Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH3:12])[CH:5]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:13]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(I)c(OC)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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(F)cc2)c(OC)c1
Temperature: 100 °C
Yield: 92.2 %

Procedure:
4-Iodo-3-methoxy-benzoic acid methyl ester (292 mg, 1 mmol) and para-fluorophenylboronic acid (160 mg, 1.14 mmol) and Pd(PPh3)4 (80 mg, 0.069 mmol) and Cs2CO3 (600 mg, 1.84 mmol) is mixed in N,N-dimethylformamide (10 mL) and degassed and then heated at 100° C. for 4 hours. After which, the mixture is allowed to cool to room temperature and an aqueous work up is performed and the residue purified to afford the desired product (240 mg, 92%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].Cl.Cl[CH2:7][C:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[C:18]([CH2:25][CH3:26])[CH:17]=1)#[N:15]>>[OH:1][CH2:2][C:3]1([NH2:4])[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]2[S:24][CH2:7][C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:13]2)=[C:18]([CH2:25][CH3:26])[CH:17]=1)#[N:15]
Reactant: CCc1cc(C#N)ccc1N=C=S
Reactant: NC1(CCl)CCCC1
Reactant: NCCO
Agent: Cl
Product: CCc1cc(C#N)ccc1N=C1NC2(CCCC2)CS1
Product: NC1(CO)CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was hydrolyzed according to Method D9a to give 2-(4-carboxy-2-ethylphenylimino)-1-2-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The benzoic acid was reacted with dimethylamine according to Method D6b to afford 2-(4-(N,N-dimethylcarbamoly)-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.OC1C=NC=CC=1.[Cl:18]CCO.C(=O)([O-])[O-].[K+].[K+].C1([O:34][S:35](=O)(=[O:37])[NH2:36])C=CC=CC=1>O1CCOCC1.C(O)(C)C.C(OC(C)C)(C)C>[ClH:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][O:10][S:35](=[O:37])(=[O:34])[NH2:36])[CH:2]=1
Reactant: OCCOc1cccnc1
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: Oc1cccnc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: Cl
Product: NS(=O)(=O)OCCOc1cccnc1
Reaction time: 18 h

Procedure:
A mixture of 4.9 g (0.035 mole) of 2-(3-pyridinyloxy)ethanol[prepared as an oil by procedure of Preparation 21 from 14 g (0.15 mole) of 3-hydroxypyridine, 27 ml (0.40 mole) of 2-chloroethanol and 85 g of potassium carbonate] and 8 g (0.046 mole) of sulfamic acid phenyl ester in 100 ml of dioxane was heated at reflux temperatue for 20 min and the solvent then evaporated. The residue was triturated with 250 ml of acetone, filtered, and the filtrate acidified with a solution of anhydrous hydrogen chloride in isopropyl alcohol and the sticky, brown precipitate collected. The brown solid was redissolved in 125 ml of methanol and diluted with 125 ml of ethanol. The solution was stirred with charcoal, filtered, and the filtrate partially evaporated to give a suspension. The suspension was diluted with isopropyl alcohol-isopropyl ether and filtered. The solid was dried at 50° C. for 18 hr and then at 70° C. for 18 hr in a vacuum oven. The yield was 4.5 g of solid, mp 156°-157° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]1(C)[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH2:18](OCC)C>[OH-].[Na+]>[C:9]1([CH3:18])[C:10]([S:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:14])=[O:15])=[CH:11][CH:12]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOCC
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1S(=O)(=O)N[C@@H](C)C(=O)O
Temperature: 4 °C
Reaction time: 4 h

Procedure:
0.01 mol of L-alanine were dissolved in 20 ml of 1-molar sodium hydroxide solution, a solution of 0.01 mol of p-toluenesulfonyl chloride in 10 ml of diethyl ether was added, and the mixture was vigorously stirred for 4 h. The ether phase was separated off, and the aqueous phase was acidified to pH 3 with concentrated hydrochloric acid. The crude n-toluenesulfonyl-1-alanine started to crystallize (cooling to 4° C. where necessary) and was filtered off and recrystallized from 60% by volume aqueous alcohol. Melting point 130°-131° C.
Reaction SMILES: COCCOC[O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.CCOC(C)=O.[Zn+2].[Br-].[Br-]>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([OH:7])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred solution of (2′-methoxyethoxymethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)butane (0.237 g, 0.583 mmol) in CH2Cl2 (6 mL) at room temperature was added anhydrous ZnBr2 (0.656 g, 2.92 mmol). After 18 h at this temperature, the resulting mixture was diluted with EtOAc (100 mL). The organic layer was washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (10% EtOAc/petroleum ether) to afford the product (0.172 g, 92%) as a solid; 1H NMR (CDCl3) δ 0.97 (t, J=10.9 Hz, 3H), 1.39-1.60 (m, 2H), 1.68-1.87 (m, 2H), 3.97 (t, J=9.5 Hz, 2H), 5.05 (s, 1H), 6.87 (s, 2H), 7.32-7.62 (m, 10H); mass spectrum [(+) ESI], m/z 319 (M+H)+, 341 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][O:25][CH2:24]4)[C:10]=3[C:17]=2[CH3:18])=[O:20])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NCCCN1CCCC1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12
Product: Cc1c(C(=O)NCCCN2CCCC2)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 4-{4-fluoro-2-[(R)-(tetrahydro-pyran-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 3-pyrrolidin-1-yl-propylamine.
Reaction SMILES: [C:1](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:3])[CH3:2].[C:14]1(=[O:21])[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.C(N(CC)CC)C>CC(C)(O)C#N.C(#N)C>[C:1]([CH:15]1[C:16](=[O:20])[CH2:17][CH2:18][CH2:19][C:14]1=[O:21])(=[O:3])[CH3:2]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 518.9 %

Procedure:
A 200-mL 2-necked round bottom flask was fitted with thermometer, reflux condenser, magnetic stirrer, and nitrogen bypass. The flask was charged with 4.53 g (25 mmol) of 4-nitrophenyl acetate, 2.94 g (26.25 mmol) of 1,3-cyclohexanedione, 5.69 g (56.25 mmol) of triethylamine, 0.22 g (2.5 mmol) of acetone cyanohydrin, and 60 mL of acetonitrile. The mixture was heated to reflux with stirring for 3 hr. The mixture was allowed to cool to room temperature and volatiles were removed under reduced pressure to give 20.0 g of red oil. Chromatographic separation on silica gel afforded the title product. 1H NMR (CDCl3): δ 1.99 (m, 2), 2.52 (m, 2), 2.62 (s, 3), 2.68 (m, 2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][S:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([S:35][CH3:34])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CSc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CSc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c23)cc1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 4-(methylthio)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 450/452 (M+H). 1H-NMR (DMSO-d6) δ 2.43 (s, 3H), 3.24 (td, J=9.0, 5.6 Hz, 1H), 3.39 (td, J=8.7, 5.2 Hz, 1H), 3.43-3.48 (m, 2H), 3.62-3.69 (m, 2H), 4.23 (s, 2H), 4.53 (t, J=5.4 Hz, 1H), 5.09 (d, J=5.1 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.6 Hz, 1H), 5.40 (d, J=9.1 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.9 Hz, 1H), 7.17 (s, 4H), 7.27 (s, 1H), 7.54 (d, J=8.2 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=O)=[CH:2]1.[C:14]([O:20][CH3:21])(=[O:19])[CH2:15][C:16]([CH3:18])=O.[NH2:22]/[C:23](/[CH3:29])=[CH:24]\[C:25]([O:27][CH3:28])=[O:26]>CO.[OH-].[NH4+]>[CH3:18][C:16]1[NH:22][C:23]([CH3:29])=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:8]([C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:15]=1[C:14]([O:20][CH3:21])=[O:19]
Reactant: O=Cc1ccccc1-c1ccsc1
Reactant: COC(=O)CC(C)=O
Reactant: COC(=O)/C=C(/C)N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1-c1ccsc1

Procedure:
To a solution of crude Compound 2c (10.6 mmol) in methanol (10 mL) was added methyl acetoacetate (10.6 mmol), methyl 3-aminocrotonate (10.6 mmol) and concentrated ammonium hydroxide (1 drop). The reaction mixture was heated at reflux under nitrogen for 4 days. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel eluted with diethyl ether:hexane (2:1) and trituration with diethyl ether:hexane (1:2) to yield Compound 2d as a pale yellow solid (m.p. 164°-166° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1I.[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>C1COCC1.CCOC(C)=O.[Cu]I>[CH3:23][O:22][C:16]([C:17]1[C:9]2[CH:10]=[C:11]([Br:14])[CH:12]=[CH:13][C:8]=2[O:19][C:18]=1[CH3:20])=[O:21]
Reactant: Brc1ccc(Br)c(I)c1
Reactant: COC(=O)CC(C)=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)oc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of 100 mg (0.525 mmol) copper(I)iodide and 1.90 g (13.7 mmol) potassium carbonate in 10 mL THF was added 1.75 g (4.84 mmol) 1,4-dibromo-2-iodo-benzene and 520 μL methyl acetoacetate under argon atmosphere. Then the mixture was stirred at 100° C. for 5 h under reflux. The reaction mixture was diluted with EtOAc and extracted with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=9/1).
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:32][C:17]([F:16])([F:33])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=3)[CH2:2][CH2:3]2)=[O:27])[N:19]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(N2CCCNCC2)nc1
Product: N#Cc1ccc(N2CCCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)nc1
Yield: 34 %

Procedure:
This compound was synthesized from 6-(1,4-diazepan-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (80 mg, yield 34%). 1H NMR (400 MHz, MeOD) δ 8.20-8.18 (m, 1H), 8.02 (m, 1H), 7.69-7.65 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.55 (m, 1H), 7.38 (d, J=7.8 Hz, 1H), 6.78-6.76 (m, 1H), 4.01 (m, 1H), 3.93-3.90 (m, 2H), 3.83-3.79 (m, 2H), 3.75 (m, 2H), 3.48-3.46 (m, 1H), 2.07-2.02 (m, 2H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 443.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:14]([C:15]=1[O:16]C(=O)C)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].CCCCO.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1O
Reaction time: 4 h

Procedure:
A mixture of 4-acetoxy-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester (671 mg, 2 mmol; can be obtained according to D. A. Walsh et al. in J. Med. Chem. 1978, 21, 582-585), n-BuOH (60 ml) and concentrated H2SO4 (1.7 ml) was refluxed with stirring for 4 h before the reaction mixture was added to concentrated aqueous NaHCO3 solution (60 ml) with stirring. Then EtOAc (120 ml) was added and the mixture was stirred vigorously for 15 min. Subsequently, the organic phase was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:EtOAc=95:5 as the eluent gave the title compound as a solid (126 mg); 1H NMR (CDCl3): δ=11.96 (s, 1H), 8.44 to 8.49 (m, 1H), 8.01 to 8.05 (m, 1H), 7.43 to 7.80 (m, 7H), 4.56 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:16]([OH:19])(=[O:18])[CH3:17].S(=O)(=O)(O)O>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([CH2:17][C:16]([OH:19])=[O:18])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O
Reactant: CCCCCCc1ccc(C(C)=O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCc1ccc(CC(=O)O)cc1
Temperature: 150 °C
Yield: 66.3 %

Procedure:
12.0 g (39.3 mmol) of 1-(4-hexylphenyl)ethanone was dissolved in 23.6 g (393 mmol) of glacial acetic acid, mixed with 4.95 g (275 mmol) of water and 5.79 g (58.9 mmol) of sulfuric acid and heated at 150° C. for 6.5 hours under reflux. After completion of the reaction, the reaction solution was diluted with 400 mL of water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (1:20 to 1:4) as the eluent to give 5.74 g of the desired product as white crystals.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)[CH2:2][CH3:3].[C:15]1(O)[C:19](=[O:20])[C:17](=O)[C:16]=1[OH:21]>C(C(O)CCCCC)C>[CH2:1]([N:4]([C+:15]1[C:16]([O-:21])=[C:17]([N:4]([CH:5]2[CH2:6][C:7]([CH3:14])([CH3:13])[NH:8][C:9]([CH3:11])([CH3:12])[CH2:10]2)[CH2:1][CH2:2][CH3:3])[C+:19]1[O-:20])[CH:5]1[CH2:6][C:7]([CH3:13])([CH3:14])[NH:8][C:9]([CH3:12])([CH3:11])[CH2:10]1)[CH2:2][CH3:3]
Reactant: O=c1c(O)c(O)c1=O
Reactant: CCCNC1CC(C)(C)NC(C)(C)C1
Solvent: CCCCCC(O)CC
Product: CCCN(c1c([O-])[c+](N(CCC)C2CC(C)(C)NC(C)(C)C2)[c+]1[O-])C1CC(C)(C)NC(C)(C)C1
Reaction time: 5 h
Yield: 75.2 %

Procedure:
Under agitation, 363.0 g (1.83 moles) of 4-n-propylamino-2,2,6,6-tetramethylpiperidine, 10.8 g (0.095 mole) of quadratic acid, and 150 cc of ethylhexanol were heated in a 1-liter agitated flask with attached water trap for five hours under reflux to boiling; the sump temperature was 205° C., and 3.0 cc of water was removed from the cycle. After concentration of the reaction solution, 33.9 g of crystals was precipitated. Yield: 75.2%, mp 198°-199° C. (from cyclohexane). Extinction (g/l.cm) at 278 nm: 27; at 335 nm: 95.
Reaction SMILES: C([N:3]1[CH2:20][CH2:19][C:6]2([O:10][C:9](=[O:11])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]2=[CH2:18])[CH2:5][CH2:4]1)=O.O.NN.C(O)(=O)C>C(O)C>[CH2:18]=[C:7]1[C:6]2([CH2:19][CH2:20][NH:3][CH2:4][CH2:5]2)[O:10][C:9](=[O:11])[N:8]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C1N(c2ccccc2)C(=O)OC12CCN(C=O)CC2
Agent: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: C=C1N(c2ccccc2)C(=O)OC12CCNCC2
Yield: 41 %

Procedure:
A solution containing 5.4 g of 8-formyl-4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane, 3.0 g of hydrazine monohydrate and 3.6 g of acetic acid in 54 ml of aqueous ethanol of 60% by volume concentration is stirred under argon at a temperature of 62°-65° C. The reaction is followed by TLC. After termination of the reaction the mixture is evaporated under reduced pressure. After taking up the residue in chloroform and saturated aqueous sodium hydrogen carbonate solution, the chloroformic phase is separated, washed to neutral, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate under clarifying by activated carbon to give the title compound in 41.0% yield, m.p.: 185°-186° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH2:14]1COC[CH2:15]1.C([Mg]Br)=C.Cl>COCCOC>[CH:14]([C:7]([CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1)=[O:9])=[CH2:15]
Reactant: O=C(O)COc1ccc(F)c(F)c1
Reactant: C1CCOC1
Agent: C=C[Mg]Br
Agent: Cl
Solvent: COCCOC
Product: C=CC(=O)COc1ccc(F)c(F)c1

Procedure:
To a suspension of 3,4-difluorophenoxy acetic acid (5.00 g, 25.7 mmol) lithium salt in DME (20 mL) was added to a 1M THF solution of vinyl magnesium bromide (38 mmol). After a period of 18h, the resulting clear solution was poured over 1N HCl (67 mL). The aqueous phase was then extracted with Et2O. The ethereal phase was washed with H2O, 1M K2CO3 then H2O. After drying over MgSO4 and evaporation an orange oil was obtained and used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]3[CH:21]=[CH:22][N:23]=[C:11]23)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.CCOC(C)=O>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2([C:7](=[O:8])[NH:9][CH:10]3[CH2:16][CH2:15][C:14]4[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=4[N:12]4[CH:21]=[CH:22][N:23]=[C:11]34)[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:30])=[CH:27][CH:26]=1
Reactant: NC1(C(=O)NC2CCc3ccccc3-n3ccnc32)CCCC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)NC2CCc3ccccc3-n3ccnc32)CCCC1)c1ccc(Cl)cc1
Yield: 44.2 %

Procedure:
Combine 1-amino-N-(5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl)cyclopentanecarboxamide (158 mg, 509.02 μmoles), 4-chlorobenzoic acid (95.64 mg, 610.83 μmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117.10 mg, 610.83 μmoles), and 1-hydroxybenzotriazole (82.54 mg, 610.83 μmoles;) in tetrahydrofuran (12 mL). Add diisopropylethylamine (106.53 μL, 610.83 μmoles) and stir the reaction at ambient temperature for approximately 16 hours. Dilute the reaction with EtOAc, wash with dilute sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (0-40% of a 5% solution of ammonia/methanol/dichloromethane (2N)/dichloromethane) to give the title compound (101.0 mg, 44%): MS (m/z): 449 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(OP([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(OCC)=O)C.[O-]CC.[Na+].C(O)C.O>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
4-Fluorobenzaldehyde (9.61 g, 80.0 mmol) in tetrahydrofuran (120 mL) was mixed with ethyl 2-(diethoxyphosphoryl)acetate (17.9 g, 80.0 mmol) under cooling with ice, and then sodium ethoxide-ethanol solution (21 wt %, 44.8 mL, 120 mmol) was added dropwise to the reaction mixture under cooling with ice, and the resulting reaction mixture was stirred at room temperature for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1→10/1 (v/v)) to give the title compound as a colorless oil (14.1 g, yield 91%).