixture, which was concentrated at 50° C. under reduced pressure. The resulting mixture was poured into water and neutralized with saturated sodium bicarbonate solution, and thereafter, extracted with chloroform. The resulting organic layer was washed with saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.31 g of 2-(4-chloro-3-methyl-2-pyridyl)-2-cyclopropylethanal (XII).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[H][H]>[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:9](=[O:10])[CH2:8]2
Reactant: [H][H]
Reactant: O=C(O)Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Product: O=C1Cc2cc(F)ccc2N1

Procedure:
A mixture of 24 g. of 5-fluoro-2-nitro-phenylacetic acid, 2.0 g. of platinum oxide (PtO2) and 250 ml. of glacial acid is hydrogenated at room temperature and 50 p.s.i. until the theoretical amount of hydrogen is taken up. The resulting mixture is filtered and the solvent evaporated off in vacuo. The residue is triturated with water and the resulting precipitate recrystallized from methylene chloride/diethyl ether to obtain 5-fluoro-oxindole, m.p. 131°-133° C.
Reaction SMILES: [C:1]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CC(C[AlH]CC(C)C)C.Cl>C1COCC1>[C:1]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1cccc(C=O)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 3-(Tridec-1-ynyl)benzaldehyde (5.68 g, 20 mmol, from example 5) in THF (70 ml) at -78° C. was added DIBAL (22 ml, 1.1 eq, 1 molar solution in hexane). After warming slowly to room temperature the solution was stirred for 2 hr and then added to dilute hydrochloric acid (50 ml). The product was then extracted into diethyl ether (2×100 ml) and after washing with brine and drying (MgSO4) the ether was removed under reduced pressure. Distillation of the resulting oil yielded the desired product, (4.55 g, 79.5%), B.p. 210° C. at 0.1 mm Hg, νmax 690, 785, 1030, 1460, 1600, 2200, 2850, 2915 and 3300 cm-1 ; δ(CDCl3) 0.92 (3H, distorted t, terminal CH3), 1.3 (18H, m, alkylene chain), 1.9 (1H, s, hydroxyl), 2.35 (2H, t J= 7 Hz, CH2 adjacent to acetylene), 4.6 (2H, s, benzylics), 7.3 (4H, m, aromatics). M+ 286.2301, (C20H30O requires 286.2297).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:27])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:9]([Br:26])[CH:8]=1)=[O:5].[C:28](OCC)(OCC)(OCC)[CH3:29]>>[Br:26][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:27])[N:1]=[C:28]2[CH3:29])[CH:12]=[CH:11][C:10]=1[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1Br
Product: CCCCCCN(CCCCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1Br
Temperature: 150 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of (Z)-3-amino-N-(3-bromo-4-(dihexylamino)phenyl)but-2-enamide (5.10 g, 11.6 mmol) and triethyl orthoacetate (100 mL) was stirred at 150° C. overnight. The mixture was then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as pale yellow oil (1.74 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[CH3:24])([O-])=O.C(=O)([O-])O.[Na+]>CO>[CH3:24][C@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]=1[NH2:5]
Reactant: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.7 %

Procedure:
Concentrated hydrochloric acid (1.00 ml, 12.0 mmol) and anhydrous tin dichloride (903 mg, 4.76 mmol) were sequentially added at 0° C. to a methanol (5 ml) solution of (S)-1-[2-nitro-4-(trifluoromethyl)phenyl]-2-methylpiperidine (275 mg, 0.953 mmol), obtained as described in [Referential Example 2-1]. The resulting mixture was warmed to room temperature and stirred for 17 hours. A saturated solution of sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=12/1). Thus, (S)-2-(2-methyl-1-piperidinyl)-5-(trifluoromethyl)aniline (233 mg, 94.6%) was yielded as a colorless oily material.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[N:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[NH:26]([C:28]([C:30]1[CH:45]=[CH:44][C:33]([CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:32][CH:31]=1)=O)[NH2:27].C(OCC)(=O)C>CN(C)C(=O)C>[N:27]1[N:26]=[C:28]([C:30]2[CH:45]=[CH:44][C:33]([CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:32][CH:31]=2)[N:8]2[C:2]=1[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[NH:5][C:6]1[N:12]=[CH:11][CH:10]=[CH:9][C:7]2=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)NN)cc1
Reactant: ClC1=Nc2cccnc2Nc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (822 mg, 3.58 mmol) and diisopropylethylamine (2 mL) in N,N-dimethylacetamide (25 mL) was added tert-butyl 4-(hydrazinecarbonyl)phenethylcarbamate (1.0 g, 3.58 mmol). The mixture was stirred at 80° C. for 24 hours then 100° C. for an additional 48 hours. The mixture was poured into ethyl acetate (150 mL) and washed with water (2×700 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness to give a brown foam. This residue was purified by silica gel chromatography eluting with ethyl acetate in hexanes (75-80%) to give a brown foam that was crystallized from dichloromethane to yield tert-butyl 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenethylcarbamate as off white crystals (717 mg). M.p.=145-148° C.; 400 MHz 1H NMR (CDCl3) δ: 8.21-8.17 (m, 2H), 7.44-7.37 (m, 3H), 7.24-7.16 (m, 3H), 7.0 (dd, J=1.6, 8.4 Hz, 2H), 6.82-6.79 (m, 1H), 6.38 (s, 1H), 4.55 (br.s, 1H), 3.42-3.37 (m, 2H), 2.84 (t, J=7.2 Hz, 2H), 1.44 (s, 9H). LCMS [M+H]: 455.
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:36]>O>[Ag+:36].[CH2:12]([O:11][P:9]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O-:29])=[O:28])=[CH:24][CH:25]=1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
To a suspension of 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetic acid (1.5 g, 3.63 mmol) in water (50 mL) at 0° C. was added 1N NaOH slowly. The mixture was stirred at rt for 10 mins. Then AgNO3 (0.68 g, 4 mmol) was added. The reaction was stirred vigorously for 1 h in the dark. The title compound (1.5 g, 79.4% yield) was collected as a grey solid by suction filtration and dried over Drierite® under vacuum.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=O)C.Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH2:59][CH3:60])[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([N:53]5[CH2:54][CH2:55][N:56]([CH2:59][CH3:60])[CH2:57][CH2:58]5)=[CH:49][N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][OH:4])[N:30]=[CH:29]2)([CH3:32])([CH3:33])[CH3:34]
Reactant: CCN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCCCO
Solvent: O
Product: CCN1CCN(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (241 mg, 0.49 mmol), 6-chloro-4-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (100 mg, 0.29 mmol), potassium phosphate (152 mg, 0.72 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.7 mg, 0.03 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (8.24 mg, 0.01 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×50 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 14% methanol in dichloromethane) and recrystallized from dichloromethane and isopropyl acetate to give 6-tert-Butyl-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one (47 mg, 26%) as a light yellow solid: mp 245-247° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.18 Hz, 4H) 1.38 (s, 10H) 2.13-2.42 (m, 2H) 3.09 (br. s., 5H) 3.77 (s, 3H) 4.16-4.72 (m, 3H) 7.20-8.10 (m, 9H) 8.28-8.64 (m, 2H) 9.23 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]2[C:6]([CH3:21])([C:7]3[C:8](=[O:20])[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]=1[C:22]([OH:24])=[O:23].[CH3:25]COCC>>[CH3:1][C:2]1[CH:15]2[C:6]([CH3:21])([C:7]3[C:8](=[O:20])[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOCC
Reactant: CC1=C(C(=O)O)CCC2(C)C3=C(CCC12)C(=O)C(C(C)C)=CC3=O
Product: COC(=O)C1=C(C)C2CCC3=C(C(=O)C=C(C(C)C)C3=O)C2(C)CC1
Reaction time: 0.5 h

Procedure:
63 Milligrams of the 3,4,4a,5,8,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-5,8-dioxo-2-phenanthrenecarboxylic acid obtained in Example 1 was dissolved in 8 ml of ether, then under ice-cooling condition, a diazomethane-ether solution was added thereto and the mixture was stirred for 30 minutes. Ether was removed by distillation. The resulting crude product was purified by a silica gel column chromatography (eluant: ether/n-hexane=1/2) to obtain 8.8 mg of methyl 3,4,4a, 5,8,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-5,8-dioxo-2-phenanthrenecarboxylate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11].O[N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:24]=[C:19]1[CH2:20][CH2:21][C:22](=[O:23])[N:18]1[O:15][C:14](=[O:16])[CH2:13][NH:12][C:10](=[O:11])[CH2:9][N:3]1[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1]
Reactant: CC1CCCC(C)N1CC(=O)NCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1CCCC(C)N1CC(=O)NCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.54 g (20 mMol) [2-(2,6-Dimethyl-piperidin-1-yl)acetylamino]-acetic acid (30) were added to 2.30 g (20 mMol) N-Hydroxysuccinimide and 4.12 g (20 mMol) N,N′-Dicyclohexyl-carbodiimide dissolved in 150 ml dichloromethane. The reaction mixture was stirred for 16 h at room temperature. The solution was filtered and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in 50 mL dichloromethane and treated with charcoal. After filtration, the solution was evaporated in vacuo to dryness and the product was recrystallised from ethyl acetate.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:11][CH:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][N:13]2[CH2:14][CH2:15]3)[C:8]([O-:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][NH2:27]>CO>[C:1]1([C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:11][CH:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][N:13]2[CH2:14][CH2:15]3)[C:8]([NH:26][NH2:27])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C([O-])C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Solvent: CO
Product: NNC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
According to this method, 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octan (IV) is treated with a butyl lithium solution in the presence of N,N,N',N-tetramethylethylenediamine followed by methyl chloroformate to yield 2,2-diphenyl-3-(1-azabicyclo[2.2.2]-oct-2-yl)propionate (V). Then the propionate (V) is treated with a solution of H2NNH2 in CH3OH to yield 2,2-diphenyl-3-(1-azabicyclo[2.2.2]-oct-2-yl)propionic acid hydrazide (VI). The hydrazide (VI) is then mixed with CH3C(OC2H5)3 to provide the product (VII), i.e., 2-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-2,2-diphenylethyl]-1-azabicyclo 2.2.2 octane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl.[H][H]>CO.O=[Pt]=O>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:11]1
Reactant: COC(=O)c1cncc(C)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNCC(C)C1

Procedure:
To methyl 5-methylnicotinate (2 g), PtO2 (100 mg) was added. The reaction flask was put under vacuum, and 125 N HCl in methanol (15 mL) was added. The reaction was put under 40 psi hydrogen gas and shaked overnight. The reaction mixture was filtered through celite and concentrated under vacuo. The crude product was progressed to the next step without further purification.