Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH:6]([OH:9])[CH2:7][CH3:8])[CH3:2].[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:9][CH:6]([CH2:7][CH3:8])[CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH3:17]
Reactant: CCOCCC(O)CC
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCOCCC(CC)OCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of 1-ethoxy-3-pentanol (1.32 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (1.0 mL, 9.5 mmol). The reaction mixture is stirred at rt for 2 h. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated. The residue is purified by chromatography on silica gel; elution with EtOAc:heptane (1:3) gives 660 mg the product 487.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[N:17]=[N:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)c1ccc(F)cc1

Procedure:
Following the procedure of Example 6, making variations only as required to use 4-fluorobenzoyl chloride in place of phenoxyacetyl chloride to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a light yellow solid (62% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.78-7.85, 7.77, 7.66, 7.52, 7.44, 7.25-7.35, 3.10-3.80.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.[CH:18](N1CCCCC1)=[O:19]>O1CCCC1>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH:18]=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCc1ccsc1Br
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1ccsc1C=O
Temperature: -40 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To the solution of 2-bromo-3-hexylthiophene (13.5 g, 54.6 mmol) in anhydrous tetrahydrofuran (200 mL) in a dry ice/acetone bath at −78° C. was added n-butyl lithium (2.5 M in hexane, 24.0 mL, 60.1 mmol) dropwise under the protection of argon. The reaction solution was warmed to −40° C. and stirred for 60 min. The solution was cooled down to −78° C. again, and 1-formylpiperidine (7.41 g, 65.5 mmol) was added in one shot. Then, the solution was allowed to warm slowly up to room temperature and stirred overnight. The solution was then poured into ice water. The organic layer was separated and the aqueous layer was extracted twice with hexane (100 mL). The organic extracts were combined and washed three times with distilled water (50 mL), dried over anhydrous magnesium sulfate, and rotary evaporated to remove the solvent. The liquid residue was subjected to silica-gel column chromatography (EtOAc/hexane=1/10, Rf=0.4) to yield a clear liquid product (9.8 g, 92% yield). 1H NMR (400 MHz, acetone-d6) δ (ppm): 10.11 (s, 1H); 7.89 (d, 1H, J=5.2 Hz); 7.17 (d, 1H, J=5.2 Hz); 3.04 (t, 2H, J=7.8 Hz); 1.69 (m, 2H); 1.28-1.42 (m, 6 H); 0.87 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)=[CH:12][CH:11]=1.Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:29][CH2:30][CH2:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[CH:19]=2)=[CH:14][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1ccc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1OCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 46.2 %

Procedure:
To a solution of N-(2-amino-phenyl)-4-[(3-hydroxy-4-methoxy-phenylamino)methyl]-benzamide (212e) (586 mg, 0.66 mmol) in DMF (10 ml) were added 2-(3-bromopropyl)-isoindole-1,3-dione (238) (176 mg, 0.66 mmol) and K2CO3 (365 mg, 2.64 mmol) at room temperature. The reaction mixture was heated at 100° C. for 1 h then overnight at 60° C., cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluent from AcOEt-hexane (40:60) to pure AcOEt) to afford 239 (168 mg, 46% yield). 1H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.84-7.75 (m, 4H), 7.44 (d, J=8.0 Hz, 2H), 7.12 (d, J=7.2 Hz, 1H), 6.92 (t, J=8.8 Hz, 1H), 6.75 (dd, J=1.2, 7.6 Hz, 1H), 6.57 (d, J=8.4 Hz, 2H), 6.27 (d, J=2.4 Hz, 1H), 6.00-5.93 (m, 2H), 4.87 (s, 2H), 4.27 (d, J=6.0 Hz, 2H), 3.89 (dd, J=5.6, 6.0 Hz, 2H), 3.74 (dd, J=6.4, 6.8 Hz, 2H), 3.42 (s, 3H), 2.06-2.01 (m, 2H). LRMS: (calcd.) 550.4; (found.) 551.5 (MH)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]1[CH2:24][CH:23]1[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[OH:22][CH:23]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:24][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: C1CN(CC2CO2)CCO1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)CN3CCOCC3)CC1)O2

Procedure:
Compound 166 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-(oxiran-2-ylmethyl)morpholine and conditions outlined in procedure X. M.P.=75-78° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 3.9 (m, 1H), 3.7 (m, 5H), 2.95 (s, 1H), 2.9 (t, 2H), 2.7-2.3 (m, 11H), 2.15 (d, 2H), 1.9 (q, 2H); LCMS: 445 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39])([O-:31])=[O:30].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N+:29]([O-:31])=[O:30])(=[O:39])=[O:40])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(F)c(-c2ccc(N)cc2CC(C)(C)C)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-amine (970 mg) in THF (34 mL) were added triethylamine (706 μL) and o-nitrobenzenesulfonyl chloride (823 mg) at 0° C., and the mixture was stirred at room temperature for 5 hr. Triethylamine (706 μL) and o-nitrobenzenesulfonyl chloride (374 mg) were further added at 0° C., and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.31 g) as a yellow gummy substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].O.O=[CH:25][C:26]([OH:28])=[O:27]>C(#N)C>[CH3:18][O:17][C:15]([C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[NH:12][CH:25]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:26]([OH:28])=[O:27])=[O:16]
Reactant: COC(=O)c1ccccc1N
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccccc1NC(C(=O)O)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A mixture of 6-methoxypyridin-3-ylboronic acid (200 mg, 1.31 mmol), methyl 2-aminobenzoate (170 μl, 1.31 mmol), and 2-oxoacetic acid hydrate (120 mg, 1.31 mmol) in acetonitrile (20 ml) was stirred at room temperature overnight. The solvent was evaporated, and the crude product was purified by flash-chromatography (DCM/MeOH=9/1) to obtain 2-(2-(methoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (118 mg, 28.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1ccc(C2=CC3CCC(C2)N3)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Fc1ccc(C2CC3CCC(C2)N3)cc1
Yield: 89.1 %

Procedure:
A solution of 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]oct-2-ene (10 g) was dissolved in glacial acetic acid (150 ml). Platinum oxide (0.5 g) was added followed by treatment with hydrogen gas at 3 atm of pressure in a conventional Parr apparatus. Filtration and removal of solvent in vacuo left a viscous oil. Water was added and the mixture made alkaline (pH >9) with aqeous NaOH. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and removal of solvent in vacuo gave 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]-octane (9 g) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)=O.[H][H].[NH3:14]>CO.[Ni]>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:14])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: [H][H]
Reactant: N
Agent: [Ni]
Solvent: CO
Product: COc1cccc(C(C)N)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 300 g of 3-methoxyacetophenone of Formula VII in 1000 ml of 10.9% ammonia in methanol, 300 g of Raney nickel in 100 ml of methanol (Raney nickel was prewashed with 2×150 ml of methanol to remove moisture) was charged, followed by heating to about 90° C. The resultant suspension was agitated at about 90° C. under 4 kg/cm2 anhydrous hydrogen gas pressure for about 45 hours. After completion of the reaction, the reaction mass was cooled to about 30° C. and the suspension was filtered through a celite bed, followed by washing the celite with 300 ml of methanol. The filtrate was distilled completely at about 55° C. under vacuum. To the residue, 300 ml of acetone was charged and distilled completely. To the residue, 900 ml of acetone was charged and dry HCl gas was passed at about 0° C. until the pH of the mass was less than 1. The resultant suspension was stirred at about 5° C. for about 3 hours. Solid was separated by filtration and the solid was washed with 100 ml of acetone. The solid obtained was dried at 50° C. for about 5 hours. The above solid is charged in a 4 neck round bottom flask and stirred for about 10 minutes and PH is adjusted to about 11.0 using 65 ml of caustic lye and extracted with 3×200 ml of dichloromethane. The obtained organic layer is distilled completely distilled at about 45° C. to afford 179.6 g of title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]=[O:12].C(N(C(C)C)CC)(C)C.C(OCC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]=[O:12])(=[O:4])=[O:3]
Reactant: O=Cc1ccc(OCc2ccccc2)c(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 85.3 %

Procedure:
Methanesulfonyl chloride (2.50 g) was added to a stirred solution of 3-(hydroxymethyl)-4-phenylmethoxybenzaldehyde (4.00 g) in dichloromethane (50 ml) at 0° C. To this solution was then added diisopropylethylamine (8.1 ml) over approx. 2 minutes. After stirring for a further 5 minutes the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with dilute hydrochloric acid, dried over sodium sulfate, filtered and concentrated under reduced pressure to give pale straw coloured oil. Addition of diethyl ether caused the product to crystallize. This material was collected and washed with more diethyl ether to give 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (4.51 g) as off-white crystals. 1H NMR (CDCl3) δ9.78 (s, 1H, CHO); 5.22 (s, 2H); 5.10 (s, 2H); 2.83 (s, 3H). TLC (silica gel): Rf=0.4 (dichloromethane: diethyl ether, 24:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25]Cl)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:27][O-:28].[Na+]>CO.[I-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:28][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COCCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-1H-indazole-7-carboxamide (Intermediate 7) in MeOH (1.5 mL) were added 3.8 M sodium methoxide in MeOH (1 mL) and sodium iodide (5.0 mg). The reaction mixture was stirred at 80° C. overnight and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and washed with water (5 mL). The organic phase was collected, dried over MgSO4, filtered and concentrated to give the crude title compound (30 mg), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:9]([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=1)=[O:5])[CH3:2].C1C(=O)N([Br:36])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:36][CH2:21][C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][CH:16]=2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(CBr)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To a stirred solution of Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (Compound 1b, 4.0 g, 9.17 mmol) in chlorobenzene (50 ml) were added NBS (1.77 g, 10.09 mmol) and AIBN (1.65 g, 10.09 mmol) at 25° C. The reaction mixture was then stirred at 85° C. for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature and was quenched in aqueous sodium chloride solution (50 ml). The mixture so obtained was then extracted with Ethyl acetate (2×50 ml). The organic layer was washed with brine (1×50 ml) and dried over sodium sulfate and concentrated under reduced pressure to obtain crude product (4.0 g). The crude product was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (2.8 g, 59.32%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([NH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.O.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>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]2[CH:4]=[CH:3][C:2]([C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:26](=[O:28])[CH3:27])=[CH:31][CH:32]=3)=[CH:7][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(-c2ccc(C(=C3CC(C)(C)CC(C)(C)C3)c3ccc(O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.1 g, 0.250 mmol) and (4-acetylaminophenyl)boronic acid (0.148, 0.826 mmol) in ethylene glycol dimethyl ether (8 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.026 g, 0.023 mmol) followed by 2 M Na2CO3 (3 mL). The reaction mixture was refluxed for 4 h, cooled to room temperature then diluted with water followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried (MgSO4) filtered and concentrated to an oil. The crude oil was dissolved in DCM, loaded onto silica gel and purified with a gradient of 100% hexanes to 40% hexanes:EtOAc over 60 mins. Pure fractions were combined and concentrated to give 0.05 g (41%) of the title compound 99 as an off white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 12H), 1.25 (s, 2H), 1.93 (s, 4H), 2.03 (s, 3H), 6.66 (d, J=8.5 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H) 7.52-7.64 (m, 6H), 9.27 (s, 1H), 9.99 (s, 1H). HRMS (ESI) Calcd for C31H36NO2: 454.2746 (M+H)+. Found: 454.2757.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH:33]([CH3:35])[CH3:34])[CH:26]=[CH:25][C:24]=1[OH:36].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:36][C:24]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][O:32][CH:33]([CH3:34])[CH3:35])=[CH:28][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OCCOc1ccc(O)c(F)c1
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Oc2ccc(OCCOC(C)C)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 118.2 %

Procedure:
Mixture of 4-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (147 mg, 0.47 mmole), 2-fluoro-4-(2-isopropoxy-ethoxy)-phenol (0.47 mmole, 1 eq) and K2CO3 (0.75 mmole, 1.5 eq) in 2 mL DMSO was heated under microwave irradiation at 150° C. for 40 minutes. Mixture was purified by HPLC to give compound C184 as a yellow oil (273 mg, 96%). 1H NMR (DMSO-d6, 400 MHz) δ 1.23 (d, 6H), 1.27 (d, 6H), 1.79-1.86 (m, 2H), 1.97-2.04 (m, 1H), 2.20 (s, 3H), 3.43-3.50 (m, 2H), 3.73-3.79 (m, 3H), 3.82 (t, 2H), 4.09 (t, 2H), 4.95 (sep, 1H), 5.33-5.36 (m, 1H), 6.70-6.78 (m, 2H), 7.08 (t, 1H), 8.27 (s, 1H). Exact mass calculated for C25H34FN3O6 491.2, found 492.4 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]#[N:40])=[CH:29][CH:28]=1>>[CH2:1]([C:4]1[N:8]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]#[N:40])=[CH:31][CH:32]=2)[C:7]2[CH:9]=[C:10]([N:14]3[C:15](=[O:24])[C:16]4=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]4[C:18]3=[O:19])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Product: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
Prepared analogously to Example la from 2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole and 4'-bromomethyl-2-cyano-biphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]3)=[O:19])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(N[C@H]1CC[C@H](O)CC1)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with (trans)-4-amino-cyclohexanol (CAS Reg. No. 27489-62-9) in the presence of DMAP to give the title compound as colorless oil. MS: m/e=466.4 [M+H+].
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].C(N(CC)CC)C.[C:17](OCC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>C(O)C>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:2]1[C:17](=[O:22])[CH2:18][C:19]([CH3:21])=[N:3]1)[CH3:9]
Reactant: CCOC(=O)CNN
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1N=C(C)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To an ethanol (250 mL) solution of ethyl hydrazinoacetate monohydrochloride (19.4 g, 125 mmol) was added triethylamine (19.2 mL, 138 mmol), and the mixture was stirred at room temperature for 10 minutes, and then ethyl acetoacetate (16.6 mL, 131 mmol) was added, and the mixture was heated to reflux for four hours. After returning the mixture to room temperature, the solvent was distilled off under reduced pressure. N-heptane (100 mL) was added to the residue to yield a solid, and the obtained solid was filtered and washed with n-heptane to obtain primary crystals of the title compound (17.1 g, 93.0 mmol). Furthermore, the solvent in the filtrate was distilled off under reduced pressure, and to the residue, n-heptane/acetone mixture (1:1) was added to yield a solid, and the obtained solid was filtered. Thus, secondary crystals of the title compound (0.44 g, 2.39 mmol) were obtained.