Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[OH-].[Li+]>C1COCC1.O>[C:15]([O:14][C:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C(=O)O)ccc1Cl
Reaction time: 18 h
Yield: 91.2 %

Procedure:
3-tert-Butyl 1-methyl 4-chloroisophthalate (0.37 g) in THF (5 mL) was treated with lithium hydroxide (0.17 g) in water (5 mL) and the mixture was stirred for 18 h. The solvent was evaporated. Water and ethyl acetate were added. The aqueous extract was separated and acidified with dilute hydrochloric acid. The product was extracted into ethyl acetate. The solution was dried over sodium sulphate, filtered and the solvent was evaporated to yield the subtitle compound as a white solid (0.32 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(=O)[O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15]1.S(=O)(=O)(O)O>>[C:14]1(=[O:20])[N:1]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[C:18](=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C1CCCC(=O)O1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(N2C(=O)CCCC2=O)cc([N+](=O)[O-])c1

Procedure:
3-Glutarimido-5-nitrobenzoic Acid [D; Y is CH2CH2CH2, Z is OH] was prepared by heating a mixture of 18.2 g. of 3-amino-5-nitrobenzoic acid, 45.6 g. of glutaric anhydride and 0.5 ml. of concentrated sulfuric acid on a steam bath for two hours. The product was isolated and recrystallized from aqueous dimethylformamide to give 3-glutarimido-5-nitrobenzoic acid, pale yellow prisms, m.p. above 300° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1cccc(CBr)c1
Temperature: 75 °C
Reaction time: 6.5 h
Yield: 76.8 %

Procedure:
Commercially available 3-methylbenzophenone (4.00 g, 20.4 mmol) was dissolved in carbon tetrachloride (100 mL), and N-bromosuccinimide (4.71 g, 26.5 mmol) and 2,2′-azobisisobutyronitrile (1.00 g, 6.09 mmol) was added to the solution, followed by stirring at 75° C. for 6.5 hours. After the reaction mixture was cooled, the precipitates were filterd out. The filtrate was combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain 3-bromomethylbenzophenone (4.31 g, yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:30]1[C:31]([C:35]#[N:36])=[N:32][NH:33][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:15]=[CH:16][C:17]([C:30]4[C:31]([C:35]#[N:36])=[N:32][NH:33][CH:34]=4)=[CH:18][CH:19]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1n[nH]cc1Br
Reactant: CC1(C)OB(c2ccc(C3(c4ccc(Cl)cc4)CCNCC3)cc2)OC1(C)C
Product: N#Cc1n[nH]cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1

Procedure:
Following the procedure of Example 1 but using 4-(4-Chloro-phenyl)-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidine instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-1H-pyrazole-3-carbonitrile instead of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride gave the title compound. LC/MS: (PS-A2) Rt 2.22 [M+H]+ 363. 1H NMR (Me-d3-OD) δ 2.52-2.70 (4H, m), 3.10-3.20 (4H, m), 7.25 (4H, s), 7.37 (2H, d), 7.58 (2H, d), 8.02 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:18][CH:19]=O.O>C(O)C>[N:1]1[CH:18]=[CH:19][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]=12
Reactant: COC(=O)c1cccnc1N
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccn2ccnc12

Procedure:
To a solution of methyl 2-amino-pyridine-3-carboxylate (5 g, 35 mmol, 1.0 eq) in ethanol (250 mL) was added NaHCO3 (5.08 g) and chloroacetaldehyde in water (35 mL of 45% in water, 148 mmol, 4.5 eq). The reaction mixture was heated at reflux for 18 h. Solvent was removed and the residue was basified with Na2CO3 and then extracted with DCM. Organic layers were combined and evaporated to give a residue, which was purified by column to give the titled compound.
Reaction SMILES: Cl.O.[N+:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=O>C(O)C>[NH2:3][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=Cc1ccccc1N
Yield: 84.1 %

Procedure:
A mixture of 2.2 g of reduced iron, 0.5 ml of conc. hydrochloric acid and 2.5 ml of water was added to a solution of 2.2 g of ethyl o-nitrocinnamate in 30 ml of ethanol. After heating under reflux for 1 hour, insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. An aqueous sodium hydrogen carbonate solution was added to the residue followed by extraction with toluene. After the extract was washed with water and dried, the solvent was distilled off to obtain 1.6 g of ethyl o-aminocinnamate as yellow crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([S:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3N)[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.O1CCOCC1.Cl.N(OCCC(C)C)=O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([S:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=3)[NH:13][C:14]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3N)[nH]c2-c2ccc(OC)cc2)cc1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
2.61 g of 4,5-bis(4-methoxyphenyl)-2-(2-amino-4-trifluoromethylphenylthio)imidazole hydrochloride is suspended in a mixture of 70 ml of absolute ethanol, 30 ml of absolute dioxane, and 365 mg of hydrochloric acid and combined at 0° with 0.586 g of isoamyl nitrite. The mixture is agitated for 30 minutes, then heated for 2 hours to boiling, and the solution evaporated to dryness under vacuum. The residue is distributed between ethyl acetate and sodium bicarbonate solution. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ether/methylene chloride, thus obtaining 2.01 g of 4,5-bis(4-methoxyphenyl)-2-(4-trifluoromethylphenylthio)imidazole, mp 184°-186°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:23]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Product: Fc1ccc(N2CCN(Cc3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(p-fluorophenyl)-4-[(4-aminophenyl)methyl]piperazine and 4,7-dichloroquinoline are reacted together at reflux to give 4-[[4-[[4-(p-fluorophenyl)-1-piperazinyl]methyl]phenyl]amino]-7-chloroquinoline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.[CH2:13]([Li])CCC.CI.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: Clc1cncc(NC2CCC2)n1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1cncc(Cl)n1)C1CCC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 6-chloro-N-cyclobutylpyrazin-2-amine (535 mg) in THF (30 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 2.4 mL) under an argon stream at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added dropwise a solution of methyl iodide (542 μL) in THF (1 mL), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added dropwise a saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→33% ethyl acetate/hexane) to give the title compound (492 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
A mixture of 3,6-dichloropyridazine (20.1 g, 135 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (25.46 g, 122 mmol) and potassium carbonate (50.7 g, 367 mmol) in 1,4-dioxane (500 mL) and water (200 mL) under nitrogen was degassed by bubbling in nitrogen for 15 min. Dichlorobis(triphenylphosphine)palladium (II) (1.2%, 1 g, 1.4 mmol) was than added and nitrogen was bubbled in the mixture for another 10 min. The reaction mixture was stirred at 90° C. for 3 h, then cooled to room temperature and concentrated in vacuo to remove the majority of the 1,4-dioxane. The residue was partitioned between 1 N aqueous potassium carbonate (400 mL) and ethyl acetate (400 mL) and the phases separated. The aqueous layer was extracted with ethyl acetate (2×300 mL) and dichloromethane (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo. The residue was stirred in diethyl ether (150 mL) and the orange precipitate was filtered and dried to return the title compound (12.76 g, 65.6 mmol, 54% yield). The filtrate was concentrated onto silica gel and purified by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate/hexane to return starting 3,6-dichloropyridazine as a white solid (9.9 g, 66.4 mmol, 49% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.[CH3:17]I.Cl>CO>[O:16]=[C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=1)[CH3:17])[C:13]([OH:15])=[O:14]
Reactant: COc1ccc(CC(=O)C(=O)O)cc1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C)C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml; 20 mmoles) was slowly added to 1.94 g (10 mmoles) of p-methoxyphenylpyruvic acid and a solution of 1.0 ml of methyl iodide in 50 m 1 of methanol. After addition, the mixture was stirred at room temperature for 4 hours. The mixture was acidified with 1N hydrochloric acid and extracted with three 30 ml portions of ether. The ether layers were dried over magnesium sulfate, and the ether was evaporated under reduced pressure to give a pale yellowish white solid. The NMR spectral analysis of this product led to the determination that this product was nearly pure 2-oxo-3-(p-methoxyphenyl)butanoic acid (1.40 g; yield 67 %).
Reaction SMILES: C(OC(=O)N[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[C:33]([CH3:34])=[C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C.C(O)C>[CH2:36]([O:35][C:32]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([CH2:23][O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:17]=2)[C:33]=1[CH3:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1c(COc2cccc(OCC3CCN(NC(=O)OC(C)(C)C)CC3)c2)nc2ccccc2c1OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(COc2cccc(OCC3CCNCC3)c2)nc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To an ice-cold solution of 4-[(3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}phenoxy)methyl]piperidine-1-carbamic acid tert-butyl ester (735 mg) in ethyl acetate-ethanol (3:1, 20 mL) was added a 4M hydrogen chloride-ethyl acetate solution (15 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then a 5% aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 4-(benzyloxy)-3-methyl-2-{[3-(piperidin-4-ylmethoxy)phenoxy]methyl}quinoline (545 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1)=O.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[CH2:17]([NH:21][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)COc1ccc(C=O)cc1C
Reactant: CCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of ethyl (4-formyl-2-methylphenoxy)acetate (3 g, 13.5 mmol) in anhydrous ethanol (50 mL) at room temperature, was added n-butylamine (1.6 mL, 16.2 mmol) and 4A molecular sieves. The resultant mixture was stirred at room temperature for 18 h under nitrogen, prior to portion wise addition of sodium triacetoxyborohydride (3.43 g, 16.2 mmol). After a further 3 h stirring at room temperature, the reaction was quenched by cautious addition of sat. sodium bicarbonate solution (40 mL) and then diluted with water (50 mL), before extracting with EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as brown oil (2.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:41](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C.CO>CO.CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:19]=3[S:20][C:21]=2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:27]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)c(OC)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 24 h
Yield: 43.6 %

Procedure:
To a mixture of (210 mg, 0.37 mmol) of 6-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-(1-pyrrolidinylmethyl)phenyl ketone (Example 163, Part C) in 2.0 mL of MeOH/CH3CN solution (1:9 ratio) was added (0.091 mL, 0.52 mmol) of diisopropylethylamine and (0.26 mL, 0.52 mmol) 2 M (trimethylsilyl)diazomethane in hexanes at room temperature. The reaction was stirred for 24 h. Another portion (0.20 mL, 0.40 mmol) of 2 M (trimethylsilyl)diazomethane in hexanes was added along with 0.5 mL of MeOH, and the solution was stirred at room temperature for 24 h. Another portion (0.10 mL, 0.20 mmol) of 2 M (trimethylsilyl)diazomethane in hexanes was added, and the solution was stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness under reduced pressure and then taken up in 30 mL of H2O and washed with 25 mL of H2O and 1:1 satd. NaHCO3-brine solution which were back extracted with CH2Cl2 (3×30 mL) and EtOAc (1×30 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 7% [10% conc NH4OH in MeOH]/CH2Cl2) afforded 92 mg (43%) of a yellow foam.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:34]([C:36]#[N:37])[K]>C(O)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:36](=[O:34])[NH2:37])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Reactant: N#CO[K]
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(C(N)=O)CC4)n3)cc2)CC1
Reaction time: 4 h
Yield: 29.4 %

Procedure:
A mixture of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (25 mg, 0.055 mmol) and KOCN (20 mg, 0.25 mmol) in acetic acid (2 mL) was stirred at 100 C. for 4 h. The mixture was then purified by HPLC to give the titled compound (8 mg). MS 496.45 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(NC(c2cnc(Cl)nc2Cl)C(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)Nc2ccccc2)C(c2cnc(Cl)nc2Cl)C(C)C)cc1
Temperature: 146 °C

Procedure:
(±)-[1-(2,4-Dichloro-pyrimidin-5-yl)-2-methyl-propyl]-(4-methoxy-phenyl)-amine (35.0 mg; 0.107 mmol) (from Example 11c supra) and phenyl isocyanate (12.8 μL; 0.12 mmol) (Aldrich) were combined in toluene (0.6 mL), sealed and heated in a microwave reactor (SmithCreator™, 160 seconds to a maximum of 146° C., then 800 seconds at 160° C., and finally 600 seconds at 180° C.). The reaction was incomplete, and the mixture was concentrated and purified by flash chromatography (Biotage 12M; 20:80 ethyl acetate-hexanes) to give the intermediate (±)-1-[1-(2,4-dichloro-pyrimidin-5-yl)-2-methyl-propyl]-1-(4-methoxy-phenyl)-3-phenyl-urea. (Yield 24.0 mg).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[O:23][CH2:22]1>COCCO>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)OCO4)nn12
Temperature: 180 °C
Yield: 3.2 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (67.0 mg, 0.000233 mol) and 1,3-Benzodioxol-5-ylamine (63.9 mg, 0.000466 mol) were dissolved in 2-Methoxyethanol (1.64 mL) and the reaction was heated at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 2.65 mg 1,3-Benzodioxol-5-yl-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a lyophilated powder. (M+H)=361.20. 1H NMR (400 MHz, DMSO, d6) δ 9.29 (s, 1H), 8.93 (s, 1H), 7.75 (d, 1H, J=7.07 Hz), 7.51 (s, 1H), 7.46 (m, 1H), 7.20 (m, 1H), 7.10 (m, 2H), 7.05 (s, 2H), 6.76 (d, 1H, J=8.34 Hz), 5.94 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [IH:1].[CH3:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:14][C:15](SC)=[NH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CC(O)(C)C>[IH:1].[CH3:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:14][C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[NH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CSC(=N)NC(c1ccccc1)c1ccc(C)cc1
Reactant: C1CCNC1
Agent: I
Solvent: CC(C)(C)O
Product: Cc1ccc(C(NC(=N)N2CCCC2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 13.3 g (0.0334 mole) of methyl N-(4-methylbenzhydryl)carbamimidothioate hydroiodide and 5.0 g (0.07 mole) of pyrrolidine in 40 mls of t-BuOH is heated under reflux for 24 hrs. The crude product crystallizes out of the reaction mixture while refluxing. The mixture is allowed to cool over night at room temperature and filtered to yield crude product; mp 227°-30° C. Recrystallization from MeOH/t-BuOH yields the pure N-(4-methylbenzhydryl)-1-pyrrolidinecarboximidamide hydroiodide; mp 229°-230° C, as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Product: CCC(=O)NC1CCCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Yield: 80 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 3-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as light brown foam in 80% yield. MS: 367.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C@H:10]1[NH:13][C:12](=[O:14])[CH2:11]1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([S:21]([O:8][CH2:9][C@H:10]2[NH:13][C:12](=[O:14])[CH2:11]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C[C@@H](CO)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C[C@@H](COS(=O)(=O)c2ccccc2)N1
Temperature: 0 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
Triethylamine (5.74 g, 56.8 mmol) was added by syringe to a solution of (S)-4-hydroxymethylazetidin-2-one (3.79 g, 37.5 mmol) and benzenesulfonylchloride (10.0 g, 56.8 mmol) in dry methylene chloride (38 ml) at 0° C. The resulting mixture was stirred at 0° C. for 4 hrs., then diluted with methylene chloride (100 ml), washed with water (50 ml) and brine (25 ml) and dried over magnesium sulfate. Solvents were removed in vacuo to give a brown gum which was chromatographed on silica gel (100 g) (ethylacetate) to yield 6.6 g (73%) of (S)-4-benzenesulfonyloxymethyl azetidin-2-one as a white solid, m.p. 102°-105° C.