Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:6][C:7]=1[C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10](F)[CH:9]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CS(C)=O>[Cl:14][C:13]1[C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:6]=2)=[CH:9][C:10]([NH:30][C@H:27]2[CH2:28][CH2:29][C@H:24]([NH2:31])[CH2:25][CH2:26]2)=[N:11][CH:12]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)cnc2Cl)c(Cl)cn1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)cnc3Cl)c(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
To a scintillation vial containing 5-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (10 mg, 0.028 mmol) and TEA (7.80 μl, 0.056 mmol) was added DMSO (1 ml) and trans-cyclohexane-1,4-diamine (32.0 mg, 0.280 mmol). The resulting homogenous reaction mixture was capped and heated to 100° C. in an oil bath for 3 hr. The reaction product was purified by reverse phase preparative HPLC to yield trans-N1-(5-chloro-4-(3-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (7.7 mg, 0.014 mmol, 48.6% yield), LCMS (m/z): 451.1 (MH+), retention time=0.63 min and a TFA salt after lyapholization.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:28])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)=[C:6]([F:29])[CH:5]=[CH:4][C:3]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]([OH:28])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:29])[CH:5]=[CH:4][C:3]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32]
Reactant: COc1cccc(S(=O)(=O)Nc2ccc(F)c(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncccc34)c2F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)Nc2ccc(F)c(C(O)c3c[nH]c4ncccc34)c2F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To N-{2,4-difluoro-3-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-3-methoxy-benzenesulfonamide (92, 0.075 g, 0.12 mmol) in tetrahydrofuran (3.0 mL), was added tetra-n-butylammonium fluoride (0.039 g, 0.15 mmol). The reaction was stirred at room temperature for 20 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to give light yellow solid (93, 0.030 g, 55%). MS(ESI)[M+H+]+=446.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:23])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)=[C:6]([N+:24]([O-])=O)[CH:5]=1)[CH3:2]>[Pd].CCOC(C)=O>[NH2:24][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=1
Reactant: CCOc1cccc(OCC(=O)Nc2ccc(OCC)cc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cccc(OCC(=O)Nc2ccc(OCC)cc2N)c1
Yield: 100.6 %

Procedure:
A 350 mL hydrogenation vessel was charged with nitroarene 48a (14.2 g, 39.4 mmol) and EtOAc (150 mL). To the resultant suspension was added 10% Pd/C (1.5 g). The mixture was hydrogenated on a Parr shaker at 58 psi overnight. The catalyst was filtered off on glass fiber paper and rinsed with EtOAc (75 mL). The filtrate was concentrated in vacuo to give 13.1 g of 49a as a white solid (100%). 1H NMR (300 MHz, CDCl3): δ 8.01 (s, 1H), 7.27 (d, 1H), 7.24 (d, 1H), 7.08 (d, 1H), 6.63-6.55 (m, 3H), 6.40-3.32 (m, 2H), 4.64 (s, 2H), 4.04 (qt, 2H), 3.99 (qt, 2H), 3.82 (bs, 2H), 1.44 (t, 3H), 1.41 (t, 3H) ppm. HPLC analysis (10:10:80 H2O:A1:MeOH) showed a purity of 98% with a retention time of 3.7 min.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:36][C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[N:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11]([C:32]4[S:36][C:35]([N:37]5[CH2:38][CH2:39][O:40][CH2:41][CH2:42]5)=[N:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Brc1cnc(N2CCOCC2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@@H](Oc1nc(-c2cnc(N3CCOCC3)s2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 15.5 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (165.5 mg, 0.401 mmol), 4-(5-bromothiazol-2-yl)morpholine (120 mg, 0.482 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (1.20 mL, 1.20 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (23.2 mg, 0.02 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH: DCM=5:95) to give brown solids, 28.3 mg (yield 15.5%). 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 5.38 (p, J=5.9 Hz, 1H), 3.76-3.69 (m, 4H), 3.69-3.60 (m, 1H), 3.42 (m, 4H), 3.40-3.36 (m, 1H), 3.23-3.13 (m, 1H), 2.93-2.71 (m, 1H), 2.33-2.30 (m, 2H), 1.39 (d, J=6.1 Hz, 3H), 1.12-1.09 (m, 2H), 1.09-1.02 (m, 2H) ppm; MS (ESI+) m/z 455.18 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=2)=[CH:4][C:3]=1[O:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)=[CH:4][C:3]=1[O:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1coc(Nc2ccc(C)c(OCC=C(C)C)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=CCOc1cc(Nc2nc(CO)co2)ccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
A solution of the compound ethyl 2-(4-methyl-3-(3-methylbut-2-enyloxy)phenylamino)oxazole-4-carboxylate (42 mg, 0.13 mmol) in anhydro THF (1 mL) was added to a suspension of LiAlH4 (10 mg, 0.25 mmol) in dry THF (1 mL) cooled at 0° C. under nitrogen atmosphere. After 2 h, the reaction mixture was quenched with H2O, filtrated, dried over MgSO4 and concentrated. The title compound was purified by flash chromatography on silica gel (hexane:EtOAc 1/1) to afford the product (13 mg, 34% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:15]([N+:1]([O-:4])=[O:2])=[CH:14][CH:13]=[C:12]([F:16])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Fuming nitric acid (11 g, 174 mmol) was added to a solution of methyl 2,6-difluorobenzoate (25 g, 145 mmol) in concentrated sulfuric acid (50 mL) at 0° C., and the reaction was stirred for 30 min at 0° C. The reaction mixture was poured over ice-water. The precipitate was filtered off by suction to give the desired product of Step B (25.1 g, 80.6%). 1H NMR (400 MHz, CDCl3) δ ppm 8.13-8.20 (m, 1H), 7.02-7.10 (m, 1H), 3.93 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:7]=1[C:8]1[CH:9]([C:27](=[O:29])[NH2:28])[CH2:10][CH2:11][CH2:12][C:13]=1[N:14]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:20]([N:14]1[C:13]2[CH2:12][CH2:11][CH2:10][CH:9]([C:27](=[O:29])[NH2:28])[C:8]=2[C:7]2[C:15]1=[C:16]([CH3:19])[CH:17]=[CH:18][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)COc1ccc(C)c2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)O)c2c3c(n(Cc4ccccc4)c12)CCCC3C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A slurry of 64 mg (0.157 mmol) of [9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester in 2 ml of tetrahydrofuran and 7 ml of methanol was treated with 0.5 ml of an aqueous 2 N sodium hydroxide solution and stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1 N HCl solution. After another extraction with ethyl acetate, the extracts were washed with brine, dried over magnesium sulfate and concentrated to afford a quantitative yield (62 mg) of the title compound. ESIMS m/e 393 (M++1), 391 (M+−1). NMR (300 MHz, d6-DMSO): δ 12.98 (br, 1H); 7.30-7.18 (m, 3H); 6.82 (d+br, J=7.0, 3H); 6.73 (br, 1H); 6.59 (d, J=7.9,1H); 6.26 (d, J=7.9, 1H); 5.53 and 5.45 (ABq, J=18.1, 2H); 4.62 (s, 2H); 3.96 (br, 1H); 2.63 (m, 1H); 2.43 (m, 1H); 2.34 (s, 3H); 2.04 (m, 2H); 1.78 (m, 2H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:20])[CH2:18][Cl:19])=[CH:12][CH:11]=1)([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8]>C(Cl)Cl.[Fe]>[Br:1][C:14]1[CH:15]=[C:10]([C:4]([CH3:3])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=[CH:12][C:13]=1[CH2:16][CH:17]([CH3:20])[CH2:18][Cl:19]
Reactant: CCCCC(C)(C)c1ccc(CC(C)CCl)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: CCCCC(C)(C)c1ccc(CC(C)CCl)c(Br)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.6 %

Procedure:
180 g of Br2 were added dropwise to amixture of 300 g of XII and 3 g of Fe powder at room temperature, and the mixture was stirred for 14 hours at room temperature. The crude product was dissolved in CH2Cl2, and the solution was washed with water, dried over Na2SO4 and distilled. 220 g of (XIII) of boiling point 160° C./0.1 mbar were obtained.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH:2](C)C.C(N(CC)CC)C.[N:25]([CH2:28][CH2:29][CH3:30])=[C:26]=[O:27]>C(Cl)Cl>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:26]([NH:25][CH2:28][CH2:29][CH3:30])=[O:27])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC(C)CN1CCN(c2ccc(N)cn2)CC1
Reactant: CCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccc(N2CCN(CC)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
A mixture of 20 mg (0.1 mmol) 6-(4-isobutyl-piperazin-1-yl)-pyridin-3-ylamine, 15 mg (0.15 mmol) triethylamine and 9.4 mg (0.11 mmol) 1-isocyanato-propane in 1 ml DCM was stirred at room temperature for 16 h. After evaporation the residue was taken up in 1 ml methanol/acetonitrile 1/1 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 15.5 mg (53%) of the title compound. (m/e): 292.3 (MH+; 100%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][C:29]2=O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]>O1CCCC1.CO>[CH2:1]([NH:8][C@H:29]1[C@H:28]([NH:27][C:25]([C:20]2[NH:21][C:22]([CH2:23][CH3:24])=[C:18]([Cl:17])[N:19]=2)=[O:26])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NCc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 41 %

Procedure:
Benzylamine (70 μL, 0.64 mmol), acetic acid (68.7 μL, 1.20 mmol) and sodium cyanoborohydride (42 mg, 0.667 mmol) were added to a mixed solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (99 mg, 0.267 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 v/v) to obtain 26 mg of the cis isomer of the title compound (21%) as a colorless solid and 50 mg of the trans isomer of the title compound (41%) as a colorless solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:67][CH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:67][CH:68]5[CH2:73][CH2:72][O:71][CH2:70][CH2:69]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3OC)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-156), 0.06 g (0.17 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.33 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.033 g (0.33 mmole) of 4-aminotetrahydropyran was then added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (30:70) to give 0.025 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-161).
Reaction SMILES: [CH2:1]([N:5]1[C:12]([NH2:13])=[CH:11][C:9](=[O:10])[N:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.Cl.[N:23]([O-])=[O:24].[Na+]>O>[NH2:13][C:12]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:7])[N:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9](=[O:10])[C:11]=1[N:23]=[O:24]
Reactant: CCCCn1c(N)cc(=O)n(CCCC)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCn1c(N)c(N=O)c(=O)n(CCCC)c1=O
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a mixture of 1,3-di-n-butyl-6-amino-uracil g, 112.8 mmol), glacial acetic acid (10 ml), and 6N HCl (18.8 ml) in water (500 ml) was added dropwise a solution of sodium nitrite (7.78, g, 112.8 mmol) in water (30 ml) on ice bath. The reaction mixture was stirred for 30 min. The violet solid was collected by filtration and washed with water (2×20 ml), dried for 2 days at 60° C. in a vacuum oven to yield 6-amino-1,3-di-n-butyl-5-nitroso-uracil (24.99 g, 82.6%), m.p. 199°-205° C.; 1H NMR (CDCl3) δ0.97-1.01 (m, 6H, 2×CH3), 1.36-1.49 (m, 4H, 2×CH2), 1.62-1.74 (m, 4H, 2×CH2), 3.94 (t, J=7.8 Hz, 2H, N--CH2), 4.08 (t, J=7.5 Hz, 2H, N--CH2), 6.46 (br s, 2H, NH2). Anal. Calc'd for C12H20N4O3 : C, 53.72; H, 7.51; N, 20.88; Found: C, 54.37; H, 7.67; N, 20.65.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O[CH:24]([C:27]1[NH:28][C:29](=[O:51])[C:30]2[C:31]3[N:40]([CH3:41])[C:39]([NH:42][C:43]4[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=4[Cl:50])=[N:38][C:32]=3[CH:33]=[CH:34][C:35]=2[C:36]=1[CH3:37])[CH:25]=[CH2:26])(=O)C.C(N(CC)CC)C.[CH3:59][NH:60][CH2:61][CH2:62][CH2:63][NH:64][CH3:65]>O1CCCC1.[Pd]>[Cl:49][C:48]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:50])[C:43]=1[NH:42][C:39]1[N:40]([CH3:41])[C:31]2[C:30]3[C:29](=[O:51])[NH:28][C:27](/[CH:24]=[CH:25]/[CH2:26][N:60]([CH3:59])[CH2:61][CH2:62][CH2:63][NH:64][CH3:65])=[C:36]([CH3:37])[C:35]=3[CH:34]=[CH:33][C:32]=2[N:38]=1
Reactant: CNCCCNC
Reactant: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNCCCN(C)C/C=C/c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reaction time: 0.33 h

Procedure:
A solution of tris(dibenzylidineacetone)dipalladium (0) (0.016 g, 0.01697 mmol) in tetrahydrofuran under nitrogen atmosphere was treated with triphenylphosphine (0.007 g, 0.0255 mmol). The reaction mixture was stirred for about 20 minutes under a nitrogen atmosphere. A solution of 1-[2-(2,6-dichloroanilino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]allyl acetate (Snow et al., 2001) (0.080 g, 0.1697 mmol) in tetrahydrofuran was added to the palladium solution. Triethylamine (0.052 g, 0.509 mmol) and N,N′-dimethyl-1,3-propanediamine (0.087 g, 0.8485 mmol) were added to the reaction solution. The reaction mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. Tetrahydrofuran was removed from the reaction mixture under reduced pressure. Acetic acid (0.5 mL) and dimethylformamide (5 mL) were added. The reaction mixture was filtered through a Gelman filter disk and was then purified by preparative HPLC chromatography. The preparative column afforded 0.012 g (14%) of pure 13, 2-(2,6-dichloroanilino)-1,6-dimethyl-7-((E)-3-{methyl[3-(methylamino)propyl]amino}-1-propenyl)-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-9-one. 1H NMR (CDCl3, 400 MHz) δ 7.8572-7.8355 (d, 1H J=8.68 Hz), 7.5408-7.5189 (d, 1H, J=8.76 Hz), 7.399-7.366 (m, 2H), 7.118-7.078 (t, 1H) 6.786-6.746 (m, 1H), 6.312-6.256 (m, 1H), 4.288 (s, 3H), 3.213-3.199 (m, 2H), 2.696-2,663 (t, 2H), 2.518-2.483 (t, 2H), 2.443 (s, 3H), 2.377 (s, 3H), 2.24 (s, 3H), 1.740-1.689 (m, 2H)); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% CH3CN over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), M+ 513.5 and 515.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.C(O)C.C(O[CH:27](OCC)[N:28]([CH3:30])[CH3:29])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9](=[CH:27][N:28]([CH3:30])[CH3:29])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: CCOC(OCC)N(C)C
Solvent: CCO
Product: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Temperature: 130 °C

Procedure:
A suspension of 50 gm of 7-chloro-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 100 ml of N,N-dimethyl-formamide diethylacetal was heated to 130°C in a vessel equipped with a descending condenser, whereby a clear solution was formed after a short time. The temperature of the reaction solution was maintained at 130°C for 40 minutes, during which time the ethanol formed by the reaction slowly distilled over. Thereafter, the reaction solution was allowed to cool, and the red precipitate was collected by vacuum filtration, washed with petroleum ether and recrystallized from methanol, whereupon it had a melting point of 239°-241°C. It was identified to be the compound of the formula ##SPC6##
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[N:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:24]([NH:23][C:21](=[O:22])[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]#[C:12][C:9]2[CH:8]=[N:7][C:6]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:11][CH:10]=2)=[CH:19][CH:18]=1)[CH3:26])[CH3:25]
Reactant: CCNC(=O)C(C)c1ccc(C#Cc2cnc(Cl)nc2)cc1
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCNC(=O)C(C)c1ccc(C#Cc2cnc(NC(C)C)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 9.3 mg (0.16 mmol) isopropylamine in 0.5 mL DMSO are added 31 mg (0.10 mmol) 2-[4-(2-chloro-pyrimidin-5-ylethynyl)-phenyl]-N-ethyl-propionamide (XVIII.1) in 1 mL DMSO, followed by 254 (16 mmol) DIPEA. The mixture is stirred at rt for 12 h. After that time, the mixture is directly purified by HPLC (preparative column: Sunfire; eluent A: water+0.1% TFA, eluent B: MeOH) to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[C:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1>>[C:21]1([CH2:27][CH2:28][NH:29][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: NCCC1=CCCCC1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(NCCC2=CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 140 °C
Reaction time: 6 h

Procedure:
A mixture of 2-chloroadenosine (0.30 g) and 2-(1-cyclohexenyl)-ethylamine (0.63 g) is stirred under nitrogen for 6 hours at 140° C. The solution is concentrated to dryness at reduced pressure; the residue is dissolved in ethanol, treated with propylene oxide (2 ml) and stirred at room temperature for 16 hours. The mixture is concentrated to dryness at reduced pressure and flash chromatographed through a 25×150 mm column of silica gel using methylene chloride and methanol saturated with ammonia (9:1) as eluent. Fractions containing the desired product are combined, concentrated to dryness at reduced pressure; the residue is redissolved in hot ethanol, the solution is decolorized with charcoal and then concentrated to dryness. The residual solid is triturated with ethanol (2 ml) and collected to afford 2-[2-(1-cyclohexenyl)-ethylamino]adenosine, m.p. 135°-38°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][C:10](=[O:12])[CH2:17][C:16]([O:15][CH3:14])=[O:21]
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: COC(=O)CC(=O)[O-]
Agent: [K+]
Product: COC(=O)CC(=O)Cc1c(F)cccc1F

Procedure:
The title compound was prepared from 2-(2,6-difluorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 3.56 (2H, s), 3.75 (3H, s), 3.92 (2H, s), 6.89-6.93 (2H, m), 7.22-7.27 (1H, m).