Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of 9.7 g of 3-(4-chlorophenoxy)-1-propanol and 10.5 g of triethylamine in 250 ml of dichloromethane chilled to -5° C. is added dropwise 6.7 g of methanesulfonyl chloride. After chilling and stirring for 1 hour, the mixture is washed with chilled 100 ml portions of water, 10% hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer is dried (magnesium sulfate) and the solvent removed under vacuum to give the product as an oil which crystallizes on standing.
Reaction SMILES: [OH:1][C:2]1([C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5][O:4][CH2:3]1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O.[OH-].[Na+]>[Cl-].[Na+].O>[OH:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:3][O:4][CH2:5]1
Reactant: COC(=O)c1ccc(C)c(-c2c(C)nc(C3(O)COC3)n2COCC[Si](C)(C)C)c1
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3(O)COC3)nc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 192.4, 180 mg, 0.42 mmol), Et3SiH (1 mL) and trifluoroacetic acid (2 mL). The reaction mixture was stirred for 4 h at room temperature. The pH of the solution was adjusted to 8 with sodium hydroxide (1 M). The reaction mixture was diluted with 100 mL of brine. The aqueous phase was extracted with 2×30 mL of ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 150 mg (crude) of the title compound as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)(Cl)Cl)=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].Cl>>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)=[CH:6][CH:5]=1)([O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: Nc1ccccc1O
Agent: Cl
Product: COC(=O)c1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 4 h

Procedure:
In the apparatus described in Example 1, 25.4 g of 4-trichloromethylbenzoic acid methyl ester (0.1 mol) and 10.9 g of 2-aminophenol (0.1 mol) were mixed and slowly heated up to 200° C, so that the stream of HCl that commences at 130° C would not become too strong. The total reaction time was about 4 hours. The ground reaction product was washed thrice with 100 ml of hot benzene and the combined and concentrated benzene phases where chromatographed through an Al2O3 : 8.9 g of raw product XVI, melting point 190°-191° C (35% of the theory), becoming 193°-194° C after recrystallization from benzene.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1)(=O)[CH3:2].Cl.[NH2:12][OH:13]>N1C=CC=CC=1>[Br:10][C:6]1[N:5]=[C:4](/[C:1](=[N:12]\[OH:13])/[CH3:2])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: C/C(=N/O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-acetyl-6-bromopyridine (10.0 g, 0.050 mol) and hydroxylamine hydrochloride (6.90 g, 0.10 mol) in pyridine (50 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate (200 mL), washed with water (100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a 10.75 g of A461.1 as an off-white solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:43])[NH:29][C:30]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1)([CH3:35])[CH:31]([OH:34])[C:32]#[CH:33])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:27][C:28](=[O:43])[NH:29][C:30]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1)([CH3:35])[C:31](=[O:34])[C:32]#[CH:33])([CH3:24])([CH3:25])[CH3:26]
Reactant: C#CC(O)C(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C#CC(=O)C(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Dess-Martin periodinane (3.04 g, 7.16 mmol) was added portionwise over 5 minutes to a solution of rac-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-but-3-ynyl]-carbamic acid tert-butyl ester (2.12 g, 5.97 mmol) in dry DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hour. The reaction mixture was quenched with NaHCO3 (aq. sat. solution) followed by NaHSO3 (aqueous sat. soltn.). Then Et2O was added and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and the aqueous layer was further extracted with Et2O. The combined organic layers were separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; DCM). The desired fractions were collected and concentrated in vacuo to yield rac-[1-(3-bromo-phenyl)-1-methyl-2-oxo-but-3-ynyl]-carbamic acid tert-butyl ester (1.89 g, 90% yield) as an oil.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=[O:32])[N:26]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]>CS(C)=O>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]4[CH2:2][O:32]4)[N:26]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]
Reactant: C[S+](C)C
Reactant: CCOc1ccc(-c2nc(-c3cccc(C=O)n3)cs2)cc1OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1ccc(-c2nc(-c3cccc(C4CO4)n3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
880 mg of trimethylsulfonium iodide was added to a suspension of 172 mg of 60% sodium hydride in 15 ml of dimethyl sulfoxide. The mixture was subjected to a reaction at room temperature for 1 hour. Thereto was dropwise added a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(6-formyl-2-pyridyl)thiazole dissolved in 20 ml of dimethyl sulfoxide. The mixture was stirred overnight at room temperature. The reaction mixture was poured into 150 ml of ice water. The mixture was subjected to extraction three times with 200 ml of ethyl acetate. The ethyl acetate layer was water-washed and dried over anhydrous sodium sulfate. The solvent was removed. The residue was purified by silica gel column chromatography (elutant: n-hexane/ethyl acetate=4/1) to obtain 760 mg of 2-(3,4-diethoxyphenyl)-4-(6-oxiranyl-2-pyridyl)thiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[N:12][C:13]([O:16][CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)=[CH:14][CH:15]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[N:12][C:13]([O:16][CH:17]2[CH2:18][C:19]([CH3:25])([CH3:26])[NH:20][C:21]([CH3:24])([CH3:23])[CH2:22]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc(OC3CC(C)(C)NC(C)(C)C3)nn2)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(Oc2ccc(-c3ccc(O)cc3F)nn2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Fluoro-4-methoxyphenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.08 g, 3.00 mmol) was dissolved in CH2Cl2 (15 mL) and a 1 M solution of BBr3 in CH2Cl2 (7.5 mL, 7.5 mmol) was added dropwise. The reaction mixture was stirred at RT overnight, then diluted with CH2Cl2 and a pH 4 buffered aqueous solution. The aqueous phase was washed with 3:1 chloroform/propan-2-ol (2×), then basified to pH 8 with saturated NaHCO3. The aqueous phase was extracted with 3:1 chloroform/propan-2-ol (4×). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. 3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol was afforded as a brown solid (0.59 g, 52%). [M+H]: 346.4; 1H NMR (400 MHz, MeOD) δ 7.88 (dd, J=9.0, 2.2 Hz, 1H), 7.69 (t, J=9.0 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.76 (dd, J=9.0, 2.0 Hz, 1H), 6.65 (dd, J=13.0, 2.0 Hz, 1H), 5.78 (tt, J=11.0, 4.0 Hz, 1H), 2.26 (dd, J=12.5, 4.0 Hz, 2H), 1.47 (t, J=12.0 Hz, 2H), 1.39 (s, 6H), 1.29 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:51]=[CH:50][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]OS(C5C=CC(C)=CC=5)(=O)=O)=[CH:28][CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:52]([O-:55])(=[S:54])[CH3:53].[K+].O>O1CCCC1.C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:55][C:52](=[S:54])[CH3:53])=[CH:50][CH:51]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCOc2ccc(-n3c4ccc(-c5ccccc5)cc4c4cc(-c5ccccc5)ccc43)cc2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=S)OCCCCCCCCOc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
The obtained toluene-4-sulfonic acid 8-[4-(3,6-diphenylcarbazol-9-yl)phenoxy]octyl ester (1.90 g, 2.7 mmol) was dissolved in a solvent mixture of tetrahydrofuran (THF) (40 mL) and ethanol (20 mL). Under nitrogen flow, potassium thioacetate (0.55 g, 4.8 mmol) was added to the resultant solution, and the mixture was refluxed for 7 hours and left to cool to room temperature. Next, the mixture was poured to water, followed by extraction with ethyl acetate. In addition, the mixture was washed with water and dried and the solvent was evaporated, to thereby obtain a crude product. The crude product was purified through silica gel column chromatography using toluene an eluent, to thereby obtain 1.32 g of thioacetic acid 8-[4-(3,6-diphenylcarbazol-9-yl)phenoxy]octyl ester as pale orange oily matter.
Reaction SMILES: [F:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[NH2:17]>C(O)(=O)C>[F:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:17]([NH:16][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:5]2=[O:7]
Reactant: COc1ccc2c(c1F)C(=O)OC2=O
Reactant: NNc1ccncc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1F)C(=O)N(Nc1ccncc1)C2=O
Yield: 72.4 %

Procedure:
To a solution of 2-(3-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (34.0 g) in dry tetrahydrofuran (300 ml) sec-butyllithium (140 ml of a 1.3 M solution in cyclohexane) was added dropwise at -78° C. with stirring, under nitrogen. The reaction mixture was stirred 15 mins, and carbon dioxide was bubbled below the surface. The reaction was stirred for 1 hr and water added dropwise. The mixture was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The aqueous extract was cooled to 0° C. and an equal volume of concentrated hydrochloric acid was added dropwise. The solution was stirred, under reflux overnight, cooled and the solid collected. The solid was washed with cold water and dried in vacuo to give 26.6 g of 3-fluoro-4-methoxyphthalic acid. A mixture of 3-fluoro-4-methoxyphthalic acid (26.6 g ) in acetic anhydride (100 ml) was stirred, under reflux, under nitrogen, for 4 hrs. The reaction mixture was cooled to -60° C. and filtered. The solid was collected, washed with ether and dried in vacuo to give 19.9 g (67%) of 3-fluoro-4-methoxyphthalic anhydride, mp 128-130° C. A mixture of 3-fluoro-4-methoxyphthalic anhydride (10.0 g) and 4-hydrazinopyridine hydrochloride (7.42 g) in glacial acetic acid (50 ml) was stirred, under reflux, under nitrogen, for 4 hrs and stirred at ambient temperature overnight. The solid was collected, washed with ether and dried in vacuo at 80° C. overnight to give 10.6 g (64%) of 4-fluoro-5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione. To a mixture of lithium aluminum hydride (3.72 g) and dry tetrahydrofuran (100 ml), 4-fluoro-5-methoxy-2-(4-pyridinylamino)isoindole-1,3-dione hydrochloride (10.60 g) was added in portions with rapid stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred at ambient temperature, under nitrogen, for 3 hrs, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter pad was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane:methanol:ammonium hydroxide. The residue was crystallized from absolute ethanol to give 3.2 g (8%) of product, (dried under vacuum at 80° C. overnight) mp 206-210° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].C(B(CC)OC)C.O1CCCC1.[BH4-].[Na+]>CO.COCCOCCOCCOC>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOCCOC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 150 mmoles) is dissolved by adding 22 mL diethylmethoxyborane and 200 mL tetrahydrofuran. The solution is stirred for about 2 hours at room temperature, then cooled to −70° C. to −75° C., and further diluted with 25 mL methanol. Sodium borohydride (6 g) as a solution in triglyme (75 mL) is added slowly at between −65° C. to −75° C. After the addition, the reaction mixture is warmed to 15° C. to 25° C., quenched by the addition of acetic acid and concentrated by vacuum distillation—keeping this distillate. The residue is diluted with methanol and concentrated by vacuum distillation—keeping this distillate and all subsequent ones separate from the first one. The residue is dissolved in a mixture of water and ethyl acetate, the layers separated, and the organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in crude [R(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:24][NH:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([N:25]([CH3:26])[CH3:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(N(C)C)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (140 mg, 0.43 mmol) and a 40% (W/V) aqueous solution of dimethylamine were reacted as starting materials at 45° C. for 30 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (139 mg, 96.5%). Melting point: 109.6-110.7° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:26])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24]C)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:26])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O)cc2c1=O
Reaction time: 20 h
Yield: 69 %

Procedure:
A stirred mixture of 2-amino-5-methoxybenzoic acid (10 g), trimethyl orthoformate (13.1 ml), and acetic acid (0.34 ml) in toluene (240 ml) was heated under reflux for 6 hours. 3-Amino-N-cyclopropyl-4-methylbenzamide (10.23 g) was added to the reaction mixture and stirring continued at reflux for 16 hours. The reaction mixture was allowed to cool and then was diluted with ethyl acetate. The organic solution was then washed with 1N HCl solution, 2N NaOH solution (×2), brine, dried (magnesium sulfate), and concentrated to a cream coloured foam/solid. Recrystallisation from ethyl acetate gave N-cyclopropyl-3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (AZ12239719) (11.33 g) as a white solid; NMR Spectrum: (DMSOd6) 0.62 (m, 2H), 0.75 (m, 2H), 2.19 (s, 3H), 2.90 (m, 1H), 3.95 (s, 3H), 7.56 (m, 2H), 7.63 (s, 1H), 7.78 (d, 1H), 7.89 (s, 1H), 7.95 (d, 1H), 8.23 (s, 1H), 8.48 (d, 1H); Mass Spectrum: M+H+ 350. B) To a solution of N-Cyclopropyl-3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (4.62 g) in methylene chloride (90 ml) was added 1M boron tribromide in methylene chloride (53 ml) and stirred for 20 hours. The reaction was quenched with water and then diluted with 2N NaOH solution until the solid dissolved. The aqueous layer was washed with methylene chloride (2×) and then acidified to pH 1 with 2N HCl solution and extracted with ethyl acetate (3×). The combined organic extracts were concentrated and the solid was dried by azeotropic removal of water using toluene to yield N-cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (AZ12266450) (3.06 g) as a white solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 2.12 (s, 3H), 2.85 (m, 1H), 7.35 (d, 1H), 7.50 (s, 1H), 7.52 (d, 1H), 7.66 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.11 (s, 1H), 8.42 (d, 1H), 10.20 (broad s, 1H); Mass Spectrum: M+H+ 336.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:22]1(=[O:33])[O:32][C@H:29]([CH2:30][OH:31])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24]>>[C:10]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]([C@@H:29]([C@H:27]([C@@H:25]([C@@H:23]([CH2:22][OH:33])[OH:24])[OH:26])[OH:28])[OH:32])=[O:31])=[CH:8][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: O=C(NCc1ccc(P(c2ccccc2)c2ccccc2)cc1)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
In a flask were placed (4-aminomethylphenyl)diphenylphosphine (2.89 g, 9.9 mmol), D-glucono-1,5-lactone (1.78 g, 10 mmol) and drybenzene (60 ml), and the mixture was heated at 80° C. for two hours with stirring, during which precipitate was formed. After cooling to room temperature, the precipitate was collected by vacuum filtration. The collected solid was washed with 10 mL of benzene five times. The product was dried at room temperature in vacuo. Yield: 4.46 g (96%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23].[Cl-].[Li+].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:24]1[CH:29]=[C:28]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:27]=[CH:26][CH:25]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(C#N)c2)CC1
Temperature: 25 °C

Procedure:
To a mixture of tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (prepared according to Wustrow, D. J., Wise, L. D., Synthesis, (1991), 993-995; 3.24 g, 9.77 mmol), 3-cyanophenylboronic acid (2.01 g, 13.7 mmol), lithium chloride (1.23 g, 29.3 mmol), and 2 M Na2CO3 solution (14 mL) in DME (35 mL) was added Pd(PPh3)4 (564 mg, 0.489 mmol), and the resulting mixture was stirred at reflux under a nitrogen atmosphere for 3.5 h. The reaction mixture was cooled to rt, stirred overnight, then partially concentrated to remove most of the DME. To the remaining aqueous mixture was added DCM, 2M Na2CO3 solution, and ˜6 mL of 28% NH4OH solution. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 45% ethyl acetate/hexanes eluent) afforded tert-butyl 4-(3-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. 1HNMR (CDCl3, 500 MHz): δ 7.66 (s, 1H), 7.61 (dd, J=8.0, 1.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 6.13 (br s, 1H), 4.12 (m, 2H), 3.68 (t, J=5.5 Hz, 2H), 2.53 (br s, 2H), 1.52 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:26][C:25]2[C:20]([O:19][CH3:18])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ncccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ncccc1Nc1cc(Cl)ncn1
Temperature: 90 °C
Yield: 31.5 %

Procedure:
To a solution of 4,6-dichloropyrimidine (660.04 mg, 4.43 mmol) in 1-butanol (10 mL) was added DIPEA (0.67 ml, 4.03 mmol) followed by 2-methoxypyridin-3-amine (500 mg, 4.03 mmol). The reaction mixture was then heated to 90° C. for 2 hr. The reaction mixture was then concentrated in vacuo and partitioned between DCM and water. A precipitate was removed by filtration and the organics extracted (2×20 ml DCM). The combined organic extracts were then washed with 0.5M HCl (5 ml) and then dried (Na2SO4), filtered and concentrated in vacuo to give the title intermediate (300 mg, LC-MS purity=83%); LC-MS: m/z=+236.95/238.90 (M+H)+.