Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[CH2:27](C(CC)(CC)C([O-])([O-])[O-])[CH3:28]>>[CH3:27][C:28]1[N:14]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=1
Reactant: O=C(NCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nc2cnc3ccccc3c2n1CCCNC(=O)c1ccccc1

Procedure:
Using the general method of Example 11 Part C, N1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide (2.0 g, 5.7 mmol) was reduced to the diamine and then reacted with triethylorthoacetate to provide 0.74 g of N1-[3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as a sticky dark yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][O:17]C(=O)C3C=CC=CC=3)[O:12]2)=[C:4]([NH:26][CH:27]2[CH2:29][CH2:28]2)[N:3]=1>N.CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][OH:17])[O:12]2)=[C:4]([NH:26][CH:27]2[CH2:28][CH2:29]2)[N:3]=1
Reactant: Nc1nc(NC2CC2)c2ncn([C@H]3CO[C@@H](COC(=O)c4ccccc4)O3)c2n1
Agent: N
Solvent: CO
Product: Nc1nc(NC2CC2)c2ncn([C@H]3CO[C@@H](CO)O3)c2n1
Yield: 41 %

Procedure:
Benzoic acid 4(R)-(2-amino-6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2(R)-ylmethyl ester crude (1304 g) was stirred with NH3/MeOH (20 L, 2M) for 20 hours at room temperature. Excess ammonia was removed by sparging nitrogen gas through the reaction mixture. The volatiles were removed in vacuo to give a black syrup which was further purified by column chromatography (MeOH/DCM:25/1) to give crude final product (910 g). The crude product was crystallized from ethyl acetate/ethanol to give [4(R)-(2-Amino-6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2(R)-yl]-methanol (455 g, 41% yield from acetoxy-sugar).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19]C(=O)C.OS(O)(=O)=O>CO.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH2:19]
Reactant: COC(=O)c1cc(C2CCCO2)c(C(F)(F)F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C2CCCO2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 2-acetylamino-5-(tetrahydro-furan-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (8.25 g, 24.9 mmol) in MeOH (100 mL) and water (10 mL) was cooled to 0° C. Concd H2SO4 (6.88 mL, 125 mmol) was added dropwise. The solution was refluxed for 45 min, cooled to r.t., diluted with ice/water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 1:4 EtOAc/hexanes) to give the title product (5.06 g, 68%) as colorless crystals. m.p.: 131-136° C., API-ES: m/z 290 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[CH:25]([N-]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=O.CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10])[CH3:25]
Reactant: COC(=O)Cc1nc(-c2ccc(Sc3ccccc3)nc2)oc1C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)c1nc(-c2ccc(Sc3ccccc3)nc2)oc1C
Yield: 34 %

Procedure:
[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acid methyl ester (4.51 g, 13.25 mmol) is dissolved in anhydrous tetrahydrofuran (200 mL) and allowed to stir under nitrogen. Lithium diisopropyl amide solution in tetrahydrofuran (6.63 mL of 2M soln., 13.25 mmol) is slowly added to the solution at room temperature. This is allowed to stir under nitrogen for 6 hours at room temperature. Hexamethylphosphor-amide (9.2 mL, 53 mmol) is added to the reaction followed by methyl iodide (1.74 mL, 26.5 mmol), added in one portion. The mixture is allowed to stir under nitrogen at room temperature overnight. The solution is quenched with a saturated solution of ammonium chloride, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester (1.6 g, 4.51 mmol) is isolated in 34% yield after column chromatography. The racemic 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester is resolved on a Chiralpak AD column (4.6×150 mm). Eluted with 15% 3A alcohol in heptane with 0.2% dimethy-ethylamine at 0.6 mL per minute with detection at 260 nm and concentrated the fractions to provide the pure enantiomer esters (isomer 1, 98.9% ee; isomer 2, 96.4% ee).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.[CH:23](/B(O)O)=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH:23](/[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Reactant: CCCC/C=C/B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC/C=C/c1nc(CON=C(c2ccccc2)c2nnnn2C)cs1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
In a dried and purged vessel were added N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.527 mmol, 1 eq.), (1E)-hex-1-en-1-ylboronic acid (0.074 g, 0.58 mmol, 1.1 eq.), Na2CO3 (0.117 g, 1.107 mmol, 2.1 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.026 mmol, 0.05 eq.). A mixture of solvent was added toluene/ethanol/water (4/1/1) was added and the vessel purged with argon and sealed. The reaction was heated to 90° C. for 6 hrs. After cooling, 10 ml of EtOAc were added and the solids were filtered through a “Celite” plug and washed with EtOAc. The organics were separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give N-({2-[(1E)-hex-1-en-1-yl]-1,3-thiazol-4-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.170 g, 80% yield) as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.O.[Fe]>[Cl:1][C:2]1[C:3]([O:4][CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:13][CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: O=[N+]([O-])c1cccc(OCCN2CCOCC2)c1Cl
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc(OCCN2CCOCC2)c1Cl
Temperature: 23 °C
Reaction time: 1.25 h
Yield: 63.2 %

Procedure:
4-(2-(2-chloro-3-nitrophenoxy)ethyl)morpholine (873 mg, 3.1 mmol) was dissolved in toluene (12 mL). Ammonium formate (866 mg, 13.7 mmol) was dissolved in H2O (12 mL) and added. Iron powder (<10 micron, 766 mg, 13.7 mmol) was added and the reaction was placed in a 120° C. oil bath. After 1.25 h, the solution was cooled to 23° C. and filtered over a pad of celite eluting with 10% MeOH/dichloromethane (250 mL). The filtrate was concentrated in vacuo and the residue was purified via flash column chromatography to give 2-chloro-3-(2-morpholinoethoxy)aniline (503 mg, 75%) as a golden oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16]C)[CH:10]=2)=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([OH:16])[CH:10]=2)=[N:4][CH:3]=1
Reactant: COc1cc(Nc2ncc(Br)cn2)ccc1F
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(Nc2ncc(Br)cn2)ccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-N-(4-fluoro-3-methoxyphenyl)pyrimidin-2-amine 44 (0.25 mmol) in 3 mL of anhydrous DCM at 0° C. is added BBr3 (1.27 mmol) drop wise. The reaction mixture is stirred at rt for 12 h. After this time the reaction mixture is diluted with a 2M solution of Na2CO3 and extracted with DCM (2×20 mL). The organic layer is washed with brine, dried over Na2SO4 and concentrated to afford 5-(5-bromopyrimidin-2-ylamino)-2-fluorophenol 45 as brownish solid which is used without further purification. MS (m/z) (M+1)+: 286.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:30]#[N:31])=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17].O=[C:33]([CH3:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[NH2:31][C:30]1[C:3]2[C:2](=[CH:29][CH:28]=[CH:27][C:4]=2[O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[O:12][C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH:19]([CH3:21])[CH3:20])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[N:1]=[C:33]([CH3:40])[C:34]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(C(=O)NC(C)C)cc1OC1CCCCC1Oc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3Oc3cc(C(=O)NC(C)C)ccc3OC)c2c1N

Procedure:
Prepared as in Example 2a from (±)-3-((2-(3-amino-2-cyanophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide (Example 129b) and ethyl 3-oxobutanoate as a yellow solid (78%). MS 536 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=1[CH:11]=[N:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26][N:27](C=O)[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=1[C:11]1[N:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:28]=[N:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(OCc2ccccc2)c(C=Nc2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(OCc2ccccc2)c(-c2cncn2-c2cccnc2)c1
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of N-(2-(benzyloxy)-5-chlorobenzylidene)pyridin-3-amine (0.929 mmol) in DMF (3 mL) at room temperature, was added NaH (1.12 mmol) and the solution was stirred for 1 h, followed by the addition of imine (0.929 mmol). After stirring for 4 d, the reaction mixture was diluted with satd. NH4Cl solution and the product was extracted with EtOAc. The combined organic extract was dried (Na2SO4) and concentrated to afford the crude. Chromatographic purification afforded the final product. Yield 21%. 1H NMR: 4.64 (s, 2H), 6.70 (d, 1H), 6.96 (m, 2H), 7.16-7.30 (m, 8H), 7.71 (s, 1H), 8.31 (d, 1H, J=2.4 Hz), 8.53 (dd, 1H, J=1.8 Hz, 3.0 Hz)
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.C(O)=O.C(N(CC)CC)C.[NH2:29][C:30](N)=[O:31]>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:29]=[CH:30][O:31][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: O=C(c1ccc(F)cc1)C(Br)c1ccncc1
Agent: Br
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1ccc(-c2ncoc2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-bromo-1-(4-fluoro-phenyl)-2-pyridin-4-yl-ethanone hydrobromide (10 g, Reference Example 9) in acetonitrile (100 ml) at 0° C. was treated with formic acid (10 ml) followed by triethylamine (35 ml). The solution was stirred at room temperature for 16 hours and urea (4 g) was added together with formic acid (100 ml). The resulting mixture was refluxed for 6 hours with concomitant removal of the acetonitrile [with a Mc Intire head]. The solvent was then evaporated, the residue taken up into ethyl acetate and the grey solid discarded. The solvent was evaporated and the resulting gum was dissolved in water (100 ml) and the solution basified to pH 11 by addition of sodium hydroxide pellets. The resulting solid was filtered and subjected to flash chromatography on silica eluting with ethyl acetate to give the title compound as a white solid. MS: 241 [MH+]. RF=0.34 (ethyl acetate, determined by thin layer chromatography on silica).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[CH2:27][CH3:28]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][CH2:26][CH:21]([NH2:20])[CH:22]([CH2:27][CH3:28])[CH2:23]4)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCC1CNCCC1N
Reactant: O=C(O)c1cn(C2CC2)c2nc(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCC1N
Yield: 71 %

Procedure:
The condensation of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-naphthyridine-3-carboxylic acid with 4-amino-3-ethylpiperidine was carried out in acetonitrile in a similar manner as described in example 1, gave the titled product. Yield 71%, m.p 218–20° C., C19H23FN4O3, m/z 375 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[N:10]([S:33]([CH:30]3[CH2:32][CH2:31]3)(=[O:35])=[O:34])[C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(Br)cc1Cl
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.26 mmol) in CH2Cl2 (10 mL) was added triethylamine (80 mg, 0.78 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (55 mg, 0.39 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (15 mL×2). The combined organic phase was washed with water (15 mL) and brine (20 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (110 mg, 86.5% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.71-7.69 (m, 2H), 7.32 (m, 1H), 3.35 (m, 1H), 1.69 (m, 2H), 0.88 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[CH:8][C:7]=12)#[N:2]>CO.CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8][C:7]=12)#[N:2]
Reactant: COc1ccc(C(=O)c2cc(C#N)c3cnc4ccccc4n23)cc1
Solvent: CC(C)=O
Solvent: CO
Product: COc1ccc(C(=O)c2cc(C#N)c3n2-c2ccccc2NC3)cc1
Reaction time: 4 h
Yield: 496.8 %

Procedure:
A mixture of 3-cyano-1-(4-methoxy-benzoyl)-pyrrolo[1,2-a]quinoxaline (14.5 mg, 0.0044 mmol) in 10 mL of methanol and 0.5 mL acetone was hydrogenated on PtO2 at 40 psi for 4 h. The reaction mixture was filtered, concentrated under vacuum and the residue was purified by chromatography (25% ethyl acetate/hexane) to yield 7.2 mg (50%) of the title compound. 1H NMR (CDCl3): 7.97 (m, 2H), 6.97 (m, 7H), 4.48 (s, 2H), 4.25 (s, broad, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH:1]([C:5]1[Se:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=3)=[C:12]([F:24])[C:11]=2[F:25])=[CH:8][CH:9]=1)=[CH:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:5]1[Se:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=3)=[C:12]([F:24])[C:11]=2[F:25])=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC=Cc1ccc(-c2ccc(-c3ccc(CC)cc3)c(F)c2F)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc(-c3ccc(CC)cc3)c(F)c2F)[se]1

Procedure:
2.40 g (5.72 mmol) of 2-but-1-enyl-5-(4′-ethyl-2,3-difluorobiphenyl-4-yl)-selenophene are hydrogenated in 25 ml of ethyl acetate, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-Butyl-5-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene is obtained as a colourless solid (m.p. 73° C.).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(C)C=CC=CC=1.O.C(O)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:18][CH:19]=2)=[N:7][CH:6]=1
Reactant: Brc1cnc(Br)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Brc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 96.6 %

Procedure:
10.43 g (0.044 mol) of 2,5-dibromopyrimidine, 10 g (0.044 mol) of 4-(phenylmethoxy)benzeneboronic acid, 0.475 g (0.00044 mol) of palladium on activated carbon (10% by weight), (0.001752 mol) of TPPTS and 9.3 g (0.0876 mol) of sodium carbonate are heated in 100 ml of toluene, 50 ml of ethanol and 30 ml of water at 80° C. for 48 hours. The palladium catalyst is subsequently separated from the reaction mixture at 80° C. by filtration. The aqueous lower phase of the reaction mixture is separated off at 80° C. before the organic phase is freed of the solvents on a rotary evaporator and is dried in a high vacuum. The crude product thus obtained is crystallized from acetonitrile (300 ml), giving 14.5 g (93% yield, based on 2,5-dibromopyrimidine) of 5-bromo-2-[4-(phenylmethoxy)phenyl]pyrimidine (content according to HPLC: 98%). ##STR26##
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:24]([CH3:25])=[N:23][CH:22]=[CH:21][N:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][C:7]=1[NH:12][C:13]1[N:18]=[C:17]([C:19]2[C:24]([CH3:25])=[N:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1ccc(C)c(Nc2nccc(-c3nccnc3C)n2)c1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2nccnc2C)n1

Procedure:
4-methyl-3-[4-(3-methylpyrazin-2-yl)-pyrimidin-2-ylamino]-benzoic acid ethyl ester prepared in Preparation 13 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@H:9]([C:11]1[N:16]=[C:15]2[CH:17]=[CH:18][N:19]([CH3:20])[C:14]2=[CH:13][C:12]=1[N:21]1[CH2:25][CH2:24][CH:23]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:22]1)[CH3:10].C([O-])(O)=O.[Na+].[NH2:42][C:43]1[N:48]=[C:47](Cl)[C:46]([C:50]#[N:51])=[C:45]([CH3:52])[N:44]=1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[NH2:42][C:43]1[N:48]=[C:47]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:25][CH2:24][C@H:23]([N:26]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])[CH2:22]2)[CH3:10])[C:46]([C:50]#[N:51])=[C:45]([CH3:52])[N:44]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCC(N2C(=O)c3ccccc3C2=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CC[C@H](N3C(=O)c4ccccc4C3=O)C2)c1C#N
Temperature: 85 °C

Procedure:
A TFA salt of 2-(1-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidin-3-yl)isoindoline-1,3-dione (110 mg, 0.218 mmol) was partitioned between saturated NaHCO3 and EtOAc. The aqueous and organic phases were separated and the aqueous layer was extracted with EtOAc (2×). The organic layers were combined, dried over MgSO4, and filtered, and then concentrated in a 50 mL pear flask. To this residue was added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (55.2 mg, 0.328 mmol) in DMSO (1.1 mL) followed by triethylamine (152 μL, 1.09 mmol). The mixture was heated to 85° C. for 3 hours and then partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by preparative HPLC (acid mode, 50-55% ACN/water gradient) to give the title diastereomers. Peak 1 (shorter retention time, 30 mg, 26%): 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (d, J=6.57 Hz, 3H), 2.33-2.40 (m, 3H), 2.40-2.60 (m, 2H), 3.31-3.48 (m, 3H), 3.70 (t, J=8.34 Hz, 1H), 3.76-3.83 (m, 3H), 5.09-5.22 (m, 1H), 5.28 (s, 2H), 5.87-5.96 (m, 1H), 6.66 (dd, J=3.28, 0.76 Hz, 1H), 7.20-7.25 (m, 2H), 7.57 (s, 1H), 7.71-7.79 (m, 2H), 7.84-7.92 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C28H27N9O2, 522. found 522. Peak 2 (longer retention time, 12 mg, 11%): ESI-MS m/z [M+H]+ calc'd for C28H27N9O2, 522. found 522.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[N:5][CH2:6][CH2:7][N:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:7][CH2:6][NH:5][CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[CH3:1]
Reactant: Cc1ccccc1C=NCCN=Cc1ccccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1CNCCNCc1ccccc1C

Procedure:
5.3 g of N,N'-di-(o-methylbenzylidene)-ethylenediamine, dissolved in 75 ml of tetrahydrofuran, are added dropwise to a suspension of 2.0 g of lithium aluminium hydride in 30 ml of tetrahydrofuran. The mixture is heated under reflux for 30 minutes, the excess of reducing agent is decomposed with water while cooling with ice, the whole is poured into 200 ml of sodium hydroxide solution (10% by weight) and extracted 3 times by shaking with 150 ml of diethyl ether each time. From the combined diethyl ether extracts the hydrochloride is precipitated, in form of a white powder, by adding a solution of hydrogen chloride in diethyl ether. The hydrochloride is separated by filtration, shaken with 150 ml of diethyl ether and 150 ml of 10% sodium hydroxide solution. The ether phase is dried over magnesium sulphate and concentrated to dryness by evaporation. The residue is recrystallised from ethyl acetate. N,N'-di-(o-methylbenzyl)-ethylenediamine having a meltinp point of 38°-39° C. is obtained.