Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=O)=[CH:15][CH:14]=1>C1(C)C=CC(C)=CC=1>[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]2[N:3]3[CH:4]=[CH:5][C:6]4[C:11]([C:2]3=[N:20][N:19]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:15][CH:14]=1
Reactant: Clc1nccc2ccccc12
Reactant: NNC(=O)c1ccc(Br)cc1
Solvent: Cc1ccc(C)cc1
Product: Brc1ccc(-c2nnc3c4ccccc4ccn23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 30.8 %

Procedure:
To a 50-mL three-neck flask were added 0.8 g (5.0 mmol) of 1-chloroisoquinoline, 1.1 g (5.0 mmol) of 4-bromobenzoylhydrazine, and 10 mL of para-xylene. This mixture was stirred at 100° C. for 4 hours under a nitrogen stream. After a predetermined time elapsed, this mixture was cooled to room temperature, and the precipitated solid was collected by suction filtration. The obtained solid was purified by silica gel column chromatography (chloroform:ethyl acetate=10:1), so that the substance which was the object of the synthesis was obtained as 0.5 g of a white powder in 29% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([NH:9]C(=O)C2C=CC=CC=2)=[S:8])=[N:2]1>[OH-].[Na+]>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([NH2:9])=[S:8])=[N:2]1
Reactant: O=C(NC(=S)Nc1cc[nH]n1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: NC(=S)Nc1cc[nH]n1
Temperature: 25 °C

Procedure:
A solution of N-[(1H-pyrazol-3-ylamino)carbonothioyl]benzamide (22 g, 0.089 mol) in 10% NaOH solution (200 ml) is stirred at 80° C. for 45 min. The reaction mixture is cooled down to rt and the solvents are removed under vacuum. The residue is acidified with 2M HCl to pH=1 and then basified with ammonium hydroxide. The product is extracted with dichloromethane (4×100 ml). The combined extracts are dried and evaporated. The solid residue is purified by flash chromatography using chloroform/methanol (9/1) as eluent. N-1H-Pyrazol-3-ylthiourea is isolated as a solid (9 g; 75%). 1H NMR (DMSO-d6, 300 MHz): δ 5.88 (br s, 1H), 7.64 (s, 1H), 8.44 (br s, 1H), 9.02 (br s, 1H), 10.30 (br s, 1H), 12.47 (br s, 1H). HPLC (Method B), Rt: 3.88 min (purity: 99.4%). TLC: Chloroform/methanol (9/1): Rf−0.2. Mp: 130-132° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(OCC)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[CH:12]=3)[CH2:17]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C(NC1Cc2ccc([N+](=O)[O-])cc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5.0 g (19.6 mmol) 4-fluoro-N-(indan-2-yl)-benzamide was given, at 5-10° C., a nitrating mixture of 10 ml conc. nitric acid and 12 ml conc. sulfuric acid, followed by stirring over 3 h at room temperature. The mixture was worked up by pouring onto an ice/water mixture, extraction with ethyl acetate, washing of the organic phase with a solution of sodium hydrogen carbonate, drying and evaporating to dryness. The thus-obtained residue was crystallized form ethyl acetate/heptane. yield: 3.2 g (54%), mp.: 167° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:29]1[CH:28]=[C:27]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ncc2cnc(Cl)cc21
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ncc2cnc(-c3cn[nH]c3)cc21
Temperature: 110 °C
Yield: 46.2 %

Procedure:
A suspension of 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (1.30 g, 4.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.16 g, 6 mmol), and Pd(dppf)Cl2 (437 mg, 0.6 mmol) in aq. Na2CO3 (2.0 M, 12 mL) and 1,4-dioxane (20 mL) was heated at 110° C. for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate/heptanes 50% to 100% as eluting solvents to afford 6-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine as a yellow oil (670 mg, 46%), and recovered 1 g of the starting material. MS (ESI) m/z: 316 [M+H]+.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[Br:2][CH2:3][CH2:4][NH:5][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: NCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C(=O)NCCBr)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred and cooled (ice-bath) solution of 27.5 parts of 2-bromoethanamine hydrobromide in 200 parts of water is added a solution of 28.9 parts of 4-methoxy-2-nitrobenzoyl chloride in 63 parts of benzene at 5°-10° C. While stirring vigorously, there is added dropwise a solution of 10.8 parts of sodium hydroxide in 250 parts of water at 5°-10° C. Upon completion, stirring is continued for 2 hours at this temperature. The supernatant phase is decanted and the oily residue is stirred in 2-propanol. The product is filtered off and dried, yielding 27.5 parts (68%) of N-(2-bromoethyl)-4-methoxy-2-nitrobenzamide; mp. 133.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]=C.C[OH:16]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]=[O:16]
Reactant: C=Cc1cc(OC(F)(F)F)ccc1Cl
Reactant: CO
Solvent: ClCCl
Product: O=Cc1cc(OC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Chloro-2-vinyl-4-(trifluoromethoxy)benzene (Description 26; 274 mg, 1.2 mmol) was dissolved in dichloromethane (15 mL) and methanol (5 mL) and the solution cooled to −78° C. Ozone was then bubbled through until the solution turned blue. Dimethyl sulfide (1 mL) was added and the solution allowed to stir to ambient temperature for 16 hours. Concentration yielded an oil which was purified by silica chromatography to give the title compound (120 mg, 0.53 mmol).
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[C:26]([C:34]1[C:42]([N+:43]([O-])=O)=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=1[O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:43][C:42]1[C:34]([C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:35]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:36]=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39]
Reactant: CCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: CCCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-5-nitro-3-n-pentyloxybenzoic acid and following the procedure described, 5-amino-4-benzoyl-3-n-pentyloxybenzoic acid is obtained with a melting point of 168.5° -170° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.Br[CH2:37][C:38]([NH2:40])=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:21]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:18]([C:15]2[CH:16]=[CH:17][C:9]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[O:1][CH2:37][C:38]([NH2:40])=[O:39])[CH2:13][CH2:12][O:11][C:10]=3[CH:14]=2)(=[O:19])=[O:20])=[CH:33][CH:32]=1
Reactant: NC(=O)CBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(N)=O)cc1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a solution of 4-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (550 mg, 1.080 mmol), 2-bromoacetamide (704 mg, 5.108 mmol, Aldrich) in DMF (10 mL) was added potassium carbonate (528 mg, 3.83 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-60% ethyl acetate in hexane) to get 2-(2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenoxy)acetamide (300 mg, 49.0%). MS (ESI, positive ion) m/z; 567.1 (M+1)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH:17]([CH3:33])[C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=2[Cl:30])[CH:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:3].[ClH:30].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH:17]([C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=4[Cl:30])[CH:21]=3)=[O:19])[CH3:33])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(c4cccc(Cl)c4)CC3)ccc2c1Cl
Yield: 127.8 %

Procedure:
A mixture of N-(3-chlorophenyl) piperazine dihydrochloride (1.35 g, 5 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.96 g, 6 mmol) and K2CO3 (2.42 g, 17.5 mmol) in DMF (40 ml) was treated according to the general preparation 2 to obtain 1.65 g of N1-(3-chlorophenyl)-N4-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl] piperazine dihydrochloride, yield 64%. The above product was reduced with NaBH4 in methanol (50 ml) according to the general preparation 3 to obtain the title compound as white solid, yield 78%.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]2[C:18]=1[NH:17][CH:16]=[CH:15]2.BrC1C=CC(C)=CC=1[N+]([O-])=O.[OH-].[Na+]>C(#N)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]2[C:18]=1[NH:17][CH:16]=[C:15]2[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(Br)c2[nH]ccc12
Agent: Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccc(Br)c2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
4.0 g (30.0 mmol) of N-chlorosuccinimide was added to an acetonitrile solution (250 ml) containing 5.8 g (27.6 mmol) of 7-bromo-4-methyl-1H-indole synthesized from 2-bromo-5-methylnitrobenzene in the same manner as in Production Example 1a, followed by stirring at room temperature overnight. 50 ml of a 1N aqueous sodium hydroxide was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 6.7 g of the title compound.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:19]=[CH:18][C:9]([C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cu][C:27]#[N:28].[C-]#N.[K+]>O.Cl.C1(C)C=CC=CC=1>[C:27]([C:6]1[CH:19]=[CH:18][C:9]([C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=1)#[N:28]
Reactant: Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 33.4 %

Procedure:
A cold solution of 3.4 g (49.3 millimoles) of sodium nitrite in 25 ml of water is added to a solution of 10.0 g (48.7 millimoles) of cis-2-(p-aminobenzoyl)-cyclopropanecarboxylic acid (see Example 9a) in 37 ml of concentrated hydrochloric acid and 190 ml of water, whilst stirring at 0° C. The mixture is then stirred for a further 10 minutes, at 0°-5° C., after which it is neutralized with sodium carbonate at the same temperature. The solution obtained is added dropwise, whilst stirring, to a cold (0°-5° C.) solution of 5.3 g (59.2 millimoles) of copper-(I) cyanide and 7.5 g (115.2 millimoles) of potassium cyanide in 150 ml of water, which is covered with a layer of 40 ml of toluene. The mixture is then stirred for 30 minutes at 5° C., followed by 12 hours at room temperature. It is filtered and the filtrate is acidified with concentrated hydrochloric acid. The solid which precipitates is filtered off, washed with water and extracted with hot ethanol. Concentrating the ethanol extract gives 3.5 g (33% of theory) of cis-2-(p-cyanobenzoyl)-cyclopropanecarboxylic acid as pale brown crystals, of melting point 180°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:13]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[CH:24]([NH2:28])[CH2:25][CH2:26][CH3:27])=[N:19][N:18]=1)([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[C:13]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[CH:24]([NH:28][C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:25][CH2:26][CH3:27])=[N:19][N:18]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)C)s1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C

Procedure:
A mixture of 3,5-di-fluoro-phenyl acetic acid (51.6 mg, 0.3 mmol), 2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide (88 mg, 0.3 mmol), HBOT (43 mg, 0.315 mmol), EDC HCl (69 mg, 0.36 mmol.) and triethylamine (0.17 ml) in methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a white solid (56 mg), LC-MS M+1=411.2, 1H NMR(CDCL3) 8.7 (d,1H,NH), 6.73(m,2H), 6.6(m,1H), 4.7(m,1H), 3.5(Abq, 2H), 1.6-1.9(m,2H), 1.3-1.6(m,2H), 1.5(s,9H), 0.92(t,3H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH3:22][O-:23].[Na+].CO>O1CCCC1>[CH3:22][O:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12
Reactant: C[O-]
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Yield: 50 %

Procedure:
4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.00 g, 3.39 mmol) and 28% sodium methoxide in methanol (9.69 g, 50.2 mmol) were added to a mixture of methanol (30 mL) and tetrahydrofuran (30 mL), and the solution was heated under reflux for 2.5 hours. After the solution was cooled to room temperature, the solvents were evaporated under reduced pressure. The residue was poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (0.73 g, 50% yield).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH:12]=2)[CH:7]=[N:6]1.[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1.C(O)(=O)C>CO>[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:21][CH:22]=4)[CH:12]=3)[CH:7]=[N:6]2)[CH2:33]1
Reactant: CC1CCCNC1
Reactant: O=CCCn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21
Solvent: CC(=O)O
Solvent: CO
Product: CC1CCCN(CCCn2ncc3ccc(NC(=O)Cc4ccc(Oc5ccccc5)cc4)cc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of N-[1-(3-oxopropyl)-1H-indazol-6-yl]-2-(4-phenoxyphenyl)acetamide (20 mg, 0.05 mmol) and 3-methylpiperidine (10 mg, 0.10 mmol) in methanol containing 2% v/v acetic acid (1 mL) was added and MP-CNBH3 (52 mg, 0.065 mmol). The mixture was shaken at 40 C for 18 hours, cooled to room temperature and filtered, eluting with additional methanol (3×0.5 mL). The filtrate was concentrated under reduced pressure and was purified by RP-HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 0.85 (d, J=6.44 Hz, 3 H), 0.99 (m, 1H), 1.71 (m, 4 H), 2.26 (m, 2H,) 2.73 (m, 1 H), 3.06 (m, 2 H), 3.35 (m, 3 H), 3.69 (s, 2 H), 4.38 (t, J=6.95 Hz, 2 H), 6.99 (m, 4 H), 7.10 (m, 2 H), 7.39 (m, 4 H), 7.69 (m, 1 H), 8.01 (s, 1 H), 8.26 (s, 1 H), and 10.39 (s, 1 H); MS (ESI) 483 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[C:22]([O:24][Si](C(C)(C)C)(C)C)=[CH:23][C:4]=2[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[C:22]([OH:24])=[CH:23][C:4]=2[N:3]=1
Reactant: Cc1nc2cc(O[Si](C)(C)C(C)(C)C)c(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1Cc1ccc(C#N)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2cc(O)c(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1Cc1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-methyl-5-(tert-butyldimethylsilyl)oxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (3 g) in THF (50 mL) was added tetrabutyl ammonium fluoride (3 mL, 1M)) at ambient temperature. After stirring at ambient temperature for 30 minutes the solvent was removed. The reaction was worked up between ethyl acetate and H2O. The organic layer was dried and concentrated to afford 2-methyl-5-hydroxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:24]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:15]3[CH:20]=[C:19]([F:21])[C:18]([CH3:24])=[C:17]([F:22])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(F)cc(F)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)cc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1F
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
2-Chloro-4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (200 mg, 0.607 mmol) was dissolved in 10 mL THF and cooled to −75° C. Lithiumdiisopropylamide (0.45 ml, 0.91 mmol) was added and the mixture stirred for 15 min at −75° C. Iodomethane (0.05 ml, 0.85 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO3— solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10->20:80 gradient) and by recrystallization from ethyl acetate. The desired compound was obtained as a white solid (40 mg, 19%), MS: m/e=344.5 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([CH:23]=[O:24])[C:15]=1[F:25])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O.C(O)C>[CH2:11]([O:13][C:14]1[C:15]([F:25])=[C:16]([CH:23]=[O:24])[C:17]([C:2]2[C:3]([CH:4]=[O:5])=[C:6]([F:10])[CH:7]=[CH:8][CH:9]=2)=[CH:18][CH:19]=1)[CH3:12]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CCOc1ccc(B(O)O)c(C=O)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-c2cccc(F)c2C=O)c(C=O)c1F
Yield: 84.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-chloro-6-fluorobenzaldehyde (84) (50.0 g, 315 mmol), compound (55) (73.5 g, 347 mmol), Pd-132 (made by Johnson Matthey Catalysis and Chiral Technologies) (0.223 g, 0.315 mmol), potassium carbonate (87 g, 631 mmol) and TBAB (20.33 g, 63.1 mmol) was refluxed in a toluene 500 mL)-ethanol (100 mL)-water (500 mL) solvent for 5 hours. The reaction mixture was extracted with 300 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-ethoxy-3,3′-difluoro-[1,1′-biphenyl]-2,2′-dicarboaldehyde (85) (77.25 g, yield 84%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:37][CH3:38])=[C:7]([C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[C:12]3[CH:17]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=4[CH3:36])[N:18]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[C:19](=[O:20])[C:11]=3[N:10]=2)[CH:8]=1.[C:39]([O:42][CH2:43][C:44](Cl)=[O:45])(=[O:41])[CH3:40]>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH:17]2[C:12]3[N:13]([CH:14]([CH3:15])[CH3:16])[C:9]([C:7]4[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=4[O:37][CH3:38])[CH2:2][NH:1][C:44]([CH2:43][O:42][C:39](=[O:41])[CH3:40])=[O:45])=[N:10][C:11]=3[C:19](=[O:20])[N:18]2[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[CH3:28])=[C:30]([CH3:36])[CH:31]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(CN)cc1-c1nc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)ccc1C)C2=O
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)COC(C)=O)cc1-c1nc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from example 16 (90 mg, 0.16 mmol) was dissolved in THF (1.6 mL) with TEA (27 μL, 0.20 mmol) and then acetoxyacetyl chloride (19 μL, 0.18 mmol) was added. The reaction mixture was stirred at RT for 30 min. It was then concentrated to give the title compound. tR: 1.24 min (LC-MS 2); ESI-MS: 649.3/651.2 [M+H]+ (LC-MS 2).