Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH:14]1[CH:19]([C:20](=O)[NH:21][CH:22]([C:25](=[O:36])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][OH:24])[CH:18]2[O:38][CH:15]1[CH2:16][CH2:17]2.CCN(S(F)(F)F)CC.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH:14]1[CH:19]([C:20]2[O:24][CH2:23][CH:22]([C:25](=[O:36])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:21]=2)[CH:18]2[O:38][CH:15]1[CH2:16][CH2:17]2
Reactant: CCCCCCCCCNC(=O)C(CO)NC(=O)C1C2CCC(O2)C1Cc1cc(F)ccc1CCC(=O)OC
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCCCCCCCNC(=O)C1COC(C2C3CCC(O3)C2Cc2cc(F)ccc2CCC(=O)OC)=N1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-{4-Fluoro-2-[3-(2-hydroxy-1-nonylcarbamoyl-ethylcarbamoyl)-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl]-phenyl}-propionic acid methyl ester (14.86 mmol) in dichloromethane (200 ml), at −78° C. and under nitrogen atmosphere, DAST (3.93 mL, 29.72 mmol) was added and the resulting mixture was stirred at room temperature for 2.5 h. After this time, potassium carbonate (4.11 g, 29.72 mmol) was added and the solution was stirred for another hour. Then saturated solution of NaHCO3 (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). Then, it was washed with Brine (150 mL), and dried over MgSO4. Filtration and concentrated in vacuo yield the crude compound as thick oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH2:4].CCCCCC.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:1][C@@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH2:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: C=C[C@@H](O)CCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=C[C@H](CCCCC)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3(S)-hydroxy-1-octene (6.41 g., 0.05 mole) in dry dimethylformamide is added dropwise to a stirred suspension of hexane (2 × 10 ml.) -- prewashed sodium hydride (50% dispersion in mineral oil, 2.64 g., 0.055 mole) in dry dimethylformamide (45 ml.) at 25° C. Upon cessation of gas evolution, the reaction mixture is cooled to 0° to 5° C. and treated with a solution of benzyl bromide (10.3 g., 0.06 mole) in dry dimethylformamide (10 ml.). The resulting mixture is stirred at 25° C. for 16 hours, then is heated at 100° C. for 1 hour. After cooling to 25° C., the reaction mixture is diluted with ice water (50 ml.) and extracted with ether four times. The combined organic extract is washed with 2N hydrochloric acid and saturated aqueous brine, dried over magnesium sulfate and filtered. In vacuo evaporation of the filtrate leaves an oily residue which affords the title compound upon distillation as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1([O:9][CH2:10][C:11]([O:13]CC)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O.CO>[CH:3]1([O:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)COC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of NaOH (4.89 g, 122 mmol) in a mixture of water (20 mL) and MeOH (20 mL) in an ice bath was added a solution of ethyl 2-(cyclohexyloxy)acetate (3.8 g, 20.4 mmol) in MeOH (10 mL) slowly and the mixture was stirred at rt for 2 h. It was then acidified to pH 4 with concentrated hydrochloric acid and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as pale yellow oil (2.7 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:29][CH3:28])=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: [Na+]
Solvent: CO
Product: COc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reaction time: 1 h
Yield: 35 %

Procedure:
According to Scheme 2 Step 4: To a cooled solution of N-(3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 2(C) (80 mg, 0.18 mmol) in 0.5 mL of methanol (0.5 mL) at 0° C., was added a solution of sodium methoxide (2M) in Methanol (85 μL 0.18 mmol). After 1 h at 0° C. the reaction mixture was allowed to reach room temperature. After 1 h the reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 5 g column, (Eluant: DCM/AcOEt/MeOH 80/18/2). 25 mg (35% yield) of N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide were recovered.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Br:11].[CH2:12]([Li])CCC.COS(OC)(=O)=O.Cl>C(OCC)C.CCCCCC>[CH3:12][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Br:11]
Reactant: Brc1sc2ccccc2c1Br
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: Cc1sc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15.88 g of 2,3-dibromobenzo[b]thiophene in 150 ml of dry diethyl ether at 0° C. was added a solution of 20 ml of diethyl ether and 34 ml of a 1.6M solution of n-butyl lithium in hexane. After stirring for one hour at 0° C., a solution of 10.2 ml of dimethylsulfate in 20 ml of diethyl ether was added and the reaction was stirred at 0° C. for 4 hours. The mixture was allowed to warm to room temperature. After the addition of 125 ml of 1N hydrochloric acid, the reaction mixture was stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined ether extracts were dried over magnesium sulfate and evaporated in vacuo giving an oil. The oil was cooled and it solidified. The resulting crystals were recovered by filtration providing 8.7 g of the desired subtitled intermediate, m.p. 39°-40° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][NH2:9])[N:3]=[CH:2]1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>CC(O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[N:3]=[CH:2]1
Reactant: NCCCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(NCCCc2c[nH]cn2)nc1

Procedure:
A solution of 0.158 g (0.97 mmol) of 3-(1H-imidazol-4-yl)propylamine and of 0.154 g (0.97 mmol) of 2-chloro-5-nitropyridine in 10 ml of 2-propanol is brought to reflux for 21 h while stirring and evaporated under reduced pressure. The resulting residue is chromatographed on a column of silica gel, using a chloroform/methanol (1/1) mixture, to give the title compound in the form of a yellow oil. The latter is treated with oxalic acid in heated absolute ethanol to provide the oxalate salt which, after crystallization from 2-propanol, melts at 181°-182° C.
Reaction SMILES: Cl[Si](Cl)(C)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([S:18](Cl)(=O)=O)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15].CN1CCN(C)C1=O>ClCCCl.[Zn]>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([SH:18])[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]
Reactant: COc1cc(S(=O)(=O)Cl)cc(OC)c1OC
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: ClCCCl
Solvent: CN1CCN(C)C1=O
Product: COc1cc(S)cc(OC)c1OC
Temperature: 75 °C

Procedure:
A room temperature suspension of zinc powder (430 mg, 6.56 mmol) and dichlorodimethylsilane (0.80 mL, 6.59 mmol) in 1,2-dichloroethane (15 mL) was treated with a solution of 3,4,5-trimethoxybenzenesulfonyl chloride (500 mg, 1.87 mmol) and 1,3-dimethyl-2-imidazolidinone (647 mg, 5.67 mmol) in 1,2-dichloroethane (15 mL). The reaction was heated to 75° C. for 1 hour, cooled to room temperature, filtered, and concentrated. The concentrate was dissolved in methanol, concentrated, dissolved in methanol, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)O)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(hexanoyl)amino]methyl}phenoxy)acetate and NaOH 1 N in the presence of MeOH/THF as a colorless oil (86%). 1H NMR (MeOD, 300 MHz) δ 7.39-7.47 (m, 4H), 7.10-7.20 (m, 6H), 6.91 (m, 2H), 4.65 (s, 1H), 4.64 (s, 1H), 4.54 (m, 4H), 2.63 (t, J=7.6 Hz, 2H), 2.45 (m, 2H), 1.62 (m, 4H), 1.23-1.40 (m, 6H), 0.90-0.97 (m, 6H), M− (ESI): 524.4; M+ (ESI): 526.4. HPLC, Rt: 5.47 min (Purity: 98.7%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:4]([CH:5]=[CH:6][C:7]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8])=[CH:3][C:2]=1[O:1][CH2:11][CH2:12][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCBr
Reactant: COc1ccc(C=CC(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOC(=O)C=Cc1ccc(OC)c(OCCCCC)c1
Temperature: 90 °C
Yield: 217.7 %

Procedure:
3-Hydroxy-4-methoxycinnamic acid (9.7 g, 0.050 mol, 1.0 eq) was dissolved in DMF (90 ml). 1-Bromopentane (22.7 g, 0.150 mol, 3.0 eq) and anhydrous potassium carbonate (41.5 g, 0.30 mol, 6.0 eq) were successively added to this solution, and the mixture was stirred under heating at 90° C. for 3 hours. This reaction mixture was cooled to room temperature, and anhydrous potassium carbonate was filtered off. Water (200 ml) was added to the filtrate, and the mixture was exracted twice with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=15/1-10/1) to give pentyl 4-methoxy-3-pentyloxycinnamate (18.2 g, 100%) as a colorless oil.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:8][C:7]=2[CH:31]=1.Cl.Cl.N1C=C(CN2CC3C=CC=CC=3N(C(C3C4C(=CC=CC=4)C=CC=3)=O)CC2)N=C1.Cl.N1C=C(CN2C3C=CC=CC=3CN(C(C3C4C(=CC=CC=4)C=CC=3)=O)CC2)N=C1>C(Cl)Cl>[ClH:1].[ClH:1].[Br:2][C:3]1[CH:31]=[CH:7][C:8]2[N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:6][C:5]=2[CH:4]=1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Agent: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)Cc2ccccc21
Agent: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccccc2C1
Solvent: ClCCl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)Cc2cc(Br)ccc21

Procedure:
Example 42 was prepared as an off white solid from 7-bromo-1,4-benzodiazepine (prepared as described in Compound B of Example 11) using the following procedure: Compound A of Example 4; Compound B of Example 4; Compound C of Example 4; Compound D of Example 1, using methylene chloride as solvent, purification by prep HPLC (YMC S5 ODS 30×250 mm; gradient elution with 0 to 100% buffer B over 45 min; buffer A=MeOH:H2O:TFA (10:90:0.1); buffer B=MeOH:H2O:TFA (90:10:0.1); 25 mL/min) and conversion to the HCl salt by lyophilization from 1M HCl. MS (M+H+) 462. 1H-NMR (CD3OD): 3.5 (br s, 2H), 3.80 (m, 2H), 4.80 (br, 2H), 5.3 (br, 2H), 6.60 (1H), 7.15-8.15 (m, 11 H), 9.10 (s, 1H).
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].S(Cl)(Cl)=O>CC(O)C>[C:14]([C:13]([C:12](=[O:17])[CH3:11])=[CH:9][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[C:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])=[CH:5][CH:6]=1)(=[O:16])[CH3:15]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(=O)C(=Cc1ccc(C=C(C(C)=O)C(C)=O)cc1)C(C)=O

Procedure:
To a mixture containing 1.34 g of 1,4-benzenedicarboxaldehyde and 2.1 g of 2,4-pentanedione in 20ml of 2-propanol was gradually added 3.0 g of thionyl chloride with stirring and cooling below 20° C. The mixture was stirred over night at room temperature, filtered and washed with 2-propanol. Yield 1.1 g (55%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of methyl 2-(1H-indol-5-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate (90 mg, 0.23 mmol) in MeOH (20 mL) was added sodium hydroxide (40 mg, 0.93 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(1H-indol-5-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylic acid as a brown solid (65.8 mg, 76%).
Reaction SMILES: [CH2:1]([C:5]([CH2:10][OH:11])([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH:3]=[CH2:4].[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=C[CH:13]=1>CC(C)=O>[CH2:1]([C:5]1([CH2:6][OH:7])[CH2:8][O:9][C:12]([CH3:17])([CH3:13])[O:11][CH2:10]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: C=CCCC1(CO)COC(C)(C)OC1

Procedure:
A mixture of crude 2-(but-3-enyl)-2-hydroxymethylpropan-1,3-diol (4.5 g), acetone (30 ml) and p-toluenesulfonic acid (0.25 g) was refluxed in a Dean and Stark apparatus for 7 hours. The mixture was cooled and washed with aqueous sodium hydrogen carbonate solution. The organic solution was dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was chromatographed on silica, eluting with 1:4 diethyl ether: hexane. 5-(But-3-enyl)-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane was obtained as a colourless oil (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[CH3:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Cc1ccc2ccc(N)nc2n1
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(C)nc3n2)cc1
Temperature: 4 °C
Yield: 72.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (12.2 g), N,N'-carbonyldiimidazole (10.3 g) and 2-amino-7-methyl-1,8-naphthyridine (9.5 g). The product produced by precipitation in water (14.4 g; m.p. 110° C.) is dissolved in boiling acetonitrile (150 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-(7-methyl-1,8-naphthyridin-2-yl)-4-methoxybenzamide (12.7 g) is produced, m.p. 119° C.
Reaction SMILES: [CH:1]12[O:8][CH:5](CC1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=1)[CH2:2]2.[CH3:22][C@H]1COCCN1>>[CH3:22][C@@H:4]1[N:3]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([NH2:19])=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)[CH2:2][CH2:1][O:8][CH2:5]1
Reactant: C[C@H]1COCCN1
Reactant: Nc1ccc(-c2ccnc(N3CC4CCC(C3)O4)n2)cc1
Product: C[C@H]1COCCN1c1nccc(-c2ccc(N)cc2)n1

Procedure:
Method as described for intermediate 26 using (S)-3-methylmorpholine. (699 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)c2OC
Yield: 45 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (75 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (89 mgs) were converted to the title compound as an off-white solid (66 mgs). 1H-NMR (CDCl3): δ 10.30 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J=15.7 Hz, 2H), 7.44-7.41 (m, 2H), 7.28-7.25 (m, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.54 (s, 1H), 3.80 (s, 3H), 2.32 (broad S, 2H), 3.15-1.5 broad absorptions, 6H), 1.15 (t, J=7.3 Hz, 3H). LC/MS, found 504.17 (M+H)+; MP:183-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:11]([CH3:27])=[C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:15])[N:13]=1.C(N(CC)CC)C.[CH3:42][CH:43]([CH3:50])[CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47].O>ClCCl>[CH3:42][CH:43]([CH3:50])[CH2:44][CH2:45][S:46]([O:34][C:31]1[CH:30]=[CH:29][C:28]([N:10]2[C:11]([CH3:27])=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:33][CH:32]=1)(=[O:48])=[O:47]
Reactant: CC(C)CCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)Nc2ccc(C(F)(F)F)cn2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C(F)(F)F)cn2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxamide, prepared as described in Ex. 13, Step 3 (139 mg, 0.27 mmol) and triethylamine (46 μl, 0.33 mmol) in dichloromethane (4.0 ml) were cooled to −78° C. 3-Methylbutane-1-sulfonyl chloride (56 mg, 0.33 mmol) was carefully added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and then allowed to reach room temperature. Water was added to the reaction, and the phases were separated. The organic phase was washed with NaHCO3, brine and dried with Na2SO4. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (81 mg, 46%) as a solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:24][O:23][C:10]1[CH:11]=[C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:4]=[C:3]([NH:25][CH3:26])[C:2]([C:27]#[N:28])=[CH:7][N:6]=1
Reactant: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1Br
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1C#N
Temperature: 105 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
TA mixture of (4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone (80 mg, 0.19 mmol), zinc cyanide (50 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.09 mmol), DPPF (11 mg, 0.02 mmol) in DMF (3 mL) was stirred at 105° C. in a pressure tube for 18 hours. The reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC to give the title compound (70 mg, 82%). Additional compounds made using the above procedure are shown in Table 7 below.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:12]1=[O:40])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:12]1=[O:40]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c3ccccc3)c2=O)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
To a solution of compound 6c (10 g, 15 mmol) in anhydrous dichloromethane (60 mL) was added trifluroacetic acid (TFA, 16 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and partitioned between ethyl acetate and diluted aqueous NaOH solution. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried with sodium sulfate, filtered and concentrated to yield 6d as a tan solid (8.0 g, 14 mmol, 94%). MS (CI) m/z 556.2 (M+H+), tR=2.354 min. (method 4). 1H NMR (CDCl3): δ 2.25 (s, 3H), 3.42 (s, 1.5H), 3.43 (s, 1.5H), 3.91 (s, 1.5H), 3.92 (s, 1.5H), 3.98–4.22 (m, 2H), 4.33–4.38 (m, 1H), 5.60 (brs, 2H), 6.80–6.89 (m, 1H), 6.97–7.03 (m, 1H), 7.11–7.17 (m, 1H), 7.22–7.37 (m, 6H), 7.46–7.54 (m, 1H), 7.95 (dd, 1H).