Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(CC)CC.[C:18]([O:22][C:23]([N:25]1[CH2:32][CH2:31][NH:30][CH2:29][C:26]21[CH2:28][CH2:27]2)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:29][C:26]21[CH2:27][CH2:28]2)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 110 °C

Procedure:
To commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol) dissolved in DMF (5 ml) was added Et3N (1.3 ml, 9.8 mmol) followed by commercially available 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (1.5 g, 7.2 mmol). The reaction mixture was heated for 16 hours at 110° C. After evaporation of the solvent in vacuo the crude mixture was treated with water (25 mL) and extracted with EtOAc (4×30 mL) the combined organic phases were washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 1.5 g crude. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1)=O.C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:33][C:34]([O:36][CH3:37])=[O:35])=[CH:4][C:5]=1[O:12][CH3:13])([OH:9])=[O:8]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1C(=O)O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Reaction time: 1 h

Procedure:
To a suspension of 4-formyl-2-methoxybenzoic acid obtained above in tetrahydrofuran was added methyl (triphenylphosphoranylidene)acetate (3.3 g) at ambient temperature, and the mixture was stirred for 1 hour at the same temperature. The mixture was concentrated in vacuo, and ethyl acetate and saturated sodium bicarbonate solution were added thereto. The separated aqueous layer was adjusted to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with hot diisopropyl ether to give methyl 4-carboxy-3-methoxycinnamate (1.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][N:16]=2.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]=1F.[K].O>CN(C)C(=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]=1[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][N:16]=2
Reactant: Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CS(=O)(=O)c1cccc(F)c1Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
(6-Hydroxy-quinazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine (100 mg; 0.34 mmol) and 116 mg (0.61 mmol) of 1,2-difluoro-3-methanesulfonylbenzene were added to a solution of 120 mg (0.61 mmol) of tert-buxoty potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a thin layer silica gel chromatography (chloroform:methanol=10:1) to give 81 mg (yield: 51%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2](I)([F:13])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH2:15](Br)[CH:16]=[CH2:17]>[Cu].CS(C)=O>[F:1][C:2]([F:13])([C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])[CH2:17][CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: C=CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of perfluorobutyl iodide (103.8 g, 0.3 mol), copper powder (50 g, 0.79 mol) and dimethyl sulfoxide (150 mL) was stirred at 110°-120° C. for 2 hr, then cooled to room temperature. Allyl bromide (36.3 g, 0.3 mol) was added dropwise and then the mixture was stirred at room temperature for 2 hr and at 50° C. for 1 hr. The reaction mixture was distilled in vacuo and the crude product was collected in a cold trap (-78° C.). Redistillation produced 55.2 g (70% yield) of the desired 4,4,5,5,6,6,7,7,7-nonafluoro-1-heptene, formula above, having a boiling point of 79°-80° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH:10]([CH3:12])[CH3:11].[OH-].[K+].O>CS(C)=O>[CH3:11][CH:10]([CH3:12])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]#[N:8]
Reactant: CC(C)Br
Reactant: N#CCc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C(C#N)c1cccs1
Yield: 71.8 %

Procedure:
47.6 g (0.39 mol) of 2-thiopheneacetonitrile and 57.0 g (0.46 mol) of 2-bromopropane were dissolved in 100 ml of DMSO, and a 50% KOH aqueous solution was added dropwise to the solution. After completion of the reaction, water was added, and the mixture was extracted with toluene. After washing with brine and an aqueous saturated ammonium chloride, the mixture was dried over magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to distillation under a reduced pressure (2 to 3 mmHg: 132 to 137 deg), to give 46.4 g (0.28 mol, 72.7%) of the title compound as a colorless oil. The physico-chemical data of the compound was as below.
Reaction SMILES: O[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CN(C=O)C.O=P(Cl)(Cl)[Cl:30]>C(Cl)Cl>[Cl:30][C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(O)c(F)cn2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Under nitrogen, ethyl 8-hydroxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (7A, 1.52 g, 5 mmol) was dissolved in methylene chloride (10 mL), and treated with DMF (0.73 g, 10 mmol) and POCl3 (1.53 g, 10 mmol). After stirring overnight, the mixture was poured into 10 mL of ice water. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (10 mL×2). The organic layers were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated to give the crude product which was chromatographed (silica gel, 50% ethyl acetate/hexane) to give the title compound (IIA, 1.3 g, 80%). 1H NMR (300 MHz, CDCl3): δ0.75 (m, 2H), 1.08 (m, 2H), 1.42 (t, 3H), 2.30 (m, 1H), 3.19 (s, 3H), 4.42 (q, 4H), 8.39 (s, 1H), 9.43 (d, 1H): MS (DCI/NH3) m/e 324 (M+H)+. Anal. Calcd for C16H15ClFNO3 : C, 59.35; H, 4.67; N, 4.32. Found C, 59.68; H, 4.76; N, 4.22.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH3:14])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: 0 °C

Procedure:
4′-Bromo-2,2,2-trifluoracetophenone (1.80 mL, 11.9 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to 0° C., and methylmagnesium bromide (19.8 mL, 59.3 mmol) was added. The reaction mixture was maintained at 0° C. for 1 hour and then allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and the crude residue was purified directly by MPLC on silica gel (using a gradient elution of 0-25% ethyl acetate in hexanes to afford a racemic mixture of the title compound. The mixture was resolved to the constituent enantiomers by Chiral SFC purification (Chiral Technology AZ-H 2.1×25 cm, 5 uM column; mobile phase: 5% methanol/CO2) to afford the title compounds as single enantiomers. Intermediate #11-1: First enantiomer to elute; (S or R)-2-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol; 1H NMR (500 MHz, CDCl3) δ 7.53-7.52 (d, 2H), 7.46-7.45 (d, 2H), 2.64 (bs, 1H), 1.76 (s, 3H). Intermediate #11-2: Second enantiomer to elute; (S or R)-2-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol; 1H NMR (500 MHz, CDCl3) δ 7.53-7.52 (d, 2H), 7.46-7.45 (d, 2H), 2.64 (bs, 1H), 1.76 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](CC)=[CH:4][CH:3]=1.CCCCC.C([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=O)=[CH:19][C:18]=1O)=O.[Cl-].[NH4+]>O1CCCC1.O>[C:2]1([CH:21]([C:20]2[CH:19]=[CH:18][CH:17]=[CH:26][CH:25]=2)[OH:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-bromo-4-ethylbenzene (0.41 mL) in tetrahydrofuran (15 mL) was added 1.45 mol/L tert-buthyllithium n-pentane solution (2.3 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 10 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.18 g) in tetrahydrofuran (5 mL) was added to the reaction mixture. After the mixture was stirred under ice-cooling for 45 minutes, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give a diphenylmethanol compound (0.27 g). The obtained diphenylmethanol compound (0.27 g) was dissolved in methanol (5 mL), and concentrated hydrochloric acid (0.08 mL) and 10% palladium-carbon powder (54 mg) were added to the solution. After the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (0.20 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)(=[O:28])[CH3:27].C(OC(=O)C)(=O)C>O>[C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(N2CCN(Cc3ncc(-c4ccccc4)o3)CC2)cc1
Reactant: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(N2CCN(Cc3ncc(-c4ccccc4)o3)CC2)cc1

Procedure:
The 4-aminophenyl compound of Example 36 (3.0 g; 0.009 mole) was warmed on a steam bath with glacial acetic acid (5 ml) and acetic anhydride (10 ml) for 1 hour. The mixture was poured into water (200 ml), stirred well and the collected precipitate washed with water and dried. After recrystallisation from methanol the product weighed 2.45 g and melted at 196°-7° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(O)=O.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][SH:17].C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl>[CH3:18][C:15]1([CH3:19])[N:14]2[C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[CH:4]=[C:1]2[S:17][CH2:16]1
Reactant: CC(C)(N)CS
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CC1(C)CSc2cc3ccccc3c(=O)n21

Procedure:
By following the same procedure as in Example 49 using a mixture of 240 mg. of 2-carboxymethylbenzoic acid, 300 mg. of 2-amino-2-methylpropanethiol, 164 mg. of sodium acetate, and 5 ml. of o-dichlorobenzene, 120 mg. of 3,3-dimethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-b]isoquinoline was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:23][CH2:24][N:25]([CH2:11][C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[CH:8]=3)[CH2:26][CH2:27]2)=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: N#Cc1cc(Cl)ccc1N1CCNCC1
Product: N#Cc1cc(Cl)ccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 62.2 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.292 g) and 5-chloro-2-(piperazin-1-yl)benzonitrile (0.385 g) are converted to 0.349 g of the title compound after chromatography on silica gel and crystallization from ethyl ether/dichloromethane/hexane. mp 191-191.5° C.; MS m/z 385, 387; IR (mineral oil) 1486, 1330, 806, 1495, 826 cm-1 ; 1H NMR (CDCl3) δ2.77, 3.24, 3.78, 6.93, 7.12, 7.42, 7.51, 8.14.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11]
Reactant: C=CC(=O)OC
Reactant: Cc1c[nH]c2c(Br)cc(F)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cc(F)cc2c(C)c[nH]c12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of 7-Bromo-5-fluoro-3-methyl-1H-indole, [which was prepared analogous to I-30, according to the method of Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (870 mg, 3.8 mmol) and methyl acrylate (819 mg, 9.5 mmol) in triethylamine (4 ml), palladium(II) acetate (112 mg, 0.5 mmol) and tri-o-tolylphosphine (428 mg, 1.42 mmol) was added under argon at rt The reaction mixture was stirred at 100° C. for 3 hrs in a sealed pressure tube and then cooled to rt The reaction mixture was diluted with CH2Cl2 (70 ml), washed with water (3×40 ml), brine, and dried over sodium sulfate. After removal of solvent, the residue purified by column chromatography on silica gel with methanol/dichloromethane as an eluent to give 690 mg of compound I-33 as a solid. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[OH-].[K+].Cl>C(O)C.O>[CH3:16][C:14]1[CH2:13][C:12](=[O:17])[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 280 g of 2,4,6-trichlorophenylhydrazine was added 180 ml of ethyl acetoacetate, and the resulting mixture was stirred at room temperature for 30 minutes. After adding thereto a solution prepared by dissolving 215 g of potassium hydroxide in 7 l of ethanol, the reaction solution was refluxed with heating for 1 hour. The reaction solution was poured into 6 l of water and neutralized with conc. hydrochloric acid. After being cooled to room temperature, a precipitate thus formed was filtered off, washed with water, and then dried under reduced pressure to obtain the titled compound. Yield: 300 g. Melting point: 178° to 180° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:25]=[C:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:26](=[O:27])[NH:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 48 h

Procedure:
Mixture of 1-benzyl-1,2,3,4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol), hexyl isocyanate (0.174 ml, 1.2 mmol) and triethylamine (1 ml) in dry chloroform (10 ml) was heated with stirring for 48 hours. The reaction mixture was cooled, washed with water (2×5 ml), dried over sodium sulphate and concentrated under vaccum. The residue so obtained was chromatographed with 20:80 chloroform:hexane as eluant to give 2 h; yield. 0.25 g. (68.3%).
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C@@H:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.C[C@@H](N)C1C=CC=CC=1>[N:1]1[C:10]2[C:9](=[N:20][C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:12])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2cccnc21
Reactant: C[C@@H](N)c1ccccc1
Solvent: CO
Product: C[C@@H](N=C1CCCc2cccnc21)c1ccccc1
Reaction time: 24 h
Yield: 104.8 %

Procedure:
To a stirred solution of 6,7-dihydro-5H-quinolin-8-one (3.02 g, 20.5 mmol) in dry MeOH (100 mL) was added (R)-(+)-α-methylbenzylamine (2.61 mL, 20.5 mmol) via syringe. The resulting mixture was stirred 24 h, at which point additional (R)-(+)-α-methylbenzylamine (0.26 mL, 2.0 mmol) was added and the reaction was stirred for an additional 24 h. The solvent was removed in vacuo and dried for 3 days at room temperature under reduced pressure (0.1 Torr) to afford 5.38 g (95%) of the title compound as a red/brown solid. [α]D=−126.0 (c 1.04, CHCl3); 1H NMR (CDCl3) δ 1.55 (d, 3H, J=6.9 Hz), 2.17-2.29 (m, 2H), 7.35 (t, 2H, J=7.8 Hz), 4.39 (q, 1H, J=6.6 Hz), 4.72 (t, 1H, J=4.7 Hz), 5.50 (br s, 1H), 7.07 (dd, 1H, J=7.5, 5.1 Hz) 7.20-7.47 (m, 6H), 8.37 (d, 1H, J=2.4 Hz); 13C NMR (CDCl3) δ 21.99, 25.68, 28.29, 53.79, 98.12, 122.43, 126.33, 127.03, 128.92, 132.63, 135.09, 139.47, 146.36, 150.48. ES-MS m/z 251 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:29][OH:30])=[CH:5][CH:4]=1
Reactant: NO
Reactant: Cc1cc(C)cc(C(CC(=O)c2ccncc2)c2ccc(N(C)C)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)cc(C(CC(=NO)c2ccncc2)c2ccc(N(C)C)cc2)c1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(3,5-dimethyl-phenyl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.9:1) as a light yellow foam, MS (ESI+): m/z=374.3 ([M+H]+).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH3:13][C:12]1[C:11]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccccc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)oc2cccc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methyl-4-phenyl-benzofuran-2-carboxylic acid tert-butyl ester was dissolved in 2 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 66 mg of 3-methyl-4-phenyl-benzofuran-2-carboxylic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.[CH3:19][O:20][C:21](=[O:38])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][C:31]=2[CH3:37])=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCCC>[CH3:19][O:20][C:21](=[O:38])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[N:11][C:12]=3[CH:16]([CH3:18])[CH3:17])=[CH:32][C:31]=2[CH3:37])=[CH:26][CH:27]=1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1ccc(NCc2ccc(O)cc2C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a 0° C. solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (309 mg, 1.08 mmol), 4-(4-hydroxy-2-methyl-benzylamino)-benzoic acid methyl ester (292 mg, 1.08 mmol), and tri-n-butylphosphine (344 mg, 1.70 mmol) in toluene (50 mL) is added 1,1′-(Azodicarbonyl)-dipiperidine (450 mg, 1.78 mmol). The reaction mixture is stirred for 1.5 h. The reaction mixture is diluted with heptane, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (40 g silica, gradient EtOAc/Hexane) to give 4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoic acid methyl ester (309 mg, 1.08 mmol). MS: 539.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[OH:15]O>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N+:3]=1[O-:15]
Reactant: CCOc1nc(N)nc2nccnc12
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc(N)[n+]([O-])c2nccnc12
Reaction time: 48 h
Yield: 32 %

Procedure:
To a cooled (0° C.) solution of the compound of example 60 (2.47 g, 12.9 mmoles) in trifluoroacetic acid (53 ml) was added dropwise 2.53 ml of a 35% aqueous H2O2 solution. The reaction mixture was kept at 4° C. for two days in the refrigerator, whereby another 1.25 ml of the same H2O2 solution was added after 1 day. The solution was concentrated in vacuo. The residue was suspended in water and neutralized by the addition of a concentrated ammonia solution. Evaporation of the solvent in vacuo and purification of the residue by flash chromatography (silica, using a CH3OH/CH2Cl2 mixture (6:94) as the eluent) provided the title compound as a yellow powder (861 mg, yield: 32%). Mass spectrum data are as follows: m/z (%): 230 ([M+Na]+, 30), 208 ([M+H]+, 100), 180 [(M+H-ethene)+, 10].