Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:29])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[CH:10]=2)[N:5]=[C:4]([C:30](OC)=[O:31])[CH:3]=1.[BH4-].[Li+].[Cl-:36].[Na+].O>O1CCCC1.C(OCC)(=O)C>[ClH:36].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:29])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[CH:10]=2)[N:5]=[C:4]([CH2:30][OH:31])[CH:3]=1
Reactant: [Cl-]
Reactant: COC(=O)c1cc(N)c2cc(NC(=O)c3ccccc3COc3ccc(C)cc3)ccc2n1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(OCc2ccccc2C(=O)Nc2ccc3nc(CO)cc(N)c3c2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of N-(4-amino-2-methoxycarbonyl-6-quinolyl)-2-[(4-methylphenoxy)methyl]benzamide (170 mg, 0.385 mmol) obtained in Example 131, Step 5 in tetrahydrofuran (10 ml) was added, by small portions, lithium tetrahydroborate (42 mg, 1.927 mmol) under ice-cooling in an argon stream. After 10 min, the mixture was warmed to room temperature and the mixture was stirred for 2 hr. The reaction mire was diluted with saturated brine and ethyl acetate to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained yellow residue was dissolved in ethyl acetate and 4N hydrochloric acid-dioxane solution (0.5 ml) was added to precipitate hydrochloride. This salt was collected by filtration and dried under reduced pressure at 80° C. to give the title compound (116 mg, 67%, pale-yellow crystals).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].CCN(CC)CC.C(OCC)(OCC)(OCC)CCCC.[NH2:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42]>C1COCC1>[NH2:15][C:14]1[N:39]([CH2:40][C:41]([OH:43])([CH3:44])[CH3:42])[C:4]([CH2:5][CH2:6][CH2:1][CH3:11])=[N:12][C:13]=1[C:16]#[N:17]
Reactant: CC(C)(O)CN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CC(N)C#N
Agent: CCCCC(OCC)(OCC)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1nc(C#N)c(N)n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a suspension of aminomalononitrile p-toluenesulfonate (2.0 g, 7.9 mmol, 1.0 equiv) in THF (30 mL) at 25° C. was added NEt3 (1.3 mL, 9.5 mmol, 1.2 equiv) in one portion. The mixture was stirred for 30 min to afford a homogeneous solution. To this solution was added triethyl orthovalerate S3 (2.2 mL, 9.5 mmol, 1.2 equiv) and the solution was heated at reflux for 3 h. TLC indicated the presence of starting material, thus additional triethyl orthovalerate (1.1 mL, 4.7 mmol, 0.6 equiv) was added. The solution was heated at reflux for another 2 h then cooled to 25° C. Next, NEt3 (1.3 mL, 9.5 mmol, 1.2 equiv) and 1-amino-2-methylpropan-2-ol S2 (844 mg, 9.5 mmol, 1.2 equiv) were added sequentially and the reaction was stirred at 25° C. for 15 h. The reaction was concentrated in vacuo and the resulting solid residue was redissolved in CH2Cl2 (100 mL) and washed with saturated aqueous Na2CO3 solution (25 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic fractions were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (CH2Cl2-9/1 MeOH/CH2Cl2, gradient) afforded the title compound (1.55 g, 83%) as an off white solid: 1H NMR (CD3OD, 600 Hz) δ 0.94 (t, J=6.0 Hz, 3H), 1.23 (s, 6H), 1.37 (hex, J=7.8 Hz, 2H), 1.66 (pent, J=6.0 Hz, 2H), 2.60 (t, J=6.0 Hz, 2H), 3.79 (s, 2H); 13C NMR (CD3OD, 150 Hz) δ 12.7, 21.9, 26.0, 26.4, 29.1, 52.9, 71.2, 89.5, 116.2, 145.2, 149.2; MS (ESI+): calcd C12H21N4O [M+H]+ 237.3. found 237.4.
Reaction SMILES: CO.O.[BH4-].[Na+].ClCCl.[CH2:9]([N:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[N:16][C@H:15]([CH2:32][C:33]([OH:35])=[O:34])[C:14]1=[O:36])[CH:10]([CH3:12])[CH3:11]>>[CH2:9]([N:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[C@@H:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[NH:16][C@H:15]([CH2:32][C:33]([OH:35])=[O:34])[C:14]1=[O:36])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CN1C(=O)[C@@H](CC(=O)O)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)CN1C(=O)[C@@H](CC(=O)O)N[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
In a mixture solvent (methanol:water=6:1) (0.7 ml) was dissolved (3R)-1-isobutyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid (30 mg) obtained in Example 13. To the solution was added sodium borohydride (10 mg). The reaction mixture was stirred for two hours at room temperature, to which were added dichloromethane (50 ml) and water (50 ml). The aqueous layer was made acid, then the organic layer was washed with a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was removed, and the residue was recrystallized from dichloromethane/petroleum ether to give 17 mg of colorless crystals, m.p. 184°-188° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
A solution of 0.65 g (5.4 mmol) 4-hydroxybenzaldehyde, 0.94 g (5.3 mmol) of 2-quinolinylmethylchloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitate is collected on a filter and purified by dry column chromatography to give 4-(2-quinolinylmethyloxy)benzaldehyde.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH:23]=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: OCC1(c2ccc(Cl)cc2)CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1(c2ccc(Cl)cc2)CCCC1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 4, using 7.0 grams (0.055 mole) of oxalyl chloride, 9.5 grams (0.120 mole) of dimethyl sulfoxide, 10.5 grams (0.050 mole) of [1-(4-chlorophenyl)-1-cyclopentyl]methanol, and 25.5 grams (0.250 mole) of triethylamine in 175 mL of methylene chloride, yielding 1-(4-chlorophenyl)-1-cyclopentanecarboxaldehyde.
Reaction SMILES: [OH-].[K+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].CI.[CH3:15]CN(CC)CC>O.C(Cl)Cl>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:15])([CH3:5])[CH3:4]
Reactant: CC(C)c1ccccc1O
Reactant: CCN(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: COc1ccccc1C(C)C
Reaction time: 0.5 h
Yield: 313.4 %

Procedure:
To a stirred 20° C. solution comprised of KOH (1154 g, 4.75 mol), Bu4N+ HSO4− (140 g, 0.41 mol) in H2O (5.6 L) was added commercially available 2-isopropylphenol (590 g, 4.33 mol) in CH2Cl2 (5.6 L). After 30 min, MeI (741 g, 5.22 mol) was added prior to stirring the reaction overnight. After separation of the layers, Et3N (185 mL, 1.3 mol) was added to the CH2Cl2 fraction to destroy the residual MeI. After 15 min, the CH2Cl2 was removed under vacuum and the salts suspended in cyclohexane (4 L) prior to filtration. The cyclohexane filtrate was sequentially washed with 2N HCl followed by 2 brine washes. Concentration under vacuum yielded 2-isopropylanisole (612 g, 94%) as a light yellow oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:29]=[O:30]>C1COCC1>[C:1]([C:3]1([CH2:29][OH:30])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CO)CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 41 %

Procedure:
To a mixture of benzyl 4-cyanopiperidine-1-carboxylate (1.0 g, 4.0 mmol, Oakwood) in THF (50 mL) at about −78° C. was added LiHMDS (1.0 M solution in THF, 6.14 mL, 6.14 mmol) dropwise via syringe. The mixture was stirred for about 1 h. Paraformaldehyde (0.25 g, 8.2 mmol) was added in one portion and the mixture was stirred overnight at rt. The mixture was concentrated in vacuo and the residue was purified by preparative TLC (1:1 EtOAc/pet ether) to give benzyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (0.45 g, 35%): LC/MS (Table 2, Method k) Rt=0.60 min; MS m/z: 274 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:34][CH2:35][CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:29]([O:31]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:38][NH2:39]>CO>[CH2:1]([O:3][CH:4]([O:34][CH2:35][CH3:36])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:38][NH:39][C:29](=[O:31])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
The crude compound ethyl 2-(4-(diethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (4.2 g, 8.54 mmol) and hydrazine monohydrate (5 mL) were added in methanol (60 mL) and the mixture was stirred at room temperature for 16 hr. The resulting mixture was concentrated under reduced pressure to a volume of 40 mL and then filtered to obtain the crude title compound (3.0 g, yield 76%). LC-MS (ESI) m/z: 460 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].O>ClCCl>[CH3:8][S:9]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([F:25])([F:13])[C:21]([F:22])([F:23])[F:24])(=[O:11])=[O:10]
Reactant: OCCCCCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCCCCC(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Triethylamine (25.83 ml, 185.3 mmol) and methanesulfonyl chloride (6.9 ml, 88.9 mmol) were added dropwise to a solution of 6,6,7,7,7-pentafluoroheptan-1-ol (14.1 g, 74.1 mmol) in dichloromethane (350 ml) at 0° C., followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to give 1-methanesulfonyloxy-6,6,7,7,7-pentafluoroheptane (17.3 g, Yield 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].IC.[C:12](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(C)cccc1C
Temperature: 60 °C
Reaction time: 10 h
Yield: 55.2 %

Procedure:
A suspension of 2,6-dimethylphenol (19.5 g), iodomethane (31 ml) and potassium carbonate (33.2 g) in dimethylformamide (200 ml) was stirred at 60° C. for 10 hours. The reaction mixture was poured into water (300 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane) to give 2-methoxy-m-xylene (12 g) as a colorless oil. A suspension of 2-methoxy-m-xylene (5.1 g), N-bromosuccinimide (4.2 g) and bezoyl peroxide (229 mg) in carbon tetrachloride (50 ml) was heated under reflux for 3 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give a yellow solid (5.4 g). The obtained yellow solid (5.4 g) and hexamethylenetetramine (5.1 g) were dissolved in acetic acid-water (1:1, 16 ml) and the mixture was heated under reflux for 2 hours. To the reaction mixture was added concentrated hydrochloric acid (6 ml) and the mixture was heated under reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) and crystallized (hexane-ethyl acetate (5:1)) to give 2-methoxy-3-methylbenzaldehyde (1.2 g) as yellow crystals. Subsequently, the title compound was prepared from 2-methoxy-3-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].CCCCCC.CCOC(C)=O.[CH3:20][CH:21]([C:23]([C@@:25]12[C@@:35]([CH2:37][CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])([CH3:36])[C@@H:34]([CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])[CH2:33][C@@:30]([CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])([C:31]1=[O:32])[C:29]([OH:53])=[C:28]([CH2:54][CH:55]=[C:56]([CH3:58])[CH3:57])[C:26]2=[O:27])=[O:24])[CH3:22].C([O-])(=O)C>O>[CH3:22][CH:21]([C:23]([C@:25]12[C@@:35]([CH2:37][CH2:38][CH:39]=[C:40]([CH3:41])[CH3:42])([CH3:36])[C@@H:34]([CH2:43][CH:44]=[C:45]([CH3:46])[CH3:47])[CH2:33][C@@:30]([CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])([C:31]1=[O:32])[C:29]([O:53][C:2]([CH3:1])=[O:3])=[C:28]([CH2:54][CH:55]=[C:56]([CH3:58])[CH3:57])[C:26]2=[O:27])=[O:24])[CH3:20]
Reactant: CC(C)=CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@]1(C(=O)C(C)C)C(=O)C(CC=C(C)C)=C2O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)OC1=C(CC=C(C)C)C(=O)[C@]2(C(=O)C(C)C)C(=O)[C@]1(CC=C(C)C)C[C@H](CC=C(C)C)[C@@]2(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 0.28 %

Procedure:
A solution of 12 g of the plant extract obtained in Example 1 in 48 mL of pyridine was added to 9.8 mL of Ac2O and stirred at room temperature. The reaction was monitored by thin layer chromatography (TLC) (hexane-EtOAc 95:5; hyperforin Rf: 0.24; acetate Rf: 0.49). After 24 hours, the reaction mixture was diluted with water and extracted with a 3:1 hexane-ether mixture. The organic phase was washed with dilute HCl, saturated NaHCO3, and saline solution. After drying (Na2SO4) and evaporation, the residue was purified by chromatography on a silica gel column (ca 30 g), eluted first with petroleum ether to remove fats, then using hexane-EtOAc 95:5 as soon as the title compound started to elute. Hyperforin acetate (3.34 g, 0.28%) was obtained as a colorless paste with the following properties:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].FC1C=C(F)C=CC=1C1C=CC=CC=1.C(Cl)(=O)C.[Al+3].[Cl-].[Cl-].[Cl-].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)([OH:3])[CH3:2])[CH3:46]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Fc1ccc(-c2ccccc2)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
23.2 g. of 4-acetyl-2',4'-difluorobiphenyl, obtainable by reacting 2,4-difluorobiphenyl with acetyl chloride in the presence of AlCl3, and 11.1 ml. of ethyl bromoacetate are dissolved in a mixture of 75 ml. of benzene and 75 ml. of toluene. A 40 ml. portion of the resulting solution is added to 7 g. of zinc powder, previously washed successively with 1% hydrochloric acid, water and acetone and dried and the mixture is warmed to 70° with stirring and under a nitrogen atmosphere. After the reaction has begun, the remainder of the solution is added dropwise, the mixture is heated under reflux for one hour and cooled and 40 ml. of 20% sulfuric acid are added drop-wise in order to decompose the alcoholate Z--C(CH3) (OZnBr)--CH2 --COOC2H5 (Z is 2',4'-difluoro-4-biphenylyl). The organic phase is separated off and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, m.p. 96°-97° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Br:7][CH2:8][C:9]([OH:11])=[O:10].C(O)C>CC(C)=O>[Br-:7].[C:9]([CH2:8][N+:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)([OH:11])=[O:10]
Reactant: Cc1cscn1
Reactant: O=C(O)CBr
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1csc[n+]1CC(=O)O
Product: [Br-]
Reaction time: 72 h
Yield: 72.3 %

Procedure:
15.6 g of 4-methylthiazole was dissolved in 50 ml of anhydrous acetone. The mixture was added with 21 g of bromoacetic acid, stirred for 3 d, filtered to obtain a solid, and a white solid was then obtained by recrystallization from ethanol, and dried to obtain 26 g product with a yield of 72%, mP=240.6-241.6° C.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=1)(C(OCC=C)=O)[C:18]([O:20]CC=C)=[O:19])#[N:12]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([CH:17]([CH2:16][CH2:15][CH2:14][CH2:13][C:11]#[N:12])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=1)([OH:20])=[O:19]
Reactant: C=CCOC(=O)C(CCCCC#N)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)c1ccc(CC(CCCCC#N)C(=O)O)cc1
Temperature: 10 °C
Reaction time: 12 h
Yield: 74.7 %

Procedure:
17.24 ml (123.71 mmol) of triethylamine and 4.24 ml (112.46 mmol) of formic acid in 500 ml of dioxane is added to a solution of 15.5 g (37.49 mmol) of diallyl 2-(4-cyanobutyl)-2-(4 methoxycarbonylbenzyl)malonate from Example 115A, 690 mg (2.62 mmol) of triphenylphosphine and 170 mg (0.75 mmol) of palladium acetate in 500 ml of dioxane at room temperature. The reaction mixture is then stirred at 10° C. for 12 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The residue is then taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid and the organic phase is separated off. The aqueous phase is extracted three times more with ethyl acetate, and then the organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated in vacuo. 8.1 g (74% yield) of a colorless solid are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1>O1CCCC1>[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCn1ccnc1)c1ccccn1

Procedure:
Following the general procedure of Example 14 and reacting the appropriate pyridinecarboxylic acid derivative with 1,1'-carbonyldiimidazole and 1H-imidazol-1-propanamine in tetrahydrofuran, the compounds of Examples 15-17 found in Table IV were prepared.
Reaction SMILES: [F:1][C:2]1[C:3](SC)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].Cl[C:38]1C=CC=C(C(OO)=O)C=1.[S:48]([O-:51])(O)=[O:49].[Na+]>ClCCl>[F:1][C:2]1[C:3]([S:48]([CH3:38])(=[O:51])=[O:49])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(S(C)(=O)=O)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
203 mg (0.391mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methylthio-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 85 (2) was dissolved in 5 mL of dichloromethane, 850 mg (3.91 mmol) of m-chloroperbenzoic acid was added under ice-cooling and the mixture was stirred at room temperature for 3 hours. An aqueous solution of sodium hydrogensulfite was added to the reaction solution and the mixture was extracted once with chloroform. The organic layer was washed once with an aqueous solution of sodium bicarbonate, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=40:l) to give 204 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methylsulfonyl-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 94%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.O[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2.N>P(Cl)(Cl)(Cl)=O>[C:9]1([C:7]2([C:6]3[CH:15]=[CH:16][C:3]([N:2]([CH3:17])[CH3:1])=[CH:4][CH:5]=3)[C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:20]3[C:21](=[CH:22][CH:23]=[CH:24][CH:19]=3)[O:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1-c1cc2ccccc2[nH]1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C2(c3ccccc3)Oc3ccccc3-c3[nH]c4ccccc4c32)cc1
Yield: 80.2 %

Procedure:
11.26 g of 4-dimethylaminobenzophenone and 10.5 g of 2-(2'-hydroxyphenyl)-indole are stirred in 50 ml of phosphorus oxychloride for 4 hours under reflux. The reaction mixture is poured onto ice and rendered alkaline with ammonia and the resulting precipitate is then filtered off. Repeated dissolving of the residue in methanol with the addition of a little 37% strength hydrochloric acid and precipitating with ammonia and water gives a slightly impure product, which is purified through a column, packed with 80 g of silica gel/ethyl acetate. Crystallisation from ethyl acetate/ethanol gives 16.7 g of 6-phenyl-6-(4-dimethylaminophenyl)-6H-chromeno[4,3-b]-indole of the formula ##STR17## in the form of yellowish crystals with a melting point of 229°-231° C. On silton clay, this colour-forming agent develops a blue colour with a λ max of 600 nm.