Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([CH3:24])=[C:8]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:16][CH2:15]3)[O:9]2)=[CH:4][CH:3]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:26]([O:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([CH3:24])=[C:8]([CH:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:18][CH2:19]3)[O:9]2)=[CH:4][CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCC(=O)N1CCC(c2oc3c(C=O)c(O)ccc3c(=O)c2C)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(c2oc3c(C=O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Yield: 96.4 %

Procedure:
A solution of 7-hydroxy-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carbaldehyde (250 mg, 0.73 mmol) obtained in Example 34-1, benzyl bromide (260 μL, 3.64 mmol), and potassium carbonate (503 mg, 3.64 mmol) in dimethylformamide (4 mL) was stirred at room temperature for 26 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained residue. Then, the supernatant was removed by decantation to obtain 305 mg of the title compound (yield: 97%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][S:5]([CH2:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])(=[O:7])=[O:6]>C(O)C.[Pd]>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][S:5]([CH2:8][CH:9]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]([OH:12])=[O:11])(=[O:7])=[O:6]
Reactant: CN(C)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)O
Yield: 91.9 %

Procedure:
The title compound of Step 11 (150 mg, 0.4 mmol) was debenzylated in ethanol with 5 psi H2 at room temperature for 1.5 hours using 4% Pd/C catalyst. After filtering, the solvent was stripped off to give the title compound as white powder (110 mg, 70%yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C14H21NO4S : C, 56.16; H, 7.07; N, 4.68. Found: C, 55.88; H, 6.99; N, 4.35.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5](Cl)[N:6]=[C:7]2[O:12][CH3:13].[CH3:15][O-:16].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:16][CH3:15])[N:6]=[C:7]2[O:12][CH3:13]
Reactant: COc1nc(Cl)cc2c(Br)cccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Br)cccc2c(OC)n1
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-3-chloro-1-methoxyisoquinoline (420 mg, 1.54 mmol) in DMSO (4.0 mL) was added NaOMe (0.5 M in MeOH, 4.0 mL, 2.0 mmol). The solution was heated at 90° C. for 1.5 hours in a microwave reactor. The mixture was poured into water then extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 15% EtOAc/hexanes to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.15 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H); 7.18 (t, J=8.0 Hz, 1H), 6.85 (s, 11-1), 4.18 (s, 3H), 4.05 (s, 3H). LC6: 3.67 min, (M+H): 268.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](O)[C:5]2[CH:9]=[CH:10][NH:11][C:4]=2[CH:3]=1.P(Br)(Br)([Br:14])=O.C([O-])(O)=O.[Na+]>>[Br:14][C:6]1[C:5]2[CH:9]=[CH:10][NH:11][C:4]=2[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc2[nH]ccc2c(O)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2[nH]ccc2c(Br)n1
Temperature: 120 °C
Yield: 8.7 %

Procedure:
A mixture of 6-methyl-1H-pyrrolo[3,2-c]pyridin-4-ol (J. Het. Chem., 1996, 303) (161 mg, 1.09 mmol) and phosphorus oxybromide (1.87 g, excess) was heated in a sealed tube at 120° C. for 50 minutes. The reaction mixture was poured onto water (10 mL), basified with aqueous NaHCO3 to pH 8 and the organic product extracted into DCM. The organic layer was dried (phase separator), evaporated and the residue purified by column chromatography (Si—PCC, cyclohexane:ethyl acetate, gradient 100:0 to 70:30) to give 4-bromo-6-methyl-1H-pyrrolo[3,2-c]pyridine (20 mg, 12%) as a white solid. LCMS RT=2.00 min, [M+H]+ 211
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:21][C@H:19]1[CH3:20]>>[OH:21][C@@H:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Reactant: C[C@H]1CO1
Product: C[C@H](O)Cn1ccc2ccc(OCc3ccccc3)cc21

Procedure:
Alternatively, compound 1 is reacted with (R)-propylene oxide according to the foregoing method to yield (R)-1-(2-hydroxypropyl)-6-benzyloxyindole (R-2). Alternatively, compound 1 is reacted with (S)-propylene oxide according to the foregoing method to yield (S)-1-(2-hydroxypropyl)-6-benzyloxyindole (S-2).
Reaction SMILES: [C:1]([S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]#[N:19])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:16]\[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:18]#[N:19])=[C:6]3[S:5][C:1]([CH3:4])([CH3:3])[CH3:2])/[C:36](=[O:37])[N:38]=1
Reactant: CC(C)(C)Sc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)Sc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 4-tert-butylsulfanyl-6-formyl-quinoline-3-carbonitrile (example 39b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-tert-butylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 369 (MH+).
Reaction SMILES: O.Cl.[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[CH:6]=1>CO.[O-2].[O-2].[Mn+4]>[CH:4]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[CH:6]=1)=[O:3]
Reactant: CNC(=O)c1cc(CO)ccn1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: O
Solvent: CO
Product: CNC(=O)c1cc(C=O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.50 g (33.989 mmol) of 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide hydrochloride hydrate (Example 40A) were initially charged in 90 ml of methanol, 23.64 g (271.915 mmol) of manganese dioxide were added and the mixture was stirred at RT overnight. The reaction mixture was filtered off with suction through silica gel, the silica gel/manganese dioxide mixture was stirred with tetrahydrofuran/methanol 1:1 overnight, the silica gel/manganese dioxide mixture was then filtered off and the filtrate was evaporated.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[N:21][O:22][S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])[N:5]=[C:4]([CH3:33])[C:3]=1[Cl:34].S(=O)(=O)(O)O>CC(OC(C)=O)=O.CO>[C:14]([N:1]([C:11](=[O:20])[CH3:12])[C:2]1[N:6]([C:7](=[N:21][O:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:24])=[O:25])[CH2:8][CH2:9][N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])[N:5]=[C:4]([CH3:33])[C:3]=1[Cl:34])(=[O:15])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)ON=C(CCN2C(=O)c3ccccc3C2=O)n2nc(C)c(Cl)c2N)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C(C)=O)c1c(Cl)c(C)nn1C(CCN1C(=O)c2ccccc2C1=O)=NOS(=O)(=O)c1ccc(C)cc1
Yield: 94.5 %

Procedure:
2.62 g (5.2 mmol) of 5-amino-4-chloro-3-methyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)pyrazole in 15 ml of acetanhydride, to which 0.15 ml of concentrated sulphuric acid has been added, are heated to boiling point and then cooled down. After careful hydrolysis the solid obtained is ground up with methanol and boiled in methanol. The crystals which are produced are filtered off under suction and washed with a little methanol. 1.44 g (47%) of 5-bisacetylamino-4-chloro-3-methyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)pyrazole with a m. pt. of 143°-147° C. are obtained.
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:7]1[N:6]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH:8]=1)=[O:10]
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2ccsc2[nH]1
Product: COC(=O)c1cc2ccsc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-naphthalene to give 6-naphthalen-1-ylmethyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 306.3 ([M−H]−).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:38][C:39]1[C:40]([N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([NH2:45])[CH:44]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:43]3[CH:44]=[C:39]([CH3:38])[C:40]([N:49]4[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Oc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC(C)C)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 34.5 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) (200 mg, 0.385 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (Example 248, Step B) (200 mg, 0.586 mmol) in trifluoroethanol (10 mL) was added p-toluene sulfonic acid (200 mg, 1.05 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and silica was added. The solvent was removed on a rotovap and the product purified on a 12 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (110 mg, 0.133 mmol, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.34 (d, J=7.0 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J=5.2 Hz, 1H), 8.07 (s, 1H), 7.75-7.73 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.46-7.34 (m, 2H), 7.29 (d, J=8.8 Hz, 1H), 7.19 (t, J=8.0 Hz, 2H), 6.95 (t, J=7.1 Hz, 1H), 6.74 (s, 1H), 6.61 (d, J=5.2 Hz, 1H), 4.91-4.81 (m, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.39-3.28 (m, 2H), 3.06 (s, 3H), 2.88-2.81 (m, 4H), 2.77 (t, J=6.8 Hz, 2H), 2.67-2.53 (m, 4H), 2.13 (s, 3H), 1.39 (d, J=5.8 Hz, 6H), 1.25 (t, J=7.0 Hz, 3H). MS (ESI) m/z=412 [M+2H]+2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:19])=O)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[H-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][NH2:19])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCC(N)=O)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCCN)ccc1OCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propionamide (7.85 g, 27.53 mmol) in anhydrous THF (210 ml) was slowly added to a stirred, ice-cooled suspension of LiAlH4 (2.09 g, 55.07 mmol) in anhydrous THF (90 ml). Upon completion of the addition, the mixture was stirred at reflux for 1 h. After cooling to 0° C., H2O (15 ml) was added dropwise to decompose the excess of hydride, and the resulting suspension was then filtered. The residue after evaporation was partitioned between H2O (50 ml) and CH2Cl2 (100 ml). The organic layer was washed with NaHCO3 and brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the crude. amine (6.03 g, 22.22 mmol, 81%) as a yellow oil.
Reaction SMILES: C1COCC1.[I:6][C:7]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:8]=1[NH2:9].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[I:6][C:7]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:8]=1[NH:9][C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=1)=[O:25]
Reactant: Nc1ccc(Br)cc1I
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1I
Temperature: 65 °C
Yield: 92.3 %

Procedure:
To a 100 mL of anhydrous THF in a 250 mL round bottom flask containing a stirring bar, 2-iodo-4-bromoaniline (2.00 g, 6.70 mmol) was added along with 3-trifluoromethylphenylisocyanate (1.51 g, 7.00 mmol) and 52 mg of pyridine. The resulting solution was heated at 65° C. overnight. THF was removed by rotary evaporation and the product was recrystallized from ethyl acetate to give 3.0 g (92%) of 1-(2-iodo-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)[OH:7])[CH3:2].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)[O:7][S:45]([CH3:44])(=[O:47])=[O:46])[CH3:2]
Reactant: C=CCCOC(C(=O)OCC)C(O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCOC(C(=O)OCC)C(OS(C)(=O)=O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 2-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxy-propionic acid ethyl ester (150 mg, 0.3 mmol) in dichloromethane (2 ml) at 0° C. was added successively triethylamine (55 μl, 0.4 mmol) and methanesulfonic acid chloride (42 μl, 0.36 mmol). The reaction was allowed to warm to ambient temperature over night and then quenched by the addition of sat. NaHCO3. The layers were separated and the aqueous phase was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford crude 2-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-methanesulfonyloxy-propionic acid ethyl ester which was dissolved in THF (2 ml). DBU (139 μl, 0.9 mmol) was added at ambient temperature and the mixture was stirred for 8 h at 50° C. The reaction was quenched by the addition of water, the layers were separated, and the aqueous phase was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure to afford a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=9/1) to give 79 mg (0.166 mmol, 55%) of the title compound as bright yellow oil and 29 mg (61 μmol, 20%) 2E-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester as bright yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:18][CH:17]=1>CN1C(=O)CCC1>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:6]3[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH3:14])[N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:35][CH:34]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(C)nc(Cl)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
Ethyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (0.5 g, 2.1 mmol) and tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (0.6 g, 2.06 mmol) were dissolved in NMP and stirred at 0° C. for 2 hour. The reaction mixture was poured onto water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to get the desired compound (0.62 g). 1H NMR (400 MHz, CDCl3): δ 10.58 (s, 1H), 7.58 (d, J=6.4 Hz, 2H), 7.31 (d, J=6.4 Hz, 2H), 4.45 (q, J=6.8 Hz, 2H), 3.56 (s, 2H), 3.41 (m, 4H), 2.69 (s, 3H), 2.47 (m, 4H), 1.45 (s, 9H), 1.43 (t, J=6.8 Hz, 3H); MS m/z 490.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[H-].[Na+].[CH2:20]([O:22][CH2:23][CH2:24]Br)[CH3:21]>CN(C=O)C>[CH3:13][C:10]1([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=[C:2]([O:1][CH2:21][CH2:20][O:22][CH2:23][CH3:24])[C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2c(O)cc(C=O)cc21
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 86 %

Procedure:
36 g (156 mmol) of 4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of anhydrous DMF. 6.5 g (163 mmol) of 60% sodium hydride are added portionwise and the reaction medium is stirred for 1 hour. 25 g (163 mmol) of 2-ethoxyethyl bromide are added portionwise and the medium is stirred at room temperature for 2 hours and then hydrolysed and extracted with ethyl ether. The organic phase is washed with 1N sodium hydroxide solution, and then three times with water. The residue obtained is purified by chromatography (eluent:heptane). A yellow oil is obtained (m=40.7 g; yield=86%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9].[NH2:14][C:15]1[C:16]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH:17][C:18]([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=2)=[N:19][CH:20]=1>CN(C=O)C>[C:28]([C:25]1[N:26]=[CH:27][C:22]([NH:21][C:18]2[N:19]=[CH:20][C:15]([NH:14][S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])=[C:16]([NH:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:17]=2)=[N:23][CH:24]=1)#[N:29]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
Triethylamine (15 μL, 0.11 mmol) and ethylsulfonylchloride (8 μL, 0.78 mmol) were added to a stirred solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylate (30.3 mg, 0.071 mmol) in DMF (1 mL) at 0° C. After 1.5 hours at room temperature, further ethylsulfonylchloride (5.5 μL, 0.53 mmol) and triethylamine (7.5 μL, 0.53 mmol) were added. After 1 hour the reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated. Preparative HPLC gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(1-Boc-piperidin-4-ylmethylamino)pyridin-3-yl)ethanesulfonamide as a solid. The material was dissolved in 20% trifluoroacetic acid in dichloromethane. After 20 minutes the mixture was loaded onto a MP-TsOH SPE cartridge and eluted with 2M ammonia in methanol. The basic fractions were combined to give N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)ethanesulfonamide (2.28 mg, 8%).
Reaction SMILES: O[C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]c(O)n2)cc1
Product: O=[N+]([O-])c1ccc(-c2c[nH]c(Cl)n2)cc1
Reaction time: 24 h

Procedure:
A mixture to 2-hydroxy-4-(4-nitro-phenyl)-1H-imidazole (15 g) and phosphorous oxychloride (750 ml) was refluxed, while stirring, for 24 hours. The solution was then evaporated to dryness, the residue was adjusted to pH 6.5 with a H2PO4- /HPO4-- buffer, and extracted with methylene chloride. After drying, the organic solution was evaporated, and the crude product was chromatographed on silica gel to give 6.7 g of the title compound. M.p. 136°-138° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][N:4]([CH3:6])[CH3:5].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:16]=1[CH3:34]>>[CH2:7]([C@H:2]([NH:1][C:19]1[C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:16]([CH3:34])=[C:15]([Cl:14])[N:20]=1)[CH2:3][N:4]([CH3:6])[CH3:5])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C[C@@H](N)Cc1ccccc1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Product: Cc1c(Cl)nc(N[C@@H](Cc2ccccc2)CN(C)C)c(=O)n1CC(=O)OCc1ccccc1
Yield: 51.8 %

Procedure:
The title compound was prepared by a similar method to preparation 18 from N-[(2S)-2-amino-3-phenylpropyl]-N,N-dimethylamine (190 mg, 1.07 mmol; prepared as described in Chem. Pharm. Bull. 1970, 18, 1731-1736) and benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (361 mg, 1.10 mmol). The crude product was purified by chromatography (SiO2; gradient elution 100% hexane; 80:20 hexane:ethyl acetate; 60:40 hexane:ethyl acetate; 40:60 hexane:ethyl acetate; 20:80 hexane:ethyl acetate) to give the desired product (yellow solid, 260 mg, 50%). 1H NMR (CDCl3) δ 2.20 (m, 9H), 2.30 (m, 1H), 2.20 (m, 1H), 2.85 (m, 1H), 3.10 (m, 1H), 4.25 (m, 1H), 4.80 (s, 2H), 5.20 (s, 2H), 6.20 (m, 1H), 7.20 (m, 5H), 7.35 (m, 5H). LRMS m/z=469.2, 471.3 (M+1)+.