Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:49])[CH:5]([NH:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:37]=1)=[O:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[C:9]([F:32])[CH:8]=1)C.C1(C)C=CC(C2N=C(C(O)=O)C=CC=2)=CC=1.C(OC(=O)C(N)CC1C=CC(C2N=C(C3C=CC(NC(OC(C)(C)C)=O)=CC=3)ON=2)=C(F)C=1)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C([O-])(O)=O.[Na+]>ClCCl>[C:28]([O:27][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([NH:33][C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]5[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=5)[N:37]=4)=[O:35])[C:4]([OH:49])=[O:3])=[CH:8][C:9]=3[F:32])[N:17]=2)=[CH:23][CH:22]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1)NC(=O)c1cccc(-c2ccc(C)cc2)n1
Agent: CCOC(=O)C(N)Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(-c2cccc(C(=O)O)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(-c4noc(-c5ccc(NC(=O)OC(C)(C)C)cc5)n4)c(F)c3)C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
3-{4-[5-(4-tert-Butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluorophenyl}-2-[(6-p-tolyl-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester. A mixture of 6-p-tolyl-pyridine-2-carboxylic acid (47 mg, 0.1 mmol), 2-amino-3-{4-[5-(4-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluorophenyl}propionic acid ethyl ester (30 mg), HATU (46 mg, 0.12 mmol), and Et3N (15 mg, 0.15 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight. TLC showed the reaction was completed. Saturated aqueous NaHCO3 (20 mL) was added to the mixture, and organic and aqueous layers were separated. The aqueous portion was extracted with dichloromethane (2×50 mL). The combined organic layers were washed sequentially with aq. HCl (1N, 2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated to give the title compound (53 mg, 80% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)=[C:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[CH:12][S:13][C:7]4=[N:6][C:5]=3[CH3:14])[CH2:25][CH2:24]2)=[CH:30][CH:31]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: Cc1nc2sccn2c(=O)c1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2sccn2c(=O)c1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 3.8 parts of 6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 3.5 parts of 4-[bis(4-fluorophenyl)methylene]piperidine, 10 parts of sodium carbonate, 0.1 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water-separator. The reaction mixture was filtered hot and the filtrate was evaporaed. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.8 parts of 6-[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 145.5° C. (compound 1).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2=[N:14][C:15]3[C:20]([C:21](=[O:22])[N:12]2[CH:11]=[CH:10][CH:9]=1)=[CH:19][C:18](I)=[CH:17][CH:16]=3)=[O:7].[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2=[N:14][C:15]3[C:20]([C:21](=[O:22])[N:12]2[CH:11]=[CH:10][CH:9]=1)=[CH:19][C:18]([C:27]1[CH:26]=[N:25][C:34]2[C:29]([CH:28]=1)=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:17][CH:16]=3)=[O:7]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CN(C)CCNC(=O)c1cccn2c(=O)c3cc(I)ccc3nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)c1cccn2c(=O)c3cc(-c4cnc5ccccc5c4)ccc3nc12
Temperature: 120 °C
Yield: 66.6 %

Procedure:
A mixture of N-[2-(dimethylamino)ethyl]-2-iodo-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide (750 mg), 3-quinolinylboronic acid (743.47 mg), tetrakis-(triphenylphosphine)palladium(0) (198.67 mg) and sodium carbonate (4.3 ml of 2 M (8.6 mmol))and 33 ml of toluene was heated at 120° C. for 7 hours and cooled to room temperature. The reaction mixture was diluted with 70 ml of water and extracted with 3×70 ml CHCl3. The organic layer was dried over Na2SO4 and evaporated in vacuo to a residue. The residue was purified by column chroma-tography on silica gel by elution with 5-10% MeOH/CHCl3 to give 501 mg of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12]CCl)=[CH:8][S:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[I:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12][O:29][C:26]2[CH:27]=[CH:28][C:23]([I:22])=[CH:24][CH:25]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: Oc1ccc(I)cc1
Reactant: COC(=O)c1cscc1NC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(I)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 4-(3-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester ([51486-30-7], 2.0 g, 8.6 mmol) in dimethylformamide (30 mL) was added potassium carbonate (1.77 g, 12.8 mmol) and 4-iodophenol (2.26 g, 10.3 mmol) and the reaction mixture was then stirred overnight at 90° C. To the reaction mixture was added ethyl acetate (approximately 30 mL). The solid was filtered and washed with ethyl acetate. The filtrate was then reduced in vacuo and dissolved in dichloromethane (approximately 50 mL). The solution was filtered again over charcoal and to the filtrate was added isopropylether. After reducing the solution slowly in vacuo the solid was filtered to yield the title compound (3.57 g, 79%).
Reaction SMILES: C1(=O)C=CC(=O)C=C1.[Cl-].[Li+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][C@@H:23]2[O:28][C:27]3[C:29]([CH2:34][CH:35]=[CH2:36])=[C:30]([NH2:33])[CH:31]=[CH:32][C:26]=3[O:25][CH2:24]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][CH:23]2[O:28][C:27]3=[C:29]4[C:30](=[CH:31][CH:32]=[C:26]3[O:25][CH2:24]2)[NH:33][C:35]([CH3:36])=[CH:34]4)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: C=CCc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=C1C=CC(=O)C=C1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(C)cc4c3O2)cc1
Reaction time: 0.08 h

Procedure:
Bis-acetonitrile (II) chloride (0.153 g, 0.60 mmole), 1,4-benzoquinone (0.64 g, 6.0 mmole) and lithium chloride (2.5 g, 60 mmole) were combined in 85 mL of tetrahydrofuran and the mixture stirred under argon for 5 minutes. A solution of (2R)-[8-allyl-7-amino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzene-sulfonate (2.2 g, 5.9 mmole) in 25 mL of tetrahydrofuran was added and the mixture stirred for 48 hours at room temperature. The mixture was then diluted with 300 mL of ethyl acetate and washed with 200 mL portions of 1 N aqueous HCl, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuum. Column chromatography on silica gel with methylene chloride as eluant gave 1.1 g of the (R)-enantiomer of the title compound as a gray foam. 1H-NMR (CDCl3): doublet 7.8 δ (2 H); broad singlet 7.75 δ (1 H); doublet 7.3 δ (2 H); doublet 6.75 δ (1 H); doublet 6.63 δ (1 H); singlet 6.1 δ (1 H); multiplet 4.5 δ (1 H); multiplet 4.25 δ (3 H); doublet of doublets 4.07 δ (1 H); singlet 2.43 δ (3 H); singlet 2.40 δ (3 H).
Reaction SMILES: [C:1]([C:9]1[N:10](C(OCC)=O)[C:11]2[C:16]([C:17]=1[NH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:23])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:20])[O:21][CH3:22])=[CH:15][CH:14]=[C:13]([Cl:23])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(=O)OC)c2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 2-benzoyl-6-chloro-3-[(methoxycarbonyl)amino]-1H-indole-1-caboxylate (step 3, 680 mg, 1.7 mmol) in ethanol (20 ml) was added 2N aqueous KOH (10 ml) at room temperature. After stirring for 2 h, the mixture was concentrated and extracted with dichloromethane (50 ml×2). The combined organic layers were dried (MgSO4) and concentrated to give an crystalline residue. Recrystallization from ethyl acetate/hexane afforded 320 mg (57%/o) of the title compound as yellow solids.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[C:14]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(Br)cc2)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A mixture of 4-bromophenyl isocyanate (0.179 g, 0.905 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzeneamine (EP 0 533 267 A1) (0.200 g, 0.905 mmol) in toluene were stirred together at room temperature. After 24 h, the resultant precipitate was filtered off, washed with petrol and dried in vacuo to give the title compound as a white solid (0.265 g, 70%). m.pt 199-201° C.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[CH3:7][C:8]1([CH3:16])[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9]1=O>>[C:1]([NH:5][N:6]=[C:9]1[C:8]([CH3:16])([CH3:7])[C:11](=[O:12])[C:10]1([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Product: CC(C)(C)NN=C1C(C)(C)C(=O)C1(C)C

Procedure:
2,2,4,4-Tetramethylcyclobutan-1,3-dione mono-t-butylhydrazone was prepared by refluxing an aqueous solution of t-butylhydrazine with an equimolar amount of 2,2,4,4-tetramethylcyclobutan-1,3-dione.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].I[C:26]1[CH:27]=[N:28][N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: COc1ccc(Cn2cc(I)cn2)cc1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(Cc4ccc(OC)cc4)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:9])[CH:3]=1.Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[ClH:9].[ClH:1].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: ClCc1cccnc1
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(Cc4cccnc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from starting compound A1 and 3-picolylchloride hydrochloride as described for compound 18. M.p. 252-254° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([O:10][C:11]2[C:16]3[C:17]([CH3:21])([CH3:20])[CH2:18][O:19][C:15]=3[C:14]([CH3:22])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O>C1COCC1.[Pd]>[CH3:20][C:17]1([CH3:21])[C:16]2[C:11]([O:10][C:7]3[N:6]=[CH:5][C:4]([NH2:1])=[CH:9][N:8]=3)=[CH:12][CH:13]=[C:14]([CH3:22])[C:15]=2[O:19][CH2:18]1
Reactant: Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)c2c1OCC2(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
5-nitro-2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyrimidine (Intermediate 32, 243 mg, 0.81 mmol) was dissolved in THF (4 mL) and Palladium on charcoal (5 mol %, 85 mg) was added. The reaction mixture was stirred under hydrogen atmospèhere (3 bar) for 1 hour at room temperature. The catalyst was filtered on a pad of celite, washed with THF and the resulting solution was concentrated under vacuum. The residue was diluted with ethyl acetate and water, the organic phase collected, dried over Na2SO4 and evaporated to afford the title compound (220 mg) as colorless oil. The crude product, was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:22]([O:23][C:24]([O:26]C3C=CC=CC=3)=O)[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[C:15]2=[O:33])=[N:12][CH:13]=1>C(#N)C.C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:22]([O:23][C:24]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[O:26])[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[C:15]2=[O:33])=[N:12][CH:13]=1
Reactant: C1CNCCN1
Reactant: O=C(Oc1ccccc1)OC1c2nccnc2C(=O)N1c1ccc(Cl)cn1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(OC1c2nccnc2C(=O)N1c1ccc(Cl)cn1)N1CCNCC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
Anhydrous piperazine (86 g.) is added to a suspension of 6-(5-chloropyrid-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (76.4 g.) in acetonitrile (760 cc.). The reaction mixture is stirred for 5 hours at a temperature of about 20° C. and then the insoluble product is filtered off, washed with acetonitrile (3×25 cc.) and with diisopropyl ether (50 cc.). After drying, a product (30.8 g.) is obtained and is dissolved in methylene chloride (750 cc.). A small amount of insoluble matter is removed by treating the solution with decolourising charcoal (2 g.). After filtration, the solution is concentrated to dryness under reduced pressure. 6-(5-Chloropyrid-2-yl)-7-oxo-5-(piperazin-1-yl)carbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (28.3 g.), which melts at 205° C., is thus obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([F:10])[F:9])=[CH:4][C:3]=1[F:11].C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[F:9][CH:8]([F:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:20]=[O:21])=[C:3]([F:11])[CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(C(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of 1-bromo-4-(difluoromethyl)-2-fluorobenzene (311 mg, 1.382 mmol) in THF (2.99 mL) was added butyllithium (1.6M solution in hexanes; 0.881 mL, 1.410 mmol) over ˜5 min at −78° C. The reaction mixture was stirred for 30 min at −78° C. then DMF (0.161 mL, 2.073 mmol) was added dropwise over ˜1 min. Stirring was continued for 20 min. The reaction mixture was quenched with aqueous 1M HCl solution/MeOH (2:1, 3 mL) and allowed to warm to room temperature. The mixture was diluted with 5 mL of water. The separated aqueous layer was with ether (5 mL). The combined organic layers were washed with 1M aqueous NaOH solution (10 mL) and saturated brine (10 mL), dried over MgSO4, filtered off and concentrated under reduced pressure. Repeated reaction with 420 mg of 1-bromo-4-(difluoromethyl)-2-fluorobenzene and combined crude materials for purification. The crude material was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate], providing 4-(difluoromethyl)-2-fluorobenzaldehyde (162.8 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C:40](=[O:44])[CH2:39]2)[C:34]([F:45])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C:40](=[O:44])[CH2:39]4)[C:34]([F:45])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
A microwave tube was placed 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (2.13 g, 4.93 mmol) and (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone in DME (22.2 mL) and aqueous Na2CO3 (5.13 mL of 2 M solution, 10.26 mmol) solution. The mixture was deoxygenated with nitrogen for 20 min. To the reaction mixture was added tetrakis triphenylphosphane palladium (0.47 g, 0.41 mmol). The reaction was sealed and heated to 120° C. for 30 min. The reaction was diluted with ethyl acetate (40 mL), filtered through Celite. The filtrate was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification via silica gel chromatography using 10-80% EtOAc/hexanes gradient afforded (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 64a.
Reaction SMILES: N([O-])=O.[Na+].FC(F)(F)C(O)=O.[CH2:12]([S:14]([C:17]1[CH:44]=[CH:43][C:20]([O:21][C:22]2[C:23]([CH:37]3[O:41][CH:40]([OH:42])[CH2:39][CH2:38]3)=[CH:24][C:25]3[N:29]=[C:28]([C:30]4[CH:35]=[N:34][CH:33]=[CH:32][N:31]=4)[NH:27][C:26]=3[CH:36]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13]>>[CH2:12]([S:14]([C:17]1[CH:44]=[CH:43][C:20]([O:21][C:22]2[C:23]([CH:37]3[O:41][C:40](=[O:42])[CH2:39][CH2:38]3)=[CH:24][C:25]3[N:29]=[C:28]([C:30]4[CH:35]=[N:34][CH:33]=[CH:32][N:31]=4)[NH:27][C:26]=3[CH:36]=2)=[CH:19][CH:18]=1)(=[O:15])=[O:16])[CH3:13]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2C2CCC(O)O2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2C2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium nitrite (5 mg) was added to a trifluoroacetic acid (1 ml) solution of 5-(6-(4-(ethylsulfonyl)phenoxy)-2-pyrazin-2-yl-1H-benzimidazol-5-yl)tetrahydrofuran-2-ol (3.3 mg) obtained in Example 9, and the reaction liquid was stirred at room temperature for 10 minutes. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid), and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow foamy substance.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[N:21][CH:22]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(N2CCN(c3ccc4ncsc4c3)C2=O)cn1
Yield: 51.7 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.685 mmol) was reacted with 5-bromo-2-methyl-pyridine (140.5 mg, 0.822 mmol), 1,4-dioxane (10 mL), copper iodide (12.92 mg, 0.068 mmol), trans-1,2-diamino cyclohexane (23 mg, 0.205 mmol) and potassium phosphate (435 mg, 2.055 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 110 mg of the product (51.80% yield).