Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.[CH2:23]([N:26]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:27][C:28](O)=[O:29])[CH:24]=[CH2:25].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:28](=[O:29])[CH2:27][N:26]([CH2:23][CH:24]=[CH2:25])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: C=CCN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CC(=O)N1CCC[C@H]1C(=O)OC)C(=O)OCc1ccccc1
Yield: 238.9 %

Procedure:
1-(3-Dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDCI) (0.453 g, 2.36 mmol) was added to a solution of proline methyl ester hydrochloride 30 (0.356 g, 2.15 mmol), acid 55 (0.590 mmol, 2.35 mmol) and triethylamine (0.481 g, 4.73 mmol) in dichloromethane (20 cm3) at 0° C. The resultant solution was stirred for 19 h, washed with 2M aqueous hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and the solvent removed to yield an oil which was purified by chromatography (silica gel, hexanes:ethyl acetate, 2:1, 1:1) to afford protected dipeptide 56 (0.508 g, 66%) as a colourless oil. Dipeptide 56 was shown to be a 76:24 trans:cis mixture of conformers by 13C NMR analysis (the ratio was estimated by integration of signals at δ22.0 and 24.5, 24.7, assigned to the Proγ-C atoms of the minor and major conformers respectively). In addition, restricted rotation about the GlyN-CO carbamate bond was also observed resulting in a further 1:1 mixture of conformers: [α]D −54.6 (c 1.17 in CH2Cl2); δH (400 MHz; CDCl3; Me4Si) 1.81-2.14 (4H, m, ProβH2, Proγ-H2), 3.29-3.58 (2H, m, Proδ-H2), 3.64, 3.66, 3.69* (3H, s, OCH3), 3.84-4.20 [4H, m, CH2(allyl), Glyα-H2], 4.40-4.48 (1H, m, Proα-H), 5.07-5.17 (4H, m, OCH2Ph, ═CH2), 5.69-5.81 (1H, m, C(H)═CH2) and 7.24-7.30 (m, 5H, Ph); δC (100 MHz; CDCl3) 22.0* (CH2, Proγ-C), 24.62, 24.73 (CH2, Proγ-C), 28.66, 28.73 (CH2, Proβ-C), 31.1,* 31.3* (CH2, Proβ-C), 45.93, 45.98 (CH2, ProδC), 46.5* (CH2, Proδ-C), 47.5, 48.0 (CH2, Glyα-C), 50.0, 50.6 [CH2, CH2(allyl)], 50.0,* 50.6* [CH2, CH2(allyl)], 52.0, (CH3, OCH3), 52.31,* 52.5* (CH3, OCH3), 58.4,* 58.5* (CH, Proα-C), 58.8 (CH, Proα-C), 67.2, 67.3 (CH2, OCH2Ph), 117.0, 117.5 (CH2, ═CH2), 127.5, 127.7, 127.8, 128.3, (CH, Ph), 133.2, 133.4 (CH, C(H)═CH2) 136.4, 136.5 (quat., Ph), 155.8, 156.3, (quat., NCO2), 167.1 (quat., Gly-CO), 167.4,* 167.5* (quat., Gly-CO). 172.0,* 172.2* (quat., Pro-CO) and 172.3, 172.4 (quat., Pro-CO); m/z (EI+) 360.1676 (M+. C19H24N2O5 requires 360.1685).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[C:18]2[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:19]=2[NH:20][CH:21]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[F:7][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[C:18]2[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:19]=2[NH:20][CH:21]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1cc2[nH]cc(C3CCCCC3O)c2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]cc(C3CCCCC3F)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Diethylaminosulfur trifluoride (1.2 eq.) was added at −60° C. to a 0.1M solution of methyl 6-(2-hydroxycyclohexyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry EtOAc, and the mixture was stirred at this temperature for 1 h, then allowed to warm slowly to RT. Aq. NaHCO3-solution was added and the mixture was extracted with EtOAc; the organic layer was washed with water and brine, dried on Na2SO4 and concentrated. Chromatography (PE/EtOAc) afforded the title compound (73%). 1H-NMR (300 MHz, CDCl3, 300 K, δ) 8.31 (bs, 1H), 7.67 (s, 1H), 7.06 (s, 1H), 4.53 (dtd, 1H, J 48.6, 10.1, 4.5), 3.88 (s, 3H), 2.88-2.77 (m, 1H), 2.41-1.17 (m, 8H); MS (ES+) m/z 282 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl-]>O>[C:2]1([NH:1][C:9](=[O:8])[CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Nc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
First, 16 g of aniline, 200 mL of tetrahydrofuran (THF), 26 g of triethylamine (Et3N) were put in a 500 mL three-neck flask, and stirred under cooling in ice. Then, a mixed solution of 18 g of btyryl chloride and 50 mL of THF was dripped to the above mixed solution through a 100 mL dropping funnel. After the dripping, the mixture was stirred for 2 hours while the temperature was increased to room temperature. After the stirring, the reaction mixture was added to 200 mL of water, and stirred at room temperature. This mixed solution was separated to an organic layer and an aqueous layer, and the aqueous layer was extracted with chloroform. The extract and the previously resulting organic layer were combined, and washed with saturated saline. After the washing, anhydrate magnesium sulfate was added to the organic layer for drying. The mixture after the drying was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with a mixed solvent of chloroform and hexane, so that N-phenylbutyramide was prepared (a white solid, yield: 92%). The synthetic scheme of Step 1 is shown by (a-7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15]/[C:16](/[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=[N:26]\[OH:27])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C2(CC(=O)c3ccnc(C)c3)CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(C2(C/C(=N\O)c3ccnc(C)c3)CCCCC2)cc1

Procedure:
In analogy to example 151, step 3, 2-[1-(4-methoxy-phenyl)-cyclohexyl]-1-(2-methyl-pyridin-4-yl)-ethanone was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=339.3 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:27][S:26](=[O:29])(=[O:28])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([CH:27]1[C:10]2[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[N:13][N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[S:26]1(=[O:28])=[O:29])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1nn(-c2ccccc2)c2c1C(Cc1ccccc1)S(=O)(=O)c1ccccc1-2)N1CCOCC1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg; 0.24 mmol; 1.0 eq.) in THF (4.0 mL) is added NaH (55% w/w in mineral oil) (12.79 mg; 0.29 mmol; 1.2 Eq.). After 15 min stirring, benzyl bromide (34.81 μL; 0.29 mmol; 1.2 eq.) is added and the reaction mixture is stirred at room temperature for 3h. The reaction is quenched with water and the product extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude residue is recrystallized from EtOH and dried under vacuum to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 300MHz) δ 8.01-7.98 (m, 1H), 7.63-7.58 (m, 4H), 7.53-7.46 (m, 3H), 7.12-7.07 (m, 3H), 6.89-6.86 (m, 2H), 6.66-6.64 (m, 1H), 5.29-5.25 (m, 1H), 3.93-3.88 (m, 1H), 3.63-3.53 (m, 5H), 3.45-3.36 (m, 2H), 3.26-3.20 (m, 1H), 2.76-2.69 (m, 1H). UPLC/MS: (ES+): 500.2, (ES−): 498.3. HPLC (max plot) 97.6%; Rt 4.32 min.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2].N.[H][H]>CO.O>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC2(CCCCC2)O1
Reactant: [H][H]
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1
Reaction time: 22 h
Yield: 97.9 %

Procedure:
A solution of 1.19 g of (±)-cis-1,1-dimethylethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate in 30 mL of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaker at 50 pounds per square inch gage (psig) and 40° C. After 22 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by silica gel flash chromatography (30:20:1; ethyl acetate:methanol:ammonium hydroxide) to give 1.18 g of (±)-cis-1,1-dimethylethyl 4-(2-aminoethyl)- 1,5-dioxaspiro[5.5]undecane-2-acetate as a clear oil which solidifies upon standing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].Cl[Sn]Cl.O>C(O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:7])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(C)cccc1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 97 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
N-[(2-Chloro-6-methylphenyl)carbonyl]-4-nitro-L-phenylalanine methyl ester (1.51 g, 4.0 mmol) and SnCl2.H2O (4.5 g, 20 mmol) were suspended in 30 mL of ethanol. The suspension was stirred at a bath temperature of 97° C. for 1 hr. After it was cooled to room temperature, the solvent was evaporated and the residue was dissolved in 15 mL of water. The aqueous solution was then made alkaline by addition of solid K2CO3 to pH>10 and was extracted with ethyl acetate (3×100 mL). The combined extracts were dried over K2CO3 and were concentrated to give 4-amino-N-(2-chloro-6-methylbenzoyl)-L-phenylalanine methyl ester as a light yellow foam (1.37 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O1CCCC1.Cl.O>O1CCCC1>[CH:19]1([CH:17]([C:3]2[S:4][C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=3)=[CH:6][C:2]=2[CH3:1])[OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (0.8 g) in tetrahydrofuran (20 mL) was added dropwise 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (0.5 g, 51%) as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=1)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)OCCOc1ccc2c(c1)CCCC2
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl methanesulfonate (1.08 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layers were dried (Na2SO4), filtered and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 4:1) to provide, after crystallization from diethyl ether-hexane, 0.86 g of alpha-oxo-4-[[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy) ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 95°-99° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)cc1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice cooled suspension of 4-benzyloxy-2-hydroxybenzaldehyde (P1) (2.28 g, 10 mmol) in 10 mL of methanol was slowly added sodium borohydride (0.38 g, 10 mmol). After addition of sodium borohydride, a clear solution was obtained. The reaction was stirred at 0° C. for 20 minutes followed by stirring at RT for 10 minutes. The solvent was evaporated under vacuum. To this solid residue was carefully added 0.1 N H2SO4 until the pH dropped to 6.5 with vigorous stirring. Additional water (ca. 100 mL) was added with continuous stirring which then caused the product to precipitate. The solid was filtered and copiously washed with water to remove all traces of acid (last wash pH≧7). The solid was immediately vacuum dried to obtain (1.75 g, 76%) of P2 as a white solid: mp 88-90° C.; TLC, Rb0.29, in hexanes:EtOAc (2:1); 1H NMR (600 MHz, DMSO-d6) δ, 9.36 (s, 1H, Ph-OH), 7.43-7.32 (m, 5H, C6H5), 7.13 (d, 1H, J=8.4 Hz, Ar—H6), 6.44-6.41 (m, 2H, Ar—H5/Ar—H3), 5.01 (s, 2H, PhCH2), 4.8 (t, 1H, CH2OH), 4.39 (s, 2H, OHCH2).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([O:17][C:18]([NH:20][C:21]1[C:22](=[O:28])[NH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:10]([O:17][C:18]([NH:20][C:21]1[C:22](=[O:28])[N:23]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
tert-Butyl bromoacetate (3.9 g, 20 mmol) was added to a stirred suspension of 3-benzyloxycarbonylamino 6-methyl-2-pyridinone (5.15 g, 20 mmol), as prepared in the preceding step, and Cs2CO3 (6.5 g, 20 mmol) in N,N-dimethylformamide (50 mL) and stirred at 40° C. overnight. The solid was removed by filtration and the filtrate concentrated under high vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with water (2×50 mL), brine (50 mL), dried over Na2SO4 and concentrated in vacuo. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (25% ethyl acetate in hexane) to give the title compound as a white crystalline solid (4.2 g, 56%). 1H-NMR (300 MHz, CDCl3) δ 7.95 (d, J=7.3 Hz, 1H), 7.76 (s, 1H), 7.37 (m, 5H), 6.09 (d, J=7.6 Hz, 1H), 5.19 (s, 2H), 4.75 (s, 2H), 2.32 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>O1CCOCC1.O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:14][C:9]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:8]=2)[N:6]=[C:11]([CH3:13])[CH:10]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(O)c2cc(I)ccc2n1
Yield: 30.7 %

Procedure:
4-Iodoaniline (25 g), ethyl acetoacetate (17.8 g) and polyphosphoric acid (112.5 g) in dioxane (500 mL) were refluxed for 20 hours. The reaction was diluted with water (2 L) and solid sodium carbonate added until the solution reached pH 10.0. The resulting precipitate was isolated by filtration, washed with water and dried under vacuum. Trituration with ether gave the sub-title compound (10 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:9](OS(C(F)(F)F)(=O)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:25]([C:9]1[CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)#[N:26]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)nc(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Zinc cyanide (4 g) and Pd(PPh3)4 (1.16 g) were added to a DMF (60 mL) solution of methyl 2-phenyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyridine-4-carboxylate (3.7 g), and stirred at 90° C. for 3 hours. The reaction liquid was filtered through Celite, the solvent was partly evaporated away, the residue was diluted with ethyl acetate, water was added to it, and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered and the solvent was evaporated away. The residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a yellow powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]=2[N:3]1[C:38]1[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.5 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol), pyridin-3-ylboronic acid (52 mg, 0.424 mmol), copper(II)acetate (58 mg, 0.318 mmol) and 5 Å molecular sieves (60 mg) in anhydrous dichloromethane (2 ml). To this was added anhydrous pyridine (34 μl, 0.424 mmol) and the resulting blue suspension stirred at room temperature under air for 24 hours. Further pyridine (1 mL) was added and the resulting deep blue solution stirred at room temperature for 24 hours. Further pyridin-3-ylboronic acid (52 mg, 0.424 mmol) and copper(II)acetate (58 mg, 0.318 mmol) were added and the mixture stirred at room temperature for 72 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as an off-white solid (32 mg 28% yield). 1H-NMR (500 MHz, CDCl3) δ 8.50-8.80 (2H, br m), 7.71 (1H, d), 7.50 (1H, br s), 7.09-7.26 (7H, m), 6.92-7.02 (2H, d), 6.71 (1H, s), 5.00 (3H, s), 2.10-2.55 (4H, m), 1.92-2.05 (1H, m), 1.66-1.80 (1H, m), 1.00-1.45 (9H, br m). LCMS (Method A) RT=6.61 min, M+H+=549.09.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:39])[NH:7][C:8]([CH:12]([N:18]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:39])[N:7]([CH2:40][C:41]3[CH:48]=[CH:47][CH:46]=[C:43]([CH3:44])[CH:42]=3)[C:8]([CH:12]([N:18]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-[[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate (29 mg, 1 eq.) in dimethyl formamide (1 ml), was added 3-methylbenzyl bromide (8 μl, 1.2 eq.) and potassium carbonate (22 mg, 3 eq.). The reaction mixture was stirred at room temperature overnight. Water was added and the material was extracted into ethyl acetate. Ethyl acetate layer was washed with water, saturated sodium carbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated. The product was purified by flash chromatography to give tert-butyl 3-[[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH2:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:22][C:23]([CH3:39])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:24]>>[CH2:32]([O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]([NH:24][C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH2:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1)([CH3:22])[CH3:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1ccc(C(=O)OC)cc1-n1cc(Br)nc(Br)c1=O
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Product: CCc1ccc(C(=O)OC)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2OCc2ccccc2)c1=O

Procedure:
The subtitle compound was prepared from methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-ethylbenzoate (Example 288b) and α,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d) using a similar method to that described for Example 252h.