Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C=O)C>[CH2:53]([O:52][C:50]([N:22]1[CH2:21][CH2:20][CH:19]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=3)[C:15]2=[O:18])[CH2:24][CH2:23]1)=[O:51])[CH3:54]
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(N2Cc3cc(OC(C)C)c(Nc4ncc(Cl)c(Nc5ccccc5S(=O)(=O)C(C)C)n4)cc3C2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m, 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1).
Reaction SMILES: [S:1](=[O:3])=[O:2].[C:4]1([S:10][C:11]([C:14]([Si](C)(C)C)([F:16])[F:15])([F:13])[F:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F-].[Cs+].[B-](F)(F)(F)[F:24].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[S:1](=[O:3])=[O:2].[C:4]1([S:10][C:11]([F:13])([F:12])[C:14]([F:16])([F:15])[S:1]([F:24])(=[O:3])=[O:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)Sc1ccccc1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S=O
Agent: [Cs+]
Solvent: CC#N
Product: O=S(=O)(F)C(F)(F)C(F)(F)Sc1ccccc1
Temperature: 25 °C

Procedure:
A solution of sulfur dioxide was prepared by bubbling sulfur dioxide (1.02 g, 16 mmol) in a solution of anhydrous acetonitrile (20 ml) at ambient temperature. This solution was added to PhSCF2CF2SiMe3 (8 mmol, prepared according to the procedure from example 2) and stirred at ambient temperature under an inert atmosphere. Anhydrous CsF (1.4 g, 9 mmol) was then added to the reaction mixture, which was stirred at ambient temperature overnight. The reaction was monitored by TLC and by 19F NMR (CDCl3) until the disappearance of PhSCF2CF2SiMe3. F-TEDA (2.9 g, 8.2 mmol) was added to the mixture, which was stirred for 1 h at ambient temperature. The mixture was concentrated and the solid residue washed with ethyl ether (10×50 ml). The filtrate was evaporated and the product purified by bulb-to-bulb distillation. The product 2-(phenylsulfanyl)-1,1,2,2-tetrafluoroethane-sulfonyl fluoride was obtained in the form of a colorless liquid (1.86 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>CO.CCOCC.Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([NH:26][CH:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(NC6CCNCC6)cc5)cc34)cn2)c1
Yield: 75.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-((4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (60 mg, 0.10 mmol) was deprotected in methanol/ether HCl (3.0/0.3 ml). This afforded 40 mg (75.4% yield) of the titled. 1H NMR (CD3OD, 400 MHz): δ 9.01-9.00 (d, 1H), 8.71-8.70 (d, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.90-7.87 (m, 2H), 7.37-7.34 (m, 3H), 7.14-7.12 (s, 1H), 7.04-7.01 (m, 2H), 5.46 (s, 2H), 3.95-3.85 (m, 1H), 3.54-3.51 (d, 2H), 3.81-3.72 (t, 2H), 3.30-3.26 (d, 2H), 2.00-1.90 (m, 2H). MS: m/z=466.9 (M+1), HPLC: 96.60% in method A.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])[CH:14]=1)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCOCC1>[CH:5]([NH:8][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])[CH:14]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(C)N
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC(C)C)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.02 mL, 2.0 mmol) was added dropwise (exothermic) to a solution of isopropyl amine (121 mg, 2.0 mmol) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 1 h. Then 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (200 mg, 0.68 mmol) was added. The resulting mixture was then heated at 70° C. for 3 h and then cooled to room temperature and then poured into Seignette's salt and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 4:1) afforded the title compound (204 mg, 93%) which was obtained as a colourless oil. MS: m/e=322.4 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[N:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:3][CH2:2]1>C(O)C.O1CCCC1.[OH-].[Na+]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[N:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:21][CH:20]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cn2)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Ethyl 3-[{[6-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridin-3-yl]carbonyl}(methyl)amino]propanoate (100 mg) synthesized in Example A210 was dissolved in ethanol (0.5 mL)-tetrahydrofuran (0.5 mL), 1N aqueous sodium hydroxide solution (0.4 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, water (0.5 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (0.4 mL) under ice-cooling, and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (77 mg, 80%) as a colorless solid.
Reaction SMILES: CC(C)=O.[CH3:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+:16]([O-])=O)[C:7]=1[NH:19][C:20](=[O:26])[C:21](OCC)=[O:22]>Cl.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[F:13][C:12]([F:15])([F:14])[C:10]1[CH:9]=[C:8]2[C:7]([NH:19][C:20](=[O:26])[C:21](=[O:22])[NH:16]2)=[C:6]([CH3:5])[CH:11]=1
Reactant: CCOC(=O)C(=O)Nc1c(C)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
355 ml of a 15% titanium trichloride solution in aqueous hydrochloric acid are dissolved in 850 ml of water and 850 ml of acetone under a nitrogen atmosphere at 0° C. A solution of 35.5 g (110.8 mmol) of ethyl N-(2-methyl-6-nitro-4-trifluoromethylphenyl)oxamate in 1.7 1 of acetone is slowly added dropwise. The resulting violet solution is stirred at 0° C. for 16 hours. 15% titanium trichloride solution in aqueous hydrochloric acid is then added until, according to 1H-NMR analysis, starting material is no longer detectable. The reaction mixture is filtered off on a suction filter, the filtrate is concentrated and the deposited solid is filtered off again on a suction filter. The crude product is washed with dilute hydrochloric acid and water. The title compound is obtained as a white solid.
Reaction SMILES: [C:1]1(C)C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].COP(CC(=O)C)(=O)OC.[C:30]([O:34][C:35](=[O:45])[NH:36][CH:37]1[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>CC#N.CO>[C:30]([O:34][C:35](=[O:45])[NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([C:43]#[CH:1])[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Agent: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: C#C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of p-toluenesulfonyl azide (10.57 g, 53.1 mmol) in MeCN (660 ml) were added K2CO3 (18.6 g, 134.5 mmol) and (2-oxo-propyl)-phosphonic acid dimethyl ester (7.3 ml, 53.1 mmol). The slurry was stirred at rt for 2 hours and a solution of (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (8.5 g, 37.4 mmol) in MeOH (100 ml) was added and the reaction proceeded overnight. The solvent was removed in vacuo. The residue was partitioned between water (100 ml) and EA (150 ml). The aq. layer was further extracted twice with EA (2×150 ml). The combined extracts were washed with brine and concentrated to dryness. The residue was chromatographed (Hex-EA 3-1) to afford the title alkyne (4.6 g, 55% yield) as a white solid.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]45[CH2:21][CH:16]6[CH2:17][CH:18]([CH2:20][C:14](Br)([CH2:15]6)[CH2:13]4)[CH2:19]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[OH:29][C:23]1[CH:28]=[CH:27][C:26]([C:2]23[CH2:9][CH:8]4[CH2:7][CH:6]([CH2:5][C:4]([C:12]56[CH2:21][CH:16]7[CH2:17][CH:18]([CH2:20][C:14]([C:26]8[CH:27]=[CH:28][C:23]([OH:29])=[CH:24][CH:25]=8)([CH2:15]7)[CH2:13]5)[CH2:19]6)([CH2:10]4)[CH2:3]2)[CH2:11]3)=[CH:25][CH:24]=1
Reactant: BrC12CC3CC(C1)CC(C14CC5CC(CC(Br)(C5)C1)C4)(C3)C2
Reactant: Oc1ccccc1
Solvent: CO
Product: Oc1ccc(C23CC4CC(C2)CC(C25CC6CC(CC(c7ccc(O)cc7)(C6)C2)C5)(C4)C3)cc1
Temperature: 55 °C
Yield: 94.1 %

Procedure:
Into a 10 liter four-necked separable flask equipped with a thermometer, a stirrer, an inlet for nitrogen gas and a reflux condenser, 64.5 g (0.15 moles) of 3,3′-dibromo-1,1′-biadamantane and 1032 g (10.95 moles) of phenol were placed, and the resultant mixture was heated under the refluxing condition at 155° C. for 30 minutes. After the mixture was cooled at the room temperature, 4.3 liters of methanol was added, and the obtained mixture was heated under the refluxing condition at 55° C. for 10 minutes. The formed precipitates were separated by filtration, washed with a flow of methanol and dried at 60° C. under a reduced pressure for 24 hours, and 64.2 g of the product was obtained (the yield: 93.7%).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C[O-].[Na+].[CH:10]1([CH2:13]Br)[CH2:12][CH2:11]1>CO>[CH:10]1([CH2:13][S:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: Sc1nc[nH]n1
Reactant: BrCC1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CC2)n[nH]1
Reaction time: 10 h
Yield: 99.1 %

Procedure:
To a solution of 3-mercapto-1,2,4-triazole (7.1 g) and sodium methoxide (3.8 g) in methanol (100 ml), there was added cyclopropylmethyl bromide (9.5 g), and the resultant mixture was allowed to stand at room temperature for 10 hours. After removal of the solvent, the residue was extracted with chloroform. Evaporation of the chloroform extract gave 10.8 g of 3-cyclopropylmethylthio-1,2,4-triazole. Yield, 99%. M.P., 69°-70° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([OH:27])[CH2:22]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[F:1][C:2]1[C:3]([C:17]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([OH:27])[CH2:22]2)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N[C@@H]1CCC[C@H](O)C1)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (19 mg, 0.07 mmol), (1S,3R)-3-aminocyclohexanol (9.3 mg, 0.081 mmol), 1-hydroxybenzotriazole hydrate (9.0 mg, 0.07 mmol), and triethylamine (10 μL, 0.07 mmol) in tetrahydrofuran (1 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (15 mg. 0.081 mmol). After stirring overnight, the volatiles were removed in vacuo and the compound was purified by silica gel chromatography eluting with 5% methanol in dichloromethane to afford the title compound: (12.1 mg, 0.03 mmol). MS (ESI) m/z (M+H+): 373.2.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27](O)=[O:28])[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN([C:46]([O:50][N:51]1N=NC2C=CC=C[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.ClCCl.C(=O)([O-])O.[Na+]>[CH3:46][O:50][N:51]([CH3:52])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:10][CH:11]=4)[N:33]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid (0.2 g, 0.451 mmol) was dissolved in dimethylacetamide (5 ml). N—O-Dimethylhydroxylamine hydrochloride (53 mg, 0.541 mmol) and di-isopropylethylamine (0.19 ml, 1.08 mmol) were added followed by HBTU (0.21 g, 0.541 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and saturated aqueous sodium hydrogencarbonate was added. The product was extracted into dichloromethane (×2), and the combined organics washed several times with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield 0.2 g, 91%. LCMS RT: 2.41 min, MI: 487 Method: 2.
Reaction SMILES: Br[C:2]1[C:3]([NH2:22])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.N#N.C(N(CC)CC)C.[C:32]([OH:40])(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[CH:38]>O1CCOCC1.C(Cl)Cl.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:22][C:3]1[C:2]([C:38]#[C:37][CH2:36][CH2:35][CH2:34][CH2:33][C:32]([OH:40])=[O:39])=[N:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:4]=1
Reactant: C#CCCCCC(=O)O
Reactant: Cc1ccc(-c2nc(N)c(Br)nc2-c2ccc(C)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc(N)c(C#CCCCCC(=O)O)nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Bromo-5,6-di-p-tolylpyrazin-2-amine (Example 1, step 3) (200 mg, 0.565 mmol) in anhydrous dioxane (10 ml), degassed with N2 was treated with triethylamine (0.708 ml, 5.08 mmol), hept-6-ynoic acid (0.179 ml, 1.129 mmol), copper(I) iodide (32.3 mg, 0.169 mmol) and PdCl2(dppf)-CH2Cl2-adduct (46.1 mg, 0.056 mmol). The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with DCM (10 ml) and dry loaded onto silica. Purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane followed by 20% MeOH in EtOAc afforded the titled compound;
Reaction SMILES: [CH3:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)=[O:3].[Br:13]Br>C(Cl)Cl>[O:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=[C:4]1[C:2](=[O:3])[CH2:1][Br:13]
Reactant: BrBr
Reactant: CC(=O)c1cc2ccccc2o1
Solvent: ClCCl
Product: O=C(CBr)c1cc2ccccc2o1
Reaction time: 2 h

Procedure:
Benzofuran-2-yl methyl ketone (20 g) is dissolved in 100 ml of methylene chloride and 3.2 ml of bromine in methylene chloride is added at 5°-10° C. Then the reaction mixture is stirred at +15° C. for 2 hours. Then it is washed with water, with diluted sodium bicarbonate solution and again with water. The organic phase is dried and evaporated to dryness to give crude 1-(benzofuran-2-yl)-2-bromoethanone.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26]C)[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]=1[O:28]C)=[O:7].B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>ClCCl>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]=1[OH:28])=[O:7]
Reactant: COc1ccc2nc3ccc4c(OC)cccc4c3nc2c1C(=O)NCCN(C)C
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1c(O)ccc2nc3ccc4c(O)cccc4c3nc12
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a cold solution of 4,10-dimethoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (96 mg) in dichloromethane (2 mL) was added a 11.0M solution of boron tribromide in dichloromethane (2.14 mL, 9 equivalents). The reaction mixture was stirred for 16 hours and then ice was added with sodium carbonate and sodium chloride. The organics were extracted into dichloromethane, dried (MgSO4), and the solvent removed in vacuo to yield an orange compound which was recrystallised from dichloromethane/methanol/hexane to yield the title compound (6 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:5]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:6][C:7]([F:10])([F:9])[F:8].[Li+].[BH4-]>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][CH:4]([CH2:3][OH:2])[CH:5]([CH2:6][C:7]([F:8])([F:9])[F:10])[CH2:11][C:12]([F:14])([F:13])[F:15])(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(CC(F)(F)F)CC(F)(F)F)c1ccc(Cl)cc1
Yield: 67.1 %

Procedure:
A solution of 2-(4-chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester (120 mg, 0.27 mmol) in THF (5 mL) was treated with LiBH4 (2M THF, 0.3 mL) for 18 hours at 25° C. The reaction was carefully quenched by the addition of 2M HCl and the organic solvent removed in vacuo. The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, dried over Na2SO4 and evaporated to afford a crude oil which was purified by flash chromatography, eluting with 30:70 EtOAc:hexanes, to provide the title compound as a white solid (75 mg) in 67% yield. Mass Spectrum (−ESI): 412.0 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16](Cl)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:22]4[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccn2c(-c3cccc(Br)n3)cnc12
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN1CCN(c2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine (from Example 38 supra) (1.44 g, 4.65 mmol), 1-methylpiperazine (2.1 g, 21 mmol), and diisopropylethylamine (2.7 g, 21 mmol) in 2-propanol (300 mL) was stirred and heated at reflux overnight. The solution was then cooled to room temperature, concentrated under reduced pressure. The resulted solid was washed with water, partitioned between CH2Cl2 and brine. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (CH2Cl2:CH3OH, 100:1) to give 3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine. (Yield 1.27 g, 73%).
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17]CC)=[O:16])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[OH-].[Li+].Cl>C1COCC1.CO>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([C:15]([OH:17])=[O:16])[CH2:3]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)C1
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of 1-tert-butyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (15 g, 55.3 mmol) in THF (87 mL) and MeOH (87 mL) was added lithium hydroxide(2M in water) (172 mL, 345 mmol) at RT and stirred at same temperature for 15 h. The reaction mixture was cooled in an ice-bath, and adjusted to pH ˜4 by adding 1N HCl solution. The aqueous layer was extracted with ethylacetate (3×200 mL) and the combined organic extracts was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to give desired 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid (13.45 g, 54.2 mmol, 98% yield) as a white solid. This material was directly used for next step with out any further purification. Anal. Calcd. for C12H21NO4 m/z 243.3, found: 242.2 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.31 (s, 1 H) 3.68-3.52 (m, 1 H), 3.32-3.02 (m, 4 H), 1.89-1.82 (m, 1 H), 1.54-1.43 (m, 11 H) 1.06 (s, 3 H).