Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(Cl)cc4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccc(Cl)cc3)C2)n1
Temperature: 150 °C
Yield: 30.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-chlorophenyl)-3-piperidinecarboxamide (190 mg, 0.421 mmol), 3 mL of EtOH, Hunig's base (0.22 mL, 1.26 mmol), and hydrazine anhydrous (0.053 mL, 1.69 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH at 50° C., EtOAc was used to triturate. When the solution turned slightly cloudy, it was cooled down to room temperature to get pure crystallized light yellow title compound (59 mg). LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (m, 1H), 1.64-1.85 (m, 2H), 1.99 (m, 1H), 2.55 (m, 1H), 2.78-3.07 (m, 2H), 4.38-4.82 (m, 2H), 5.37 (s, 2H), 6.10 (s, 2H), 6.64-6.74 (m, 1H), 7.31-7.40 (m, 2H), 7.53-7.76 (m, 4H), 7.97 (s, 1H), 10.18 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6](O)=[O:7].S(Cl)([Cl:25])=O>ClC(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([Cl:25])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a stirred solution of 29.5 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid in 300 parts of trichloromethane were added 28.8 parts of thionyl chloride and the whole was stirred and refluxed for 3 hours. The reaction mixture was evaporated, yielding 30 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetyl chloride as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9][C:8](=[O:14])[C:7]=2[CH:15]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][N:12]1[C:6]2[CH:5]=[C:4]([O:16][CH3:17])[C:3]([O:2][CH3:1])=[CH:15][C:7]=2[C:8](=[O:14])[CH2:9][CH2:10][C:11]1=[O:13]
Reactant: ClCCCCBr
Reactant: COc1cc2c(cc1OC)C(=O)CCC(=O)N2
Product: COc1cc2c(cc1OC)N(CCCCCl)C(=O)CCC2=O
Yield: 36.1 %

Procedure:
Analogously to Example 1, reaction of 7,8-dimethoxy-3,4-dihydro-1H-1-benzazepine-2,5-dione (1.70 mmol, 0.40 g, preparation according to Arch. Pharm. 1991, 324, 579) and bromo-4-chlorobutane (2.04 mmol, 0.35 g) afforded 0.20 g of the contaminated title compound. The compound is reacted further without purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].[O:14]1C=CC=[CH:16][CH:15]1OCCBr.Cl>CO.CC(N(C)C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:15][OH:14])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: BrCCOC1C=CC=CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(OCCO)cc1
Yield: 37.9 %

Procedure:
A mixture of 4-methanesulfonylphenol (1.72 g, 10 mmol), DMA (25 ml) and 4 N sodium hydroxide (7 ml) was stirred under an atmosphere of nitrogen. 2-(2-Pyranyloxy)ethylbromide (2.8 g, 14 mmol) was added dropwise and then the mixture was stirred overnight at ambient temperature. The solvent was evaporated in vacuo and the residue was taken up in water (100 ml). The aqueous mixture was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with a 0.5 N sodium hydroxide solution and brine. The organic phase was concentrated to give an oily residue that was dissolved in methanol (50 ml). A solution of 5 N HCl (20 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and a small portion of ice was added followed by 4 N sodium hydroxide until approximately pH 10. The alkaline mixture was extracted with ethyl acetate (3×75 ml) and the combined organic extracts were washed with water and dried (MgSO4). The solvent was evaporated to give 0.82 g (38%) of 2-(4-methanesulfonylphenoxy)ethanol. M.p. 89–90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]([CH2:12][CH2:13][C:14]([CH3:19])([N+:16]([O-])=O)[CH3:15])[C:8](=[O:11])[N:9]([CH3:10])[C:5]=2[CH:4]=1.Cl[Sn]Cl>C(O)C>[NH2:16][C:14]([CH3:19])([CH3:15])[CH2:13][CH2:12][N:7]1[C:6]2[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]([CH3:10])[C:8]1=[O:11]
Reactant: COc1ccc2c(c1)n(C)c(=O)n2CCC(C)(C)[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccc2c(c1)n(C)c(=O)n2CCC(C)(C)N

Procedure:
2.7 g (8.7 mmol) 5-methoxy-3-methyl-1-(3-methyl-3-nitro-butyl)-1,3-dihydro-benzimidazol-2-one and 9.93 g (44.0 mmol) SnCl2 2H2O in 200 mL ethanol are refluxed for 3 hours. The reaction mixture is evaporated down, combined with sodium carbonate solution and filtered. The filtrate is extracted with ethyl acetate and the combined organic phases are washed with water, dried and freed from the solvent. The residue is dissolved in ethanol and the solution is combined with ethereal hydrochloric acid. After the solvent has been distilled off the solid remaining is stirred with diisopropylether.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]1[CH2:22][CH2:21][C@@H:20](O)[CH2:19]1.O>CN(C=O)C>[CH3:17][N:18]1[CH2:22][CH2:21][C@@H:20]([O:8][C:7](=[O:9])[C@:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([OH:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:19]1
Reactant: CN1CC[C@@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC[C@@H](OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
0.545 g (0.0025 mol) of (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetic acid were dissolved in 8 ml of dry DMF. To this solution 0.481 g (0.003 mol) of 1,1′-carbonildiimidazol were added and the mixture was stirred at room temperature for 1 h. After this time, the mixture obtained was added to a suspension of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19, 0.531 g, 0.0046 mol) and HNa (0.065 g, 0.0027 mol) in 3 ml of dry DMF. After stirring 26 h at room temperature the reaction mixture was treated with water and extracted two times with Et2O. The organic layers were combined, washed with water and dried. The residue was purified by silica gel column chromatography (eluent: CHCl3 plus isopropanol 0%→10%) to obtain 450 mg (60%) of the title product as an oil.
Reaction SMILES: Cl.[C:2]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>C(O)C>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:2]3[C:10]4[C:5]([CH2:4][C:3]=3[C:16]=2[CH:15]=1)=[CH:6][CH:7]=[CH:8][CH:9]=4
Reactant: O=C1CCc2ccccc21
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Temperature: 25 °C
Yield: 91.9 %

Procedure:
In a 250 mL round bottom flask, 180 mL of ethanol, 10 mL of HCl, 16.3 grams of 1-indanone (0.124 mole) and 19.5 grams of p-methylphenylhydrazine hydrochloride (0.124 mole) are heated to reflux for six hours. After cooling to 25° C., the resulting precipitate is filtered, washed twice with 100 mL of 10% aqueous ethanol, twice with 50 mL of water, and then twice with 50 mL of hexane. After drying, 25 grams of 8-methyl-5, 10-dihydroindeno[1,2-b]indole is obtained.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([C:16]1[CH:31]=[CH:30][C:19]([O:20][CH2:21][CH:22]([OH:29])[CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[CH2:8]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:29])[CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)=[CH:30][CH:31]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2cccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.24 g (12.1 mmol) acetic anhydride are mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.100 g (0.304 mmol) 1-(4-octylphenoxy)-3-(pyrrol-1-yl)propan-2-ol in 10 ml absolute DMSO. Having stirred for 19 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps using saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave a brownish oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 97:3) and yields the product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-:3])=[O:2].[Hg](C#N)C#N.[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@@H:21]1Br)(=[O:18])[CH3:17]>>[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@H:21]1[S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccccc1S
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2[N+](=O)[O-])SC[C@H]1OC(C)=O
Yield: 48 %

Procedure:
If the procedure described in Preparation I is followed starting from 6 g (38.7.10-3 mol) of 2-nitrobenzenethiol, 10.75 g (42.5.10-3 mol) of mercuric cyanide, Hg(CN)2, and 15.12 g (42.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 8 g (yield: 48%) of the expected product are obtained.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])(=O)C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)(=O)C>[OH:11][C:9]([CH3:12])([CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][SH:4]
Reactant: CC(=O)SCCCCC(C)(C)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCS
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Under an argon atmosphere, to a solution of methyl magnesium bromide (0.99M solution in tetrahydrofuran, 70 ml, 69.3 mmol) in dry tetrahydrofuran (80 ml) was added a solution of ethyl 5-bromovalerate (3.66 ml, 23.1 mmol) in dry tetrahydrofuran (10 ml) dropwise at 0° C., and the mixture was stirred at room temperature for 1.5 hour, then quenched with an aqueous saturated ammonium chloride solution, poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crude 6-bromo-2-methyl-2-hexanol (5.28 g). This crude product was dissolved into acetone (80 ml) and potassium thioacetate (3.96 g, 34.7 mmol) was added. The mixture was stirred at room temperature for 1.5 hour and filtered, then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate: 4:1) to give 6-acetylthio-2-methyl-2-hexanol (3.75 g). Thus obtained 6-acetylthio-2-methyl-2-hexanol was dissolved into tetrahydrofuran (130 ml) and lithium aluminum hydride (2.24 g, 59.0 mmol) was added by portions at 0° C. After this suspension was stirred at room temperature for 1.5 hour, excessive lithium aluminium hydride was treated with ethyl acetate and the reaction solution was acidified with 4N hydrochloric acid. The solution was extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (2.95 g, 3 steps, 85%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[N:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C(NC(C)C)(C)C>CS(C)=O.C(Cl)Cl>[CH:16]1([N:9]2[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:21]4[N:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: Clc1ncc2ccccc2n1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Agent: Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CC(C)NC(C)C
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Temperature: 90 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1099 g, 0.390 mmol), 2-chloroquinazoline (0.128 g, 0.780 mmol, Waterstone), and diisopropylamine (0.204 ml, 1.170 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO. The reaction was heated to 90° C. for 24 h. The reaction was taken up in DCM and loaded onto an Accubond SCX cartridge and washed with DCM (2×), MeOH (2×), and 2.0 ammonia in MeOH (2×). The ammonia fractions were combined and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 1% to 5% MeOH in CH2CL2, to provide the title compound (0.0445 g, 0.119 mmol, 30.6% yield). LCMS showed product peak at 1.511 min (m+1=374.0). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12-1.23 (m, 4 H) 2.65 (t, J=9.29 Hz, 2 H) 2.97-3.08 (m, 1 H) 3.41-3.53 (m, 2 H) 5.30-5.42 (m, 1 H) 7.36 (t, J=6.85 Hz, 1 H) 7.69 (d, J=8.41 Hz, 1 H) 7.73-7.85 (m, 2 H) 7.92-7.99 (m, 2 H) 9.11 (br. s., 1 H)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[C:32](Cl)(Cl)=[O:33].N1C=CC=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1>[O:11]=[C:10]1[N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:13]2[C:32](=[O:33])[N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:30])[F:31])=[CH:4][CH:5]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=c1n(-c2ccc(C(F)(F)F)cc2)c(=O)n2n1CC(c1ccccc1)C2c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To 2.0 g (4.4 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-phenyl-2,3,4,5-tetrahydro-1H-pyrazole-1-carboxamide (Example 3) in 5 ml of methylene chloride was added 4.2 ml (8 mmole) of 1.9M phosgene in toluene. After stirring for 5 minutes 0.8 g (10 mmole) of pyridine was added. The mixture was stirred for 1 hour and then partitioned between diethyl ether and dilute aqueous hydrochloric acid. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration, concentration in vacuo, and chromatography on silica gel using diethyl ether and hexanes gave the title compound, mp 148°-150° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28]>>[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Product: Cc1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(Cl)n3)c2F)[nH]1
Yield: 98.6 %

Procedure:
The previously described 2-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.040 g, 0.13 mmol) and 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.064 g, 0.14 mmol) were employed in a similar process described herein to prepare the title compound (0.064 g, quant.) as a white solid after purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) followed by neutralization. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.11 (br. s., 1H) 7.36 (t, J=5.84 Hz, 1H) 7.18-7.31 (m, 4H) 4.73 (d, J=5.91 Hz, 2H) 2.37 (s, 3H). ES-LCMS: m/z 497.9, 499.9, 501.9 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][C:12]=1[CH:20]=[O:21].C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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]>[F:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([F:10])=[C:12]([CH:20]=[O:21])[CH:13]=1
Reactant: O=Cc1cc(B(O)O)ccc1F
Reactant: Fc1cccc(F)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(-c2c(F)cccc2F)ccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 2-bromo-1,3-difluorobenzene (100 g, 477.46 mmol) and 4-fluoro-3-formylphenylboronic acid (96.2 g, 572.95 mmol) in toluene (1432 mL) at RT was added Na2CO3 (2M in H2O) (477.46 mL, 954.2 mmol) and PdCl2(dppf) (7.798 g, 9.54 mmol). The reaction mixture was stirred at 100° C. for 8 h and cooled to RT. Water was added to the reaction mixture and extracted with EtOAc (2×500 mL). Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated and purified by column using silica (100-200 mesh) and 0-5% EtOAc-hexane to provide 2′,4,6′-trifluorobiphenyl-3-carbaldehyde (54.3 g, 49.4% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[N:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Cc1nccc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1nccc(N2CCN(c3cnccc3C3CC3)C2=O)n1
Yield: 52.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 11 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 4-chloro-2-methylpyrimidine (68 mg, 0.541 mmol), 2-dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl (23 mg, 0.0492 mmol), Pd2(dba)3 (23 mg, 0.024 mmol), cesium carbonate (400 mg, 1.23 mmol) and toluene (5 mL) in seal tube at 110° C. for 14 hours. Purification by column chromatography on silica gel (1.5% methanol in chloroform) afforded 76 mg of the product (52% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(OC)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester prepared in Example 15, step (f)) and 4-methoxybenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.Br[CH2:23][CH2:24][CH2:25][OH:26].[I-].[K+].Cl>O.CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: OCCCBr
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1O2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1

Procedure:
A solution of 3.5 g. (11.8 mmol) of 4-(2-chloro-9-xanthenylidene)piperidine (prepared as in Example 14), 2.0 g. (13.4 mmol) of 3-bromo-1-propanol and 50 mg. of potassium iodide in 50 ml. of dimethylformamide is stirred at 23° C. for 18 hours and 100° C. for 12 hours. The reaction mixture is poured into water, basified and extracted with a mixture of ether and ethyl acetate. The extract is washed with water, dried and the solvent evaporated. The residue is chromatographed on an alumina column using ethyl acetate-ether 1:1 as the eluent. The first fraction yields the product which is treated with ethereal hydrogen chloride to give 4-(2-chloro-9-xanthenylidene)-1-(3-hydroxypropyl)piperidine hydrochloride, m.p. 225°-258° C.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[OH-].[K+].[CH3:24][N:25]=[C:26]=[O:27]>C1C=CC=CC=1>[CH3:24][NH:25][C:26]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:20])[F:21])=[CH:19][CH:18]=2)[CH2:17]1)=[O:27]
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h

Procedure:
The oxalic acid salt of 3-(4-trifluoromethylphenoxy) azetidine (13.0 g., 0.042 mole) was partitioned between 50 ml. of benzene and 50 ml. of potassium hydroxide solution. The benzene layer was dried over calcium sulfate and filtered, and to the stirring dried benzene solution was added 2.6 g. (0.046 mole) of methyl-isocyanate. Stirring was continued overnight. The mixture was concentrated at reduced pressure and the solid residue was recrystallized from a mixture of isopropyl ether-ethyl acetate. The product weighed 7.5 g. (65%) and melted at 154°-157° C.
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[C:17]2[C:22]([C:23]=1[O:24]CC1C=CC=CC=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])C1C=CC=CC=1.CCOC(C)=O>[Pd].CO>[CH3:34][N:33]([CH3:35])[C:32]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:12]([NH:11][CH2:10][C:9]([OH:37])=[O:8])=[O:13])[N:15]=1)=[O:36]
Reactant: CN(C)C(=O)c1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1nc(C(=O)NCC(=O)O)c(O)c2ccccc12
Reaction time: 18 h
Yield: 91.5 %

Procedure:
A mixture of [(4-Benzyloxy-1-dimethylcarbamoyl-isoquinoline-3-carbonyl)-amino]-acetic acid benzyl ester (209 mg, 0.42 mmol), Pd/C (100 mg, 10 wt % Pd), EtOAc (10 ml) and MeOH (50 ml) was stirred under a H2-atmosphere at ambient pressure and temperature for 18 h. Then the mixture was filtered through a pad of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to give the title compound as a brown solid (122 mg); MS-(−)-ion: M−1=316.1.