Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:7](=[O:25])[C:6]=1[OH:26])=[O:4].[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O>[CH3:1][CH:2]([CH3:27])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)=[CH:20][CH:19]=2)[C:7](=[O:25])[C:6]=1[OH:26])=[O:4]
Reactant: OB(O)c1ccsc1
Reactant: COc1ccccc1C1C(C(=O)C(C)C)=C(O)C(=O)N1c1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1C1C(C(=O)C(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 29.1 %

Procedure:
After a mixture of (−)-4-(2-methylpropionyl)-3-hydroxy-1-(4-bromophenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (0.10 g, 0.23 mmol), 3-thiophene-boronic acid (0.045 g, 0.35 mmol), tripotassium phosphate (0.148 g, 0.7 mmol), 1,2-dimethoxyethane (3 mL) and water (3 mL) was placed in a flask under nitrogen, 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.019 g, 0.023 mmol) was added to the mixture, and the resulting mixture was stirred at reflux for 3 hours. To the reaction mixture was added water (50 mL), and the resulting mixture was extracted with dichloromethane (50 mL). The extract was washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (methanol/chloroform). The resulting compound was triturated with ethyl acetate/n-hexane to give (−)-4-(2-methylpropionyl)-3-hydroxy-1-(4-thiophene-3-ylphenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (0.029 g, yield: 29%) as pale brown powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH:6]([CH2:5][CH2:4][CH2:3][CH3:2])[C:7]([O:9][CH3:10])=[O:8])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: COC(=O)CCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.7 %

Procedure:
8.80 g (42 mmole) of methyl 6-bromohexanoate, 8.20 g (42 mmole) of 4-hydroxy-4'-cyanobiphenyl, 20 ml dimethyl formamide and 5.8 g (42 mmole) potassium carbonate were placed in a 100 ml flask equipped with a calcium chloride drying tube, and stirred at room temperature for 24 hours, after which time the mixture was poured into water and the suspended solids filtered out and washed with water. The resultant product was dried in a vacuum desiccator for 48 hours to yield 11.50 g (85%) of the ester which was recrystallized from aqueous ethanol to yield a product with a melting point of 80° C.-81° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3ccnc3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3ccnc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-imidazol-1-yl-benzylamino)-methyl]phenoxy}-acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 3H), 7.62-7.52 (m, 3H), 7.22 (m, 6H), 7.15 (t, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 6.56 (s, 1); MS 534 (M+1).
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:37][CH2:38][CH:39](CO)[OH:40]>>[CH2:1]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH:39]([OH:40])[CH2:38][OH:37])=[O:21])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)OC)cc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(4-tetradecenylamino)benzoate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:24])([CH3:23])[C:12]=2[CH:11]=1)([O-])=O.P(OCC)(OCC)OCC>>[CH3:23][C:13]1([CH3:24])[C:12]2[CH:11]=[C:10]3[C:5]4[C:4]([NH:1][C:22]3=[CH:21][C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)=[CH:9][CH:8]=[CH:7][CH:6]=4
Reactant: CC1(C)c2ccccc2-c2ccc(-c3ccccc3[N+](=O)[O-])cc21
Agent: CCOP(OCC)OCC
Product: CC1(C)c2ccccc2-c2cc3[nH]c4ccccc4c3cc21

Procedure:
A mixture of 75 g (238 mmol) of 2-(2-nitrophenyl)-9,9-dimethyl-9H-fluorene and 290.3 ml (1669 mmol) of triethyl phosphite is heated under reflux for 12 h. The triethyl phosphite which remains is subsequently removed by distillation (72-76° C./9 mm Hg). Water/MeOH (1:1) is added to the residue, and the solid is filtered off and recrystallised. Yield: 61.3 g (216 mmol), 92%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)=[CH:18]\[CH2:19][O:20][C:21]2[C:26]3[O:27][CH:28]=[CH:29][C:25]=3[C:24]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[N:4]1([CH2:1][C:2]#[C:3][C:11]2[CH:12]=[CH:13][C:14](/[C:17](/[C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][CH:38]=3)=[CH:18]\[CH2:19][O:20][C:21]3[C:26]4[O:27][CH:28]=[CH:29][C:25]=4[C:24]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)c2occc12
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(F)(F)F)cc2)c2occc12
Temperature: 0 °C
Reaction time: 120 h

Procedure:
N-Propargylmorpholine (0.64 g, 5.1 mmol) was added under nitrogen atmosphere to a degassed solution of ethyl (Z)-[7-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-benzo[b]furan-4-yl]oxyacetate (0.68 g, 1.09 mmol) in a mixture of tetrahydrofuran (20 mL) and triethylamine (10 mL) The solution was cooled to 0° C., tetrakis(triphenylphosphine)-palladium (0.17 g, 0.147 mmol) and copper(I) iodide (0.03 g, 0.16 mmol) were added. The reaction mixture was stirred at ambient temperature for 120 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding ethyl (E)-[7-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]benzo[b]furan-4-yl]oxyacetate.
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].[CH2:21]([CH:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:29](O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:35]([O:34][C:32](=[O:33])[CH:28]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:29]([NH:20][C@H:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:30])[CH3:36]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)O
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Cc1ccccc1)C(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1nc(CC)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.406 g, 1.13 mmol), 2-benzyl-3-ethoxy-3-oxopropanoic acid (0.277 g) and 1-hydroxybenzotriazole (HOBt) (0.191 g, 1.41 mmol) in DMF (10 mL) at 0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.240 g, 1.25 mmol) followed by diisopropylethylamine (DIPEA) (0.306 g). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.169 g (31% yield) of the desired product which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:22](=[O:24])[CH3:23])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 80 °C
Yield: 16.2 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.45 g, 1.5 mmol) in tetrahydrofuran (10 mL), was added acetyl chloride (0.63 mL, 8.8 mmol) and heated at 80° C. for one hour. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide (80 mg, 16% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.15 min (98.6%); mp, 320-322° C.; 1HNMR (DMSO-d6)2.16 (s, 3H, CH3), 2.18-2.24 (m, 1H, CHH), 2.59-2.90 (m, 6H, CHCH2, CH3), 5.32 (dd, J=6, 11 Hz, 1H, CH), 7.28-8.54 (m, 3H, Ar), 11.08 (s, 1H, NH), 11.70 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.65, 23.35, 25.29, 30.57, 56.71, 107.39, 115.09, 120.38, 135.63, 139.84, 147.84, 154.71, 163.01, 168.67, 169.29, 172.60. LCMS MH=329; Anal Calcd For C16H16N4O4+2.2H2O: C, 52.23; H, 5.59; N, 15.23. Found: C, 52.20; H, 5.57; N, 15.21.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[CH:45][C:40]([CH:38]=[O:39])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(C=O)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene from Example 159-(1) and 4-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-formylphenyl)-2-thienylmethyl)-4-methylbenzene as a colorless solid. APCI-Mass m/Z 640 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-formylphenyl)-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 130-(2) to give the desired 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene as colorless crystals. APCI-Mass m/Z 662 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 494 (M+NH4).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>CO.O1CCCC1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:12])[CH3:11]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reaction time: 8 h
Yield: 91 %

Procedure:
5-Acetyl-2-benzyloxybenzoic acid methyl ester (5.69 g, 20 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (20 mL). 2 N sodium hydroxide (11 mL) was added dropwise, and the mixture was stirred for 8 hours. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with dichloromethane. After the dichloromethane layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was washed with isopropyl ether to give the title compound (4.92 g, 91.0%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[N:16]=[N:17][N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:3]1.C(N(C(C)C)CC)(C)C.Br[CH2:49][CH2:50][CH2:51][CH2:52][C:53](Cl)=[O:54]>C1COCC1.O>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]1[N:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:17]=[N:16][C:15]=1[C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@@H:6]1[CH2:5][N:4]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:3][C@H:2]([N:1]2[CH2:49][CH2:50][CH2:51][CH2:52][C:53]2=[O:54])[CH2:7]1)=[O:14]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](N)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](N3CCCCC3=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-amino-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (150 mg) was dissolved in THF (3 ml), diisopropylethylamine (74 μl) and 5-bromovaleryl chloride (42 μl) were added at 0° C. and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), potassium tert-butoxide (96 mg) was added at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (1:3-1:0) was concentrated under reduced pressure to give the object product (150 mg).
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.[CH3:21][C:22](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:21]([N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH3:22]
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)Oc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.82 g) in dry tetrahydrofuran (150 ml) was added potassium tert-butoxide (2.42 g), with stirring. After 20 mins, bromoethane (5.37 ml) was added, and the reaction mixture was refluxed overnight. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, concentrated, and the residue was adhered to silica and flash chromatographed (30% ethyl acetate/hexane). The appropriate fractions were concentrated. Trituration of the residue with diethyl ether/pentane (1/1) gave 4.51 g (85%) of 1-ethyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:32][CH:31]=1)[C:9](=[O:29])[NH:10][C@H:11]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:21]=2[N:20]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.Cl.O1CCOCC1>C(#N)C.O1CCOCC1>[NH2:7][C@H:8]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:34][CH:35]=1)[C:9]([NH:10][C@H:11]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:21]=2[N:20]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:29]
Reactant: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(I)ccc3[nH]2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(C)(C)OCCOc1ccc([C@@H](N)C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(I)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (260 mg, 0.36 mmol) in 6:1 v/v acetonitrile/p-dioxane (14 mL) at 0° C. under an atmosphere of nitrogen was added 4.0 M hydrogen chloride in p-dioxane (420 μL, 1.68 mmol) and the resulting solution stirred at room temperature for 1 hour. Additional 4.0 M hydrogen chloride (420 μL, 1.68 mmol) was added and stirring continued for 30 minutes. The solvent was removed in vacuo and the residue was basified with saturated aqueous sodium hydrogen carbonate solution. The aqueous mixture was extracted with ethyl acetate (2×25 mL), washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-N-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-acetamide which was used in the subsequent step without further purification (210 mg, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:45])[CH:44]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[Cl:45][C:43]1[CH:44]=[C:39]([O:1][C:2]2[CH:24]=[N:23][C:5]3[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:9](=[O:10])[C:4]=3[CH:3]=2)[CH:40]=[N:41][CH:42]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Reactant: Clc1cncc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(Cl)c3)cnc21
Temperature: 135 °C
Yield: 78.8 %

Procedure:
To a mixture of 6-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 2, 500 mg, 1.49 mmol), CuI (85.2 mg, 0.45 mmol), Cs2CO3 (971.6 mg, 2.98 mmol) and 2-(dimethylamino)acetic acid (76.87 mg, 0.75 mmol) in dioxane (20 mL) was added 3-bromo-5-chloropyridine (717.3 mg, 3.73 mmol). The reaction was heated at 135° C. for 5 h followed by heating at 100° C. for 18 h, cooled to RT then diluted with EA (25 mL) and water (10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (525 mg, 78.8% yield) as a yellow oil. LCMS [MH+-THP] 363 and TR=1.403 min.
Reaction SMILES: CO[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[C:10]([NH2:14])(=[O:13])[CH:11]=[CH2:12].C1(C)C(S(O)(=O)=O)=CC=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.N#N>>[N:4]1([CH2:3][NH:14][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: COCN1CCCC1=O
Reactant: C=CC(N)=O
Agent: Cc1ccccc1S(=O)(=O)O
Agent: N#N
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)NCN1CCCC1=O
Yield: 40 %

Procedure:
The mixture of 1-methoxy methyl-2-pyrrolidone (65.6 g), acrylamide (75.5 g), toluene sulfonic acid (0.20 g) and phenothiazine (0.20 g) was stirred under the condition of N2 for 1 hour at 150° C. while removing methanol by distillation. The residue was cooled, then recrystallized in acetone to give the title compound in the yield of 40%.
Reaction SMILES: ClCC([NH:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=O.NC(N)=S.C(O)(=O)C.[OH-].[Na+]>C(O)C.O>[CH3:16][C:6]([NH2:5])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CC(C)(C)NC(=O)CCl)cc1
Agent: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(CC(C)(C)N)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
6.24 g (26.0 mmol) of 2-chloro-N-(2-methyl-1-p-tolylpropan-2-yl)acetamide and 1.98 g (26.0 mmol) of thiourea were dissolved in 50 mL of ethanol, and 10.2 mL of acetic acid was added dropwise at room temperature. After 3 hours of stirring at 85° C. the resulting white suspension was allowed to cool and diluted with 300 mL of water. The reaction solution was basified with 20 wt % aqueous sodium hydroxide and extracted with hexane, and the extract was washed with saturated aqueous sodium chloride. The organic layer was concentrated under reduced pressure to give 4.04 g of the desired product as a yellow green liquid.