Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])[C:3]([OH:5])=[O:4].[CH3:15]O>S(=O)(=O)(O)O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])[C:3]([O:5][CH3:15])=[O:4]
Reactant: O=C(O)C(O)c1ccccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccccc1[N+](=O)[O-]

Procedure:
Methyl 2-hydroxy-2-[2-nitrophenyl]acetate (FIG. 2; Compound 6) was prepared by dissolving crude acid 2-hydroxy-2-[2-nitrophenyl]acetic acid (entire amount) in methanol (100 ml). Sulfuric acid (5 drops) was added, and the mixture was refluxed for 2.5 hr. The solvent was then evaporated. The residue was taken up in ethyl acetate and extracted with saturated sodium bicarbonate, followed by water and brine. After drying over MgSO4, the solvent was evaporated to give 9.13 g (90%) of crude ester which was recrystallized from isopropyl ether to give 7.92 g (78%) of methyl 2-hydroxy-2-[2-nitrophenyl]acetate. mp. 69-71° C. 1H-NMR: 8.01 (d, J=8.19 Hz, 1H), 7.70-7.63 (m, 2H), 7.55-7.49 (m, 1H), 5.83 (d, J=4.88 Hz, 1H), 3.76 (s, 3H), 3.66 (d, J=4.89 Hz, 1H). HRMS(CI): calculated for C9H10NO5 [M+ +H] m/z=212.0559, observed 212.0555.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([C@H:10]([NH:12][C:13]2[C:14]3[N:15]([CH:22]=[C:23]([C:25]4[O:26][C:27](SC)=[N:28][N:29]=4)[CH:24]=3)[N:16]=[CH:17][C:18]=2[C:19]([NH2:21])=[O:20])[CH3:11])[CH2:9][CH2:8]1>CN1C(=O)CCC1>[CH:7]1([C@H:10]([NH:12][C:13]2[C:14]3[N:15]([CH:22]=[C:23]([C:25]4[O:26][C:27]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[N:28][N:29]=4)[CH:24]=3)[N:16]=[CH:17][C:18]=2[C:19]([NH2:21])=[O:20])[CH3:11])[CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: CSc1nnc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)o1
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(N4CCOCC4)o3)cc12)C1CC1
Temperature: 200 °C
Yield: 44.9 %

Procedure:
Morpholine (13 mg, 0.14 mmol) was added in one portion to a solution of (R)-4-(1-cyclopropylethylamino)-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 127, 10 mg, 0.028 mmol) in NMP (0.1 mL). The resulting mixture was heated in the CEM microwave at 200° C. for 1 hour before purifying by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aqueous sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded the title compound (5 mg, 45% yield). HPLC (condition B): retention time=0.73 min. LCMS (condition B): MH+ m/z 398.3. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.84 (1 H, br. s.), 8.28 (1 H, s), 8.15 (1 H, d, J=1.39 Hz), 7.22 (1 H, d, J=1.39 Hz), 3.99 (1 H, d, J=1.39 Hz), 3.68-3.82 (4 H, m), 3.44-3.53 (4 H, m), 1.34 (3 H, d, J=6.38 Hz), 1.11 (1 H, d, J=6.94 Hz), 0.44-0.56 (1H, m), 0.39 (1 H, br. s.), 0.31 (2 H, br. s.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6](N)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C(OCC)(=O)C>[CH2:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCO
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
3-amino-1-propanol (150 g) was dissolved in tetrahydrofuran (200 mL), followed by the addition of benzylamine(23.8 g). The mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The solvent was removed to obtain 3-(benzylamino)-1-propanol (20.1 g, 61%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37].O>CN(C=O)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CN(CCCCl)Cc1ccccc1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCCN(C)Cc3ccccc3)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry DMF (100 ml) and N-(3-chloropropyl)-N-methylbenzylamine hydrochloride (4.1 g, 16 mmol) added. The temperature was raised to 90° and the mixture stirred for 2 hours, then poured into water and extracted with ethyl acetate. Drying, evaporation of the solvent, chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and crystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(N-benzyl-N-methylamino)propoxy)quinoline (0.7 g, 15%), m.p. 100°-102°.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-phenylbenzoate (0.13 g) in ethyl acetate (1 mL) and methanol (1 mL), 10% palladium-carbon (63 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.081 g of tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36])=O>>[CH3:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:3]([CH3:2])[C:4]=1[CH:5]=[CH:30][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: Cc1cccc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [Br-]
Product: COC(=O)c1cccc(C=Cc2c(C)cccc2C)c1
Yield: 71 %

Procedure:
Coupling of (2,6-dimethylbenzyl)triphenylphosphonium bromide with methyl 3-formylbenzoate following the method described in Example 1 gave methyl 3-(2,6-dimethylstyryl)benzoate as a white solid 2.20 g (71%), isomer ratio 2:1 trans:cis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[O:23][C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:23][C:24]([F:26])([F:27])[F:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc([N+](=O)[O-])ccc2OC(F)(F)F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)ccc2OC(F)(F)F)CC1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
0.41 g of 4-(5-Nitro-2-trifluoromethoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.055 mmol) were dissolved in 10 mL ethyl acetate and 10 mL acetic acid. 0.12 g 10% Palladium/charcoal were added and the mixture hydrogenated for 3 h at room temperature. The catalyst was filtered over Celite, washed with ethyl acetate and the combined filtrates evaporated to dryness. The residue was treated with water, the pH adjusted to 9-10 with 1 N aquous sodium hydroxide and the aquous phase extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 0.372 g of the product.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][Cl:14])=[CH:4][C:3]=2[O:2]1.[ClH:16].Cl.[CH2:18]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:14].[ClH:16].[CH2:18]([N:27]1[CH2:32][CH2:31][N:30]([CH2:13][C:12]([NH:11][CH2:10][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[O:15])[CH2:29][CH2:28]1)[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: O=C(CCl)NCc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCN(CC(=O)c2ccccc2)CC1)NCc1ccc2c(c1)OCO2

Procedure:
A mixture of N-[1-(3,4-methylenedioxyphenyl)methyl]-2-chloroacetamide (5 mmol), N-phenacyl piperazine dihydrochloride (5 mmol) and K2CO3 (17.5 mmol) in 60 ml of acetone was treated according to the general preparation 2 to give compound (IV-32), 0.76 g (63.45%), M+ 395.
Reaction SMILES: [CH2:1]([CH:4]1[N:10]2[C:11](=[O:14])[O:12][N:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C(=O)(O)[O-:17].[Na+].OO>O1CCCC1.CO>[OH:17][CH2:3][CH2:2][CH2:1][CH:4]1[N:10]2[C:11](=[O:14])[O:12][N:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C([O-])O
Reactant: C=CCC1CCCCc2noc(=O)n21
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1onc2n1C(CCCO)CCCC2
Reaction time: 2 h

Procedure:
A solution of the product of Example 6 (3.0 g, 0.0155 mol) in tetrahydrofuran (44 mL) under nitrogen was treated with a Borane.THF complex (1M, 18.56 mL) and this reaction was stirred for 2 hours. Methanol (2.50 mL) was added before a solution of saturated sodium bicarbonate (2.32 mL) and hydrogen peroxide (30%, 2.32 mL) were added resulting in a white precipitate. The precipitate was filtered off and the solvent was removed from the filtrate under reduced pressure to afford the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>O.O1CCCC1>[CH3:19][O:18][C:16]([NH:1][C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])=[O:17]
Reactant: COC(=O)Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113863.6 %

Procedure:
A solution of D-phenylalanine (25.00 g, 0.151 mmol) and sodium hydroxide (6.05 g, 0.151 mol) in water (170 ml) and tetrahydrofuran (225 ml) was cooled to −15° C. and a solution of methyl chloroformate (18.6 g, 0.197 mol) in tetrahydrofuran (50 ml) was added dropwise. When the addition was -half complete, a solution of sodium hydroxide (9.10 g, 0.227 mol) in water (20 ml) was also added dropwise. When the additions were complete, the mixture was stirred at room temperature for an additional 2 hours and acid fixed with 10% hydrochloric acid. The acid was extracted twice with diethylether, and the extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave a clear oil (38.38 g). HPLC 6.01 min (78.9%), 7.32 min. (5.0%), 8.29 min (10.8%), 8.42 min (0.5%), 9.95 min (1.2%), 10.27 min (2.8%), 11.92 min (0.7%).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[C:37]1([CH:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:37]1([CH:43]([N:45]2[CH2:46][CH2:47][N:48]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:31])([F:32])[F:33])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:49][CH2:50]2)[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CC(c1ccccc1)N1CCNCC1
Solvent: ClCCl
Product: CC(c1ccccc1)N1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 190.3 mg of 1-(1-phenylethyl)piperazine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14])([O-:9])=[O:8]>O1CCCC1>[C:2]([O:4][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 63.5 %

Procedure:
Potassium t-butoxide solid (3.82 g, 32.30 mmol) was added to a solution of 3-nitrobenzoyl chloride (5.00 g, 26.94 mmol) in dry tetrahydrofuran (70 mL) and stirred under nitrogen for 2 hrs. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. After separating the phases, the aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo. The crude product was purified on flash grade silica gel using 0-5% gradient of ethyl acetate in n-hexane. Fractions containing the product were combined, concentrated in vacuo, and then dried under high vacuum to provide 3.82 g of the title compound as an oil. 1H NMR (300 MHz, CDCl3) d 8.79 (m, 1H), 8.35 (m, 2H), 7.62 (m, 1H), 1.63 (s, 9H); low resolution MS (Cl) m/e 224 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[C:6]([C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:31])=[C:19]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:10][CH:9]=1)#[N:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:31])=[C:19]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:4][CH2:3][O:2][CH3:1])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:32][CH:33]=1)#[N:7]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(O)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: 80 °C

Procedure:
2-Bromoethyl methyl ether (0.023 ml) was added to a suspension of N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-hydroxybenzamide (0.06 g) and potassium carbonate (0.045 g) in DMF (3 ml) and the reaction mixture was stirred and heated to 80° C. for 5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extract was dried (MgSO4) and evaporated. The residue was triturated under diethyl ether and the resultant solid was isolated and dried under vacuum at 55° C. There was thus obtained the title compound (0.038 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.27 (s, 3H), 3.66 (s, 2H), 4.17 (m, 2H), 7.04 (d, 2H), 7.24 (d, 1H), 7.57 (d, 1H), 7.82 (s, 1H), 7.96 (m, 4H), 8.1 (d, 2H), 9.71 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M−H− 428.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1.[CH2:14]([O:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][Sn](CCCC)(CCCC)CCCC)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1CCCC1=O>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][C:2]2[CH:3]=[N:4][N:5]([C:7]3[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=2)=[CH:40][CH:41]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ncccc1-n1cc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN1CCCC1=O
Product: Nc1ncccc1-n1cc(Cc2ccc(OCc3ccccc3)cc2)cn1
Temperature: 120 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
To a mixture of 3-(4-bromo-pyrazol-1-yl)-pyridin-2-ylamine (34 mg, 0.14 mmol) described in Manufacturing Example 39-1-4, (4-benzyloxy-benzyl)-tributyl-stannane (84 mg, 0.17 mmol) described in Manufacturing Example 39-2-1 and N-methylpyrrolidinone (1.5 mL) were added tri-o-tolylphosphine (17 mg, 0.057 mmol) and palladium (II) acetate (3.2 mg, 0.014 mmol) at room temperature, which was stirred for 5 hours at 120° C. The reaction mixture was cooled to room temperature, and filtered after addition of an aqueous potassium fluoride solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (2.6 mg, 4%) as a trifluoroacetic acid salt.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Br)[N:7]=1>CS(C)=O.O>[N:1]([CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[N:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1cccc(Br)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium azide (3.11 g, 47.8 mmol) and 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (4.00 g, 15.94 mmol) were combined in DMSO (30 mL) and stirred at room temperature for 4 h. The mixture was subsequently diluted with water and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (0-10% EtOAc/hexanes) to yield the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16]O>S(Cl)(Cl)=O>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1ccc(-c2nnn[nH]2)cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2nnn[nH]2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution of 2-fluoro-4-(1H-tetrazol-5-yl)-benzoic acid (100 mg, 0.48 mmol) in methanol (5 ml), thionyl chloride (0.5 ml) was added at 0° C. and the reaction mixture was stirred at 25° C. for 12 h. The solvents were distilled off in vacuo, and the residue was purified by chromatography over silica gel (5% methanol/dichloromethane) to afford the title compound as a yellow solid (58%). MS (Turbo Spray): m/z=222.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][C:5]2[C:11]3([CH3:14])[CH:12]([OH:13])[C:7]([CH3:15])([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:16]=1.N1C(C)=CC=CC=1C.O([Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][C:5]2[C:11]3([CH3:14])[CH:12]([O:13][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:7]([CH3:15])([CH2:8][CH2:9][CH2:10]3)[C:6]=2[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCCCCCOc1cc2c(cc1Br)C1(C)CCCC2(C)C1O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCCCCCOc1cc2c(cc1Br)C1(C)CCCC2(C)C1O[Si](C)(C)C(C)(C)C
Temperature: 35 °C
Reaction time: 8 h

Procedure:
4.49 g of the thus-obtained (5RS,9SR,10RS)-2-bromo-3-heptyloxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocycloheptene were placed in 12 ml of CH2Cl2 under argon and treated with 2.58 ml of 2,6-lutidine followed by 3.08 ml of t-butyldimethylsilyl triflate. The mixture was stirred at 35° C. overnight and then poured on to ice. The mixture was extracted with diethyl ether, washed with 1N HCl and water, dried over Na2SO4 and evaporated. Column filtration (SiO2/hexane) gave 5.39 g of (5RS,9SR,10RS)-2-bromo-10-t-butyldimethylsilyloxy-3-heptyloxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocycloheptene as a colourless oil.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)[C:3]#[N:4].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>C(O)C>[C:12]([C:15]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[NH:1][C:16]=1[CH3:17])(=[O:14])[CH3:13]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cccc(C(N)C#N)c1
Solvent: CCO
Product: CC(=O)c1c(C)[nH]c(-c2cccc(C)c2)c1N

Procedure:
Starting from 2-amino-2-(m-tolyl)acetonitrile and acetylacetone, the open-chain intermediate compound is obtained, b.p. 170° C./0.02 mm Hg. The title compound is obtained in a 59% overall yield, m.p. 195°-197° C. (from ethanol).
Reaction SMILES: C([O-])(O)=O.[Na+].Cl.[OH:7][CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[NH2:10].[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][C:28]([NH:10][C@H:9]1[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][CH:8]1[OH:7])=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(COCc1ccccc1)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 68 %

Procedure:
To a round-bottom flask containing sat. NaHCO3 (9 mL) was added mannosamine hydrochloride (500 mg, 2.30 mmol). The solution was stirred for 1 h under N2, at which point benzyloxyacetyl chloride (0.44 mL, 2.8 mmol) was added dropwise via syringe. The biphasic mixture was stirred vigorously for 4 h resulting in a clear light yellow solution. The solution was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of 20:1 to 10:1 CHCl3/MeOH to afford 512 mg (68%) of a viscous oil. IR (thin film): 3331, 2918, 2356, 1652, 1524 cm−1. 1H NMR (400 MHz, D2O): δ 3.26 (s, 1H), 3.33 (app d, 1H, J=6.7), 3.45 (app t, 1H, J=9.7), 3.54-3.66 (m, 1H), 3.69 (app d, 1H, J=4.8), 3.72 (d, 1H, J=2.0), 3.74-3.86 (m, 2H), 3.98 (dd, 1H, J=4.5, 9.8), 4.06 (s, 2H), 4.10 (s, 1H), 4.24-4.27 (m, 1H), 4.38-4.40 (m, 1H), 4.55 (s, 2H), 4.57 (d, 1H, J=4.3), 4.97 (s, 1H), 4.99 (s, 1H), 7.32-7.36 (m, 10H), 7.49 (d, 1H, J=10.7), 7.58 (d, 1H, J=9.6). 13C NMR (100 MHz, D2O): δ 52.9, 60.4, 66.8, 68.5, 68.7, 72.0, 73.5, 76.5, 89.3, 92.8, 128.5, 128.6, 128.7, 128.8. HRMS (FAB) m/z 328.1396 (MH+C15H22NO7 requires 328.1396).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](O)[CH3:11])=[CH:7][C:6]=2[CH:13]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[N:26]([CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=2[CH:7]=1)[CH3:11])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1cc2cc(Br)ccc2o1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc2cc(Br)ccc2o1
Yield: 77.2 %

Procedure:
Using 1-(5-bromo-1-benzofuran-2-yl)ethanol (6.11 g, 25.4 mmol), DMF (50 mL), methanesulfonyl chloride (2.9 mL, 38.0 mmol), triethylamine (7.5 mL, 50.8 mmol) and sodium azide (8.64 g, 127 mmol), an operation in the same manner as in Reference Example 22 was performed to give the title compound 5.22 g as an oil. This was used for the next step without purification.