Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:17]([O:24][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: OCc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, benzyl alcohol and DBU in dioxane. ES-MS m/e (%): 304 (M{37Cl}+H+, 30), 302 (M{35Cl}+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1[OH:11])[CH:6]=O.[C:15]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18].N1(CC(O)=O)CCCCC1>C1C=CC=CC=1>[CH2:22]([O:21][C:15](=[O:20])[C:16]([C:17](=[O:18])[CH3:19])=[CH:6][C:5]1[CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: COc1cc(C=O)cc(C(C)C)c1O
Reactant: CC(=O)CC(=O)OCCC(C)C
Agent: O=C(O)CN1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C=C(C(C)=O)C(=O)OCCC(C)C)cc(C(C)C)c1O

Procedure:
Condensation of 3-methoxy-4-hydroxy-5-isopropyl benzaldehyde with isoamyl acetoacetate in the presence of piperidine-acetic acid and benzene as the reaction medium at reflux temperature under continuous azeotropic water removal yields the title product. The reaction takes about 4 hrs for completion. The yield obtained is typically 90–95%.
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH3:28])[CH:4]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:27]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:28]
Reactant: CCC(CC)C(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(F)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1oc2ccc(F)cc2c1C
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a mixture of methyl 4-{[2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl]amino}benzoate (709 mg) synthesized above, tetrahydrofuran (6 mL) and ethanol (6 mL) was added 1N aqueous sodium hydroxide solution (3.7 mL), and the mixture was heated under reflux for 14 hr. 1N Aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was further stirred with heating under reflux for 2 hr. 8N Aqueous sodium hydroxide solution (2.0 mL) and ethanol (2 mL) were added to the mixture, and the mixture was further stirred with heating under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (4.0 mL), ethanol (4 mL) and tetrahydrofuran (4 mL) were added, and the mixture was further stirred with heating under reflux for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-70:30, v/v) to give the title compound (412 mg, 61%) as a colorless amorphous form.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>>[O:18]=[C:17]1[N:7]2[CH:6]=[C:5]([C:8]([NH2:10])=[O:9])[CH:4]=[CH:3][C:2]2=[N:11][C:12]2[S:13][C:14]([CH2:22][CH2:23][CH3:24])=[CH:15][C:16]1=2
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Product: CCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 312 %

Procedure:
From 4.6 g (0.0029 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 8.6 g (0.040 mol) of 2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester, following the procedure of Example 22 there is obtained 2.6 g of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 260-264° C. after recrystallization from pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=N)[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[N:14]3)=[CH:4][CH:3]=1.Cl.C([O-])(O)=[O:32].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[N:14]3)=[O:32])=[CH:4][CH:3]=1
Reactant: COc1ccccc1CNc1ccc2c(C(=N)c3ccc(F)cc3)cccc2n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2c(C(=O)c3ccc(F)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 23 h
Yield: 88 %

Procedure:
A mixture of {5-[(4-fluoro-phenyl)-imino-methyl]-quinolin-2-yl}-(2-methoxy-benzyl)-amine (130 mg, 0.34 mmol), 2N HCl (4 ml) and THF (1 ml) was stirred at room temperature for 23 h, poured into saturated NaHCO3 solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light yellow gum (115 mg, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]1([CH2:29][CH2:30]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][N:12]([CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:14]2)=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: BrCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Product: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCN(CCc3ccccc3)CC2)cc1

Procedure:
from 4-(4-nitrophenoxy)-4-phenylpiperidine and 2-phenylethyl bromide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12](=[O:18])[NH:13][CH:14]=[C:15]([I:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:21]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12]([O:18][CH3:21])=[N:13][CH:14]=[C:15]([I:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(Nc1cc(I)c[nH]c1=O)OCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(I)cc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
(5-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester (3.68 g, 9.94 mmol) was dissolved in chloroform (50 mL) at room temperature under nitrogen in the dark (foil wrapped). Silver carbonate (3.70 g, 13.2 mmol) was added followed by iodomethane (6.2 mL, 99.4 mmol). The reaction mixture was allowed to stir at room temperature for 48 hours. The silver salts were removed by filtration through a pad of celite, washing with more chloroform and the filtrate concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a white solid (3.14 g, 82% yield). MS (ES+) m/e=385. 1H NMR (CDCl3) δH 3.97 (3H, s), 5.23 (2H, s), 7.15 (1H, br s), 7.35-7.47 (5H, m), 8.00 (1H, s), 8.64 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][C:3]=1[S:15](=[O:18])(=[O:17])[NH2:16].O1CCCC1.ClC(OCC)=O.[CH3:30][NH2:31]>C(N(CC)CC)C>[OH:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:4]=2)[N:31]([CH3:30])[C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: CN
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1S(N)(=O)=O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2(O)CCC(=O)N2C)cc1S(N)(=O)=O

Procedure:
9.4 g of 4-(4-methyl-3-sulfamoylphenyl)-4-oxobutanoic acid are reacted analogously to the instructions indicated in Example 1 using 64 ml of absolute tetrahydrofurane, 6.7 ml of triethylamine, 4.7 ml of ethyl chloroformate and 90 ml of 40% strength aqueous methylamine solution to yield 5-hydroxyl-1-methyl-5-(4-methyl-3-sulfamoylphenyl)-2-oxopyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[N:7]=[CH:6][N:5]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CC(NC(=O)c1cc(N)ncn1)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)ncn1

Procedure:
The title compound is prepared from 6-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (30 mg, 0.08 mmol, Step-1, single enantiomer) and propionyl chloride (11 mg, 0.12 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=2[C:14]([OH:16])=O)[N:7]=1)=[O:5])[CH3:2].[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@@H:26]([CH2:34][OH:35])[NH:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:35][CH2:34][C@@H:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][N:25]1[C:14]([C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[N:8]1[C:9]([CH3:11])=[CH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7]1)=[O:16]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
To an ice cooled solution of 2-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)-5-nitrobenzoic acid (25.0 g, 78.4 mmol) in DMF (250 mL) were added (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (31.0 g, 62.7 mmol), EDC.HCl (23.0 g, 117.5 mmol), HOBT (13.75 g, 101.9 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water, extracted with EtOAc (500 mL×2) twice. The combined organic layers were washed with water (500 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the ‘off white’ title compound 18 g (49%). Rf=0.45 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.70-8.35 (m, 2H), 8.15-7.98 (m, 1H), 7.25-6.95 (m, 4H), 6.82-6.58 (m, 1H), 5.20-3.80 (m, 8H), 3.40-2.40 (m, 2H), 2.38-2.10 (m, 3H), 1.30-0.80 (m, 3H); ES-MS: m/z 465.3 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH:8]2[CH:4]1[CH2:5][NH:6][CH2:7]2.Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][N:6]1[CH2:7][CH:8]2[CH:4]([CH:3]2[N:2]([CH3:9])[CH3:1])[CH2:5]1
Reactant: ClCCCBr
Reactant: CN(C)C1C2CNCC21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CN(C)C1C2CN(CCCCl)CC21
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of N,N-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine (1.45 g), 1-bromo-3-chloropropane (4.05 mL) and cesium carbonate (11.20 g) in acetone was heated to reflux for 7 h, cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 35:1 (v/v) DCM/MeOH) to afford the title compound as yellow oil (0.93 g, 40.00%), HPLC: 80.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 203.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8]/[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10]\[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH2:22]1CCN2C(=NCCC2)CC1.IC>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8]/[C:9](/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10]\[C:11]([O:13][CH3:22])=[O:12])=[CH:20][CH:21]=1
Reactant: COc1ccc(CS/C(=C\C(=O)O)c2ccccc2)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)/C=C(\SCc1ccc(OC)cc1)c1ccccc1
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
Z-3-(4'-Methoxybenzylthio)-3-phenyl-2-propenoic acid (5.46 g, 18.2 mmol) was suspended in 22 mL of dry acetonitrile. Addition of DBU (3.30 mL, 22.1 mmol) gave a clear yellow solution. The mixture was stirred in an ice bath and iodomethane (1.32, 21.2 mmol) was then added over 5 minutes. After an additional 15 minutes, the ice bath was removed and the solution was stirred for 1.25 hours. The reaction was poured into 100 mL of ethyl acetate and washed with 75 mL of water, 2×25 mL of 2N aqueous hydrochloric acid, 2×25 mL of saturated aqueous sodium bicarbonate, and 25 mL of saturated aqueous sodium chloride. The ethyl acetate solution was dried over sodium sulfate, decanted, and evaporated to give 4.53 g of crude methyl Z-3 (4'-methoxybenzylthio)-3-phenyl-2-propenoate as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[S:3][C:4](Cl)=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2.C([O-])=O.[NH4+].C(O)CC>[Pd].O>[CH:2]1[S:3][CH:4]=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2
Reactant: O=c1[nH]c2c(Cl)sc(Cl)c2c(=O)c2cscc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCCO
Solvent: O
Product: O=c1[nH]c2cscc2c(=O)c2cscc12
Temperature: 100 °C
Yield: 83 %

Procedure:
A mixture of 125 g (0.411 mole) of 1,3-dichloro-4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione, 125 g (1.982 moles) of ammonium formate, 50 g of 5% strength Pd/C, 50 g of active carbon, 3.125 l of propanol and 165 ml of water was refluxed for 3 hours, while stirring, after which 2.5 l of solvent were distilled off under about 100 mbar, while stirring. The residue was poured onto 3 l of ice water, and the resulting suspension was acidified with concentrated hydrochloric acid, while stirring. Stirring was continued for a further hour, after which the mixture was filtered under suction and the residue was added to 1.8 l of dimethylformamide. The stirred mixture was heated at 100° C. and then filtered again under suction. The residue (Pd/C and active carbon) was washed with 5 times 100 ml of hot dimethylformamide. The original dimethylformamide mother liquor was combined with the dimethylformamide used for washing, and the still warm combined solutions were poured onto 9 l of cold water, while stirring. The precipitate formed during this procedure was filtered off under suction, washed with water and dried at 50° C., in a drying oven under reduced pressure. 80.6 g (83% OF 4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione were obtained in the form of beige crystals of melting point 268.5°-271° C.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[C:20]([NH:26][C@H:27]([C:30]([OH:32])=O)[CH2:28][OH:29])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].[CH:33]1[C:43]2[CH:42]=[CH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[C:38](=[C:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)[C:37]=2[CH:36]=[CH:35][CH:34]=1.Cl>ClCCl>[CH:33]1[C:43]2[CH:42]=[CH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[C:38](=[C:48]3[CH2:49][CH2:50][N:51]([C:30](=[O:32])[C@@H:27]([NH:26][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:28][OH:29])[CH2:52][CH2:53]3)[C:37]=2[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)N[C@@H](CO)C(=O)O
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N[C@@H](CO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
880 mg (4.59 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 0.63 ml (4.52 mmol) of triethylamine and 860 mg (4.55 mmol) of pivaloyl-L-serine were added to 1.231 g (4.50 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine in 20 ml of dichloromethane in the ice bath, and they were stirred at room temperature overnight. 1 N hydrochloric acid was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3 to 1:2) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[NH:22][C:23]1[C:28]([C:29]([O:31]CC)=[O:30])=[C:27]([CH3:34])[N:26]=[CH:25][N:24]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[NH:22][C:23]1[C:28]([C:29]([OH:31])=[O:30])=[C:27]([CH3:34])[N:26]=[CH:25][N:24]=1
Reactant: CCOC(=O)c1c(C)ncnc1Nc1cc(OCc2c(OC)ccc(F)c2F)c(OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Cl)c(Nc2ncnc(C)c2C(=O)O)cc1OCc1c(OC)ccc(F)c1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate (0.3 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.49 g) and N,N-diisopropylethylamine (0.26 mL) in acetonitrile (4.5 mL) was stirred at 130° C. in a reaction vessel equipped with a reflux condenser for 1 day. To the reaction mixture was added water (3 mL), and the resulting mixture was stirred at room temperature for 40 minutes. The insoluble material was collected by filtration. The collected material was washed with water and diethyl ether, and dried under reduced pressure to give ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.71 g). The obtained ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.2 g) was dissolved in tetrahydrofuran (1.6 mL)−methanol (1.2 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (3 mL), and the precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylic acid (0.1 g). To this material were added 1,4-dioxane (4.5 mL), triethylamine (0.12 mL) and diphenylphosphoryl azide (0.071 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (0.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=3)[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2C#N)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NC(=O)c3ccc(F)cc3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 789.1 %

Procedure:
To a solution of 4-(3-Amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.976 g, 3.23 mmol) and NEt3 (0.9 ml, 6.48 mmol) in THF (40 ml) was added 4-fluoro-benzoyl chloride (0.42 ml, 0.355 mmol). The solution was stirred with a magnetic stirrer at room temperature overnight and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (2×30 ml) and brine (30 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 4-[2-cyano-3-(4-fluoro-benzoylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1.189 g, 87%). MS: (M+H)+425.2.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1([CH3:33])[C:18]2[CH:17]=[C:16]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:15]=[CH:14][C:13]=2[C:12](=[O:32])[CH2:11][CH2:10]1>C1C=CC=CC=1.[Zn]>[OH:32][C:12]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:11][CH2:10][C:9]([CH3:8])([CH3:33])[C:18]2[CH:17]=[C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Temperature: 25 °C

Procedure:
To a refluxing solution of 1.00 g (15.30 mmol) of 20 mesh, granular zinc (activated prior to use by washing with 2% HCl, water, 95% ethanol, acetone, anhydrous Et2O and then dried in vacuum for several hours) in 20 ml of dry benzene was slowly added a mixture of 0.23 ml (1.62 mmol) of ethyl bromoacetate, 0.28 g (0.81 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 10 ml of dry benzene. The resulting mixture was refluxed for 2 hours, cooled to room temperature and the precipitate filtered through Celite. The filtrate was washed with cold 15% H2SO4, sat. aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a light yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].[OH-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Br:25])[C:17]=1I.O>CN(C)C=O>[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Br:25])[C:17]=1[O:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(O)cc1C(C)C
Reactant: O=[N+]([O-])c1cc(Br)c(I)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)cc1C(C)C
Temperature: 5 °C

Procedure:
3-Isopropyl-4-methoxyphenol (197.2 g, 1.19 moles) was dissolved in dimethylformamide (4 L). The mixture was stirred while the reaction vessel was cooled in an icewater bath. Sodium hydroxide (1.278 L of 11.0M aqueous solution, 1.278 moles) was added while maintaining the temperature of the reaction mixture below 35° C. 1,3-Dibromo-2-iodo-5-nitrobenzene (400.0 g, 0.983 moles) dissolved in dimethylformamide (portion of 4 L) was added to the reaction mixture over approximately 45 min. The reaction mixture was stirred at 20° to 25° C. for 24 h. Deionized water (2 L) was added over 2 h and the reaction mixture was cooled to 5° C. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature.