Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[CH3:23][NH2:24]>C(O)C>[CH:9]1([CH2:8][C@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][NH:24][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Solvent: CCO
Product: CNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 55 °C
Yield: 47 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (28 g, 83.6 mmol) was dissolved into a solution of methylamine in ethanol (about 30% by weight, 300 mL). The reaction was heated at 50-60° C. overnight and concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine (2×100 mL), dried over MgSO4, and concentrated to give the crude product. This crude product was purified by flash chromatography (AcOEt:Hex.=2:1 first, then EtOAc:MeOH=1:1) to afford pure (S)-tert-butyl 1-cyclohexyl-3-(methylamino)propan-2-ylcarbamate (10.6 g, 47%). 1H NMR (400 MHz, CDCl3): 4.81 (brs, 1H), 3.89 (m, 1H), 2.77 (m, 2H), 2.54 (s, 3H), 2.44 (m, 2H), 1.78 (m, 1H), 1.67 (m, 4H), 1.44 (s, 9H), 1.50-1.10 (m, 6H), 1.00-0.77 (m, 2H), 0.05 (s, 9H). MS (E/Z): 271 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Cl[C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][N:44]=1>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][N:44]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
2 M aqueous Na2CO3 solution (1.04 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.50 g) and 6-chloro-nicotinonitrile (0.22 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 5 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (51 mg) is added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2→80:20) to afford (S)-6-(4-{(S)-1-[6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-nicotinonitrile as an oil (0.50 g) which is crystallized from a mixture of ethyl acetate (15 mL) and iPr2O (5 mL). Yield: 0.32 g (67% of theory). Mass spectrum (ESI+): m/z=456 [M+H]+. mp=160-162° C.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[CH:16]1>N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[CH:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 194.5 %

Procedure:
4-Morpholinecarbonyl chloride (0.15 ml, 1.3 mmol) was added to a stirring solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.3 g, 1.2 mmol) and pyridine (70 ml). The reaction was maintained at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.86 g of N4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-morpholinecarboxamide as a tan powder, m.p. 177.0–179.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.47 (t, J=7.1 Hz, 1H), 7.28 (t, J=7.1 Hz, 1H), 6.72 (broad s, 2H), 6.52 (t, J=5.4 Hz, 1H), 4.61 (t, J=6.9 Hz, 2H), 3.48 (t J=4.6 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H), 3.05 (m, 2H), 1.84 (m, 2H), 1.44 (m, 2H); MS (EI) m/e 368.1966 (368.1961 calcd for C19H24N6O2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]2[N:23]([CH3:24])[CH:11]([CH2:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH:15]=1)[CH2:10][N:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8]2)=[O:5])[CH3:2].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]2[N:23]([CH3:24])[CH:11]([CH2:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([CH2:19][CH2:20][CH2:21][O:22][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42])[CH:15]=1)[CH2:10][N:9]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:8]2)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1=C(c2cc(CCCO)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(c2cc(CCCO[Si](C)(C)C(C)(C)C)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of compound B3 (3.56 g, 8.17 mmol), imidazole (1.39 g, 20.4 mmol), and TBDMS-Cl (1.85 g, 12.2 mmol) in DMF (70 mL) was stirred at 0° C. for 30 min, then at rt for 1 h. The mixture was diluted with EtOAc and washed with aq. 10% Na2CO3 (2×), and brine (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:6→1:3→1:1) yielded the title compound (2.47 g, 55%). LC-MS: tR=0.94 min; ES+: 550.40.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[C:18](Br)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:24][C:25]1[CH:26]=[C:27](OB(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([NH2:24])[CH:30]=3)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Nc1cccc(OB(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2nc(Cl)c(Br)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2nc(Cl)c(-c3cccc(N)c3)cc2o1
Yield: 40.3 %

Procedure:
The 2-(1-Boc-2-(R)-pyrrolidinyl)-5-chloro-6-bromo furo[3,2-b]pyridine (0.469 g, 1.2 mmol), obtained in Example 50a above, was dissolved in toluene (10 mL). 3-Aminophenyl boric acid (0.445 g, 2.87 mmol), Pd(O) tetrakis(tri-phenylphosphine) (0.04 g) and 2 M aqueous NaHCO3 (1.5 mL) were added to the solution. The mixture was refluxed for two days. The solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 2:1) to afford an oil (0.20 g, 41%). MS (CI/NH3) m/z: 414 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 1.34, 1.46 (s, 9H), 1.95-2.08 (m, 2H), 2.15 (m, 1H), 2.28 (m, 1H), 3.58-3.68 (m, 2H), 4.98, 5.10 (br s, 1H), 6.24 (m, 1H), 6.63 (s, 1H) 6.76 (d, J=9.3 Hz, 2H), 6.82 (d, J=9.3 Hz, 1H) 7.62 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([C:7]1[N:8]=[C:9](Cl)[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:7]1[N:8]=[C:9]([NH:26][CH:23]([CH3:25])[CH3:24])[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(Cl)n1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(NC(C)C)n1
Temperature: 25 °C

Procedure:
A solution of 215 mg of 2-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid methyl ester and 388 mg of isopropylamine in THF (5.0 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated to provide 2-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid methyl ester as a light yellow solid. MS (M+H+)=350.4.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Product: CC(C)S(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and 2-propanesulfonyl chloride (144 mg, 1.01 mmol) affords the title compound. MS (ES) 426 (M+Na), 402 (M−H); HPLC shows 93% purity.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[CH2:11]([C@H:13]1[NH:18][CH2:17][C@@H:16]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[O:15][CH2:14]1)[CH3:12].CCN(C(C)C)C(C)C>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH3:10])[N:3]=[C:2]([N:18]2[C@H:13]([CH2:11][CH3:12])[CH2:14][O:15][C@H:16]([C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:17]2)[CH:7]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1c1cc(Cl)nc(NC)n1
Temperature: 100 °C
Yield: 256.5 %

Procedure:
4,6-Dichloro-N-methyl-2-pyrimidinamine (0.143 g, 0.805 mmol) was added to a 20 mL microwave vial followed by the addition of (2S,5R)-5-ethyl-N-(phenylmethyl)-2-morpholinecarboxamide (0.200 g, 0.805 mmol) in CH3CN (5 mL) and Hunig's base (0.703 mL, 4.03 mmol). The reaction was irradiated at 150° C. for 10 minutes. The reaction was left in the 20 mL sealed microwave vessel and heated to 100° C. over the weekend. The reaction mixture was diluted with water and extracted with EtOAc (2×). The organic layers were combined and dried to afford the title compound (0.805 g) as an oil. LC-MS (ES) m/z=376 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:4]=[O:3])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
116.1 g of 2(S)-benzyloxycarbonylamino-3-cyclohexyl-propionic acid ethyl ester are placed in 2.2 liters of toluene and cooled to -65°. 836 ml of diisobutylaluminium hydride are added dropwise at -65° within 30 minutes and the mixture is then stirred for 20 minutes. Then 84.2 ml of methanol are added dropwise within 10 minutes at -65° and subsequently 825 ml of aqueous potassium sodium tartrate solution without cooling. The reaction mixture is discharged onto 3 liters of potassium sodium tartrate solution/ice and extracted with 5 liters of ether. The ether phase is washed with 2 liters of water, then immediately poured into a solution consisting of 106 g of semicarbazide hydrochloride and 156.5 g of sodium acetate in 620 ml of water and 620 ml of ethanol. The reaction mixture is then stirred at room temperature for 1 hour and subsequently separated in a separating funnel, and the aqueous phase is extracted with 2×1.5 liters of ether. The organic phase is dried over magnesium sulphate and concentrated by evaporation. The crude product is purified by means of flash chromatography (2 kg of silica gel 60, 40-63 μm, eluant A). Concentration by evaporation of the combined product-containing fractions yields the semicarbazone of the title compound, Rf (I)=0.51. 130 g of this semicarbazone are dissolved in 1 liter of THF, and 282 ml of 37% formaldehyde solution and then, at 10°, 143 ml of 0.5N HCl are added thereto. The reaction mixture is stirred at room temperature for 2 hours and is filtered, and the filtrate is washed with 0.5 liter of water, 0.5 liter of NaHCO3 and 0.5 liter of water. The aqueous phases are extracted with 600 ml of ether. The ether phases are dried over magnesium sulphate and concentrated by evaporation. 100 ml of toluene are added to the residue and the whole is concentrated by evaporation to yield the title compound. The latter is further processed immediately.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.B([O-])[O-].CC1(C)C(C)(C)OB([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C:47]([O:49][CH3:50])=[O:48])=[CH:42][CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.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].O1CCOCC1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][C:47]([O:49][CH3:50])=[O:48])=[CH:44][CH:45]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Temperature: 100 °C

Procedure:
Under Ar, 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (429 mg, 1.0 mmol) was mixed with Pd(dppf)Cl2 (82 mg, 0.1 mmol, boronate, methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (480 mg, 1.65 mmol, not very pure), K3PO4 (424 mg, 2.0 mmol) and dioxane (10 mL). The resulting mixture was heated at 100° C. and stirred over night. After cooled to room temperature, the mixture was diluted with EtOAc (100 mL) and filtered through celite. After concentration, the crude was purified with column (silica gel, 10˜30% EA/hexane) gave the product, methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate (188 mg) and recovered the starting material 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (289 mg). HPLC-MS tR=2.50 min (UV254 nm); mass calculated for formula C28H44N4O4Si2 556.3, observed LCMS m/z 557.3 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][N:30]=[C:29]([NH:32][C:33]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5C(OC(C)(C)C)=O)=[O:34])[C:28]=4[CH:47]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][N:30]=[C:29]([NH:32][C:33]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)=[O:34])[C:28]=4[CH:47]=3)=[CH:22][CH:23]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1noc2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc12)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of (S)-tert-butyl 2-(5-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)benzo[d]isoxazol-3-ylcarbamoyl)pyrrolidine-1-carboxylate (TFA salt 400 mg, 0.622 mmol) in DCM (5 mL) was added TFA (2 ml, 26.0 mmol) and the reaction mixture was stirred for 3 h at room temp. The solvents were removed in vacuo and the residue was taken up in 10% Methanol/CH2Cl2 and filtered through an MCX cartridge (Strata XC). The cartridge was washed with methanol and the compound was eluted with a solution of NH3 in methanol (2M). The appropriate fractions were concentrated in vacuo to afford the title compound (248 mg, 0.560 mmol, 90% yield) as yellow solid. 1H NMR (500 MHz, CD3OD) δ 8.31 (s, 1H), 7.93 (dd, J=1.8, 8.9 Hz, 1H), 7.83 (app d, J=8.5 Hz, 2H), 7.68 (app d, J=8.5 Hz, 2H), 7.65 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 4.74 (t, J=7.9 Hz, 1H), 4.37 (s, br, 1H), 3.42-3.47 (m, 1H), 3.32-3.38 (m, 2H), 3.22-3.27 (m, 1H), 2.43-2.51 (m, 2H), 2.30-2.37 (m, 1H), 2.20-2.27 (m, 1H), 2.09-2.18 (m, 2H), 1.98-2.05 (m, 1H). LCMS: Anal. Calcd. for C25H26N6O2: 442; found: 443 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([CH3:23])[C:19](=O)[CH2:20]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([C:19]1[N:7]=[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]2[CH:20]=1)[CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cnccn1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)CBr
Solvent: CCO
Product: CC(NC(=O)OCc1ccccc1)c1cn2ccncc2n1
Temperature: 25 °C

Procedure:
A mixture of pyrazin-2-ylamine (3 g, 31.5 mmol) and (3-bromo-1-methyl-2-oxopropyl)-carbamic acid benzyl ester (12 g, 41.05 mmol) in EtOH (20 mL) was heated to reflux overnight. After completion, the reaction mixture was cooled to rt. EtOH was removed in vacuo. The residue was dissolved in EtOAc and washed with satd. sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-5% MeOH in DCM to provide (1-imidazo[1,2-a]pyrazin-2-yl-ethyl)-carbamic acid benzyl ester: LC-MS (ESI) m/z 297.2 [M+H]+.
Reaction SMILES: [NH4+].[N+:2]([C:5]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16]([O-:19])(=[O:18])=[O:17])([O-])=O>C(O)(=O)C.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:2][C:5]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16]([OH:19])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)O

Procedure:
The 2-(2-nitro-4-trifluoromethylphenoxy)-4,5-dichlorobenzenesulfonic acid, ammonium salt (5 g, 11.2 mmol) was dissolved in acetic acid (75 mL). The mixture was diluted with water (75 mL), and a 20% aqueous solution of titanium trichloride (65 mL) was added. After aqueous workup the crude product was flash chromatographed (silica gel, methylene chloride/ethanol/ammonium hydroxide) to give the title compound. 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 6.94 (dd, 1H),6.87 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O
Product: O=C(NCCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(1-pyrrolidinylsulfonyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-aminopropyl morpholine employing methods similar to those described in Example 202 and was obtained as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.22 (t, J=5.3 Hz, 1 H), 8.57 (s, 1 H), 7.76 (s, 1 H), 7.22 (dd, J=8.5, 5.5 Hz, 2 H), 7.02 (t, J=8.6 Hz, 2 H), 4.39 (t, J=8.0 Hz, 2 H), 4.13 (s, 2 H), 3.84-3.82 (m, 4 H), 3.53 (q, J=6.6 Hz, 2 H), 3.38-3.34 (m, 4 H), 3.06 (t, J=6.5 Hz, 2 H), 2.71-2.62 (m, 6 H), 2.17 (m, 2 H), 1.98-1.93 (m, 6 H); HRMS C30H38FN5O6S (M+H)+ calcd 616.2527, found 616.2609.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1.[CH:33](=O)[CH3:34].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1)[CH3:34]
Reactant: CC=O
Reactant: CC(Nc1cc(-c2cc(N3CC4CC3CN4)c3ccccc3n2)ccn1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCN1C[C@@H]2C[C@H]1CN2c1cc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)nc2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 60 mg (0.14 mmol) {4-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-quinolin-2-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.1 mL (1.8 mmol) acetaldehyde, 113 mg (1.8 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES+): 450 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([Sn](CCCC)(CCCC)[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)CCC.O.CCOC(C)=O>CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-c1nc2ccccc2o1
Temperature: 110 °C
Yield: 200.6 %

Procedure:
A mixture of ethyl 2-chloronicotinate (100 mg, 0.539 mmol), 2-(tributylstannyl)benzo[d]oxazole (314 mg, 0.539 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]-dichloropalladium (II) (39.4 mg, 0.054 mmol) in DMF (2 mL) was heated to 110° C. for 1 h by applying microwave radiation to the mixture. The reaction was repeated on the same scale and the thus obtained reaction mixtures obtained were combined. Excess water and EtOAc were added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and dried over MgSO4. Purification by flash column chromatography (EtOAc/DCM, gradient: 1-10% DCM) provided the title compound (290 mg, 90%);