Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CS(C)=O.O>[CH2:4]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17][C:1]#[N:2])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CN(Cc2ccccc2)CCO1

Procedure:
The mixture of finely ground sodium cyanide (39.6 g.) and 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine (144.4 g.) in dimethyl sulphoxide (600 ml.) is stirred and heated at 60°-65° C. for 3.5 hours. The mixture is cooled, diluted with water (6 1.) and extracted with ether (3 × 2 1.). The ether extracts are combined and washed with brine (2 × `1.) and dried over anhydrous magnesium sulphate and the solvent removed by evaporation in vacuo. The residue is recrystallised from petroleum ether (b.p. 40°-60° C.) to give 4-benzyl-2-cyanomethylmorpholine, m.p. 62° C.
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)C1C=CC=CC=1>C(O)C.O.[Pd]>[ClH:1].[ClH:1].[CH3:23][N:22]([CH3:24])[C:19]1[CH:18]=[CH:17][C:16]([CH:13]2[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C2CCNCC2)cc1
Reaction time: 10 h
Yield: 86.7 %

Procedure:
1-Benzyl-4-(4-dimethylaminophenyl)-1,2,3,6-tetrahydropyridine dihydrochloride (3.65 g) prepared in Example 46 was dissolved in a solvent mixture of 20 ml of ethanol and 5 ml of water. Using 10% palladium-on-carbon as the catalyst, the mixture was subjected to catalytic reduction at atmospheric temperature and pressure for 10 hours. The catalyst was then filtered off and the solvent was distilled off. The residual oil was diluted with a saturated aqueous solution of sodium chloride, made basic by addition of solid sodium hydrogen carbonate and extracted with acetonitrile. The extract was dried and 5 ml of 2N-ethanolic hydrochloric acid was added. Finally the solvent was distilled off and the residue was recrystallized from ethanol to give 1.2 g of colorless crystals melting at 215°-220° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.N#N>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cccnc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Yield: 109.6 %

Procedure:
A solution of 3-bromopyridine (2.5 g, 15.8 mmol) and 4-fluorophenylboronic acid (2.8 g, 20.0 mmol) in DME (20 ml) and 2N Na2CO3 (aq, 20 ml) was deoxygenated by evacuation/refill with N2 (×2). PdCl2dppf (600 mg, 0.8 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 80° C. under N2 for 16 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2).The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/Petrol) to give the title compound (3.0 g, oil). 1H NMR (400 MHz, CDCl3): 8.83 (1H, brs), 8.61 (1H, brs), 7.85 (1H, d), 7.54 (2H, dd), 7.39 (1H, brs), 7.18 (2H, t).
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18]([CH3:19])=[C:17]([CH:20]=[N:21]O)[C:16]([CH3:23])=[N:15]3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1.CN(C)C=O.ClC1N=C(Cl)N=C(Cl)N=1>O>[CH:1]1([C:4]2[C:5]([CH2:6][O:7][C:8]3[CH:13]=[CH:12][C:11]([N:14]4[C:18]([CH3:19])=[C:17]([C:20]#[N:21])[C:16]([CH3:23])=[N:15]4)=[CH:10][C:9]=3[CH3:24])=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-n2nc(C)c(C=NO)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-n2nc(C)c(C#N)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At room temperature, to the mixture of 1-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-3,5-dimethyl-1H-pyrazole-4-carbaldehyde oxime (described in Reference Preparation example 118) 1.5 g and N,N-dimethylformamide was added 2,4,6-trichloro-[1,3,5]triazine 0.6 g and the resulting mixture was stirred at room temperature for three hours. To the resulting mixture was added water 100 ml and the precipitates were filtrated. The precipitates were washed with water and dried under reduced pressure to give 1-{3-cyclopropyl-2-[2-methyl-4-(4-cyano-3,5-dimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 52”) 1.0 g.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[O:25]>CC(C)=O>[ClH:32].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[O:25])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCN(Cc2ccccc2)CC1)c1ccc(Cl)cc1
Yield: 114.5 %

Procedure:
A mixture of N-benzyl piperazine dihydrochloride (2.49 g, 10 mmol), K2CO3 (4.14 g, 30 mmol) and 2-bromo-1-(4-chlorophenyl)ethanone (2.8 g, 12 mmol) in 100 ml of acetone was refluxed for 5 hours, and then treated according to general preparation 2 to give 2.76 g of compound (IV-6), yield 68.7%, mp 231-233° C. M+ 328.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:10].[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.CCCCCCC>CO>[ClH:10].[NH2:9][C:8]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=2)[N:18]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
A solution of pivaloylacetonitrile (750 g, 6.0 mol) and p-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L) was refluxed for 3 h. Heptane was added, and methanol was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 1.05 kg, 94%. 1H NMR δ(CDCl3) 7.50 (d, 2H), 7.30 (d, 2H), 5.60 (s, 1H), 2.45 (s, 3H), 1.40 (s, 9H). MS (CI) m/z 229 (M++H).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[C:1]([C:4]1[O:5][C:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccco1
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)c1ccc(Cc2ccc(F)cc2)o1
Yield: 42 %

Procedure:
To a solution of 19.71 g (0.18 mol) of 2-acetylfuran in 120 ml of methylene chloride were added 42.9 ml (2.0 eq) of 4-fluorobenzylchloride and 36.6 g (1.5 eq) of zinc chloride. The mixture was refluxed for 12 hours. The precipitated crystal was filtered and washed with methylene chloride. The obtained solid was dissolved in water and extracted with ethylacetate. The organic layer was washed with water and a diluted aqueous solution of sodium hydrogencarbonate and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from n-hexane to give 16.4 g of 2-acetyl-5-(4-fluorobenzyl)furan. Yield: 42%. Mp: 27-29° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetate (0.331 g, 0.736 mmol in methanol/THF was added 1.23 mL (3.5 eq) of a 1.0 N solution of LiOH and the reaction was stirred at room temp overnight. The solvent was removed in vacuo and the residue was suspended in water, adjusted to pH to 3 with 2N HCl. The resulting solid was rinsed with ether and dried in vacuo to afford 0.27 g (89%) of [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetic acid. Electrospray Mass Spec 392.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].Cl.[NH2:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][NH2:19])[CH:26]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: NCc1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Agent: Cl
Product: NCc1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-aminomethyl-phenylboronic acid hydrochloride gives “A76”; method 1: HPLC/MS: 0.94 min, [M+H]=320;
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[C:36]([CH3:38])[N:35]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M115) (0.52 g, 0.91 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (337 mg, 82%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[O:32]([CH2:39][CH2:40][CH2:41][CH2:42]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[O:32]([CH2:39][CH2:40][CH2:41][CH2:42][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCCCCOc1ccccc1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(CCCCOc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (27.5 mM) of triethylamine in ethanol (6 ml) was added 0.45 g (1.96 mM) of 4-phenoxybutyl bromide at room temperature and the mixture was refluxed under nitrogen for 14 hours. To this reaction mixture was further added 0.23 g (1.0 mM) of 4-phenoxybutyl bromide and the mixture was refluxed for 6 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/chloroform=1/15-1/10-1/5) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=C[C:36]2N(O)N=[N:39][C:37]=2C=1.CCN=C=NCCCN(C)C.C(N)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:39][CH2:37][CH3:36])=[O:32])[CH2:27][CH2:28]4)=[O:22])=[CH:19][CH:20]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)CN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.5 h

Procedure:
2-{4-[(4-{[4-(4-Chlorophenyl)pyrimidin-2-yl]amino}phenyl) carbonyl]piperazinyl}acetic acid (0.200 g, 0.44 mmol) was dissolved in DMF then stirred for 15 minutes in ice-brine solution, then the HOBT (0.072 g, 0.53 mmol] then EDCI(0.102 g, 0.53 mmol) were added and stirred for another 30 minutes. Ethylamine (0.030 mL, 0.53 mmol) was added and the reaction was left to stir at room temp overnight. The reaction was quenched with 10 mL of water and a precipitate formed. The precipitate was colleted by filtration, and purified by preparative HPLC to yield 2-{4-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]piperazinyl}N-ethylacetamide: HPLC Retention time; 9.508 min. (Method B) M+1; 479.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](=[O:12])[C:5]2([NH:20][C:21](=[O:30])[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[H-].[Na+].[C:33]1([C:39](Cl)=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C=O)C>[C:39]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=2)[C:5]([NH:20][C:21](=[O:30])[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]1=[O:12])(=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)Nc3cc(Cl)c(Cl)cc32)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)N(C(=O)c3ccccc3)c3cc(Cl)c(Cl)cc32)CC1

Procedure:
0.14 g of the compound of Example 1 is placed in 9 ml of DMF in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. 0.01 g of 60% NaH is added, at 0° C. PhCOCl is then added dropwise and the mixture is left to react at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 120 mg of oil are obtained, which product is purified on a column by flash chromatography, eluting with 95/5 ethyl acetate/methanol, to isolate 20 mg of white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)[CH3:2].[CH3:14][CH:15]([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][CH:7]=2)[N:12]=[C:16]([CH:15]([CH3:21])[CH3:14])[CH:17]=1
Reactant: CCOC(=O)c1ccc(NN)cc1
Reactant: CC(C)C(=O)CC#N
Product: CCOC(=O)c1ccc(-n2nc(C(C)C)cc2N)cc1
Yield: 88.2 %

Procedure:
Using the same method as Example A83, 4-hydrazinobenzoic acid ethyl ester (from Example A82, 3 g, 16.6 mmol) and 4-methyl-3-oxopentanenitrile (from Example A83, 2.7 g, 27.9 mmol) were combined to afford ethyl 4-(5-amino-3-isopropyl-1H-pyrazol-1-yl)benzoate (4 g, 88% yield), which was used to the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][OH:29]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][OH:29])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCO)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 2-bromoethanol (0.052 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (2% methanol/chloroform) to give the subject compound (72 mg, yield 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].N1C=CC=CC=1>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:10])[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminopyridine (2.0 mL, 21.25 mmol) in DCM (35 mL) at 0° C. was added a solution of 4-nitrophenyl chloroformate (4.28 g, 21.25 mmol) in DCM (35 mL) and pyridine (1.73 mL, 21.25 mmol, anhydrous). After the addition was completed, the reaction mixture was stirred at RT for 16 h under an atmosphere of nitrogen. A white precipitated was observed and it was collected by filtration. The filtrate was washed with DCM (3×50 mL) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 260 (M+H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:17]=[CH2:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[C:21]([CH3:27])=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:17]=[CH2:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1cccc2c(Cl)c(C(=O)CCC)cnc12
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: C=Cc1cccc2c(Nc3ccc(O)cc3C)c(C(=O)CCC)cnc12
Yield: 33.7 %

Procedure:
3-Butyryl-4-chloro-8-vinylquinoline (20.0 g, 77 mmol) and 4-amino-m-cresol (9.5 g, 77 mmol) were heated together under reflux in 1,4-dioxan (150 ml) for 2.5 hours. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, 2M hydrochloric acid, sodium hydrogen carbonate solution and brine. The solution was dried (anhyd. MgSO4), filtered and evaporated to an oil which was chromatographed (silica gel, 1% methanol in dichloromethane) to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-vinylquinoline as orange crystals (9.0 g, 32%) m.p. 150°-2°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:43]=[CH:44][C:39]([N:38]([CH3:48])[CH3:37])=[CH:40][CH:41]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 60.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 4-(dimethylamino)-phenyl boronic acid (0.12 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded {4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-dimethyl-amine (80 mg, 59%) as a white solid: LC/MS m/e calcd for C28H29N3O2S [M+H]+ 472.63, observed 472.2.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29]S(C2C=CC(C)=CC=2)(=O)=O)=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1.CCN(CC)CC>C(#N)C>[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29][C:3]2[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:18][OH:19])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=2[OH:1])=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1
Reactant: CC(C)C1(CCc2ccsc2CO)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3CO)(C(C)C)OC2=O)c(C(C)(C)C)cc1N

Procedure:
The title compound was prepared as described in General Method 16b using 4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-24; 1 mmol), toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl)ester (Example BB-11; 1.05 mmol), NEt3 (2.2 mmol) in acetonitrile (5 mL). The product was triturated from Et2O, mp 107-115° C. MS (APCI): 488 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][S:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][S:6]([C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)c1ccccc1CSc1cnc2ccccc2n1
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CS(=O)c1cnc2ccccc2n1
Yield: 21.3 %

Procedure:
In 50 ml of chloroform was dissolved 1.47 g of 2-(2-dimethylaminobenzylthio)quinoxaline. To the chilled solution kept at -10° C. was portionwise added 1.54 g of m-chloroperbenzoic acid (purity: 80%). To the reaction liquid were washed successively with saturated aqueous NaHCO3 solution, water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (hexane/acetone) to give 330 mg of 2-(2-dimethylaminobenzylsulfinyl)quinoxaline as a yellow powder, m.p. 114°-115° C.