Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]([OH:17])=O.S(Cl)(Cl)=O.[C:22]([C:27]1[CH:37]=[C:36]([C:38]([CH2:41][CH3:42])([CH3:40])[CH3:39])[CH:35]=[CH:34][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][NH2:33])([CH2:25][CH3:26])([CH3:24])[CH3:23].N12CCN(CC1)CC2>C1C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]([NH:33][CH2:32][CH2:31][CH2:30][O:29][C:28]1[CH:34]=[CH:35][C:36]([C:38]([CH2:41][CH3:42])([CH3:39])[CH3:40])=[CH:37][C:27]=1[C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[O:17]
Reactant: CCOc1cc(C(=O)O)c(O)c2ccccc12
Reactant: CCC(C)(C)c1ccc(OCCCN)c(C(C)(C)CC)c1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOc1cc(C(=O)NCCCOc2ccc(C(C)(C)CC)cc2C(C)(C)CC)c(O)c2ccccc12
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
A mixture of 23.2 g of Intermediate 1 prepared above, 18 g of thionyl chloride, and 100 ml of benzene was stirred for 3 hours at 40-45° C and after adding to the mixture a solution of 60 g of -(2,4-di-tert-amylphenoxy)propylamine, 23 g of 1,4-diazabicyclo[2,2,2]octane, and 100 ml of benzene, the resultant mixture was stirred for 2 hours to provide the desired product. The solvent used for the recrystallization of the product was methanol. The melting point of the product was 130-131° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH3:34].CO>>[NH3:8].[NH2:34][CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29])=[CH:23][CH:22]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: N
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Temperature: 140 °C

Procedure:
To a 20 mL of microwave vial was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (1.0 g, 1.9 mmol, Intermediate B) and ammonia, 2M solution in methanol (9.5 mL, 19 mmol, Aldrich, St. Louis, Mo.). The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. The reaction mixture was concentrated and the crude product was purified by column chromatography (80 g of silica gel, 100% CH2Cl2 first then 2 to 5% 2M NH3 in CH2Cl2) to afford 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.540 g) as a white foam.
Reaction SMILES: C12BC(CCC1)CCC2.[F:10][C:11]([F:33])([F:32])[CH2:12][NH:13][C:14]([C:16]1([CH2:29][CH:30]=[CH2:31])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15].[OH-:34].[Na+].OO>C1COCC1.O>[F:10][C:11]([F:32])([F:33])[CH2:12][NH:13][C:14]([C:16]1([CH2:29][CH2:30][CH2:31][OH:34])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15]
Reactant: C=CCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)C1(CCCO)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12 ml of 9-borabicyclo[3.3.1]nonane are added dropwise to a solution of 1.5 g (4.52 mmol) of 9-allyl-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide in 40 ml of THF under nitrogen. Then the mixture is stirred for three hours at ambient temperature. 6 ml of 1M sodium hydroxide solution and 4 ml of 33% hydrogen peroxide solution are then added successively and the resulting mixture is stirred for one hour. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=1:1).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1([C@@H:19]2[CH2:23][O:22][C:21](=[O:24])[NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:24]=[C:21]1[N:20]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[C@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][O:22]1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CCOC(=O)c1ccc(N2C(=O)OC[C@H]2c2ccccc2)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using ethyl 4-iodobenzoate (1.7 mL) and (R)-(−)-4-phenyloxazolidin-2-one (2 g), the title compound (4 g) was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[O:10][CH2:9]2)=O.Cl.[OH-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[O:10][CH2:9]2
Reactant: O=C(CCl)Nc1ccc2c(c1)COC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1OCc2cc(NCCCl)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a suspension of 2-chloro-N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-acetamide (1.0 g, 4.43 mmol) in THF (15 ml) was added 2M borane-methyl sulfide complex solution in THF (6.6 ml, 13.2 mmol) under nitrogen. After stirred at 60° C. under nitrogen for 2 hours, the resulting mixture was cooled in an ice bath, followed by the addition of aqueous HCl solution. The mixture was stirred at room temperature for 20 minutes, then heated at 60° C. for 40 minutes. After cooled to room temperature, the mixture was basified with aqueous NaOH solution, and then it was partitioned between water (50 ml) and CHCl3 (50 ml). The aqueous layer was extracted with CHCl3 (2×50 ml). The combined organic layers were washed with water, dried over anhydrous Na2SO4 Removal of the solvent led to a crude product. Trituration of the crude product with MeOH gave 5-(2-chloro-ethylamino)-3H-isobenzofuran-1-one as a light brown solid (0.4 g, 42%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:15])([CH3:14])[CH2:12]Cl)[CH:5]=1>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:12][C:11]([CH3:15])([CH3:14])[C:6]=2[CH:5]=1
Reactant: CC(C)(CCl)c1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a stirred, cooled (ice bath) suspension of sodium hydride (60% dispersion in mineral oil, 0.024 g, 0.6 mmol) in 10 mL of anhydrous tetrahydrofuran under argon, a solution of 4-bromo-2-(2-chloro-1,1-dimethyl-ethyl)phenol (Intermediate 1, 0.13 g, 0.5 mmol) in 2 mL of anhydrous tetrahydrofuran was added. After 0.5 h, the excess sodium hydride was quenched with methanol and the reaction mixture was evaporated in vacuo. The residue was diluted with water, extracted with ether and the organic phase was washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography of the oil over silica gel (230-400 mesh) using 2.5% ethyl acetate in hexane as the eluent afforded the title compound as a pale yellow oil (0.085 g, 75.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[O:9]=[C:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:15]2[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][C:10]2=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)C(=O)C1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1-bromo-4-iodo benzene (1.00 g, 3.53 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (0.71 g, 3.53 mmol), N,N′-dimethylethane-1,2-diamine (62 mg, 0.71 mmol), CuI (0.135 g, 0.71 mmol) and K3PO4 (2.25 g, 10.6 mmol) in DMF (50 mL) was stirred at 100° C. for 3 h. The mixture was partitioned between 0.1 N HCl and 2:1 hexanes:EtOAc. The organic layer was washed with saturated aq. NaHCO3 and concentrated. Purification by chromatography on silica gel (20 to 35% EtOAc in hexanes provided the title compound: LCMS m/z 356.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.7 Hz, 2 H),7.17 (d, J=8.7 Hz, 2 H),4.23 (s, 2 H), 3.77 (m, 2 H),3.70 (m, 2 H),1.48 (s, 9 H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow foam (35%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[N:44]=[CH:43][C:42]3[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=3)[C:36]2=[O:50])=[CH:33][CH:32]=[CH:31][C:30]=1[B-](F)(F)F)(=[O:26])[CH3:25].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.O.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]>[C:24]([O:27][CH2:28][C:29]1[C:30]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:31][CH:32]=[CH:33][C:34]=1[N:35]1[N:44]=[CH:43][C:42]2[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:47])([CH3:46])[CH3:48])[CH:41]=2)[C:36]1=[O:50])(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 110 °C
Yield: 75.6 %

Procedure:
A mixture of 6-chloro-2-methyl-4-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (1.06 g, 3.18 mmol), potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (1.51 g, 3.18 mmol), xPhos (227 mg, 476 μmol) and potassium phosphate (1.48 g, 6.99 mmol) in 60 ml of butanol/water (5:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (137 mg, 238 mmol) was added. The reaction mixture was heated to 110° C. for 3 hr. The crude reaction mixture was extracted with DCM, washed with water, dried over Na2SO4, filtered and concentrated to form a solid during concentration. This solid was triturated with ether to afford 1.67 g of crude product. Combined with 300 mg of crude material from a previous batch and purified by silica chromatography to afford 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (1.6 g) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH:7]([C:13]1[C:18](I)=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:21]([O:23][C:24]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[C:25]#[CH:26])[CH3:22]>C(#N)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:26]#[C:25][C:24]([O:27][CH2:28][CH3:29])([O:23][CH2:21][CH3:22])[O:30][CH2:31][CH3:32])[C:13]=1[C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C#CC(OCC)(OCC)OCC
Reactant: CCOC(=O)C(CCOCCBr)c1c(Cl)cccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C1(c2c(Cl)cccc2C#CC(OCC)(OCC)OCC)CCOCC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of ethyl 4-(2-bromoethoxy)-2-(2-chloro-6-iodophenyl)butanoate (5.8 g, 12 mmol) and TEA (15 mL, 110 mmol) in 24 mL ACN was degassed by vacuum and back filled with nitrogen 3 times. The mixture was treated with 3,3,3-triethoxyprop-1-yne (2.7 g, 16 mmol), dichlorobis(triphenylphosphine)palladium(ii) (0.17 g, 0.24 mmol) and copper(I) iodide (0.12 g, 0.61 mmol). The mixture was stirred at 55° C. for 2 hours. The mixture was cooled to room temperature, diluted with 100 mL EtOAc, and washed with water (3×20 mL) and then with 20 mL saturated NaCl. The organic layers were dried and concentrated. The crude product was evaporated from 50 mL toluene and dissolved in 50 mL DMF. The mixture was treated with 0.7 g NaH. The mixture was stirred at room temperature for 15 hours. The mixture was quenched with 50 mL water and neutralized with 10% HCl to pH=5. The mixture was then extracted with ether (3×100 mL). The combined organic layers were washed with water (3×20 mL) and saturated NaCl (20 mL), and then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (10% EtOAc/hexane) to give 2.42 g yellow oil. MS m/e: (M+H)+ 487.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[CH:21][CH:22]=[O:23])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc2cccnc2c1
Product: O=CC=Cc1ccc2cccnc2c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 7-quinolinecarboxaldehyde (prepared as described in J. Med. Chem. 1993, 36, 3308) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:11]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26][CH2:25]2)=[O:17])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CC(=O)Nc1ccc(C#N)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(C#N)cc2)CC1
Yield: 46.5 %

Procedure:
In a manner similar to the procedure described in Example B except that a 100 milliliter three-necked Morton flask was used, 10.0 grams (43.0 mmol) of ethyl 3-[(4-cyanophenyl)amino]-3-oxopropanoate, 14.8 grams (108.0 mmol) of anhydrous potassium carbonate, 40 milliliters of anhydrous dimethylformamide and 3.7 milliliters (43.0 mmol) of 1,2-dibromoethane were reacted for a period of 8 days to give 5.19 grams (20.0 mmol) of ethyl 1-(4-cyanophenylaminocarbonyl)cyclopropanecarboxylate as a colorless solid having a melting point of 132.0° C.-133.5° C. The total yield was 47 percent. An analytical sample was prepared by recrystallization from hexane-ethyl acetate having a melting point of 133.0° C.-134.0° C. NMR analysis of the product indicated the following:
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:63][C:64]1[CH:72]=[CH:71][C:67]([C:68](O)=[O:69])=[CH:66][CH:65]=1>CN(C=O)C.O>[F:63][C:64]1[CH:72]=[CH:71][C:67]([C:68]([N:38]2[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][CH:28]=3)=[O:22])[CH2:36][CH2:37]2)=[O:69])=[CH:66][CH:65]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(F)cc2)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 47.3 %

Procedure:
DIPEA (77.35 mg, 0.60 mmol) was added to a stirred solution of biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (70 mg, 0.16 mmol) in DMF (2 mL). HOBT (19.8 mg, 0.14 mmol) and EDCI.HCl (63.74 mg, 0.33 mmol) were then added. After 2 minutes 4-fluorobenzoic acid (18.6 mg, 0.133 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water and the product was precipitated and filtered to afford 28 mg (46.7% yield) of biphenyl-4-carboxylicacid {2-[4-(4-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 94.8%, 1H NMR Values: (CDCl3) δ 7.9 (d, 2H), 7.7-7.6 (q, 4H), 7.5-7.4 (m, 5H), 7.3 (t, 1H), 7.2-7.1 (t, 2H), 4.4 (d, 2H), 4.0-3.5 (d, 8H).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)[CH:12]=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:35](=[O:36])[CH2:34][NH:33][C:32]2=[S:37])=[CH:27][CH:26]=1>C(O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)/[CH:12]=[C:34]1/[C:35](=[O:36])[N:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[C:32](=[S:37])[NH:33]/1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: COc1ccc(N2C(=O)CNC2=S)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(N2C(=O)/C(=C/c3ccc(-n4cnc(C)c4)c(OC)c3)NC2=S)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
Piperidine (0.019 mL) was added to an ethanol (2 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (20 mg) obtained in Example 1 and 3-(4-methoxyphenyl)-2-thioxoimidazolidine-4-one (21 mg), and heat-refluxing of the reaction solution was carried out for 12 hours. The reaction solution was allowed to be cooled to room temperature and the solid deposited was separated by filtering, and 18 mg (47%) of the title compound was obtained by washing with ethanol and ether. The physical properties of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 60 °C
Yield: 82.4 %

Procedure:
1-Bromo-4-(bromomethyl)benzene (8.078 g, 32.3 mmol) and tert-butyl piperazine-1-carboxylate (6.625 g, 35.6 mmol) were dissolved in DMF (40 ml) and K2CO3 (8.93 g, 64.6 mmol) was added. The reaction mixture was heated to 60° C. for 4 h and then filtered through a pad of celite. The filtrate was evaporated and the residue was triturated in hexanes to produce compound 451 as white solid (9.46 g, 82% yield). LCMS: 255.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](Cl)[C:8]=1Cl)[NH2:5].[Cl:11][C:12]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:11][C:12]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: Nc1cccc(Cl)c1Cl
Product: Nc1cccc(Cl)c1

Procedure:
Example 9 is repeated, the 3,4,5-trichloroaniline being replaced by 2,3-dichloroaniline. After a reaction time of 28 hours under the same conditions, 3-chloroaniline is obtained with a yield of 100% for a degree of conversion of 100% of the 2,3-dichloroaniline. The degree of hydrodechlorination of the solvent is 0.09%.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])=[O:22]
Reactant: Cc1cccc(Cl)c1N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: Cc1cccc(Cl)c1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 29 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound (0.31 g, 29%). EI-MS m/z 322 (M+H)+
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]=[O:26])[CH:23]=4)[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[CH3:36][Mg]Br>C1COCC1>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:26])[CH3:36])[CH:23]=4)[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C=O)cc34)nc12
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C(C)O)cc34)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
In a round-bottomed flask, 2-(5-formyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (111 mg, 0.225 mmol) was suspended in THF (3 ml). The pale yellow suspension was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether, 0.23 ml, 0.69 mmol) was added dropwise. The dark red suspension was stirred at 0° C. for 1 h then quenched with saturated aqueous NH4Cl and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-80% EtOAc) to afford 42 mg (37%) of 2-[5-(1-hydroxy-ethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a light yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:17]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:30]4[CH2:29][CH2:28][N:27]([C:17]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[O:18])[CH2:32][CH2:31]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: O=C(OCc1ccccc1)N1CCN([C@H]2CC[C@H](c3ccc4c(c3)OCO4)CC2)CC1

Procedure:
4-(1,3-Benzodioxol-5-yl)cyclohexanone and carbobenzyloxy piperazine were reacted as described in example 9 to give the product (31%, mp: 107°-108° C.). Calc'd for C25H30N2O4 : C, 71.07%; H, 7.16%; N, 6.64%. Found: C, 70.95%; H, 7.16%; N, 6.36%.