Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C)=O.[NH2:32][CH:33]([C:35]1[N:40]=[N:39][C:38]([NH:41][C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:37][CH:36]=1)[CH3:34].[CH3:54][N:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:57]([C:64](O)=[O:65])=[CH:56]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:54][N:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:57]([C:64]([NH:32][CH:33]([C:35]2[N:40]=[N:39][C:38]([NH:41][C:42]3[CH:43]=[C:44]([O:52][CH3:53])[C:45]([O:50][CH3:51])=[C:46]([O:48][CH3:49])[CH:47]=3)=[N:37][CH:36]=2)[CH3:34])=[O:65])=[CH:56]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cn(C)c4ccccc34)nn2)cc(OC)c1OC
Yield: 70.2 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1-methyl-1H-indole-3-carboxylic acid (150 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 1-methyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-3-carboxamide (211 mg, 70%) as a yellow solid. MS m/z 462 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[CH2:8][O:7][C@H:6]1[N:19]1[C:23]2[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:22]=2[N:21]=[C:20]1[Cl:30])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>C(O)C.O>[C@@H:6]1([N:19]2[C:23]3[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:22]=3[N:21]=[C:20]2[Cl:30])[O:7][CH2:8][C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)CO[C@H]1n1c(Cl)nc2cc(Cl)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O[C@@H]1[C@H](O)[C@@H](O)CO[C@H]1n1c(Cl)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 100 ml round bottom flask was charged with 1-(2,3,4-Tri-O-acetyl-α-L-lyxopyranosyl)-2,5,6-trichlorobenzimidazole (303 mg, 0.65 mmol) and this was dissolved in 50 ml of an equimolar mixture of ethanol and water. To the stirred solution was added anhydrous sodium carbonate (212 mg, 2.0 mmol) and the reaction mixture allowed to stir at room temperature for 3 hours. The solution was neutralized with acetic acid and the solvent evaporated in vacuo. the resultant solid was dissolved in ethyl acetate and this was washed successively with water, sat. NaHCO3 solution, and sat. NaCl solution (1×50 ml each). The organic layer was dried over sodium sulfate and the solvent evaporated in vacuo to yield, upon vacuum drying, 205 mg (89.1%) of the title compound as a white foam. mp 184-184.5° C. 1H NMR (DMSO-d6, 360 at MHz) δ7.980 (s,1H), 7.922 (s, 1H), 5.644 (d,1H, J=9.26 Hz), 5.489 (d, 1H, J=3.24 Hz), 5.401 (d, 1H, J=3.76 Hz), 5.266 (d, 1H, J=6.52 Hz), 4.245 (m, 1H), 3.924 (d, 1H, J=2.81 Hz), 3.905 (dd, 2H, J=11.64 Hz, J=72.50 Hz). Anal. Calcd. for C, 40.76; H, 3.14; N, 7.92. Found: C, 40.78; H, 3.28; N, 7.75.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1(OC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:26]3([O:25][CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC1(OC)CCCCCC1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Product: COC1(OCCOCn2c(C)nc(C(C)C)c2Sc2cc(C)cc(C)c2)CCCCCC1
Yield: 69.5 %

Procedure:
The compound 1 (301 mg, 0.9 mmol) was converted to the acetal with 1,1-dimethoxycycloheptane (1.30 g, 9 mmol) in the same manner as the example 1 to give the compound 4 (288 mg, 67%). Rf 0.68 (Al2O3 60-type E, 2:1 hexane -EtOAc).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]=O)=[C:5]([CH3:7])[N:6]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:17][C:18](=[O:20])[CH3:19])C=CC=CC=1.O>CS(C)=O>[CH3:1][C:2]1[S:3][C:4]([CH:8]=[CH:17][C:18](=[O:20])[CH3:19])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C=O)s1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C=Cc1sc(C)nc1C
Yield: 81.8 %

Procedure:
A solution of 2,4-dimethylthiazole-5-carboxaldehyde (2.0 g) and 1-triphenylphosphoranylidene-2-propanone (8.2 g) in dimethylsulphoxide (140 ml) was stirred at ambient temperature for 24 hr. The solution was poured into water (400 ml) and extracted with dichloromethane. The dried (Na2SO4) organic extract was evaporated and the residue was purified by column chromatography over silica with ethyl acetate/n-hexane (1:1 v/v) elution to give 1-(2,4-dimethyl-5-thiazolyl)but-1-en-3-one (2.1 g). Pmr spectrum (CDCl3 ; δ in ppm): 2.32 (3H, s); 2.49 (3H, s); 2.67 (3H, s); 6.30 (1H, d); 7.60 (1H, d).
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[N:12][C:11]([OH:14])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C.CS(C)=O>[CH2:20]([O:19][C:17]([CH:16]([O:14][C:11]1[N:12]=[CH:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[N:10]=1)[CH3:22])=[O:18])[CH3:21]
Reactant: Oc1ncn(-c2cccc(F)c2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(F)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A 1.7 g portion of sodium was dissolved in 50 ml of absolute ethanol, and that solution was added to a solution of 13.3 g of 1-(3-fluorophenyl)-3-hydroxy-1,2,4-1H-triazole in 150 ml of dimethylsulfoxide. The solution was heated on the steam bath for 15 minutes, and then 13.5 g of ethyl 2-bromopropionate was added and the mixture was held on the steam bath for 2 hours. It was then poured over ice-water, and the aqueous mixture was extracted with diethyl ether. The organic layer was washed with water and with brine, and was then dried with sodium sulfate and phase separation paper. The solvent was removed under vacuum, and the product was recrystallized from aqueous ethanol to obtain 6.7 g of the desired product, m.p. 35°-37°.
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:6]=1.C(=O)=O.C(O)=O.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:22]([CH3:24])[CH3:23])[CH:16]([CH3:17])[CH3:18])[CH:6]=1
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O=CO
Product: CC(C)[Si](Oc1cc(CN)ccc1N)(C(C)C)C(C)C

Procedure:
A solution of 4-nitro-3-[(triisopropylsilyl)oxy]benzaldehyde O-methyloxime (0.70 g, 2.0 mmol) in ethanol (13 mL) and tetrahydrofuran (3 mL) is degassed with solid carbon dioxide, then charged with 5% palladium on carbon (100 mg) and 88% formic acid (0.8 mL). The mixture is stirred under 1 atm hydrogen gas overnight. The mixture is then filtered through a pad of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give {4-(aminomethyl)-2-[(triisopropylsilyl)oxy]phenyl}amine as its diformic acid salt. This material is used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:7]2([C:15]3[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)[CH2:6][C:5]([NH2:8])=[CH:4][N:3]([C:15]3[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)[C:2]2([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[NH2:1])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Nc1ccc(N)nc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC1=CN(c2ccc([N+](=O)[O-])cc2)C(N)(c2ccc([N+](=O)[O-])cc2)C(c2ccc([N+](=O)[O-])cc2)(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 96 h

Procedure:
0.1 mole of 2,5-diaminopyridine, 0.43 mole of p-nitrochlorobenzene, 0.23 mol of anhydrous potassium carbonate, and 2 parts by weight of powdery copper in 130 parts of dimethylformamide was refluxed with stirring for 4 days. After the reaction, the reaction mixture was filtered. The filtered matter was washed with dimethyformamide, water, and acetone, and was dried to obtain 26 parts of tetrakis(p-nitrophenyl)-2,5-diaminopyridine.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 64.5 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol) and (2-phenylethyl)amine (0.121 g, 1.001 mmol) in MeCN (2 ml) was heated in a the microwave reactor at 120° C. for 15 nm ins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 15-20% EtOAc in petroleum ether 40-60° C. to give the title compound (0.124 g, 65%). 1H NMR (500 MHz CDCl3): δ 7.58-7.51 (m, 2H), 7.51-7.45 (m, 3H), 7.30-7.18 (m, 3H), 6.87 (d, 2H), 5.35 (t, 1H), 3.14 (q, 2H), 2.62 (t, 2H), 1.73 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 137.6, 135.0, 131.8, 129.9, 128.9, 128.7, 127.0, 125.4, 107.5, 61.7, 45.1, 36.0, 27.8; Mass Spectrum M−H+ 384.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=1)(=O)=O.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=1)=[CH2:6]
Reactant: CS(=O)(=O)OCCc1ccc(C#N)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-cyano-3-fluorophenyl)ethyl methanesulfonate (35.0 g, 144 mmol) and triethylamine (50 mL) in DCM (200 mL) was added DBU (50 mL) dropwise to at 0° C. After stirring at room temperature overnight, the solution was diluted with DCM, washed with 1 N HCl and brine, and dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography to give 4-ethenyl-2-fluorobenzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.53˜7.57 (m, 1H), 7.20˜7.26 (m, 2H), 6.64˜6.71 (m, 1H), 5.48˜5.90 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:63]=[CH:62][C:55]([C:56]([NH:58][CH:59]3[CH2:61][CH2:60]3)=[O:57])=[CH:54][CH:53]=2)[N:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:12])[NH:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:53]=[CH:54][C:55]([C:56](=[O:57])[NH:58][CH:59]3[CH2:61][CH2:60]3)=[CH:62][CH:63]=2)[N:51]=1)=[O:4]
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reaction time: 0.25 h

Procedure:
Rac-trans-cyclopentane-1,2-dicarboxylic acid monomethyl ester (86 mg) was dissolved in DMF (5 mL) and treated with HATU (1.1 eq. 214 mg) and DIEA (3 eq, 267 μL) and stirred for 15 minutes. Then 4-(2-amino-thiazol-4-yl)-N-cyclopropyl-benzamide (1 eq, 129.5 mg) was added and the mixture stirred at ambient temperature overnight. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. Yield 14 mg. MS: 414.5 (M+H+); H1-NMR (DMSO-d6): δ(ppm) 12.4 (s, 1H), 8.4 (m, 2H), 7.9-7.7 (m, 5H), 3.6 (s, 3H), 3.2 (m, 2H), 2.8 (m, 1H), 2.0 (m, 2H), 1.7 (m, 4H) 0.7-0.6 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.ClCCl.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.N1CCCC1>>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3ccc4nc(NC(C)=O)sc4c3)c2)cc1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a mixture of N-(6-(3-aminophenyl)benzo[d]thiazol-2-yl)acetamide (0.030 g, 0.1 mmol), pyridine (0.03 g, 0.3 mmol) in dichloromethane (2 g, 24 mmol) was added 4-methoxybenzene-1-sulfonyl chloride (0.05 g, 0.2 mmol) at RT. The resultant was stirred for 4 h, and then pyrrolidine (0.02 g, 0.3 mmol) was added. The resulting mixture was concentrated and diluted with DMSO (2 ml) and purified by HPLC (5-95% acetonitrile in water). Collected pure solutions were concentrated and diluted with DCM, washed with aq. Na2CO3 solution. The organic layer was dried over sodium sulfate and concentrated to give a white solid (0.035 g, 73%). MS (ESI pos. ion) Found m/z: 454, (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH:12]([CH3:16])[O:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: COCC(C)Oc1cc(Cl)cnc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 22 %

Procedure:
5-Chloro-3-(2-methoxy-1-methyl-ethoxy)-2-nitro-pyridine (2 mmol) is dissolved in DMF (15 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 100° C. in the microwave for 45 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-1-methyl-ethoxy)-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 22%. HPLC (method C): 2.03 min; LC-MS (method A): 1.99 min, 305.15 (MH+).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]1[CH2:14][CH2:13]OCC1>>[C:1]1([C:14]([C:13]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: C1COCCO1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylmagnesium chloride (2M, 6.8 mmol, 1.5 eq.) was slowly added to a stirred solution of the aldehyde from Part A (3.00 g, 4.5 mmol, 1.0 eq.) in dioxane (25 mL) at 0° C. After 1 h, the reaction was quenched with methanol (5 mL), followed by water (25 mL). Trifluoroacetic acid (25 mL) was then added, and the mixture stirred at room temperature for 1 h. 10N NaOH was added to adjust the pH to 10 and the organic solvents removed in vacuo leaving solid triphenylmethanol and an aqueous phase behind. The triphenylmethanol was filtered and the aqueous was acidified to pH=3 with conc. HCl producing a precipitate. The solids were filtered, dried, and recrystallized from hexane/ethyl acetate yielding 532 mg of a white solid; m.p. 137.0°-145.0° C. NMR (DMSO-d6): δ7.77-7.46 (m, 4H); 7.46-7.30 (m, 5H); 6.94 (d, 2H, J=9 Hz); 6.76 (d, 2H, J=9 Hz); 6.37 (d, 1H, J=5 Hz); 5.97 (d, 1H, J=5 Hz); 5.09 (s, 2H); 2.25 (t, 2H, J=7 Hz); 1.34 (t of t, 2H, J=7,7 Hz); 1.17 (t of q, 2H, J=7,7 Hz); 0.74 (t, 3H, J=7 Hz). Anal. calcd. for C28H27ClN6O.(H2O)0.5 : C, 66.20: H, 5.56; Cl, 6.98. Found: 66.12; H, 5.51; Cl, 7.25.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:35](=[O:36])[C:32]2[C:33]3[C:34]4[C:29](=[CH:30][CH:31]=2)[C:28]2[C:37]5[C:24]([C:25]([C:38]#[C:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:26][CH:27]=2)=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]=4[CH:18]=[CH:17][C:16]=3[C:14]1=[O:15])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:52](Cl)(=[O:56])[C:53]([CH3:55])=[CH2:54].O>O1CCOCC1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:35](=[O:36])[C:32]2[C:33]3[C:34]4[C:29](=[CH:30][CH:31]=2)[C:28]2[C:37]5[C:24]([C:25]([C:38]#[C:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:52](=[O:56])[C:53]([CH3:55])=[CH2:54])=[CH:26][CH:27]=2)=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]=4[CH:18]=[CH:17][C:16]=3[C:14]1=[O:15])([CH3:2])[CH3:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc3c4cccc5c(C#CCCCCO)ccc(c6ccc(c2c36)C1=O)c54
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)OCCCCC#Cc1ccc2c3ccc4c5c(ccc(c6cccc1c62)c53)C(=O)N(c1c(C(C)C)cccc1C(C)C)C4=O
Temperature: 45 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A solution of 1 g (1.72 mmol) of N-(2,6-diisopropylphenyl)-9-(6-hydroxy-1-hexynyl)perylene-3,4-dicarboximide in 100 ml of dry dioxane was heated to 45° C. under nitrogen, admixed with 0.4 ml of triethylamine and 0.28 ml of methacryloyl chloride, stirred at 45° C. for 4 h, admixed with 0.28 ml of methacryloyl chloride, stirred at 45° C. for a further 12 h, cooled to room temperature, again admixed with 200 ml of water and extracted with a total of 400 ml of methylene chloride. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel using methylene chloride as eluent. Following removal of the solvent under reduced pressure, 800 mg (78%) of the desired product were isolated as a red, finely crystalline solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.CCOCC>[F:16][C:2]([F:1])([F:15])[CH:3]([NH:14][S:27]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:29])=[O:28])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1cccc2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 99 mg (0.44 mmol) of 1-naphthylsulfonyl chloride in 4 mL of pyridine was warmed at 70° C. After 3 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with ether and washed twice with 10% aqueous acetic acid and brine, dried over sodium sulfate, decanted and concentrated in vacuo. The crude material was crystallized from ether-hexanes to afford 102 mg (55%) as off white needles, MS: m/z 419.3 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([F:19])[CH:4]=1)#[N:2].C(O)C.O.[H][H]>[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=O)NC2CCCCCC2)c(F)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: NCc1ccc(C(=O)NC2CCCCCC2)c(F)c1
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
Add 4-cyano-N-cycloheptyl-2-fluoro-benzamide (1.4 g, 5.4 mmol), 10% Pd/C (Degussa type E101, 415 mg), ethanol (40 mL), water (15 mL) and acetic acid (1.8 mL) to a pressure vessel. Pressurize the vessel to 55 psi with hydrogen, and stir the mixture for 0.5 h (monitor the reaction by TLC). Filter the mixture through Celite® and wash the cake with warm ethanol followed by dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain the product as the acetic acid salt. Use SCX chromatography to obtain the title compound (1.36 g, 95%). GC-MS m/z: 264 (M+).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:25]=1.[OH:43][CH2:44][CH2:45][NH:46][C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][CH:51]=1)=[O:48]>>[OH:43][CH2:44][CH2:45][NH:46][C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:24]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[CH:27]=[C:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:25]=2)=[CH:52][CH:51]=1)=[O:48]
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(-c2ccccn2)nc(Cl)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1cc(-c2ccccn2)nc(-c2ccc(NC(=O)NCCO)cc2)n1
Yield: 64 %

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(pyridin-2-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 21) and 1-(2-hydroxyethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 18). Material was purified by prep HPLC (low pH) to afford a grey solid. Further purification was achieved using an SCX-2 cartridge to afford a grey solid (122 mg, 64%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[O:19]([C:26]1[CH:32]=[CH:31][C:29](N)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH3:33]>ClCCl.CO>[O:19]([C:26]1[CH:32]=[C:31]([CH:29]=[CH:28][CH:27]=1)[NH:33][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Solvent: CO
Solvent: ClCCl
Product: c1ccc(Oc2cccc(Nc3nnc(Cc4ccncc4)c4ccccc34)c2)cc1
Temperature: 90 °C

Procedure:
A mixture of 256 mg (1.00 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 556 mg (3.00 mmol) 4-phenoxyaniline (Aldrich) is heated for 2 h at 90° C. The melt is cooled and stirred with 6 ml NH3 solution (10% in water: or 10 ml sat. NaHCO3 solution) and 15 ml dichloromethane/methanol 50:1 for 30 min. The aqueous phase is then separated off and extracted again with dichloromethane. The organic phase is dried (Na2SO4), concentrated by evaporation, and chromatographed (SiO2; ethyl acetate→ethyl acetate/CH3OH, 19:1→10:1). Crystallization from acetonitrile yields the title compound: m.p.: 186-189° C.; Anal. calc. (C26H21N4O) C, 77.02%; H, 5.22%; N, 13.82%; found C, 77.2%; H, 4.9%; N, 13.8%. The starting material is prepared as follows:
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[C:17]1(/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12]1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccccc2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-phenyl-acrylic acid.