Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([C:3](=[O:5])[CH3:4])[CH2:7][CH2:8]2
Reactant: CC(=O)N1CCc2ccccc21
Reactant: ClCl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCc2cc(Cl)ccc21

Procedure:
74.5 g (1.05 moles) of chlorine were added with stirring at 20° to 30° C. to a mixture of 161 g (1 mole) of 1-acetyl-indoline in 1,050 ml of glacial acetic acid and the mixture was stirred for 15 minutes after which 8500 ml of water were added thereto with stirring. The mixture was stirred for 30 minutes and sodium bisulfite was added to destroy excess chlorine and was then vacuum filtered. The recovered product was dissolved in 250 ml of hot isopropanol and the mixture was cooled with stirring and then vacuum filtered. The product was rinsed with 250 ml of isopropanol to obtain 5-chloro-1-acetyl-indoline which was saponified as in Example 1 to obtain 70 g (45% yield) of 5-chloro-indoline.
Reaction SMILES: [O:1]([NH2:3])[CH3:2].S([O-])([O-])(=O)=O.[CH3:9][NH:10][C:11](=[O:30])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])=O.Cl>C1(C)C=CC=CC=1.CO>[CH3:9][NH:10][C:11](=[O:30])/[C:12](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])=[N:3]/[O:1][CH3:2]
Reactant: CNC(=O)C(=O)c1ccccc1COc1cc(C)ccc1C
Reactant: CON
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 80 °C
Yield: 95.5 %

Procedure:
Methyl alcohol (10 ml) and a 50% aqueous solution (1.15 g, 6 mmol) of methoxylamine.1/2 sulfate were added to N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-oxo-acetamide (1.49 g, 5 mmol). The mixture was refluxed for 6 hours. After completion of the reaction, methyl alcohol was evaporated under reduced pressure. Toluene (10 ml) and conc. hydrochloric acid (1.04 g, 10 mmol) were added to the resulting residue (E/Z=47/53). The mixture was heated at 80° C. for 2 hours. After cooling, toluene (100 ml) was added to the reaction mixture. The mixture was washed with water (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (1.56 g, Yield: 95.5%, E/Z=95/5).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5](F)[CH:4]=1)#[N:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)#[N:2]
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=O)c(Oc2ccccc2)c1
Temperature: 120 °C

Procedure:
A stirred mixture of 4-cyano-2-fluorobenzaldehyde (2.23 g, 15 mmol), phenol (1.6 g, 17 mmol) and potassium carbonate (2.35 g, 17 mmol) in dried dimethylformamide (15 ml) was heated to 120° C. for 1 hour. After cooling, the mixture was diluted with water (50 ml) and extracted with diethyl ether (2×25 ml). The extracts were washed with 0.1M sodium hydroxide (2×50 ml), brine (50 ml), dried, filtered and evaporated to a yellow oil. Flash chromatography on silica, eluting with diethyl ether:hexane 1:1, gave 4-cyano-2-phenoxybenzaldehyde as a yellow oil that crystallised on standing.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:14]#[N:15].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:13][C:4]1[C:3]([CH2:2][C:14]#[N:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CC#N)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of methyl 3-(bromomethyl)-2-chlorobenzoate (748 mg, 2.84 mmol) in N,N-dimethylformamide (7 mL) was added sodium cyanide (412 mg, 8.41 mmol), and the mixture was stirred under a nitrogen stream at 80° C. for 1 hr. The reaction mixture was diluted with a mixed solvent of ethyl acetate and hexane (1:1). The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=98/2→80/20) and crystallized from ethyl acetate/hexane to give the title compound (470 mg, 79%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1C=O.[CH2:12]([CH2:14][NH2:15])[OH:13].[C:16](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CCO.O>[CH3:11][N:2]([CH3:1])[C:3]1[CH:4]=[CH:7][C:8]([CH2:16][NH:15][CH2:14][CH2:12][OH:13])=[CH:9][CH:10]=1
Reactant: CN(C)c1ccccc1C=O
Reactant: NCCO
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(CNCCO)cc1
Reaction time: 4.5 h

Procedure:
A solution of 2-(dimethylamino)benzaldehyde (0.50 g, 3.35 mmol) and ethanolamine (0.409 g, 6.7 mmol) in anhydrous EtOH (13 mL) was stirred at rt for 17 hours before sodium triacetoxyborohydride (1.42 g, 6.7 mmol) was added. The reaction mixture was stirred for 4.5 hours, added water, and the pH was adjusted to 12 with 5 M NaOH. The mixture was extracted with EtOAc, and the organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of DCM:MeOH 9:1 to 1:1, to provide the desired product 2-(4-(dimethylamino)benzylamino)ethanol (51A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=C(C=C)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[N+]1([O-])CC[O:18]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+].[CH3:29][C:30]([CH3:32])=[O:31]>O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:29]([CH:30]([OH:31])[CH2:32][OH:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc(Br)cc(C(=O)OC)c1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Br)cc(C(O)CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 3-bromo-5-vinylbenzoate (1.6 g, 6.6 mmol) and N-methylmorpholine N-oxide (2.0 g, 17.1 mmol) in acetone (40 mL) and water (10 mL) was added dropwise a 5% solution of osmium tetraoxide in water (0.50 g, 0.10 mmol). The reaction mixture was stirred at rt for 3 h, and then a saturated aq. Na2S2O3 solution was added. After being stirred for 30 min, the reaction mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine, dried, and concentrated. The residue was purified by flash column to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[Cl-].[C:19](O)(=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]>O1CCCC1.O>[C:19]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1])(=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CC=CC=CC(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC=CC=CC(=O)n1c(N)nc2ccccc21
Yield: 60 %

Procedure:
A solution of 2-amino benzimidazole (4 g, or 0.030 mole) and triethylamine (4.2 ml, or 0,029 mole) in 70 ml of anhydrous tetrahydrofuran, is chilled to a temperature of between -5° and 0° C. To this solution is slowly added 4 g (0.030 mole) chloride of 2,4 hexadienoic acid in solution in 50 ml of anhydrous tetrahydrofuran. After being agitated, the mixture is left to return to ambiant temperature, after which it is poured into water. The precipitate is drained and washed with water. After recrystallization in toluene, 4.12 g (60% yield) is obtained of a crystallized compound having a melting point of 215° C. and the following structure (90% purity): ##STR4##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]1([OH:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: BrCCCCCBr
Product: Nc1ccc(Br)cc1C1(O)CCCCC1

Procedure:
1-(2-Amino-5-bromo-phenyl)cyclohexanol was prepared, according to the procedure of Example 1 using 2-amino-5-bromobenzoic acid and the Grignard reagent prepared from 1,5-dibromopentane, as a clear oil: 1H-NMR (DMSO-d6) δ 7.07 (d, 1H, J=2.3 Hz), 7.03 (dd, 1H, J=8.4, 2.4 Hz), 6.55 (d, 1H, J=8.6 Hz), 5.49 (s, 2H, D2O exchangeable), 5.00 (s, 1H, D2O exchangeable), 2.01 (d, 2H, J=1.8 Hz), 1.66-1.77 (m, 2H), 1.44-1.61 (m, 4H), 1.16-1.34 (m, 2H); MS (ESI) m/z 270/272 ([M+H]+, 98%/100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[C:13]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[CH:4][CH:3]=2
Reactant: COc1cccc(F)c1CCC#N
Reactant: Nc1ccncc1C=O
Product: COc1cccc(F)c1Cc1cc2cnccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 4-aminonicotinaldehyde and 3-(2-methoxy-6-fluorophenyl)propionitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[OH:9].[CH3:25]N(C)C=O.CI.[H-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[O:9][CH3:25]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(O)c2ccccn2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COC(c1ccccn1)c1ccccc1COc1cc(C)ccc1C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a mixture of 0.42 g (1.3 mmol) of 2-[2-(2,5-dimethylphenoxymethyl)-α-hydroxybenzyl]pyridine, 4 ml of N,N-dimethylformamide and 0.12 ml (2 mmol) of methyl iodide was added 0.07 g (1.7 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)-α-methoxybenzyl]pyridine (0.40 g, 92.3%) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[C:14](=[O:27])[NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]COC(C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[C:14](=[O:27])[NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[CH2:17][O:18][CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: CCOC(C)=O
Product: COC[C@@H](NC(=O)[C@@H]1[C@H]2C[C@H]2CN1C(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step B) from (1S,2S,5R)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. TLC, Rf (EtOAc): 0.65; MS (UPLC/MS): 413.4/415.4 [M+H]+, 457.4/459.4 [M+HCOO]−; tR (HPLC conditions a): 3.67 min.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.O>[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25])=[O:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C(=O)[C@@H]1CCCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(2S)—N,N-Dimethyl-2-piperidinecarboxamide hydrochloride (880 mg, 4.567 mmol) was dissolved in a mixture of CH2Cl2 (15 mL) and water (15 mL), and then solid sodium bicarbonate (1.534 g, 18.268 mmol) was added, followed by benzoyl chloride (0.556 mL, 4.795 mmol). After stirring overnight, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-10% methanol/dichloromethane) to provide (2S)—N,N-dimethyl-1-(phenylcarbonyl)-2-piperidinecarboxamide (883 mg, 74%). LCMS: (M+H)+: not detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9](Br)=[CH:10][CH:11]=1.[NH:14]1[CH2:19][CH2:18]C[CH2:16][CH2:15]1.CC[O:22]C(C)=O>>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([N:14]2[CH2:19][CH2:18][O:22][CH2:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: C1CCNCC1
Reactant: CCOC(C)=O
Reactant: COC(=O)C=Cc1ccc(Br)nc1
Product: COC(=O)C=Cc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
3-(6-Bromo-pyridin-3-yl)-acrylic acid methyl ester (100 mg, 0.413 mmol) was added to piperidine (1 ml) and the mixture was stirred for 1.5 hrs at room temperature. The reaction mixture was diluted with EtOAc and then washed three times with H2O, brine, dried. Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield 3-(6-Morpholin-4-yl-pyridin-3-yl)-acrylic acid methyl ester (40 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][NH:23]2)=[CH:19][CH:18]=1>CN(C=O)C>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Nc3ccc4cn[nH]c4c3)c2cc1OC
Product: Cl
Temperature: 140 °C
Yield: 53.8 %

Procedure:
A suspension of 4-chloro-6,7-dimethoxyquinoline (200 mg, 0.89 mmol), (prepared as described for the starting material in Example 2), and 6-aminoindazole (131 mg, 0.98 mmol) in DMF (2.5 ml) was heated at 140° C. for 1.5 hours. The solid was collected by filtration, washed with isopropanol and dried under vacuum to give 6,7-dimethoxy-4-(1H-indazol-6-ylamino)quinoline hydrochloride (171 mg, 54%).
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][C:35]1[CH:45]=[C:44]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:43]=[C:42]([Cl:52])[C:36]=1[O:37][CH2:38][CH2:39][CH2:40][OH:41].O[C:54]1[CH:59]=[CH:58][C:57]([CH2:60][C:61](=[O:63])[CH3:62])=[CH:56][CH:55]=1>O1CCCC1>[Cl:34][C:35]1[CH:45]=[C:44]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:43]=[C:42]([Cl:52])[C:36]=1[O:37][CH2:38][CH2:39][CH2:40][O:41][C:54]1[CH:59]=[CH:58][C:57]([CH2:60][C:61](=[O:63])[CH3:62])=[CH:56][CH:55]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reaction time: 0.5 h

Procedure:
P4.1) At 0-2° C., 4.3 g of azodicarboxylic acid diisopropyl ester are added dropwise to 5.6 g of triphenylphosphine in 100 ml of tetrahydrofuran. After 30 minutes' stirring, a solution of 6.7 g of 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propan-1-ol and 2.9 g of 1-(4-hydroxy-phenyl)-propan-2-one in 100 ml of tetrahydrofuran is added dropwise at 0-2° C. in the course of 45 minutes. After 2 hours at from 0 to 2° C. and 6 hours at room temperature, the reaction mixture is concentrated and the residue is purified over silica gel. 1-(4-{3-[2,6-Dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-propan-2-one is obtained. 1H-NMR (CDCl3) 300 MHz: 2.16 (s, 3H), 2.30 (m, 2H), 3.63 (s, 2H), 4.17 (t, 2H), 4.27 (t, 2H), 4.58 (d, 2H), 6.11 (t, 1H), 6.83 (s, 2H), 6.90 (d, 2H), 7.11 (d, 2H)
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>>[C:13]([NH:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2)(=[O:15])[CH3:14]
Reactant: NC1CCCc2c(O)cccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCCc2c(O)cccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
50 mmol of 5-amino-1-hydroxy-5,6,7,8-tetrahydronaphthalene are stirred in a solution of 200 mmol of acetic anhydride and 200 mmol of triethylamine, to which a spatula-tip of dimethylaminopyridine has been added, for 2 hours. The mixture is filtered, the residue is rinsed thoroughly with tetrahydrofuran and the filtrate is evaporated. The residue is taken up in ethyl acetate and the mixture is washed with 1N HCl, saturated NaHCO3, 1N, HCl, saturated NaHCO3 and saturated NaCl solution, dried over Na2SO4 and evaporated. The bis-acetate which remains is dissolved in 100 ml of MeOH and the solution is then added dropwise to 100 ml of 1N KOH at room temperature. The mixture is stirred at an internal temperature of 50° C. for 2 hours and acidified with concentrated HCl and the MeOH is stripped off. The acid aqueous phase is extracted by shaking 2 to 3 times with ethyl acetate and the combined organic phases are dried with Na2SO4 and evaporated. The residue is recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:36])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[CH2:30][CH2:31][CH3:32])=[CH:25][C:24]=1[O:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH3:37].CCCCCC.C(OCC)(=O)C>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH2:37])=[CH:7][C:6]=1[NH:14][C:15](=[O:36])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[CH2:30][CH2:31][CH3:32])=[CH:25][C:24]=1[O:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(=O)CCC)cc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C(=O)CCC)cc1OC
Reaction time: 0.58 h
Yield: 96.5 %

Procedure:
210 mg (1.30 mmol) of N,N'-carbonyldiimidazole were added to a suspension of 530 mg (1.07 mmol) of N-(2-t-butyl-5-carboxyphenyl)-3-(4-butyryl-2-methoxyphenyl)octanamide prepared as described in Preparation 64C), in 10 ml of acetonitrile, and the resulting mixture was stirred for 35 minutes, after which 1.0 ml (15 mmol) of concentrated aqueous ammonia were added. The reaction mixture was stirred for 20 minutes, after which it was freed from the organic solvent by distillation under reduced pressure. The concentrate was extracted with ethyl acetate. The extract was washed with 2N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:9 to 0:9 by volume as the eluent, to give 511 mg (yield 97%) of the title compound as a foam-like substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1.N[C@@H](CC1C=CC=CC=1)CO>CCCCCCC>[Cl:1][C:2]1[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2[O:10][C@H:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)c1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: N[C@H](CO)Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)c1cc2c(cc1Cl)C=C(C(=O)O)[C@@H](C(F)(F)F)O2
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a solution of 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 8)(11.4 g, 34.1 mmol) and (S)(−)-2-amino-3-phenyl-1-propanol (2.57 g, 17.00 mmol) was added n-heptane (200 mL) and the mixture set aside for 16 hours. The resulting suspension was filtered yielding a solid (3.8 g). This solid was recrystallized from 2-butanone (20 mL) and n-heptane (200 mL) yielding upon filtration a white solid (3.0 g). This solid was dissolved in ethyl acetate (100 mL) and washed with 1 N HCl (50 mL) and brine (2×50 mL), dried over MgSO4 and concentrated in vacuo yielding a white solid. This solid was recrystallized from n-heptane yielding the title compound of high optical purity as a crystalline solid (1.7 g, 30%): mp 175.4-176.9° C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 5.83 (q, 1H, J=7.1 Hz), 1.48 (s, 9H). Anal. Calc'd for C15H14O3F3Cl: C, 53.83; H, 4.22; N, 0.0; Cl, 10.59. Found: C, 53.78; H, 4.20; N, 0.0; Cl, 10.65. This compound was determined to have an optical purity of greater than 90% ee. Chiral purity was determined as describe in Example 66.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[C:32]2[C:5]([CH2:6][C:7]3[C:11]([C:12](=[O:25])[CH:13]([C:23]#[N:24])[C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:15])=[N:10][N:9]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:8]=32)=[CH:4][CH:3]=1.N1[CH:39]=[CH:38]C=CC=1.C(O)(=O)C[C:42](CC(O)=O)([C:44]([OH:46])=[O:45])[OH:43]>CN(C)C=O>[C:23]([CH:13]([C:12]([C:11]1[C:7]2[CH2:6][C:5]3[C:32](=[CH:33][C:2]([NH:1][C:42]([C:44]([O:46][CH2:38][CH3:39])=[O:45])=[O:43])=[CH:3][CH:4]=3)[C:8]=2[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:10]=1)=[O:25])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])#[N:24]
Reactant: c1ccncc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccc(N)cc1-2
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)Nc1ccc2c(c1)-c1c(c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn1-c1ccccc1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(7-Amino-1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl) -2-cyano-3-oxo-N-phenyl-propanamide (1.1 g) dissolved in anhydrous dimethylformamide (70 ml) containing pyridine (1 ml) is reacted with ethyl oxalyl chloride (0.7 g) under stirring at room temperature for 6 hours. The reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered and washed with water. Crystallization from CHCl3 /ethanol yields 1.1 g of 2-cyano-3-(7-ethoxalylamino -1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl) -3-oxo-N-phenyl-propanamide.
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[CH:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=O>C1COCC1.CCCCCCC>[C:19]([C:18]1[CH:17]=[C:16](/[CH:14]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(C=O)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)/C=C/c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Methyl 2-(dimethoxyphosphoryl)acetate (20.83 g, 114.39 mmol) was dissolved in THF (500 mL). Sodium hydride (4.58 g, 114.39 mmol) was added in small portions. 3-formylbenzonitrile (10 g, 76.26 mmol) was added dissolved in 50 mL of THF and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with heptane, washed with H2O, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated in heptane, filtered, washed with heptane and dried under vacuum, giving 13.26 g title compound (93%) as a white powder. 1H NMR (400 MHz, CDCl3) δ ppm 3.83 (s, 3H) 6.50 (d, J=16.02 Hz, 1H) 7.52 (t, J=7.81 Hz, 1H) 7.61-7.84 (m, 4H).