Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([O-:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].[K+].CC(C)([O-])C.[K+]>C1COCC1>[F:11][C:12]1[CH:18]=[CH:17][C:15]([O:16][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: [O-]c1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium 4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of potassium t-butoxide in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the reaction mixture was treated with cold H2O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product could be used directly for further transformation.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11]1.O>CS(C)=O>[CH3:9][N:10]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[C@@H:19]2[CH2:4][C@H:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nn(C)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (0.650 g, 15.6 mmol) in dimethyl sulfoxide (5.0 mL) was added a solution of trimethylsulfoxonium iodide (3.34 g, 15.6 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl-2H-indazol-4-yl)acrylate (3.00 g, 13.0 mmol) in dimethyl sulfoxide (30 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (1.10 g, yield 35%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:23][CH:19]2[CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: NC1CCC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(NC2CCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (0.53 g 2 mmol) and cyclobutylamine (1.387 g, 19.5 mmol) in methanol (15 mL) was heated at 70°-75° C. (oil bath) for 29 hours. After cooling to room temperature, 2 mL of 1.0N NaOH was added. The solution was concentrated and the residue chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as colourless foam which solidified to white powder in acetonitrile (454 mg, 75.7%), m.p. 181°-183° C.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:12]([F:22])[CH:11]=2)=[CH:6][N:5]=[C:4]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:19]1([CH2:18][O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([C:9]3[O:23][C:2]4[CH:3]=[C:4]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[N:5]=[CH:6][C:7]=4[N:8]=3)=[CH:11][C:12]=2[F:22])[CH2:21][CH2:20]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2cc(F)c(OCC3CC3)c(F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)-3,5-difluorobenzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (4.40 g), potassium carbonate (2.38 g) and copper(I) iodide (164 mg) in DMF (20 mL) was stirred at 160° C. for 4 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.42 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[C:12]([NH2:20])(=[S:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:20]=[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:19][CH:2]=1
Reactant: NC(=S)c1cccnc1
Reactant: Cc1ccncc1C(=O)CBr
Product: Cc1ccncc1-c1csc(-c2cccnc2)n1
Yield: 39.5 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (432 mg) and thionicotinamide (152 mg), the title compound (110 mg) was obtained as colorless powder crystals.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:11])[NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O>>[CH3:11][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]2[N:1]=[CH:14][CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][CH:23]=3)[N:3]2[N:4]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1c(N)n[nH]c1C
Product: COC(=O)c1c(C)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
As for Example 1, methyl 3-amino-5-methylpyrazole-4-carboxylate is reacted with 3-dimethylamino-3'-(trifluoromethyl)acrylophenone to give the product as crystals, m.p. 177°-179° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=1
Reactant: COCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(3-methoxypropylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-methoxypropylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].C1COCC1>>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 15.7 mL of 1.6 M n-butyllithium (25.1 mmol) in anhydrous other (25 mL) was stirred under Ar at −78° C. and to this was added a solution of 2-bromopyridine (3.97 g, 25.1 mmol) in anhydrous other (12.5 mL). The resulting orange solution was stirred for 2 h, and trimethyltin chloride in THF (26.0 mmol, 26 and, 1.0 M) added over 30 min. The reaction was stirred for 1 h at −78° C. then warmed to room temperature over 1 h, filtered and the filtrate evaporated. Distillation afforded 3.1 g (51%) of the title compound as a colorless liquid which solidified in the receiver flask. B.p. 65° C./2 mm Hg; Literature B.p. 75° C./4 mm Hg.
Reaction SMILES: [OH-:1].[Li+].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]1[CH2:21][CH:20]([C:22]([O:24]C)=[O:23])[NH:19][C:18]1=[O:26].Cl>O.O1CCCC1>[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]([C:18]([OH:1])=[O:26])[CH2:21][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:19]
Reactant: COC(=O)C1CC(Oc2ccc3oc4ccccc4c3c2)C(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc2oc3ccccc3c2c1)C(=O)O)C(=O)O
Temperature: 61 °C
Reaction time: 2.4 h

Procedure:
A mixture of lithium hydroxide (0.0943 g) in water (1.4 ml) and tetrahydrofuran (4.3 ml) was treated with methyl 3-(2-dibenzofuranoxy)-2-pyrrolidone-5-carboxylate (0.427 g), and heated to 61° C. After about 2.4 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (787 ml). The reaction mixture was then treated with water (3 ml). The insolubles were collected by filtration, washed with 1:1 tetrahydrofuran:water (2 ml), tetrahydrofuran (5 ml). The insolubles were dried overnight in at vacuum oven at 70° C. to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:11])=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15]>>[Cl:1][C:2]1[C:3]([I:11])=[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: CCC(N)CC
Reactant: N#Cc1ncc(Cl)c(I)c1F
Product: CCC(CC)Nc1c(C#N)ncc(Cl)c1I
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-chloro-3-fluoro-4-iodopicolinonitrile (46 mg, 0.16 mmol) in 3-aminopentane (1 mL) was heated to 80° C. for 1 h. The reaction mixture was allowed to cool to RT, concentrated in vacuo, and then diluted with EtOAc and water. The organic layer was washed with water and filtered through a silica gel plug to provide the title compound as a white powder (55 mg, 100%) which was characterized by LCMS (m/z=350.1 [M+H]+) and 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]([OH:18])=O)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:16](=[O:18])[NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22](=[O:23])[NH2:24])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC(=O)c1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)Nc1ccccc1C(N)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h
Yield: 53.3 %

Procedure:
A mixture of 4-(1-carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (28.6 g, 0.11 mol), 2-aminobenzamide (13.7 g, 0.1 mol), EDCI (21.3 g, 0.11 mol), HOBT (15 g, 0.11 mol) and Et3N (25 mL) in CH2Cl2 (500 mL) was stirred for 48 hr. The reaction mixture was diluted with CH2Cl2 (1000 mL) and washed with NaHCO3 (aq), the organic layer was dried with Na2SO4 and concentrated in vacuo to give the product a yellow solid (20 g, 48%) which was used directly for the next step.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1NC2CCC1C2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C2CCC(C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (664 mg, 3.92 mmol) in chloroform (8 ml) were added triethylamine (0.55 ml, 3.92 mmol) and 4-methoxybenzene sulfonyl chloride (892 mg, 4.32 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl 2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (927 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9](Br)[CH:8]=[CH:7][CH:6]=2.[CH2:13]([CH:17]([Sn])C=C(CCCC)CCCC)[CH2:14]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:17]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]2)[CH:13]=[CH2:14]
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Reactant: Cc1cc2c(Br)cccc2cn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1cccc2cnc(C)cc12

Procedure:
3-Methyl-5-bromoisoquinoline (1.0 g, 4.5 mmol), tributylallyltin (1.6 mL, 5.0 mmol), and dichlrobis(tri-o-tolylphosphine)palladium (II) were combined in toluene (100 mL) and refluxed for 14 hours. The mixture was cooled, diluted with ethyl acetate, and washed twice with aqueous NH4Cl. The organic phase was separated, concentrated, and the residue was purified by chromatography (ethyl acetate:hexanes, 30:70) to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 9.21 (s, 1H), 8.00 (d, 1H), 7.63 (m, 2H), 7.58 (m, 1H), 4.18 (s, 2H), 3.62 (s, 3H), 2.62 (s, 3H). MS (DCI/NH3) m/e 216 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CS(C)=O.Cl.[NH+]1C=CC=CC=1>O>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4]1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
4-(6-Methoxypyridin-3-yl)benzoic acid (3.34 g, 14.6 mmol), dimethylsulfoxide (6 mL), and pyridinium hydrochloride (8.43 g, 72.9 mmol) were heated together, with stirring, at 160° C. for 15 minutes. The reaction mixture was cooled to ˜90° C., and water added slowly (100 mL). The solution/suspension was cooled to 0° C., the precipitate filtered off and washed with water. The wet product was dried by azeotroping off the residual water with methanol to give the product as a white solid (2.38 g, 11.1 mmol). 1H NMR (DMSO) δ 7.93 (d, 2H), 7.91-7.78 (m, 2H), 7.68 (d, 2H), 6.43 (d, 1H). ESI MS (M+1)+: 216.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=NN)[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:16]([N:22]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]1=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CO>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:16]([N:22]1[C:23](=[O:28])[CH:24]2[CH:25]([C:10]2([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:11][CH2:12][CH3:13])[C:26]1=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=NN)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCN1C(=O)C=CC1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCN1C(=O)C2C(C1=O)C2(CCC)c1cccc([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1-(3-Nitrophenyl)-1-butanone hydrazone (Preparation 63, 1.0 g, 4.8 mmol) was dissolved in dioxan (20 ml) and cooled to 10° C., manganese dioxide (grade CMD-1 from Sumitomo, 10 g, 117 mmol) was added portionwise. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. This suspension was filtered over a pad of Celite® directly into a solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 0.88 g, 4.5 mmol) in dioxan (20 ml). The Celite® pad was washed with dioxan (125 ml) and then stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo to give a crude orange oil. Methanol (8 ml) was added and the mixture was cooled to 0° C. and upon scratching a white solid precipitated. The solid was filtered off and washed with cold methanol to give the pure product, the mother liquors were concentrated in vacuo and treated again with methanol under the procedure described above to give further product. The title compound was obtained as a white solid (0.28 g, 16%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(O)CO>O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: OCCO
Product: CCOC(=O)Cn1c(-c2cccc(C(F)(F)F)c2)nc2cccnc21
Yield: 88.3 %

Procedure:
A mixture of N-[3-[[3-(trifluoromethyl)benzoyl]amino]-2-pyridinyl]glycine ethyl ester (22.0 g, 0.06 mole) and ethylene glycol (100 ml) was heated at reflux for 40 minutes. The reaction mixture was poured into water (300 ml) and cooled. The solid was collected by filtration, washed with water (200 ml), and dried. The solid was recrystallized from isopropyl ether/tetrahydrofuran to give in 2 crops 18.4 g (0.053 mole) of crude 2-(3-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester. This solid together with potassium hydroxide pellets (4.7 g, 0.084 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed for 21/2 hrs. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (100 ml) and extracted wth methylene chloride (2×30 ml). The aqueous portion was acidified with glacial acetic acid and filtered after precipitation was complete. The filter cake was suspended in water (200 ml) and filtered. Recrystallization from tetrahydrofuran-isopropyl ether gave 15.3 g (91%). A 1.6-g sample was recrystallized from tetrahydrofuranisopropyl ether to give 1.0 g of an off-white solid, mp 240°-241.5° C.
Reaction SMILES: C(Cl)Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:16](=[O:17])[C:15]=2Br)=[CH:6]1.ClS(O)(=O)=O.CC(C)C(N)=O.[CH3:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(#N)C>[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:16](=[O:17])[C:15]=2[C:36]2[CH:35]=[CH:34][CH:39]=[CH:38][CH:37]=2)=[CH:6]1
Reactant: CN1C(=O)C(Br)=C(c2cn(C)c3ccccc23)C1=O
Reactant: CCCCCC
Agent: CC(C)C(N)=O
Agent: O=S(=O)(O)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CN1C(=O)C(c2ccccc2)=C(c2cn(C)c3ccccc23)C1=O
Temperature: 25 °C

Procedure:
Into methylene chloride (83 ml) was dissolved the resultant IM-4 (25 g, 80.5 mmol) obtained as described above, and to this was added dropwise chlorosulfonic acid (8.3 ml) at room temperature. After this mixture was stirred for an hour at room temperature, to the reaction system were added dropwise at a low speed dimethylacetoamide (90 ml)/acetonitrile (45 ml). To this was added dropwise oxy-salt phosphor (15 ml) while being heated and refluxed. After this mixture was heated and refluxed for an hour, hexane (150 ml) was added, then, the mixture was stirred and stood still, and thereafter, the upper layer of hexane was separated and concentrated. The concentrated substances were refined with silica gel column chromatography to obtain 21 g of IM-5.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: NCCN1CCSCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 150 ml of methylene chloride under nitrogen atmosphere add 3.1 g (14.3 mmole) of 4-thiomorpholinethanamine and 4.42 g (43.6 mmole) of triethylamine. Stir the mixture at ambient temperature for 1 hour, then cool the mixture to -10° C. To the cooled mixture add slowly 3.67 g (15.1 mmole) of 4-[(methylsulfonyl)amino]benzoyl chloride, keeping the temperature below 5° C. When the addition is complete, allow the reaction mixture to stir at ambient temperature. Monitor the progress of the reaction by thin layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 9:1). Upon completion of the reaction, remove the solvent in vacuo. To the resulting solid add 50 ml of water. To the mixture add 50% sodium hydroxide until pH of 14 is reached. Wash the aqueous layer with 3×50 ml of diethyl ether. Add concentrated hydrochloric acid until a white precipitate forms (pH=8.5). Filter the solid and recrystallize from methanol/ethanol to yield the title compound.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N1C(=O)[C:23]([CH3:26])=[C:22]([CH3:27])[N:21]=[C:20]1[C@H:28]([N:32]([CH2:42][CH2:43][N:44]1C(=O)C2C(=CC=CC=2)C1=O)[C:33](=O)[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)[CH:29]([CH3:31])[CH3:30])C1C=CC=CC=1.O.NN>C(O)C>[CH2:4]([N:5]1[C:1](=[O:11])[C:23]([CH3:26])=[C:22]([CH3:27])[N:21]=[C:20]1[C@H:28]([N:32]1[CH2:42][CH2:43][N:44]=[C:33]1[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)[CH:29]([CH3:31])[CH3:30])[C:3]1[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(C(=O)N(CCN2C(=O)c3ccccc3C2=O)[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(C2=NCCN2[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 120 °C

Procedure:
The phthalimide protected amine, N-[(R)-1-(1-benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-N-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-methyl-benzamide, (0.075 g, 0.13 mMol) was treated with hydrazine monohydrate (0.013 ml, 0.26 mMol) in ethanol (1 mL at 70° C. for 12 h. The reaction was filtered, concentrated under vacuum and dissolved in toluene (1 mL) and heated to 120° C. for 20 h. The reaction was concentrated under vacuum, taken up in CH3CN and purified by reverse phase HPLC (YMC, ODS-A, 20 min, 5–90% gradient, CH3CN : H2O, 0.1% TFA) The fractions were collected and evaporated to give the title compound as a clear oil. (0.016 g): MS (ES) m/e 429.4 (M+H)+.