Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[O:29][CH3:30].[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](O)(=[O:40])=[O:39]>>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([CH3:28])[C:26]([S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH3:31])(=[O:40])=[O:39])=[CH:27][C:22]=1[O:21][CH3:20]
Reactant: COc1ccc(C)cc1OC
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cc(C)c(S(=O)(=O)c2ccccc2C)cc1OC
Temperature: 0 °C

Procedure:
50 g of phosphorus pentoxide are covered, by pouring, with 400 ml of methanesulphonic acid and the whole is stirred at 60° until a clear solution has formed. 30.4 g (0.2 mol) of 1,2-dimethoxy-4-methylbenzene and 43 g (0.2 mol) of 2-methylbenzenesulphonic acid (80% strength) are then added, and the internal temperature is increased to 80° for 30 minutes. The mixture is poured onto 4 liters of ice-water and extracted with ethyl acetate. The extract solution is washed twice with water, dried over sodium sulphate, filtered and concentrated by evaporation in a rotary evaporator. The oil remaining crystallises immediately. It is triturated with diethyl ether and filtered off. In this manner colourless crystals of 1,2-dimethoxy-4-(2-methylphenylsulphonyl)-5-methylbenzene having a melting point of 126°-128° are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=O)C(F)(F)F)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C=O.[C:21](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:21][N:12]([CH3:13])[C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: CC(=O)O
Reactant: Nc1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
In 3 mL of methanol, 150 mg (0.55 mmol) of N-(3-amino-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroacetamide, 0.076 mL (0.9 mmol) of a 37% formaldehyde aqueous solution and 0.05 mL of acetic acid were dissolved, and 47 mg (0.74 mmol) of sodium cyanoborohydride was added thereto, and the mixture solution was stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution and concentrated, and the residue was dissolved in 6 mL of tetrahydrofuran. To this solution, 10 mL of a saturated sodium bicarbonate solution was added and the mixture solution was heated at 50° C. for 20 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the extract was dried on anhydrous magnesium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain 100 mg (89%) of a brownish oily target product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28]CC)=[O:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(-c2cccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3OCc3ccc4ccccc4c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3cccc(C(=O)O)c3)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred mixture of (3R*,4R*)-4-(3-bromo-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (300 mg, 0.6 mmol), 3-ethoxycarbonylphenyl boronic acid (136.8 mg, 0.71 mmol), dimethoxyethane (3 mL), H2O (1 mL), tetrakis-(triphenylphosphin)-palladium (46.5 mg, 0.04 mmol) and Na2CO3 (96 mg, 0.91 mmol) is heated at reflux under argon for 16 h. The mixture is cooled to RT, dimethoxyethane is removed in vacuo and the residue is diluted with aqueous 2N Na2CO3 solution containing a few mL of concentrated NH4OH. The aqueous layer is extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the dark residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-(3′-ethoxycarbonyl-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a yellowish resin. The ester (138.7 mg, 0.245 mmol) is dissolved in MeOH (1 mL) and THF (1 mL), treated with aqueous NaOH (2 M, 0.5 mL, 1 mmol) and the mixture is stirred for 14 h at RT. The solvents are removed in vacuo, the residue is diluted with H2O and the pH adjusted to 5 by the addition of 1N HCl. The aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo to afford (3R*,4R*)-4-(3′-carboxy-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a white amorphous solid. A mixture of this acid (110.1 mg, 0.20 mmol) and HCl (5M in 2-propanol, 2 mL, 10 mmol) is stirred for 1 h at RT. The reaction mixture is evaporated in vacuo and the residue purified using preparative HPLC (H2O/CH3CN). The combined pure fractions are treated with solid K2CO3 and CH3CN is removed in vacuo. The aqueous layer is extracted twice with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. The residue is stirred with HCl (5M in 2-propanol, 1 mL, 5 mmol) for 2 h at RT. Evaporation of the solvent affords 3′-[(3R*,4R*)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-biphenyl-3-carboxylic acid hydrochloride as a white solid: MS 438.6 [M+H]+; retention time 5.23 min (HPLC, Nucleosil C18; 5→100% CH3CN in H2O within 8 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc(Cl)cc1Cl)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:15]#[N:16]>CN1C(=O)CCC1.O>[C:15]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: N#C[Cu]
Reactant: CCc1ccc(C(=O)OC)cc1Br
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc(C(=O)OC)cc1C#N
Temperature: 20 °C
Yield: 48.8 %

Procedure:
Methyl 3-bromo-4-ethyl-benzoate (D44) (5 g) in NMP (180 mL) was treated with copper (I) cyanide (3.69 g). The mixture was then heated at reflux for 5 h, under argon. After cooling to 20° C. the reaction mixture was diluted with water, then filtered through kieselguhr, washing well with water and EtOAc. The organic layer was washed with water, brine and dried over MgSO4. The solvent was evaporated to dryness in vacuo and the residue was purified by chromatography on silica eluting with EtOAc-Hexane (1:9) to give the title compound (1.9 g) 1H NMR (CDCl3) δ 1.33 (3H, t), 2.94 (2H, q), 3.94 (3H, s), 7.43 (1H, d), 8.17 (1H, dd), 8.28 (1H, d).
Reaction SMILES: Cl.Cl.[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:22]1[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)[N:27]=1.C(N(CC)CC)C>O1CCCC1>[C:3]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([C:22]2[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)[N:27]=2)[CH2:13][CH2:14]1
Reactant: c1ccc(-c2ccccc2N2CCNCC2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(c3ccccc3-c3ccccc3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a solution of 1-biphenyl-2-yl-piperazine dihydrochloride (311 mg, 1.0 mmol) and 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (202 mg, 0.91 mmol) in tetrahydrofuran (20 mL) was added triethylamine (404 mg, 4.0 mmol). The mixture was stirred at 90° C. for 4 h. The solvent was evaporated off in vacuo and the residue treated with water and chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate gave 2-[4-(biphenyl-2-yl)piperazin-1-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (250 mg, 65%) as colorless crystals.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1ncccc1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 2-fluoro-3-(pyridin-4-yl)pyridine (1.0080 g, 5.787 mmol), 4-aminophenol (0.7102 g, 5.793 mmol), and cesium carbonate (2.387 g, 6.945 mmol) in dimethyl sulfoxide at 90° C. The reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (3×10 mL), satd sodium chloride solution (3×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(3-(pyridin-4-yl)pyridin-2-yloxy)benzenamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO.Cl>O>[OH:7][CH:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C/C(O)c1nc2ccccc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCC/C=C/C(O)C1=Nc2ccccc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of 502 mg (3.63 mmols) of potassium carbonate in 2 ml of water was added to a solution of 1.23 g (3.63 mmols) of 2 (trans-1-hydroxy-2-nonenyl)-3-methyl-4-acetoxyquinoline, 15 ml of water and 80 ml of methanol and stirred at room temperature for 10 minutes. After neutralization by addition of 1N hydrochloric acid, the solvent was distilled off under reduced pressure and 30 ml of chloroform was added to the resultant residue, followed by washing with water and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane : ethyl acetate=1:2) to obtain 746 mg (yield 69%) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-4-quinolone.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[C:40]([O:43][CH2:44][C:45]([CH3:59])([CH3:58])[C@@H:46]([C:55](O)=[O:56])[NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])(=[O:42])[CH3:41].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:40]([O:43][CH2:44][C:45]([CH3:59])([CH3:58])[C@H:46]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:55](=[O:56])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30])(=[O:42])[CH3:41]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)COC(C)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a solution of the product of Example 2C (0.275 g, 0.517 mmol) in tetrahydrofuran (0.40 mL) were added the product from Example 174E (0.15 g, 0.519 mmol), DEPBT (0.233 g, 0.779 mmol), and N,N-diisopropylethylamine (0.45 mL, 2.58 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.214 g, 50% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (m, 15 H), 1.39 (s, 9 H), 1.47-1.56 (m, 2 H), 1.99 (s, 3 H), 2.72-2.79 (m, 3 H), 3.49 (s, 3 H), 3.62-3.65 (m, 2 H), 3.80-3.84 (m, 2 H), 4.05 (d, J=9.9 Hz, 1 H), 4.10-4.24 (m, 2 H), 4.94 (d, J=4.8 Hz, 1 H), 6.60-6.65 (m, 2 H), 7.10-7.21 (m, 8 H), 7.29-7.31 (m, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 7.77 (d, J=8.5 Hz, 1 H), 7.82-7.89 (m, 4 H), 8.64 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:36])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:35])[C:18]([O:26]C(C3C=CC=CC=3)=O)=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].N(C)C.[C:40]1([CH2:46][NH2:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>C(O)C>[CH2:46]([NH:47][C:21]([C:19]1[N:20]=[C:9]2[C:8]3([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:36])[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]3)[CH2:11][N:10]2[C:17](=[O:35])[C:18]=1[OH:26])=[O:23])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Reactant: NCc1ccccc1
Agent: CNC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccccc2)c(O)c1=O
Temperature: 50 °C
Reaction time: 0.12 h
Yield: 37.5 %

Procedure:
To a mixture of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (20 mg, 0.040 mmol) in ethanol (2 mL) was added 2M Me2NH (0.040 mL, 0.081 mmol) and the mixture heated at 50° C. for 1 h (mixture became clear after 5-10 min at 50° C. and then precepitate formed). Phenylmethanamine (0.022 mL, 0.201 mmol) followed by triethylamine (0.028 mL, 0.201 mmol) were then added and the mixture heated at 90° C. for 18 h. After work-up the crude product was purified by preparative HPLC to afford the title compound (7 mg, 0.015 mmol, 38% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 12.04 (1 H, s), 8.53 (1 H, brs), 8.29 (1 H, s), 7.35-7.39 (2 H, m), 7.28-7.34 (2 H, m), 7.24-7.27 (1 H, m), 4.57 (2 H, d, J=6.27 Hz), 4.14 (2 H, d, J=4.02 Hz), 3.26 (3 H, s), 2.87 (3 H, s), 2.44-2.58 (3 H, m), 2.01-2.10 (2 H, m), 1.86-1.99 (2 H, m), 1.64-1.75 (2 H, m). LCMS (M+H)=454.73. HPLC purity: >95%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:34]2[C:39]([C:40]([C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=3)=[C:41]3[C:46]=1[CH:45]=[C:44](B(O)O)[CH:43]=[CH:42]3)=[CH:38][CH:37]=[CH:36][CH:35]=2.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:34]2[C:39]([C:40]([C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=3)=[C:41]3[C:46]=1[CH:45]=[C:44]([C:2]1[CH:3]=[CH:4][C:5]([N:8]4[C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[N:10]=[C:9]4[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:6][CH:7]=1)[CH:43]=[CH:42]3)=[CH:38][CH:37]=[CH:36][CH:35]=2
Reactant: Brc1ccc(-n2c(-c3ccccc3)nc3ccccc32)cc1
Reactant: OB(O)c1ccc2c(-c3ccc4ccccc4c3)c3ccccc3c(-c3ccc4ccccc4c3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2nc3ccccc3n2-c2ccc(-c3ccc4c(-c5ccc6ccccc6c5)c5ccccc5c(-c5ccc6ccccc6c5)c4c3)cc2)cc1
Yield: 83.9 %

Procedure:
1.0 g (2.9 mmol) of 1-(4-bromophenyl)-2-phenyl-1H-benzimidazole, 1.5 g (3.2 mmol) of 9,10-di(2-naphtyl)anthracene-2-boronic acid, and 0.067 g (0.058 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 1.7 g of a greenish white solid (84% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 698 with respect to a molecular weight of 698.27.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].O>O1CCCC1>[F:8][C:4]1[CH:3]=[C:2]([CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)[OH:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)c1
Reactant: O=Cc1cccc(F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cccc(F)c1)c1cccc(F)c1
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a solution of 1-bromo-3-fluorobenzene (10.0 g, 57.1 mmol) in tetrahydrofuran (100 mL) was added n-BuLi (1.6M, 35.7 mL, 62.8 mmol) at −78° C. and the mixture was stirred at that temperature for 20 minutes. To the mixture was added 3-fluorobenzaldehyde (7.80 g, 62.8 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture was added water and the product was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 10.1 g of bis(3-fluorophenyl)methanol. To a solution of this compound (6.60 g, 30.0 mmol) in diisopropylether (50 mL) was added phosphorus tribromide (5.41 g, 20.0 mmol) with ice-cooling and the mixture was stirred at that temperature for 1 hour. This reaction mixture was diluted with water and extracted with diisopropylether. The organic layer was washed with water and saturated with aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 5.61 g of the title compound. Yield 53%. Oil.
Reaction SMILES: [H-].[Na+].CO.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:7]=1[N+:13]([O-:15])=[O:14].C[CH2:17][O:18]C(C)=O>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:18][CH3:17])[C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 100 mL three-necked flask containing 10 mL of THF and 0.255 mL of MeOH. The mixture is stirred at room temperature for 1 hour, and a solution of 2,6-difluoronitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of THF is added. The reaction medium is left at room temperature for 16 hours. 10 mL of EtOAc are added and the resulting mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. 0.93 g of product 52 is obtained (cream-coloured solid).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:15])[CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O.[CH3:22][C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)[N:27]=1>>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:15]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([C:26]3[N:27]=[C:23]([CH3:22])[S:24][CH:25]=3)[CH:29]=2)[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)CCCC(N)c1ccccc1-c1ccccc1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: Cc1nc(-c2cccc(CN3C(=O)CCCC3c3ccccc3-c3ccccc3)c2)cs1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-([1,1′-biphenyl]-2-yl)-5-aminopentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 439.10 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:40]2[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)=[CH:15][N:14]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:11]2=[N:12][CH:13]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:40]2[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)=[CH:15][N:14]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:32])=[O:31])[C:11]2=[N:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4F)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4F)cnc32)cc1
Yield: 93.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (150 mg, 0.206 mmol) was deprotected in TFA/DCM (2/1 ml) to afford 120 mg (93% yield) of the titled compound. MS: m/z=625.1 (M+1).