Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:38])[CH2:36][CH3:37]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 19 h
Yield: 52 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Propionyl chloride (0.22 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 19 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.116 g, 52%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.00 (d, J=9 Hz, 2 H), 7.53 (d, J=9 Hz, 1 H), 7.02 (d, J=9 Hz, 1 H), 5.73 (d, J=9 Hz, 1 H), 5.69-5.64 (m, 1 H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3 H), 2.34 (q, J=7 Hz, 1 H), 1.47 (d, J=6 Hz, 3 H) and 1.02 (t, J=8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc3ccccc3n2)CC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(Cc2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-4-hydroxy-4-(2-quinolylmethyl)piperidine (5.95 g) was dissolved in anhydrous THF (50 ml), and methane sulfonylchloride (2.99 g) and triethylamine (7.3 ml) were added to the solution. The mixture was stirred at room temperature for two hours and concentrated under reduced pressure. Water and ethyl acetate were added to the mixture to thereby separate an organic phase, which was further washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was dissolved in toluene (50 ml), and DBU (5.30 g) was added to the solution. The mixture was stirred at 60° C. for three hours and concentrated under reduced pressure. Water and ethyl acetate were added to the mixture to thereby separate an organic phase, which was further washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (developer: hexane-ethyl acetate (1:1)). The title compound was obtained through crystallization from hexane.
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[C:23]([OH:30])=[CH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2].[Br:33]N1C(=O)CCC1=O.O>ClCCl>[Br:33][CH:24]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:23]([C:8]1[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][C:7]=1[O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:32])[CH3:31])=[O:30]
Reactant: COc1ccc(COc2ccc(C(O)=CC(=O)C(C)C)c(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)C(Br)C(=O)C(C)C)c(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-4-(4-methoxy-benzyloxy)-phenyl]-1-hydroxy-4-methyl-pent-1-en-3-one (5.81 g, 12.72 mmol) is dissolved in dry dichloromethane (100 ml) at room temperature. N-bromosuccinimide (2.38 g, 13.36 mmol) is added portionwise. The reaction mixture is stirred at room temperature for 30 minutes, poured into water (200 ml) and extracted with dichloromethane (3×75 ml). The dichloromethane extracts are combined, washed with saturated brine (100 ml), dried (MgSO4), filtered and evaporated to give a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH:22]=2)[O:19][C:18]([CH3:30])([CH3:29])[CH2:17][C:16]3([CH3:32])[CH3:31])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:26]1([N:24]([CH2:23][C:21]2[CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][CH:7]=3)[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([CH3:29])([CH3:30])[CH2:17][C:16]3([CH3:32])[CH3:31])[CH3:25])[CH2:28][CH2:27]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of (4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}phenyl)-acetic acid methyl ester (Intermediate 12, 0.057 g, 0.13 mmol) in methanol (1 mL) and tetrahydrofuran (3 mL) was treated with a 1M solution of sodium hydroxide (0.4 mL, 0.4 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo to a residue that was washed with hexane, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow oil (0.046 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[O:17])=[CH:14][CH:13]=1
Reactant: Cc1ccccc1CCN
Reactant: O=C(Cl)c1ccc(F)cc1
Product: Cc1ccccc1CCNC(=O)c1ccc(F)cc1

Procedure:
1-Amino-2-(2-methylphenyl)ethane was reacted with 4-fluorobenzoyl chloride in the same way as in step (a) of Example 1 to afford 1-(4-fluorobenzoylamino)-2-(2-methylphenyl)ethane as colorless needles having a melting point of 82° to 83° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)CCl.[CH:36]1([C:42](O)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:36]1([C:42]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][NH:11][C:12]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:18])[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[N:27][CH:26]=[CH:25]4)=[O:20])=[CH:7][CH:8]=2)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(COC(=O)C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139) in pyridine was added EDC, DMAP, and cyclohexanecarboxylic acid, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl cyclohexanecarboxylate (E142).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[CH:8]=3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(-c3cn4cc(C)ccc4n3)cc2)cc1C(F)(F)F
Yield: 38.5 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.20 g, 0.897 mmol) and 4-methoxy-3-trifluoromethylbenzoyl chloride (0.21 g, 0.897 mmol) in dry pyridine (15 ml) to give the title compound as a colourless solid (0.147 g, 38%) after work-up and flash chromatography (15:1 EtOAc/Hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[Br-].[CH2:12]([Zn+])[C:13]([CH3:16])([CH3:15])[CH3:14].O1CCCC1>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:8][C:7]1[CH:6]=[C:5]([NH2:9])[C:4]([NH2:10])=[CH:3][C:2]=1[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: Nc1cc(F)c(Br)cc1N
Reactant: CC(C)(C)C[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1cc(N)c(N)cc1F
Temperature: 140 °C
Yield: 28 %

Procedure:
A mixture of 4-bromo-5-fluorobenzene-1,2-diamine (82.1 mg, 0.400 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.2 mg, 0.0276 mmol), and neopentylzinc bromide in tetrahydrofuran (0.5 M, 3.0 mL, 1.5 mmol) was degassed for 5 minutes using argon. The reaction mixture was heated under microwave irradiation for 5 minutes at 140° C. The solution was concentrated in vacuo and purified by silica gel column chromatography eluting with 0-100% ethyl acetate/hexanes to afford the title compound (22 mg, 28%) as an orange oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1.C([Sn](CCCC)(CCCC)[C:21]([O:23][CH2:24][CH3:25])=[CH2:22])CCC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:24]([O:23][C:21]([C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:15])=[N:9][C:10]=1[S:13][CH3:14])=[CH2:22])[CH3:25]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1nc(N)nc(-c2ccco2)c1I
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=C(OCC)c1c(SC)nc(N)nc1-c1ccco1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a stirred solution of 1.12 g (3.37 mmol) 4-furan-2-yl-5-iodo-6-methylsulfanyl-pyrimidin-2-ylamine in 30 ml dioxane under argon at room temperature were added 1.25 ml (3.70 mmol) tributyl(I-ethoxyvinyl)tin, 236 mg (0.34 mmol) bis(triphenylphosphine) palladium(II) chloride and 2.19 g (6.74 mmol) cesium carbonate. The reaction mixture was heated at reflux for 16 h, then cooled to room temperature, 1 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (1/2 ethyl acetate/hexane) afforded 730 mg (78%) 5-(1-ethoxy-vinyl)-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine as an orange crystalline solid. ES-MS m/e (%): 278 (M+H+, 100).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[NH:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]([NH2:13])=[O:12])[CH3:3].[O:14]1[CH2:24][CH:15]1[CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>C(O)CCCC>[C:11]([CH2:10][N:5]1[C:6](=[O:9])[CH2:7][N:8]([CH2:24][CH:15]([OH:14])[CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:4]1[CH:2]([CH3:1])[CH3:3])(=[O:12])[NH2:13]
Reactant: CC(C)C1NCC(=O)N1CC(N)=O
Reactant: CC(C)COC(=O)CC1CO1
Solvent: CCCCCO
Product: CC(C)COC(=O)CC(O)CN1CC(=O)N(CC(N)=O)C1C(C)C
Yield: 49.1 %

Procedure:
A solution of 1.2 g (6.4 mmol) of 2-(1-methylethyl)-5-oxo-1-imidazolidineacetamide and 2 g of 2-methylpropyl 3,4-epoxybutanoate in 40 ml of anhydrous pentanol was stirred at 80° C. for 48 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in 15 ml of 15% HCl, washed with 2×25 ml dichloromethane, basified with sodium carbonate with sodium carbonate and extracted with 3×35 ml dichloromethane. The organic layer was dried and evaporated to afford 1.08 g of the title compound as a colorless oil (mixture of two diastereoisomers, Rf 0.27 and 0.32 respectively (dichloromethane/methanol 9:1; silica gel plates). Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=300 (M+ --C3H7). IR spectrum (neat): 3400, 3200, 1730 and 1690 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and morpholine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.08 g, 70%). LCMS: 560.30 (M+1)+; HPLC: 99.22% (@254 nm) (Rt; 3.944; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C. Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min. 5% B); 1H NMR, (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.76 (s, 1H), 8.17 (t, 1H), 8.02 (d, 1H, J=7.6 Hz), 7.50 (d, 1H, J=8 Hz), 7.41 (s, 1H), 7.23 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.85 (d, 2H, J=11.2 Hz), 3.61 (s, 3H), 3.59-3.60 (m, 3H), 3.24-3.29 (m, 2H), 3.02-3.05 (m, 1H), 2.64 (s, 3H), 2.42 (bs, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.61 (bs, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>>[C:4]([C:3]1[C:2]([Cl:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=1)([O:6][CH3:7])=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: COC(=O)c1cccc(N)c1Cl
Product: COC(=O)c1cccc(NC2=CC(=O)CCC2)c1Cl
Temperature: 120 °C
Yield: 83.9 %

Procedure:
A mixture of methyl 2-chloro-3-aminobenzoate (11.11 g, 59.86 mM) and 1,3-cyclohexanedione (9.05 g, 80.8 mM) was heated at 120° C. under a stream of nitrogen for 4 hours. The resultant solid was triturated with hot ethyl acetate, then dried in vacuo to afford 14.05 g (84%) of 3-(3-carbomethoxy-2-chloroanilino)cyclohex-2-en-1-one as a yellow orange solid. 1H NMR (CDCl3) δ7.6 (dt, 1H, J=1 and 8 Hz), 7.3 (t, 1H, J=8 Hz), 6.6 (br s, 1H), 5.62 (s, 1H), 3.95 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1729, 1536, 1351, 1299, 1290, 1267, and 1135. MS (ES) m/e 278, 280, 282.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]1[C:12]2[CH2:13][NH:14][CH2:15][C:11]=2[CH2:10][N:9]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:17].Cl[C:29]1[N:30]=[N:31][C:32]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:34]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([O:35][C:32]1[N:31]=[N:30][C:29]([N:14]2[CH2:13][C:12]3[CH2:8][N:9]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:25])[F:26])=[O:17])[CH2:10][C:11]=3[CH2:15]2)=[CH:34][CH:33]=1)[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Reactant: Clc1ccc(OCCc2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCCc3ccccc3)nn1)C2

Procedure:
(3,4,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (example 1b) (500 mg, 1.26 mmol), 3-chloro-6-phenethyloxypyridazine (example 4a) (296 mg, 1.26 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (67.9 mg, 65.6 μmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (81.7 mg, 131 μmol) and cesium carbonate (1.645 g, 5.048 mmol) were stirred in 5 ml of dioxane under an argon atmosphere at 80° C. for 4 h. The reaction mixture was concentrated and admixed with ethyl acetate and water, and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 104 mg (14%), M+H+: 481.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>>[C:23]1([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=2)[NH:16][CH:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][O:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCOc4ccccc4)CC3)c[nH]c12
Yield: 9.3 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), phenol (94 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (4.2 mg, 9.3%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1.Cl>CCO>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][CH:14]=[C:4]3[N:3]=2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Clc1cc(NC2CC2)n2nccc2n1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(Nc2cc(NC3CC3)n3nccc3n2)cc1Cl
Yield: 76.9 %

Procedure:
To 5-chloro-N-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (500 mg, 2.396 mmol) in EtOH (10 mL) was added 4-amino-2-chlorophenol (516 mg, 3.59 mmol) followed by concentrated HCl (0.218 mL, 2.64 mmol). The reaction mixture was stirred at reflux temperature for 4 days. Removed 5 mL of EtOH on rotavap followed by addition of 5 mL of diethyl ether. The resulting solid was filtered off and rinsed with diethyl ether. Dried under nitrogen to provide 582 mg (77%) of 2-chloro-4-(7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)phenol as the HCl salt. LCMS (ES): >95% pure, m/z 316 [M+1]+.
Reaction SMILES: [OH-].[K+].[CH2:3]1[CH:5]2[CH2:6][C:7]3[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9][NH:10][C:11]=3[CH:4]12.Br[CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CS(C)=O>[O:22]1[CH2:23][CH2:24][CH:19]([CH2:18][N:10]2[C:11]3[C@@H:4]4[CH2:3][C@@H:5]4[CH2:6][C:7]=3[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1n[nH]c2c1CC1CC21
Reactant: BrCC1CCOCC1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)c1nn(CC2CCOCC2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
To potassium hydroxide (561 mg, 10.00 mmol) in DMSO (10 mL) was added ethyl 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylate (356 mg, 1.852 mmol) under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour and added 4-(bromomethyl)tetrahydro-2H-pyran (962 mg, 5.37 mmol). The reaction was stirred at room temperature for 1.5 h, poured into 50 mL of ice cold water and added glacial acetic (0.71 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were concentrated under reduced pressure and purified by HPLC to give the title compound (127 mg, 24% yield) as a yellow solid. LCMS m/z=291.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:9]CC)=[O:8])[S:5][CH:6]=1.[OH-].[Na+].Cl.O>C1COCC1.CO.O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1
Reactant: CCOC(=O)c1scc(Br)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Br)csc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of ethyl 4-bromo-3-methyl-2-thiophenecarboxylate (5.0 g, 0.0201 mol) in THF/MeOH/H2O (4:1:1, v/v/v, 50 mL) was added NaOH (1.00 g, 0.0251 mol) and the resulting mixture was stirred at ambient temperature overnight. The mixture was acidified by adding 6 N HCl (100 mL) and water (100 mL). The resulting fine white precipitate was filtered off, washed with water and dried to give 3.80 g (86%) of 4-bromo-3-methyl-2-thiophenecarboxylic acid as a fine white solid, mp 188-189° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.[CH2:28]([OH:32])[CH2:29][CH:30]=[CH2:31]>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21](/[CH:31]=[CH:30]/[CH2:29][CH2:28][OH:32])=[CH:22][CH:23]=1
Reactant: Clc1ccc(Br)cc1
Reactant: C=CCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCC/C=C/c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 52 %

Procedure:
To a suspension of triphenyl phosphine (2.1 g, 8.0 mmole) in 300 ml of triethylamine and 30 ml of acetonitrile under nitrogen is added successively palladium (II) acetate (0.45 g, 2.0 mmole), 1-bromo-4-chlorobenzene (19.1 g, 110 mmole) and 3-buten-1-ol (7.21 g, 100 mmole) in a pressure tube. The tube is sealed and heated in an oil bath to 100° C. for 24 hr. The tube is opened under nitrogen, charged with additional palladium (II) acetate, resealed and heated 20 hr longer at 100°-120° C. The mixture is cooled, vented to nitrogen and partitioned between 300 ml of 2N hydrochloric acid and ether. The layers are separated and the aqueous layer is extracted with two additional volumes of ether. The combined ether extracts are washed with 2×100 ml portions of 2N hydrochloric acid and then dried over sodium sulfate. The filtered ether extract is concentrated under vacuum to give 12.7 g of crude product which is purified by chromatography on silica gel using toluene eluent. There is obtained 9.5 g of the title compound. Rf =0.77 (silica gel, toluene).