Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.S(O)(O)(=O)=O.[NH2:16][OH:17].[OH-].[NH4+]>O>[CH3:1][C:2]([NH:16][OH:17])=[C:4]1[CH:5]=[CH:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(NO)=C1C=CC(=O)C=C1
Yield: 173.7 %

Procedure:
A solution was prepared by adding 20.4 g (0.15 mol) of 4-hydroxyacetophenone and 13.0 g (0.08 mol) of hydroxylamine sulfate to 100 mL of water at 70° C. To the solution was added 16.3 mL of 30% ammonium hydroxide which was then heated at reflux for 0.5 h. White crystals formed upon cooling yielding 21.0 g (92.6%) of 4-hydroxyacetophenone oxime.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:22][CH2:30][CH3:31])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 2-amino-5-chloropyridine as starting materials and by an operation similar to that of Example 293-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile=50:50 to 5:95) to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][C:27]1([CH3:35])[O:34][C:32](=[O:33])[CH2:31][C:29](=[O:30])[O:28]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([CH:31]1[C:32](=[O:33])[O:34][C:27]([CH3:35])([CH3:26])[O:28][C:29]1=[O:30])=[O:13]
Reactant: O=C(O)Cc1cc(F)c(F)cc1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(=O)Cc2cc(F)c(F)cc2F)C(=O)O1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
114 g (0.60 mol) of 2,4,5-trifluorophenylacetic acid was dissolved in 600 mL of THF. To this mixture, 107 g (0.66 mol) of carbonyldiimidazole was added with stirring (when a part of carbonyldiimidazole was added, a lot of solid was formed; subsequently, the solid thereby dissolved in the solution with further addition). Upon completion of the addition, the reaction mixture was warmed to 50° C. 95.1 g (0.66 mol) of Meldrum's acid was added, and the mixture was aged for 3 hours at 50° C. The mixture was concentrated to remove THF and the residue was dissolved in water (600 mL) and dichloromethane (800 mL), and then the pH value was adjusted to 2. The aqueous phase was separated and the organic phase was washed with 0.1N HCl and water (600 mL) respectively. The organic phase was dried and concentrated to obtain 182 g of a condensate, 5-[2-(2,4,5-trifluorophenyl)-acetyl]-2,2-dimethyl-1,3-dioxane-4,6-dione, as a solid (the re-crystallization can be carried out in ethyl acetate to obtain a white solid). Melting point: 101.5-103.5° C., Yield: 96%.
Reaction SMILES: [CH2:1]([S:13](Cl)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:17][C:18]1[C:35]([Cl:36])=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([NH2:31])[CH:30]=3)=[N:24][C:20]=2[CH:19]=1.O.Cl>N1C=CC=CC=1>[Cl:36][C:35]1[C:18]([Cl:17])=[CH:19][C:20]2[NH:24][C:23]([C:25]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([NH:31][S:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH:30]=3)=[N:22][C:21]=2[CH:34]=1
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCS(=O)(=O)Nc1cc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)ccc1OC
Temperature: 80 °C
Yield: 4 %

Procedure:
1-Dodecanesulfonyl chloride (0.38 g, 1.4 mmol) was added to a stirred suspension of 5-(5,6-dichloro-1H-benzoimidazol-2-yl)-2-methoxy-phenylamine from Step B (0.6 g, 1.4 mmol) in pyridine (6 mL) under an inert atmosphere, warmed briefly to 80° C. then stirred at room temperature. After approximately 20 hours the mixture was poured into water (60 mL), stirred, and acidified with aqueous HCl. After several hours the mixture was extracted with dichloromethane (60 mL, 30 mL) and the combined extracts were washed with water then 0.5 M sodium bicarbonate solution. A little saturated brine was added to assist with stratification. The organic phase was washed with saturated brine, dried over MgSO4, and stripped of solvent to leave the crude product as a crystalline residue. Recrystallization from acetonitrile followed by chromatography on silicagel in CHCl3/EtOAc (9:1) afforded the product (0.03 g), mp 203-204° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16]>>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCCCCBr
Product: N#Cc1ccc(OCCCCCCl)cc1

Procedure:
In step 1-1, 4-hydroxy-benzonitrile (2; R4=H, X3=O) is reacted with 1-bromo-5-chloropentane (3; Br—X2—Cl: X2=pentylene), giving 4-(5-chloro-pentoxy)-benzonitrile (4). The reaction temperature is preferably maintained in the range of 10 to 90° C., for 1 to 9 hours and the reaction solvent is acetonitrile, dimethylformamide, etc. To ensure that the above reaction occurs under a basic condition, an inorganic basic compound such as potassium carbonate, sodium hydroxide, sodium hydride, etc, may be used.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.O.[NH2:23][NH2:24].C(O)CO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:24][N:23]=1
Reactant: NN
Reactant: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Solvent: O
Solvent: OCCO
Product: Nc1n[nH]c2nc(N3CCOCC3)cc(-c3ccccc3)c12
Temperature: 130 °C

Procedure:
A mixture consisting of 15.0 gm (0.05 mol) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine (see Example C), 20 ml of 80% hydrazine hydrate and 100 ml of ethylene glycol was heated for 3 hours at 130° C. Thereafter, the resulting solution was poured into about 1 liter of water, whereupon a virtually colorless precipitate formed which was collected by suction filtration, washed with water and then immediately reprecipitated from 700 ml of 0.1 N hydrochloric acid with concentrated ammonia. The reprecipitated product was collected by suction filtration, washed and dried, yielding 13.7 gm (93% of theory) of practically pure 3-amino-6-morpholino-4-phenyl-1H-pyrazolo[3,4-b]pyridine, m.p. 178°-180° C., of the formula ##STR6## After recrystallization from ethanol it had a melting point of 180°-182° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[C:11]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:18][CH:17]=1)([OH:13])=[O:12]
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)CCc1ccc(-c2ccc(C(=O)O)nc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to 4 ml 1,2-dimethoxyethane are added 5-bromo-pyridine-2-carboxylic acid (93 mg, 0.46 mmol), 4-(2-carboxyethyl)benzeneboronic acid (106 mg, 0.55 mmol), 0.51 ml of a 2M aqueous sodium carbonate solution and dichlorobis- (triphenylphosphin) palladium (II) (20 mg, 0.03 mmol). The mixture is stirred at 90° C. overnight, cooled and quenched with water. Ethyl acetate is added and the mixture adjusted to pH=2 with 1M hydrochloric acid. After threefold extraction with ethyl acetate, the combined organic layers are dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue is purified by silica gel chromatography (eluent: dichloromethane/methanol 5:1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[O:14][C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH2:7][C:6]2=[O:18].[C:19]([O:24][C@@H:25]([C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(O)(C)C>[C:19]([O:24][C@@H:25]([C:27]1[N:28]=[C:29]([N:11]2[CH2:12][CH2:13][C:8]3([CH2:7][C:6](=[O:18])[C:5]4[C:15](=[CH:16][CH:17]=[C:3]([Cl:2])[CH:4]=4)[O:14]3)[CH2:9][CH2:10]2)[CH:30]=[CH:31][N:32]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(Cl)cc21
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCC3(CC2)CC(=O)c2cc(Cl)ccc2O3)n1
Yield: 100 %

Procedure:
To a solution of 6-chloro-spiro[chroman-2,4′-piperidin]-4-one hydrochloride (prepared according to the method of Example 78, Step A, 175 mg, 0.61 mmol) in isopropanol (5 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 160 mg, 0.70 mmol) followed by triethylamine (0.29 mL, 2.1 mmol). This mixture was stirred at reflux for 1.5 h, concentrated, and purified by flash column chromatography (1% methanol/chloroform) to give 270 mg (100%) of the title compound of Example 78, Step B as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ8.19 (d, 1H), 7.83 (d, 1H), 7.44 (dd, 1H), 6.97 (d, 1H), 6.37 (d, 1H), 5.64 (q, 1H), 4.18 (app s, 2H), 3.34 (t, 2H), 2.72 (s, 2H), 2.37 (t, 2H), 2.10 (d, 2H), 1.71-1.60 (c, 4H), 1.55 (d, 3H), 0.94 (t, 3H); MS (APCI) 444, 446 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:23][CH2:21][C:20]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH3:19])=[O:22]
Reactant: [Br-]
Reactant: CC(=O)c1c(C)cc(Oc2ccc(C(F)(F)F)cc2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 1-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)ethanone (1.80 g, 5.84 mmol) in acetonitrile (11.7 mL) was added tetrabutylammoniumtribromide (TBABr3, 2.82 g, 5.84 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)ethanone (2.16 g), which was used directly for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([NH:43][CH2:44][CH2:45][F:46])=O>>[F:46][CH2:45][CH2:44][NH:43][CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:37][CH:38]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)NCCF
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCNCCF)cc2)C(C)C)c1
Yield: 36.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-fluoroethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (8.9 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(#N)C.CN(C)C=O.[I:20]N1C(=O)CCC1=O>>[OH:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5]([I:20])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ncccc1C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: Oc1ncc(I)cc1C(F)(F)F
Temperature: 80 °C
Yield: 80 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[CH:26]1([C:29](=[O:34])[CH2:30][C:31](=O)[CH3:32])[CH2:28][CH2:27]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:26]1([C:29]([C:30]2[C:31]([CH3:32])=[N:17][C:15]3[S:16][C:10]4[CH2:9][NH:8][CH2:13][CH2:12][C:11]=4[C:14]=3[C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:34])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2)C1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C1CC1)CCNC3
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a stirred solution of 1.0 g (2.79 mmol) 2-amino-3-benzoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (the preparation of which is described in example 23) in 15 ml acetic acid was added 0.70 g (5.55 mmol) of 1-cyclopropyl-butane-1,3-dione and three drops of sulfuric acid. The mixture was then stirred at 100° C. for 30 minutes and then concentrated in vacuo. Flash chromatography (dichloromethane/methanol 95:5) afforded 0.47 g (48%) cyclopropyl-(2-methyl-4-phenyl-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl)-methanone as a brown oil. ES-MS m/e (%): 349 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClCCl.C(OC(=O)[NH:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([NH:27][C:28](=[O:44])[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:33][CH2:32]3)=[O:30])=[CH:26][C:20]=2[N:19]=1)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([NH:27][C:28](=[O:44])[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:33][CH2:32]3)=[O:30])[CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ccc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)cc2[nH]1
Temperature: 20 °C
Reaction time: 48 h
Yield: 97.1 %

Procedure:
To a solution of 5 ml of 5% trifluoroacetic acid in dichloromethane 0.8 g (1.67 mmol) of {5-[2-(4-benzyl-piperidin-1-yl)-2-oxo-acetylamino]-1H-benzimidazol-2-yl}-carbamic acid tert-butyl ester is added. The reaction mixture is stirred for 48 hours at 20° C. The precipitated crystals are filtered off and washed with dichloromethane to yield 0.8 g (97.1%) of the title compound. Melting Point: 121° C.
Reaction SMILES: Cl.C([N:6]1[C:15](=[O:16])[C:14]2[C:17](O[SiH3])=[C:18]([NH2:21])[C:19](C)=[C:12]3[C:13]=2[C:8](=[CH:9][C:10]([NH2:25])=[C:11]3C)[C:7]1=[O:26])(C)(C)C.C([OH:29])C>>[NH2:25][C:10]1[CH:11]=[C:12]2[CH:19]=[C:18]([NH2:21])[CH:17]=[C:14]3[C:13]2=[C:8]([CH:9]=1)[C:7](=[O:26])[N:6]([OH:29])[C:15]3=[O:16]
Reactant: Cc1c(N)cc2c3c(c(O[SiH3])c(N)c(C)c13)C(=O)N(C(C)(C)C)C2=O
Reactant: CCO
Agent: Cl
Product: Nc1cc2c3c(cc(N)cc3c1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1% HCl in ethanol (100 mL) was added to 2-tert-butyldimethyl-silyloxy-5,8-diamino-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.0 mmol, from Example I1) with stirring at room temperature. After 1 hour, the solids formed were filtered, washed with ether, and dried to give 0.2 g of the title compound, mp 329-336° C.;
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.Cl.N>CO.O>[NH2:6][C:5]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:21]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: COc1ccc(-n2ncc(N=O)c2N)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 3.74 g (21 mmol) of 4-methoxyphenylhydrazine hydrochloride with a purity of 98% by weight, 1.4 ml of water, 10 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 25 ml of water and 5 ml of methanol were added to the mixture to cool the same up to 10° C., and 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 10 ml of cold water and dried under reduced pressure to obtain 3.07 g of 5-amino-1-(4-methoxyphenyl)-4-nitrosopyrazole (Isolation yield: 55.3%) as a yellowish solid with a purity of 78.6% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2C=CC=CC=2N=N1.Cl.[N:26]1([CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3([C:48]([OH:50])=O)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.Cl.CN.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:12][NH:8][C:48]([C:42]1([C:39]2[CH:40]=[CH:41][C:36]([O:35][CH2:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:37][CH:38]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:50]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (640 mg, 1.7 mmol) was added to a solution of 4-[4-(3-Morpholin-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid hydrochloride (500 mg, 1.3 mmol), methylamine hydrogen chloride (130 mg, 1.9 mmol) and Hunig's base (790 μL, 4.5 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was partitioned between 2M NaOH solution (20 mL) and DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume) to provide the title compound (355 mg, 76%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.93-2.00 (m, 2H), 2.01-2.08 (m, 2H), 2.37-2.40 (m, 2H), 2.48 (m, 4H), 2.50 (t, 2H), 2.70 (d, 3H), 3.67-3.80 (m, 8H), 4.02 (t, 2H), 6.88 (d, 2H), 7.22 (d, 2H). LRMS APCI+ m/z 363 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C)C=O>[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[C:4](=[O:15])[C:5]3[C@H:6]4[C:11]([CH3:12])([CH3:13])[C@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:19][CH:18]=1
Reactant: BrCc1ccc(I)cc1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(I)cc1)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 80 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
A mixture of (4R,7S)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 104 mg, 0.50 mmol) and 4-iodo-benzyl bromide (163.5 mg, 0.55 mmol) in N,N-dimethylformamide (5 mL) was heated at 80° C. over the weekend and then allowed to stand at room temperature for three days. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4R,7S)-2-(4-iodo-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (144 mg, 68%) as an off-white solid. APCI-MS (M+H) 423.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([NH:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>O>[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[O:11])=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2nc3ccccc3[nH]2)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CNC(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 83.4 %

Procedure:
To a mixture of methyl 4-{[(1H-benzimidazol-2-ylcarbonyl)amino]methyl}benzoate (230 mg), potassium carbonate (257 mg), and DMF (4.6 mL) was added p-chlorobenzylbromide (191 mg), followed by stirring at room temperature for 2.5 days. To the reaction mixture was added water (30 mL), followed by extraction with ethyl acetate (30 mL). The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained residue was washed with methanol (2 mL) to obtain methyl 4-[({[1-(4-chlorobenzyl)-1H-benzimidazol-2-yl]carbonyl}amino)methyl]benzoate (269 mg) as a white solid.