Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[O:16]C)=[O:10])=[CH:5][CH:4]=1.O>ClCCl>[OH:16][C:15]1[CH:14]=[CH:13][S:12][C:11]=1[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: COc1ccc(C(=O)c2sccc2OC)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2sccc2O)cc1

Procedure:
993 mg of (4-methoxy-phenyl)-(3-methoxy-thiophen-2-yl)-methanone were dissolved in 20 ml of dry dichloromethane, and 7 ml of boron tribromide/dimethyl sulfide complex were added. The mixture was stirred at room temp. until the reaction was complete (TLC check). It was then poured into water and extracted several times with dichloromethane. The organic phase was dried and concentrated, and the residue was purified by column chromatography (SiO2, ethyl acetate/n-heptane=1:4). The product with the molecular weight of 234.3 (C12H10O3S), MS (Cl): 235 (M+H+) was obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])=[CH:5][CH:4]=1.[CH3:20][N:21]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:22]([C:24]1[S:25][C:26]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:28]=1)=[O:23]>>[CH3:20][N:21]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:22]([C:24]1[S:25][C:26]([C:29]([NH:31][N:32]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)[S:10][CH:11]=2)[CH3:17])=[O:30])=[CH:27][CH:28]=1)=[O:23]
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: CN(Cc1ccccn1)C(=O)c1ccc(C(=O)NN)s1
Product: CC(=NNC(=O)c1ccc(C(=O)N(C)Cc2ccccn2)s1)c1csc(-c2ccc(C(F)(F)F)cc2)c1O

Procedure:
Synthesis was carried out in the same manner as in Synthetic Example 7 by using 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid methyl-2-picolylamide prepared in Reference Synthetic Example 10.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N+:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[CH3:21].[Cl-:22].[Br-].F[C:25]1C=CC(C[N+]2C(C)=C(C)N(CC3C=CC(F)=CC=3)C=2)=CC=1>CC(C)=O>[CH3:21][C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([CH3:25])=[N+:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]=1[CH3:1].[Cl-:22]
Reactant: Cc1c(C)[n+](Cc2ccccc2)cn1Cc1ccccc1
Reactant: Cc1c(C)[n+](Cc2ccc(F)cc2)cn1Cc1ccc(F)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: Cc1c(C)[n+](Cc2ccccc2)c(C)n1Cc1ccccc1

Procedure:
The novel compound 1 was obtained as white needles in acetone, and its molecular formula of C19H19N2 was determined by HRFABMS. The IR spectrum of 1 showed a strong aromatic absorbance at 1560 cm−1. In 13C NMR spectrum of 1, only eight carbon signals were observed at δ 8.1 (q), 49.6 (t), 127.2 (s), 127.8 (d), 128.6 (d), 129.1 (d), 134.3 (s), and 135.5 (d), suggesting that the molecule of 1 is symmetrical to match the mass spectral data. Analysis of the 1H NMR signals at δ 5.41 (s), 7.31 (dd, J=8.8, 2.2 Hz), and 7.37-7.46 (m) and corresponding 13C NMR signals (gHMQC) at δ 49.6 (t), 127.8 (d), 128.6 (d), 129.1 (d), and 134.3 (s), indicated the appearance of a phenylmethylene group. This is supported by the COSY and gHMBC spectral data. A proton signal due to methyl group was observed as a singlet at δ 2.18, but the correlative carbon appeared in a very high field at δ 8.1 (q) in the gHMQC NMR experiment, similar to those of 1,3-di(4-fluorobenzyl)-4,5-dimethylimidazolium bromide, a synthesized product for the application as probes for intracellular pH determination. In the gHMBC NMR experiments of (1), the proton signal at 5.41 (s) exhibited other relevant cross-peaks at 127.2 (s) and 135.5 (d) attributable to C-2 and C-4 (5), respectively, apart from the ones of phenylmethylene moiety. On the other hand, H-2 showed two relevant cross-peaks at 49.6 (t) and 127.2 (s), assignable to the methylene group and C-4 (5), respectively.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[N+:13]([O-])([OH:15])=[O:14].C(O)(=O)C>C(OC(=O)C)(=O)C>[OH:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1CCc2c(ccc([N+](=O)[O-])c2O)N1
Temperature: 5 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
In 110 ml of acetic anhydride was dissovled 25 g of 5-hydroxy-3,4-dihydrocarbostyril, and to the solution was added dropwise a mixture of 12 g of fuming nitric acid and 75 ml of acetic acid at 5° C. After stirring at 5° C. for 2 hours, 20 g of ice was added to the reaction mixture, and the precipitated crystals were collected. The crystals were suspended in a 3N sodium hydroxide aqueous solution, followed by filtration. The filtrate was neutralized with hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 22 g of the named compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=[CH2:15].[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]=[CH:14][CH:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=1)[CH2:16][CH:17]=[CH2:18]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCC(C=C)OCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCC(C=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Yield: 75.9 %

Procedure:
10 g of the compound (1), 4.8 g of methyl p-hydroxybenzoate and 4.4 g of potassium carbonate were refluxed in 2-butanone for 12 hours. The insoluble matter generated was filtered off, and the solvent was evaporated. The residue was purified by column chromatography, to obtain 9.3 g of the objective compound (2). (Yield: 76%)
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC(C)([O-])C.[K+].[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[O:32][C:31](SC)=[N:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14]>C(O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[O:32][C:31]([NH:4][C:3]([NH2:5])=[NH:2])=[N:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: N=C(N)N
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)O1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2OC(NC(=N)N)=NC2=O)cc(C(C)(C)C)c1O
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of 2.0 g (0.021 mole) of guanidine hydrochloride in 75 mL of ethanol is cooled in ice and treated in portions with 2.2 g (0.020 mole) of potassium tert-butoxide. The mixture is stirred for 15 minutes, and then rapidly filtered into a suspension of 4.6 g (0.013 mole) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-(methylthio)-4(5H)-oxazolone in 75 mL of ethanol. The new reaction mixture is stirred at reflex for 3 hours, then cooled and filtered. The filtrate is evaporated 50% and added to 500 g of ice and water. The precipitated solid is filtered, washed with water, and dissolved in 200 mL of ethyl acetate. The solution is washed with brine (3×200 mL), dried (anhydrous sodium sulfate), and evaporated. The residue is chromatographed over silica gel, using elution with 10% acetonitrile in ethyl acetate. The purified product, [5-[[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]methylene]-4,5-dihydro- 4-oxo-2-oxazolyl]guanidine, is 2.6 g (55% yield). A sample recrystallized from aqueous acetonitrile has mp 258°-dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][O:17][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(c1cccc(N)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g), PPh3 (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (1.55 mL) slowly. The reaction was stirred at RT for 4 h and at reflux overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken up into Et2O. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a viscous brown oil, which was purified by chromatography through silica gel (500 g, 30% to 50% EtOAc in hexanes) to afford 2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@H:7]([C:25]([OH:27])=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5].C(Cl)(=O)C([Cl:36])=O.CN(C=O)C>C1COCC1>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@H:7]([C:25]([Cl:36])=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine (0.1 g) in THF (5 mL) at 0° C. under N2 was added oxalyl chloride (0.055 mL) followed by a drop of DMF. The solution was stirred at 0° C. for 2 h followed by stirring at room temperature for 2 h. THF was evaporated and fresh THF (5 mL) was added and the solution was evaporated again. This process was repeated one more time and the residue was dried under vacuum to yield N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16](=[O:33])[NH:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([NH:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
(6-{[(6-oxo-5,6-dihydro-phenanthridin-2-ylcarbamoyl)-methyl]-amino}-hexyl)-carbamic acid tert-butyl ester was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature overnight, evaporated, taken up with diethyl ether, filtered and the collected solid was dried under vacuum to afford 30 mg (65% yield) of the title compound as a light-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].Br[CH2:34][C:35]#[N:36]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:34][C:35]#[N:36])[CH2:9][CH2:8]1)=[O:5]
Reactant: N#CCBr
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCN1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:11][CH2:12][CH2:13][C:14]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:18][CH2:17][CH2:16][O:15]1)C)C1C=CC=CC=1.Cl.[H][H]>[Pd].CO>[ClH:1].[CH3:2][NH:9][CH2:11][CH2:12][CH2:13][C:14]1([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[O:15][CH2:16][CH2:17][O:18]1
Reactant: [H][H]
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCCCC1(c2ccc(F)cc2)OCCO1
Temperature: 25 °C
Yield: 93 %

Procedure:
A suspension of 12 g of 5% palladium on carbon, 135 g (0.369 mol) of 2-[3-(N-benzyl-N-methylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride, 0.1 ml of a saturated solution of hydrogen chloride in methanol and 1 liter of methanol was shaken at 40° for 5 hours under 50 psi hydrogen. The suspension was allowed to cool to room temperature, filtered and the solvent evaporated. Trituration with anhydrous ether, followed by filtration provided 94.6 g (0.343 mol, 93%) of 2-(3-[methylamino]propyl)-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride. Crystallization from isopropyl alcohol provided analytically pure material.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(F)c1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1cccc(F)c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and commercial commercial 3-fluoroacetophenone, 3-(4-chlorophenyl)-1-(3-fluorophenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:7]=1[Cl:17])=[O:4].[NH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C1COCC1>[Cl:17][C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:19][CH2:20][OH:21]
Reactant: NCCO
Reactant: N#Cc1cc(NC(=O)CBr)c(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1cc(NC(=O)CNCCO)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution of 2-bromo-N-(2-chloro-5-cyano-3-nitrophenyl)acetamide (30 mg, 0.094 mmol) in DCM (2 mL) was added a solution of 2-aminoethanol (5.75 mg, 0.094 mmol) in THF (2 mL) then CESIUM CARBONATE (30.7 mg, 0.094 mmol) was added. After stirring at room temperature for 1.5 h, LC-MS indicated completion. After concentration purification via flash chromatography (0-100% EtOAc in Hexane, 12 g) gave N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)amino)acetamide as a yellow solid (15 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[O:2].[CH2:24](O)[CH2:25][OH:26]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:26]1[CH2:25][CH2:24][O:2][CH:1]1[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: NCCCOc1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A solution of 2-[3-(3-formylphenoxy)propyl]-1H-isoindole-1,3-(2H)-dione (90 g) and p-toluenesulphonic acid, monohydrate (200 mg) in benzene (900 ml) and ethane-1,2-diol (25 g) was heated under reflux using a Dean-Stark separator for 8 h. The cooled solution was washed successively with sodium carbonate solution, water, sodium chloride solution, and evaporated in vacuo. The resulting oil was dissolved in tetrahydrofuran (1 liter) and stirred with hydrazine hydrate (50 ml) at room temperature for 24 hr. The mixture was diluted with ether and filtered. The filtrate was distilled to give the title compound as a colourless oil (55.2 g) b.p. 134°-6° (0.7 mm). TLC silica; methanol:ammonia 80:1; Rf 0.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19](O)[CH3:20]>>[CH2:19]([O:10][C:9](=[O:11])[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:2]([F:1])[CH:7]=1)[CH3:12])[CH3:20]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Product: CCOC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To 2-(2-fluoro-4-biphenylyl)-propionic acid (30.0 g, 0.123 mol) in ethanol (300 ml) was added conc. sulfonic acid (3.0 g). After the addition, the mixture was stirring at 50° C. for 5 h, the concentrated and extracted with benzene. The benzene extracts were washed with aqueous sodium hydrogen carbonate solution then with water, and dried over. The extracts were evaporated under reduced pressure to afford ethyl-2-(2-fluoro-4-biphenylyl)propionate (33.6 g, 0.123 mol) as oily residue.
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)#[CH:2].[CH3:11][CH2:12][CH2:13][CH2:14][SnH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:9][N:6]1[CH2:7][CH2:8][C:3](/[CH:1]=[CH:2]/[Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH3:11])([OH:10])[CH2:4][CH2:5]1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC1(O)CCN(C)CC1
Product: CCCC[Sn](/C=C/C1(O)CCN(C)CC1)(CCCC)CCCC

Procedure:
1-Methyl-4-((E)-2-tributylstannanyl-vinyl)-piperidin-4ol is prepared in analogy to the procedure described in example 9 from 4-ethynyl-1-methyl-piperidin-4-ol and Bu3SnH.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5](=[O:23])[CH2:6][C:7]([C:9]1[C:10]([CH3:22])=[N:11][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH:13]=1)=[O:8])C.[OH-].[Na+]>CO>[CH3:22][C:10]1[C:9]([C:7](=[O:8])[CH2:6][C:5](=[O:23])[C:4]([OH:24])=[O:3])=[CH:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:11]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cn(Cc2cccc(Cl)c2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(Cc2cccc(Cl)c2)cc1C(=O)CC(=O)C(=O)O

Procedure:
In a similar manner to AI-3-1, 4-[3-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester (crude from above) was reacted with 5 ml 1N NaOH in 20 ml methanol for two hours to give the title compound as a light tan solid. MP=183-184° C. 1H NMR (400 MHz, CDCl3) δ 2.54 (s, 3H), 5.23 (s, 2H), 6.67 (s, 1H), 7.12-7.18 (m, 1H), 7.25 (s, 1H), 7.31-7.36 (m, 2H), 7.97 (2, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:13]=[CH:12][N:11]([C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([O-:18])=O)[N:10]=2)[CH2:5][CH:4]([CH3:23])[O:3]1.[Na+].[NH2:25][CH:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:27]([OH:31])[C:28]([NH2:30])=[O:29]>>[NH2:30][C:28](=[O:29])[CH:27]([OH:31])[CH:26]([NH:25][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[N:22][C:14]=1[N:11]1[CH:12]=[CH:13][C:9]([CH2:8][N:6]2[CH2:7][CH:2]([CH3:1])[O:3][CH:4]([CH3:23])[CH2:5]2)=[N:10]1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: CC1CN(Cc2ccn(-c3ncccc3C(=O)[O-])n2)CC(C)O1
Agent: [Na+]
Product: CC1CN(Cc2ccn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)n2)CC(C)O1
Yield: 83.3 %

Procedure:
Coupling of sodium 2-(3-((2,6-dimethylmorpholino)methyl)-1H-pyrazol-1-yl)nicotinate (400 mg, 0.946 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (220 mg, 1.135 mmol) according to the procedure described for example 1.3 and work-up gave 448 mg of the crude product, which further purified by treatment with a mixture of 30 mL of n-pentane/MTB (10 mL). Filtration and drying gave 388 mg of amorphous white solid; ESI-MS [M+H]+: 493.2.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[S:12][N:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:9]=1[C:16]#[N:17]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH:1]1([C:4]([NH:7][C:8]2[S:12][N:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:9]=2[C:16]#[N:17])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)c1nsc(N)c1C#N
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)c1nsc(NC(=O)C2CC2)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.5 g of cyclopropanecarbonyl chloride in 30 ml of toluene are added dropwise to a solution of 16.7 g of 5-amino-4-cyano-3-isopropylisothiazole and about 0.5 g of DMAP (N,N-dimethylaminopyridine) in 200 ml of toluene and 200 ml of pyridine. The solution is stirred for 16 hours at room temperature and then evaporated to dryness, and the residue is taken up in ethyl acetate. The organic phase is extracted with aqueous sodium bicarbonate solution and 10% strength hydrochloric acid and is dried and evaporated down.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1
Reactant: O=c1ccc2cnccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2cnccc2n1
Temperature: 120 °C
Yield: 58.45 %

Procedure:
1,6-Naphthyridine-2-one (1.0 g, J. Org. Chem. 4744 (1990)) was dissolved in phosphorous oxychloride (19 ml), followed by heating under reflux at 120° C. for 2 hours. After cooling, the solvent was evaporated, and the residue was basified with water and potassium carbonate. Then, the mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (0.658 g, 58.45%) as orange crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](/[C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=3[CH:13]=2)\[CH3:11])=[CH:5][CH:4]=1.Cl>CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10](/[C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=3[CH:13]=2)\[CH3:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Solvent: CO
Product: C/C(=C\c1ccc(O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 113.5 %

Procedure:
3.8 g (11 mmol) of (E)-1-(4-methoxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-propene from Example 1 were suspended in 50 ml of methanol saturated with hydrogen chloride, and the suspension was stirred for 20 minutes at 60° C. Thereafter, the reaction solution was poured into about 150 ml of ice water and extracted with three times 100 ml of methyl tert-butyl ether. The organic phase was washed with twice 100 ml of saturated sodium chloride solution and twice with water, dried over Na2SO4 and evaporated down to give 4 g of a solid crude product. This crude product was recrystallized from isopropanol to give 1.5 g of the title compound of melting point 138°-140° C.