Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:31]([C:25]1([C:22]2[CH:21]=[CH:20][C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]3[C:6]4[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH3:18])=[CH:24][CH:23]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)#[N:32]
Reactant: CC(N)c1ccc(C2(C#N)CCCCC2)cc1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C2(C#N)CCCCC2)cc1

Procedure:
N-{1-[4-(1-Cyanocyclohexyl)phenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 5 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (233 mg, 1.10 mmol) prepared according to scheme 2, 1-[4-(1-aminoethyl)phenyl]cyclohexanecarbonitrile (250 mg, 1.10 mmol) prepared according to scheme 11, Et3N (111 mg, 1.10 mmol, 0.153 mL) and HATU (418 mg, 1.10 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (336 mg, 0.796 mmol, 72%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (d, J=7.03 Hz, 3H) 1.23-1.35 (m, 1H) 1.51-1.69 (m, 2H) 1.69-1.78 (m, 1H) 1.77-1.89 (m, 4H) 1.99-2.09 (m, 2H) 4.87-5.00 (m, 1H) 5.07 (s, 2H) 7.14-7.28 (m, 1H) 7.37 (d, J=8.40 Hz, 2H) 7.42-7.53 (m, 3H) 8.19 (s, 1H) 8.83 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 424.0. found: 423.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCC(=O)O)c1
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-methoxyphenyl)propanoic acid (2.00 g, 11.10 mmol) in THF (2.0 mL) was added dropwise to a stirred solution of borane-tetrahydrofuran complex (24.42 mL, 24.42 mmol) so as to maintain reaction temperature below 35° C. The mixture was allowed to stir at room temperature overnight. Methanol was added dropwise to the stirred mixture until visible reaction had ceased. An additional 20 mL of methanol was added and the reaction was stirred for 4 hours. The crude mixture was concentrated, filtered and purified by silica gel chromatography (1:1 heptane:EtOAc as eluant). Fractions containing product were combined and concentrated to give 3-(3-methoxy-phenyl)-propan-1-ol as an oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[C:3]=1[F:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:3]1[C:4]([F:16])=[CH:5][C:6]2[CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:9]3[C:10]=2[C:2]=1[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1NCCn2c1cc1cc(F)c(F)c(Br)c12
Product: COc1ccc(-c2c(F)c(F)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, off-white solid (65 mg, 79%), MS (ISP) m/z=329.1 [(M+H)+], mp 274.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-7,8-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (75.3 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C@@H:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28]([O:32][C:33]([NH:35][C:36]([CH3:41])([C:38](O)=[O:39])[CH3:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[C@H:10]([NH:11][C:38](=[O:39])[C:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])([CH3:41])[CH3:37])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
D-Homophenylalanine benzyl ester (0.87 g; 3.23 mmol), triethylamine (900 ml) and N-(t-butoxycarbonyl)-α-methylalanine (656 mg; 3.23 mmol) were dissolved in dry methylene chloride (6.5 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP-reagent) (1.43 g; 3.23 mmol) was added with stirring in small batches over 10 minutes. The reaction mixture was stirred at room temperature for 2.5 h then quenched by adding saturated brine (25 ml). The two phase system was extracted with methylene chloride (3×25 ml) and the combined methylene chloride extracts dried over magnesium sulfate powder, filtered and evaporated on a rotary evaporator under reduced pressure to give a colorless oil that solidified to an off white solid on standing at room temperature. This solid material was taken up in the minimum volume of methylene chloride and chromatographed on silica gel using an eluant composed of ethyl acetate and hexanes in the ratio 1:3 v/v. The product was isolated after evaporation of the volatiles as a white solid. The yield of the desired product was 1.30 g (88.5%). FAB-MS: -calculated for C26H34N2O5 454.2; found 455.5 (M+1).
Reaction SMILES: [N:1]([CH2:4][C:5]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6])=[N+]=[N-]>CO.[Pt]=O>[NH2:1][CH2:4][C:5]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: COc1ccccc1CN(C(=O)CN=[N+]=[N-])c1ccccc1Oc1ccccc1
Agent: O=[Pt]
Solvent: CO
Product: COc1ccccc1CN(C(=O)CN)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 647 mg of N-azidoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline in 7 ml of methanol was added 20 mg of platinum oxide, followed by stirring under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered through Celite, and after concentration under reduced pressure, purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:6) and recrystallized from ethyl acetate-isopropyl ether to give 0.24 g of N-aminoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:20])[N:12]=[C:13]([NH:16][N+]([O-])=O)[NH:14][CH:15]=2)=[CH:5][N:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36]N)=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:38]([F:41])([F:40])[F:39]>C(O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][NH:16][C:13]3[NH:14][CH:15]=[C:10]([CH2:9][C:6]4[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=4)[C:11](=[O:20])[N:12]=3)=[CH:33][CH:34]=2)=[CH:24][C:23]=1[C:38]([F:39])([F:40])[F:41]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COc1ncc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
To the solution of 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-(nitroamino)-4(1H)-pyrimidinone (100 mg, 0.359 mmol) in ethanol (5 mL) was added neat 2-(4-{[4-chloro-3-(trifluoromethyl)-phenyl]oxy}phenyl)ethanamine (189 mg, 0.599 mmol). It was heated with a microwave reactor at 100° C. overnight. Purification via MDAP then afforded the title compound (92 mg, 35.6% yield). LCMS: rt=3.04 min, [M+H+]=532.2
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]1.Cl[C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[F:23][C:21]1[C:20]([F:24])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:12][C:11]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[CH:9][CH:10]=2)[CH:22]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccnn1-c1ccccn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccnn1-c1ccccn1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A solution of 1-(2-pyridinyl)-1H-pyrazol-5-ylamine (6.94 g, 43.3 mmol), 2-chloro-4,5-difluorobenzoic acid (10.0 g, 51.9 mmol), copper acetate (II) (0.787 g, 4.33 mmol) and potassium carbonate (5.98 g, 43.3 mmol) in N,N-dimethylformamide (40 mL) was heated under reflux under an argon atmosphere for 3 hours. The solution was allowed to cool to room temperature, and poured into water. The solution was made weakly acidic by the addition of 6N hydrochloric acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give the title compound (8.99 g, 55% yield).
Reaction SMILES: [OH:1][CH:2]([C:25]([O:27][CH3:28])=[O:26])[C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].CS([C:39]1[N:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([CH3:47])[N:40]=1)(=O)=O>CN(C=O)C.O>[CH3:28][O:27][C:25]([CH:2]([O:1][C:39]1[N:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([CH3:47])[N:40]=1)[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[O:26]
Reactant: COC(=O)C(O)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
10 g (25.9 mmol) of methyl 3-(2-hydroxy-2-methoxycarbonyl-1,1-di-phenylethoxy)-2,2-dimethylpropionate were dissolved in 40 ml of DMF under N2, 1.78 g (13 mmol) of K2CO3 and 5.2 g (25.9 mmol) of 2-methanesulfonyl-4-methoxy-6-methylpyrimidine were added, and the mixture was stirred at 80° C. for 2 h. It was subsequently diluted with 40 ml of H2O and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate/cyclohexane mixtures. Crystallization from diethyl ether/hexane resulted in 11.8 g (90%) of the product as colorless crystals.
Reaction SMILES: Cl[O-].[Na+].[CH3:4][CH:5]1[C:10]([CH3:12])([CH3:11])[CH:9](/[CH:13]=[CH:14]/[C:15]([CH3:17])=[O:16])[C:8]([CH3:18])=[CH:7][CH2:6]1.C(Cl)[Cl:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:20][CH:7]1[C:8](=[CH2:18])[CH:9]([CH:13]=[CH:14][C:15](=[O:16])[CH3:17])[C:10]([CH3:11])([CH3:12])[CH:5]([CH3:4])[CH2:6]1
Reactant: CC(=O)/C=C/C1C(C)=CCC(C)C1(C)C
Reactant: ClCCl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: C=C1C(Cl)CC(C)C(C)(C)C1C=CC(C)=O
Reaction time: 1 h

Procedure:
To a mixture of commercial bleach (42.6 ml of a 5.25% solution of sodium hypochlorite), α-irone (6.24 g), and methylene chloride (200 ml) was added a solution of potassium phosphate (monobasic) (8.16 g) in water (40 ml) during a 30 minute period. The mixture was stirred for 1 hour at 25°. The methylene chloride solution was washed with sodium bicarbonate solution and evaporated to give 7.3 g of crude product. Purification by column chromatography gave 4.59 g of 4-(5-chloro-6-methylene-2,2,3-trimethylcyclohexyl)-3-buten-2-one. NMR (CDCl3) δ0.70-0.78 (2H, d, J=5 Hz, >CHCH3), 0.90, 0.93 and 0.99 (6H, 3s, >C(CH3)2), 0.9-1.3 (1H, m, >CHCH3), 1.5-2.1 (2H, m, --CH2 --), 2.25, 2.26 and 2.28 (3H, 3s, --COCH3), 2.67 and 2.83 (1H, 2s, >CH--CH=CH--), 4.6-4.9 (1H, m, >CHCl), 4.93 and 5.12 (2H, 2s, >C=CH2, 5.8-6.3 (1H, m, --CH=CH--CO--), 6.6-7.6 (1H, m, --CH=CHCO--). IR (film) ν max 2960, 1695, 1675, 1620, 1460, 1430 cm-1. MS m/e 207, 163.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH:11]([C:13]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:12])=[CH:8][CH:7]=1>C(OC(=O)C)C>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([C:13]2[S:17][C:16]([N:18]=[C:1]=[O:2])=[N:15][N:14]=2)[CH3:12])=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(OC(C)c2nnc(N)s2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(C)c2nnc(N=C=O)s2)cc1
Reaction time: 8 h

Procedure:
A 500 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethylacetate which was saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene) and cooled in an ice bath. An additional 50 milliliters of ethylacetate was added and then 4.8 grams of 5-[1-(4-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole (prepared above) was added, the solution was stirred overnight and then filtered to remove a small amount of insoluble sediment. The clear solution was topped on a roto-vac at 70° C. to form 4.0 grams of a viscous orange oil of 5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C:5]([CH2:17][CH2:18][F:19])([C:6]#[N:7])[C:8]#[N:9]
Reactant: FCCBr
Reactant: N#CC(C#N)Cc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccccc1Br
Yield: 41.8 %

Procedure:
Using 0.24 g of (2-bromobenzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.10 g of sodium hydride (60% in oil), and 0.13 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(2-bromobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (69)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].[F-].[K+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[OH:15][CH:8]([C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([CH:16]=[O:17])=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(O)c1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCC(O)c1cccc(-c2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
To a solution of 1-bromo-3-(1-hydroxyhept-1-yl)benzene (1.00 g, 3.70 mmol, from Step A), 4-formylphenylboronic acid (0.83 g, 5.55 mmol) and potassium fluoride (0.65 g, 11.10 mmol) in tetrahydrofuran (10 mL) was added palladium(II) acetate (0.016 g, 0.071 mmol) and 2-(dicyclohexylphosphino)biphenyl (0.052 g, 0.148 mmol). After stirring for 24 h at rt, the reaction was diluted with ethyl acetate (50 mL), washed with water (50 mL), sat'd sodium chloride (50 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 25% ethyl acetate/hexanes gave 0.81 g of product as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added N-methyl piperazine (0.141 mL, 1.278 mmol) followed by diisopropyl ethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 24 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (21 mg, 8.3%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.25 (m, 5H), 6.45 (s, 1H), 4.35 (m, 2H), 4.00 (m, 3H), 2.80-2.25 (m, 10H), 2.15 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 592 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25]#[N:26]>CC(=O)CC.O>[CH3:14][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[C:9]([O:13][CH2:24][C:25]#[N:26])[C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: N#CCCl
Reactant: Cc1ccc2c(Cl)cc(Cl)c(O)c2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc2c(Cl)cc(Cl)c(OCC#N)c2n1
Temperature: 25 °C

Procedure:
10.7 g of 5,7-dichloro-8-hydroxyquinaldine are dissolved at elevated temperature in 150 ml of 2-butanone; 10.4 g of potassium carbonate are then added portionwise, and the mixture is refluxed for one hour. After the addition of 1 g of potassium iodide, there are added dropwise, with stirring and refluxing, 7.1 g of chloroacetonitrile in 30 ml of 2-butanone, and the mixture is subsequently heated for 3 hours at an internal temperature of 75° C. To the resulting reaction mixture, after cooling to room temperature, is added 1 liter of water, and the whole is filtered; the residue is washed with water, dried, and recrystallised from chloroform/petroleum ether (40°-60° C.) to thus obtain 2-methyl-5,7-dichloro-8-(cyanomethoxy)-quinoline, m.p. 157°-158° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].S(Cl)([Cl:19])=O>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Cl:19])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(CCl)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.3 grams (0.004 mole) of 4-(diethylphosphono)phenylmethanol and two drops of pyridine in 10 mL of methylene chloride was added 0.39 mL (0.005 mole) of thionyl chloride. Upon completion of the addition, the reaction mixture was stirred for 30 minutes, then washed with 10 mL of water and 10 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding the intermediate 4-(diethylphosphono)phenylmethyl chloride. The chloride was not further characterized. A solution of 2.7 grams (0.005 mole) of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine (prepared as in Step A of Example 17) in 10 mL of dimethyl sulfoxide was stirred, and 2.5 mL (excess) of diisopropylethylamine was added. To this was then added a solution of the methyl chloride, prepared above, in one mL of dimethyl sulfoxide. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for one hour, then poured into water, and the mixture was extracted with one 150 mL portion of methylene chloride. The extract was washed with one 50 mL portion of an aqueous solution saturated with ammonium chloride and one 50 mL portion of water. The extract was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with pure ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of N-[4-(diethylphosphono)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[CH3:18][C:19]1([CH3:28])[CH:24]2[CH2:25][CH:20]1[CH2:21][CH:22]=[C:23]2[CH:26]=O.CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH3:18][C:19]1([CH3:28])[CH:24]2[CH2:25][CH:20]1[CH2:21][CH:22]=[C:23]2[CH2:26][NH:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC1(C)C2CC=C(C=O)C1C2
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NCC1=CCC2CC1C2(C)C
Yield: 50.8 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-leucine methyl ester hydrochloride (2.0 gm, 11.0 mmol), THF (25 mL), MgSO4 (2.24 gm, 18.7 mmol), (1R)-(−) myrtenal (3.30 g, 22.0 mmol), Et3N (1.54 mL, 11.0 mmol), sodium borohydride (832 mg, 22.0 mmol), and methanol (20 mL) to give 11l (1.56 gm, 51%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.82 (3H, s), 0.89 (3H, d, J=6.59 Hz), 0.91 (3H d, J=6.83 Hz), 1.15 (1H, d, J=8.54 Hz), 1.27 (3H, s), 1.38-1.54 (3H, m), 1.68 (1H, m), 2.08 (2H, d, J=5.37 Hz), 2.24 (2H, q, J=16.11 Hz), 2.32-2.4 (1H, m), 2.94 (1H, dd, J=1.7, 13.91 Hz), 3.08 (1H, dd, J=1.46, 13.67 Hz), 3.29 (1H, t, J=7.32 Hz), 3.71 (3H, s), 5.36 (1H, s). ESI-MS: 302.2 (M+23).
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6]2[NH:8][C:9](=[O:12])[CH2:10][CH2:11][C:5]=2[C:4](=[O:13])[N:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=1.[C:26](=O)([O-])O.[Na+].IC.O>C(#N)C>[CH3:26][S:1][C:2]1[N:3]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:18][CH:19]=2)[C:4](=[O:13])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:6]=2[N:7]=1
Reactant: O=C([O-])O
Reactant: O=C1CCc2c([nH]c(=S)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Agent: [Na+]
Solvent: CI
Solvent: CC#N
Solvent: O
Product: CSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3,5,6-tetrahydropyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione (2.05 g) in acetonitrile (40 mL) were added 1M aqueous sodium hydrogen carbonate solution (5.52 mL) and iodomethane (1.73 mL), and the mixture was stirred at 50° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.1 g).