Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>N1C=CC=CC=1>[CH3:19][C:18]1[CH:20]=[CH:21][C:15]([S:12]([O:11][CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(C)(C)C1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(tert-butyl)cyclohexan-1-ol (500 mg, 3 mmol) was dissolved in pyridine (50 mL) and stirred at room temperature for 30 min. Tosyl chloride (915 mg, 4.79 mmol) was added to the reaction mixture and allowed to stir overnight. The reaction was quenched by addition of water (50 mL) and extracted with ether. (3×20 mL) washed with saturated CuSO4, water, saturated aqueous NaHCO3, water, and dried, (Na2SO4) concentrated and purified (10% EtOAc in hexane) to give 38 as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21](=O)[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:24][NH2:25]>>[CH3:2][C:1]1[C:4]2=[C:8]([CH3:9])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=3)[C:6]([CH3:20])=[C:5]2[C:21]([CH3:22])=[N:25][N:24]=1
Reactant: CCCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1
Reactant: NN
Product: CCCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)cc1

Procedure:
As outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (Example 52, 20 mg) reacted with 1-bromo-propane (100 μL), in the presence of K2CO3 powder (50 mg), to afford 1-[4-acetyl-2,5-dimethyl-1-(4-propoxy-phenyl)-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-2,5-dimethyl-1-(4-propoxy-phenyl)-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 1,4,5,7-Tetramethyl-6-(4-propoxy-phenyl)-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.04 (d, 1H), 6.95 (br s, 1H), 6.91 (d, 1H), 4.03 (t, 2H), 2.85 (s, 6H), 2.42 (s, 6H), 1.86 (q, 2H), 1.79 (s, 3H), 1.09 (t, 3H); MS (ESI) 328 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O>ClCCl>[Cl:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(O)c2cccc(I)c2)cc1
Solvent: ClCCl
Product: Cc1ccc(C(Cl)c2cccc(I)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (3-iodophenyl)-p-tolylmethanol (2.68 g) in dichloromethane (50 mL) at 0° C. is slowly added thionyl chloride (633 μL). After stirring at room temperature for 2 days, the mixture is washed with aqueous NaHCO3, dried over magnesium sulfate and concentrated under reduced pressure to afford chloro-(3-iodophenyl)-p-tolylmethane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N+:11]([O-])=[CH:10][CH:9]=[CH:8]2)=[O:4].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[N:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc2c(ccc[n+]2[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To 6-(methoxycarbonyl)quinoline-N-oxide from the above step was added phosphoryl trichloride (5 mL, 54.6 mmol). The resulting mixture was then stirred at rt under N2 for 2 h. The reaction was then slowly quenched by addition to an ice cold solution of saturated aqueous NaHCO3 (50 mL) in an ice bath with rapid stirring. The aqueous solution was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (25 mL), H2O (25 mL), dried (MgSO4), and concentrated. Purification by ISCO (40 g SiO2, 0-50% EtOAc/hexanes) gave as the major product, methyl 4-chloroquinoline-6-carboxylate (330 mg, 1.489 mmol, 25.8% yield over 3 steps) (m/z=221.9) as a white solid. Also isolated was the more polar, methyl 2-chloroquinoline-6-carboxylate with same mass (m/z=221.9).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:9]=[N:10][C:11](I)=[N:12][CH:13]=1.[OH:15][CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[Br:7][C:8]1[CH:9]=[N:10][C:11]([C:22]2[CH:23]=[CH:24][C:19](/[CH:18]=[CH:17]/[CH2:16][OH:15])=[CH:20][CH:21]=2)=[N:12][CH:13]=1
Reactant: Brc1cnc(I)nc1
Reactant: OC/C=C/c1ccc(B(O)O)cc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccc(-c2ncc(Br)cn2)cc1
Yield: 17.9 %

Procedure:
2 M aq. Na2CO3 (2 mL) was added to a mixture of 5-bromo-2-iodopyrimidine (0.57 g, 2.00 mmol), Pd(Ph3P)4 (23 mg, 0.020 mmol), and [4-[(1E)-3-hydroxy-1-propenyl]phenyl]boronic acid (360 mg, 2.02 mmol, prepared as described in Reference Example 238) in toluene (5 mL) and the resulting mixture was heated to reflux for 24 h. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and the organic layer was separated, washed with brine (10 mL), dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) provided 104 mg (18%) of the title compound as a yellow solid. MS 291, 293 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:30])[CH2:9][NH:10][C:11]([C:13]2[CH:29]=[CH:28][C:16]3[N:17]=[C:18]([C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:27])[NH:19][C:15]=3[CH:14]=2)=O)=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:30][C:11]([C:13]3[CH:29]=[CH:28][C:16]4[N:17]=[C:18]([C:20]5[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:27])[NH:19][C:15]=4[CH:14]=3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1)c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-3H-benzimidazole-5-carboxylic acid [2-(4-chlorophenyl)-2-oxo-ethyl]-amide (310 mg, 0.68 mmol) and Burgess reagent (644 mg, 2.70 mmol) THF (10 mL) was heated in a microwave apparatus at 150° C. for 30 min. The mixture was poured into ethyl acetate and extracted with water and brine. The organic phase was dried, filtered, and the solvent removed under reduced pressure. The residue was purified by chromatography using a gradient of 40-75% heptane/ethyl acetate followed by a second chromatography with dichloromethane/acetone (0-20% gradient) to give the title compound. H1-NMR (DMSO-d6): δ 8.69 (m, broad, 1H), 8.34 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.2, Hz 2H), 8.04 (s, broad, 1H), 7.95 (s, 1H), 7.84 (m, 3H), 7.75 (d, J=8.6 Hz, 2H). MS: m/z 441.9 (M+1); High resolution MS (M+H): theory 440.0124, measured 440.0126.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=O)[CH3:2].Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][NH2:31])=[CH:26][CH:25]=1.CC([O-])=O.[Na+]>CCO>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][N:31]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=2[NH:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH3:2])=[CH:26][CH:25]=1
Reactant: NOc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Yield: 89.7 %

Procedure:
A solution of N-(2-acetyl-5-trifluoromethylphenyl)trifluoromethanesulfonamide 35 (250 mg, 0.75 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (148 mg, 0.82 mmol) and anhydrous NaOAc (67 mg, 0.82 mmol) in EtOH (15 mL) was stirred for 20 hours at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2) and the solvent removed under reduced pressure. The residue was purified by recrystallization from CH2Cl2/PE to afford N-{2-[1-(4-chlorophenoxyimino)ethyl]-5-trifluoromethylphenyl}trifluoromethanesulfonamide 199 (310 mg, 90%), as a pale yellow solid. M.p. 89-90° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.41, br s, 1H, 8.02, s, 1H, 7.76, d, J=8.6 Hz, 1H, 7.56, m, 1H, 7.36, d, J=9.2 Hz, 2H, 7.12, d, J=9.2 Hz, 2H, 2.60, s, 3H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[O:19])[CH:15]=[N:14]1.[OH2:20]>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[N:14]1
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: O=C(O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde (1 g) was oxidised using chromium trioxide (26.67 g) in water (40 ml) and concentrated sulphuric acid (23 ml), made up to 100 ml. The product was extracted with ether and worked up in conventional manner to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxylic acid, m.p. 155°-157°.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([S:18][CH2:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][N:12]=1.[OH-].[Na+].C(OC(C)C)(C)C>>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH2:19][S:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:10][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:16]=1[CH3:17]
Reactant: Sc1ccncc1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: Cc1c(SCc2ccco2)ccnc1CSc1ccncc1
Yield: 89 %

Procedure:
According to the procedure indicated in Example 1, reaction of 4-mercaptopyridine with 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride and sodium hydroxide solution, subsequent chromatography on silica gel (ethyl acetate/ethanol) and crystallization from diisopropyl ether gives the title compound as a colorless powder; m.p. 126-128° C.; yield 89% of theory.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]1=[O:22].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32](O)=[O:33].ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:15][C:13]1[CH:12]=[CH:11][C:6]2[N:7]([CH3:10])[C:8](=[O:9])[CH:2]([NH:1][C:32]([C:24]3[NH:23][C:31]4[C:26]([CH:25]=3)=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:33])[C:3](=[O:22])[N:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH:14]=1
Reactant: CN1C(=O)C(N)C(=O)N(c2ccccc2)c2cc(Cl)ccc21
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)C(=O)N(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
A mixture of 1.58 g (5 mmoles) of 3-amino-2,4-dioxo-7-chloro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 0.89 g of 2-indol carboxylic acid, 1.05 g of 1-ethyl-3-(3-dimethylamino)-propyl carbodiimide, 1.02 g of 1-hydroxy benzotriazole and 50 ml of dichloromethane was stirred at ambient temperature for 18 hours and the precipitate formed was separated and washed with dichloromethane to obtain 1.36 g of the expected product melting at about 280° C. (yield 59%)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:22]#[N:23])([CH3:9])[CH3:8].[CH2:28](I)[CH3:29].C(OCC)(=O)C>CN(C=O)C>[CH2:28]([N:12]1[C:11]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])=[C:10]([CH:7]([CH3:9])[CH3:8])[C:15](=[O:16])[NH:14][C:13]1=[O:17])[CH3:29]
Reactant: CCI
Reactant: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(Oc2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
Potassium carbonate (24 mg, 0.172 mmol, 1.0 eq.) was added to 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzonitrile (103) (59 mg, 0.207 mmol, 1.2 eq.) in 2.0 mL DMF. The reaction mixture was stirred at room temperature for 10 minutes, then ethyl iodide (14 μL, 0.172 mmol) was added. The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was then washed with brine. The organic layer was concentrated and purified (silica gel, 20-80% EtOAc/hexane), followed by reverse phase HPLC (MeCN/water) to give a white powder (15 mg, 28%). LC-MS shows 314.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.17 (br, 1H), 7.25 (s, 1H), 7.08 (s, 1H), 7.00 (s, 1H), 3.77 (t, 2H), 2.69 (m, 1H), 2.42 (s, 3H), 1.2 (m, 9H).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:8][C:7]2[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH:1]=[O:13])=[CH:3][C:4]=2[O:5][CH3:6])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CC(C)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccc(C(C)C)cc1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
Syringaldehyde (4-hydroxy-3,5-dimethoxybenzaldehyde) (10.2 g, 55 mmol) was dissolved in DMF (45 ml), and 4-isopropylbenzylchloride (9.7 g, 55 mmol) and potassium carbonate (11.5 g) were added successively. The resulting mixture was heated at 60° C. for 16 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (3×100 ml). The combined organic extracts were washed with water (100 ml), saturated NaCl (100 ml), dried (MgSO4), treated with activated carbon, filtered and concentrated in vacuo to afford 15 g (100%) of 4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl-].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][NH+:14]=1>>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Reactant: ClCc1cccc[nH+]1
Agent: [Cl-]
Product: Cc1cc(=O)[nH]c(SCc2ccccn2)n1
Yield: 45 %

Procedure:
The title compound is prepared from 6-methyl-2-thiouracil and 2-chloromethylpyridinium chloride by using the process described in Example 12. After recrystallization from 2-propanol the title compound is obtained as a yellowish crystalline substance in a yield of 45%, m.p.: 154°-156° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[CH3:21][N:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[N:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:23])[C:24]1[CH:25]=[CH:26][C:27]([N:30]=[N:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH2:2][C:3]3[CH:16]=[CH:15][C:14]4[O:13][C:12]5[C:7]6=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]6[C:5]=4[CH:4]=3)[CH:9]=[CH:10][CH:11]=5)(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:28][CH:29]=1
Reactant: NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: CN(C)C=O
Product: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)NCc3ccc4c(c3)-c3n[nH]c(=O)c5cccc(c35)O4)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of compound 49 (0.5 mmol) in anhydrous DMF (20 mL) was added 4-dimethylaminoazobenzene-4′-sulfonyl chloride (0.5 mmol). The mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated in vacuo, and 50 mL of 50% EtOAc in hexanes was added. The precipitate was formed and collected through filtration. The crude product was recrystallized in 50% ethanol to afford a orange solid 55 in 59% yield. MS (ES+): 553; Mp: >300° C.; 1H-NMR (DMSO-d6, 400 MHz): 12.63 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.86-7.74 (m, 6H), 7.67 (d, J=9.0 Hz, 2H), 7.62 (dd, J=6.6 and 2.5 Hz, 1H), 7.44 (dd, J=8.5 and 2.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.81 (d, J=9.0 Hz, 2H), 4.15 (s, 2H), 3.09 (s, 6H); Anal. Calcd. for C29H24N6O4S.(1.3H2O): C, 60.47; H, 4.65; N, 14.59; S, 5.57. Found: C, 60.72; H, 4.93; N, 15.39; S, 4.93.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([F:15])[CH:3]=1.[Cu][C:17]#[N:18].C(N)CN>CN(C=O)C>[C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([C:17]#[N:18])=[CH:3][C:4]=1[F:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: N#C[Cu]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: NCCN
Product: CC(C)(C)NC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Combine 4-bromo-N-tert-butyl-2-fluoro-benzamide (1.0 g, 3.65 mmol) and copper(I) cyanide (0.7 g, 7.29 mmol) in anhydrous DMF (10 mL) and reflux for 17 h. Cool the reaction mixture to ambient temperature and treat with 50% (v/v) aqueous ethylenediamine (20 mL). Extract the reaction mixture with diethyl ether (3×10 mL), combine the organic extracts, wash with brine (2×10 mL) and dry the organic layer over Na2SO4. Evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1, 7:3 and 3:2) to obtain the desired intermediate as a white solid (0.6 g, 77%). MS (ES+) m/z: 221 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[C:42]=2[CH3:48])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[C:42]=2[CH3:48])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Product: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)c1C

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (330 mg, 70%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:20]([C:19]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:45](=[O:46])[CH2:44][Cl:43])[CH2:30][CH2:29]3)=[N:18][C:17]=2[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c(CC3CCN(C(=O)CCl)CC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reaction time: 0.17 h

Procedure:
1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round bottom flask was dissolved in 2.00 mL of methylene chloride and was charged with PS-DIEA (150 mg, 0.46 mmol). Chloroacetyl chloride (10 μL, 0.42 equiv) was added in one portion. After 10 min., another 5 μL of chloroacetyl chloride (0.21 equiv) was added. After another 10 min., another 2.5 μL of methoxylacetyl (0.11 equiv) was added. The reaction was filtered through a flitted funnel, and the resins were rinsed multiple times with methylene chloride. The crude product was purified by a 5 g Jones silica gel (dry loaded with silica, wetted with 100% ethyl acetate and eluted with 5% NH3 in MeOH/Ethyl Acetate) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.74 (1 H, s), 8.30 (1 H, d, J=8.68), 8.21 (2 H, d, J=7.01), 7.98 (2 H, m), 7.86 (1 H, dd, J=1.70, J=1.70), 7.53 (3 H, m), 7.24 (1 H, d, J=5.34), 7.08 (1 H, d, J=5.31), 4.63 (1 H, d, J=13.24), 3.90 (1 H, d, J=13.2), 3.15 (1 H, t), 2.97 (2 H, d, J=5.64), 2.70 (1 H, t), 2.34 (1 H, m), 2.05 (2 H, s), 1.92 (2 H, t), 1.42 (2 H, m); MS (ES+): m/z 511.06/513.02 (50/25) [MH+]; HPLC: tR=2.20 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.NC(N)=[S:15]>C(O)C>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][SH:15]
Reactant: NC(N)=S
Reactant: BrCc1ccc2ccccc2c1
Solvent: CCO
Product: SCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.4 %

Procedure:
To a stirred solution of 2-(bromomethyl)naphthalene (10 g) in ethanol (40 ml) was added thiourea (3.79 g) and the reaction heated to reflux. After 6 h, the reaction was cooled in an ice bath, the precipitate was filtered off and washed with ice-cold ethanol. This was then added to NaOH solution (25%, 30 ml) and heated to reflux. After 2 h, the reaction was cooled to room temperature and water (200 ml) was added. The mixture was extracted with diethylether 3 times, the organic phase was separated, dried and concentrated to afford 5 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[Na+].Br[CH2:13][CH2:14][O:15][CH3:16]>C(O)C.O>[CH3:16][O:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: OCc1cccc(O)c1
Reactant: COCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCOc1cccc(CO)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxybenzyl alcohol (27A) (12.41 g, 100 mmol) in ethanol (150 mL) was added aqueous NaOH (10 N, 10 mL), followed by 1-bromo-2-methoxyethane (27B) (13.9 g). The reaction mixture was heated to reflux overnight. Then the reaction mixture was allowed to cool to RT, and diluted with water. The mixture was subsequently extracted with CH2Cl2, and the combined organic phase was dried with anhydrous MgSO4 filtered, and concentrated in vacuum to give the product (27C) a yellow oil, which was used for the next reaction without further purification. 1H NMR (300 MHz, CDCl3): δ 1.82 (br, 1H), 3.44 (s, 3H), 3.74 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J=4.8 Hz), 4.65 (s, 2H), 6.84-6.95 (m, 3H), 7.22-7.26 (m, 1H). LCMS: purity >94%. ESI-MS: M/Z 183(M+H)+.