Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:18][C:17]3[C:16]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:20])([CH3:19])[C:7]=2[CH:21]=1.Cl([O-])=[O:23].[Na+].ON1C(=O)C2=CC=CC=C2C1=O.C(OCC)(=O)C>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:23])[C:17]3[C:16]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:19])([CH3:20])[C:7]=2[CH:21]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc2c(c1)C(C)(C)c1oc3cnccc3c1C2
Agent: O=C1c2ccccc2C(=O)N1O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc2c(c1)C(C)(C)c1oc3cnccc3c1C2=O
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-2-aza-benzo[b]fluorene (Compound GT15-10, 20 mg) was dissolved in acetonitrile (0.2 ml) and water (0.15 ml), added with sodium chlorite (16 mg) and N-hydroxyphthalimide (2.3 mg), and the mixture was stirred at 40° C. for 40 min. To the reaction mixture, ethyl acetate was added. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (12 mg, 57%).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)C.ClCCl>[OH:1][C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C[C@H](O)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In 0.5 ml of dried and degassed DMF were dissolved 4.9 mg (15 μmol) of (R,R)-t-Bu-QuinoxP*(1) and 3.4 mg (6.7 μmol) of [RuCl2(η6-C6H6)]2 in a nitrogen atmosphere. The mixture was heated at 100° C. for 10 minutes. After cooling to 50° C., the solvent was removed by evaporation under reduced pressure to give a catalyst as a reddish to purple solid. The resulting catalyst was dissolved in 3 ml of degassed ethanol in a glove box. To the solution was added a solution of 129 mg (0.67 mmol) of ethyl 3-oxo-3-phenylpropionate in 1 ml of dichloromethane, and the mixture was transferred into a stainless steel autoclave. After purging the autoclave with hydrogen four times, hydrogen was introduced into the autoclave to 20 atm. The reaction mixture in the autoclave was stirred at 50° C. for 24 hours. After cooling to room temperature, hydrogen gas was released from the autoclave. The solvent was removed, and the residue was dissolved in diethyl ether. The resulting solution was washed successively with water and a sodium chloride aqueous solution, and the organic layer was dried over anhydrous sodium sulfate. Any volatile matter was removed by evaporation, and the residue was purified by silica gel column chromatography to give the title compound, ethyl (S)-3-hydroxy-3-phenylpropionate.
Reaction SMILES: [CH2:1]([C:14]1[S:15][C:16]([CH3:19])=[N:17][N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:20][N:21]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]1[CH:29]=O.C(OC(=O)C)(=O)C>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:14]1[S:15][C:16]([CH:19]=[CH:29][C:22]2[N:21]([CH3:20])[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=2)=[N:17][N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: CCCCCCCCCCCCCc1nnc(C)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCc1nnc(C=Cc2ncc([N+](=O)[O-])n2C)s1
Yield: 56.6 %

Procedure:
8.45 g of 2-tridecyl-5-methyl-1,3,4-thiadiazole, 4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 0.5 g of zinc chloride are heated in 40 ml of acetic acid and 15 ml of acetic anhydride for 24 hours at reflux temperature. After the solvent has been removed, the residue is recrystallized from alcohol. 7.1 g of product is obtained, corresponding to 61% of the theory. The melting point is 91° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)(C)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:15]
Reactant: NCCOCc1ccccn1
Reactant: CN=C=S
Solvent: CC(C)O
Product: CNC(=S)NCCOCc1ccccn1

Procedure:
2-(2-Aminoethoxymethyl)pyridine is caused to react with methyl isothiocyanate (1.21 g.) in isopropyl alcohol (25 ml.) by the procedure of Example 1 to give N-methyl-N'-[2-(2-pyridylmethoxy)ethyl]-thiourea.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14](=[O:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>C(Cl)(Cl)Cl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[C:14]([C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1)(=[O:16])[NH2:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(C(N)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NC(=O)C1=CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 20 ml of chloroform, 3.7 g of 1-tert-butoxycarbonyl-4-carbamoyl-1,2,3,6-tetrahydropyridine was dissolved, and 13 ml of trifluoroacetic acid were added thereto. The reaction mixture was stirred for 1 hour at room temperature, and subsequently was concentrated under reduced pressure to yield 4.1 g of crude 4-carbamoyl-1,2,3,6-tetrahydropyridine trifluoroacetate as a crystal.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30](Cl)[CH:29]=[CH:28]3)[C:20](=[O:36])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].[OH-].[Na+]>C(Cl)Cl>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:29]=[CH:28]3)[C:20](=[O:36])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2nc(Cl)ccc2c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2nc(Oc3ccccc3)ccc2c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
A mixture of phenol (15.1 g, 160 mmol) and 4-(2-chloroquinolin-6-ylmethyl)-3-oxopiperazine-1-carboxylic acid benzyl ester (6.60 g, 16.1 mmol) is melted together at 70° C. until a homogeneous mixture is obtained. Potassium hydroxide (3.15 g, 56.1 mmol) is added and the resulting mixture is heated overnight at 120° C. After 24 hours, the brown/black residue is cooled to room temperature, diluted with CH2Cl2 and stirred with 1N NaOH (100 mL) for 30 minutes. The two layers are separated and the aqueous layer is extracted with CH2Cl2. The combined organic layers are washed with 1N NaOH, saturated NaCl, dried over Na2SO4, filtered and concentrated. The crude title compound (6.92 g, 14.8 mmol) is obtained as a beige foam and used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.07 (d, 1H), 7.76 (d, 1H), 7.63 (s, 1H), 7.50 (dd, 1H), 7.42 (m, 2H), 7.34 (m, 6H), 7.25 (m, 2), 7.09 (d, 1H), 5.14 (s, 2), 4.75 (s, 2H), 4.27 (s, 2H), 3.66 (m, 2H), 3.30 (bs, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]([CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=[O:6]>CO.Cl.[Pd]>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)=[O:6]
Reactant: CC(C)(C)CNC(=O)CCc1ccc(C#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)CNC(=O)CCc1ccc(CN)cc1
Yield: 96.2 %

Procedure:
Bubble nitrogen into a solution of 4-[2-(2,2-dimethylpropyl-carbamoyl)-ethyl]-benzonitrile (740 mg, 3.0 mmol) in methanol (60 mL) with 3 drops of concentrated HCl for 10 min. Add 10% Pd/C (Degussa type E101, 148 mg) and submit the mixture to hydrogenation at atmospheric pressure overnight. Filter the catalyst over Celite® and concentrate the filtrate in vacuo. Elute the compound through a SCX column to obtain the title compound (717 mg, 95%). MS (ES+) m/z: 249 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:15][NH2:16]>CCO>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:15][NH2:16])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-nitrobenzoate (5.42 g; 29.92 mmol; 1 eq.) is dissolved in EtOH (120 ml). Hydrazine hydrate (7.27 ml; 149.60 mmol; 5 eq.) is added and the mixture is stirred 1 hour at rt. It is stirred at 60° C. for 6 hours and rt overnight. The precipitate formed is filtrated and dried under vacuo, affording 4-nitrobenzohydrazide as white-off solid (4.31 g; 79%). 1H NMR (DMSO-d6) δ: 4.63 (s, 2H), 8.03 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 2H), 10.12 (s, 1H). HPLC (method A), Rt: 0.78 min (purity: 100.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22](F)=[O:23])[CH:19]=[C:18]([Cl:25])[CH:17]=4)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27](=[CH2:30])[CH2:28][CH3:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]([N:39]5[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]5)=[O:23])[CH:19]=[C:18]([Cl:25])[CH:17]=4)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27](=[CH2:30])[CH2:28][CH3:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)F)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)N3CCN(S(C)(=O)=O)CC3)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 0.9 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-fluorocarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 36 mmol) prepared in example 94a was reacted with N-methylsulfonylpiperazine (59 mg, 36 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-[3-chloro-5-(4-methanesulfonyl-piperazine-1-carbonyl)-phenyl]-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.2 g, 92%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6]CC(O)=O.[H-].[Na+].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O[C:31]([CH:33]([CH2:40][C:41]#[N:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32])C>O1CCCC1.O>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][C:31]([CH:33]([CH2:40][C:41]#[N:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:32]
Reactant: CCOC(=O)C(CC#N)c1ccccc1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(C(=O)Cc1cccc(C(F)(F)F)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 16.5 h
Yield: 54 %

Procedure:
In this example 42 g of 3-trifluoromethylbenylacetic acid in 100 ml of tetrahydrofuran was added to a cooled slurry containing 9.65 g of sodium hydride in 50 ml of tetrahydrofuran. The resulting mixture was allowed to stand for about 15-18 hours at room temperature, under a nitrogen atmosphere. The mixture was cooled to 0° C. and then 201 ml of a 1 molar solution of lithium bis[trimethylsilyl]amide in tetrahydrofuran was added. This mixture was stirred for 20 minutes at 0° C. and then 20.4 g of (α-ethoxycarbonylbenzyl)acetonitrile in 50 ml of tetrahydrofuran was added. The mixture was stirred and allowed to warm toward room temperature for 11/2 hours, and then added to 1,200 ml of water at room temperature. The aqueous mixture was extracted twice with petroleum ether. The extracts were combined and concentrated under vacuum, to a white paste. The solids were collected by suction filtration and dissolved in methylene chloride. The solution was washed once with aqueous 10% hydrochloric acid; twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated yielding 17.2 g of the title compound as a white solid. 2.2 g of this solid was further purified by recrystallization from methanol, MP 111° to 112° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH2:19][CH2:18]2)=[CH:5][N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.FC(F)(F)C(O)=O>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH2:19][CH2:18]2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(CC(N)=O)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(CC(N)=O)CC3)c2c1
Yield: 34.7 %

Procedure:
39 mg 2-{4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]piperazin-1-yl}acetamide obtained in Example 190 and 1 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 8 mg of the title compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:21])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC(c1ccccc1)c1ccc(Br)cn1
Temperature: -70 °C

Procedure:
2,5 dibromopyridine (15.0 g, 63.3 mmol) was added to toluene (450 ml) and it was cooled at −70° C. BuLi (1.6 M in hexanes)(41 ml, 66.5 mmol, 1.05 eg) was added dropwise over 1 hour, then reaction mixture was stirred at −70° C. for another hour. Benzaldehyde (7.4 g, 69.6 mmol, 1.1 eg) dissolved in toluene (5 mL) was added slowly. The mixture was stirred at −70° C. for 30 min., then warmed to 0° C. Quenched with Sat NH4Cl (200 mL) and phases partitioned. Aqueous phase was extracted with EtOAc (100 mL) and combined organic washed with brine, dried, evaporated. Residue was chromatographed with 15% EtOAc/hexane to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-methyl-3-nitrobenzotrifluoride (41.0 g, 0.2 m) in methanol (100 ml) was stirred under an atmosphere of dry nitrogen at room temperature and palladium on charcoal catalyst (10% w/w, 1.0 g) was added. The stirred mixture was warmed to 40°-45° and then hydrogen was passed into the solution at atmospheric pressure until the reduction, as observed by thin-layer chromatography, was complete (4-5 hours). The solution was cooled to room temperature and the catalyst removed by filtration. Distillation of the solvent at atmospheric pressure followed by steam distillation of the crude product gave 3-amino-2-methylbenzotrifluoride (32.2 g, 92% yield), as a pale-brown oil which slowly crystallized.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH2:15]([O:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25](OC)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>O1CCOCC1>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:25](=[O:26])[C:24]1[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=1[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:3]
Reactant: COC(=O)c1ccccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)c2ccccc2OCc2ccccc2)c1
Reaction time: 5 h
Yield: 65.8 %

Procedure:
A solution of methyl 3-acetyl-4-hydroxy-benzoate (54 g) and methyl 2-benzyloxy-benzoate (135 g) in dioxane (400 ml) was slowly added under stirring at room temperature to a suspension of sodium hydride 50% (40 g) in dioxane (150 ml). The mixture was kept for 5 hours at 70° C, then cooled and diluted with petroleum ether, and subsequently filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethylacetate. The organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness. After crystallisation from methanol, (2-hydroxy-5-carbomethoxy-benzoyl)-(2-benzyloxy-benzoyl)-methane (74 g; m.p. 95°-97° C) was obtained, which was then refluxed for 24 hours with formic acid 99% (500 ml). After cooling and dilution with ethanol (500 ml), the precipitate obtained was filtered and washed with ethanol to give 6-carbomethoxy-2'-hydroxy-flavone (31 g; m.p. 290°-291° C) which was then reacted in dimethylformamide (150 ml) with 1-chloro-2-benzoyloxy-propane (26 g) and potassium carbonate (18 g) at 70° C for 16 hours. The mixture was cooled, diluted in water (600 ml), filtered, then washed with water to obtain 6-carbomethoxy-2'-(2-benzoyloxy-propoxy)-flavone (45 g), which was hydrolysed with a solution of potassium hydroxide 1% (l. 1,250) in ethanol (95%) at reflux temperature for an hour. After cooling, acidification with acetic acid, concentration to small volume under vacuum and dilution in water, the precipitate obtained was filtered, then washed with water to give, after crystallisation with methylene chloride/ethylacetate, 6-carboxy-2'-(2-hydroxy-propoxy)-flavone (18.5; m.p. 211°-213° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:22][CH2:23][CH3:24])=[C:16]([N+:19]([O-])=O)[CH:17]=2)[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=S)=[S:26].C(N(CC)CC)C.O>C(O)C>[CH2:1]([NH:8][C:9]1[C:18]2[CH:17]=[C:16]3[NH:19][C:25](=[S:26])[N:22]([CH2:23][CH3:24])[C:15]3=[CH:14][C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: CCNc1cc2ncnc(NCc3ccccc3)c2cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCn1c(=S)[nH]c2cc3c(NCc4ccccc4)ncnc3cc21
Yield: 60.6 %

Procedure:
6-Amino-4-benzylamino-7-ethylaminoquinazoline (4.5 g, 15.4 mmol) obtained, according to the procedures in Example 1, from 4-benzylamino-7-ethylamino-6-nitroquinazoline obtained in Reference Example 3 was suspended in ethanol (300 ml). To the suspension were added carbon disulfide (25 ml) and triethylamine (9.3 ml, 66.4 mmol), followed by heating under reflux for 6.5 hours. Water was added to the reaction mixture and the resulting crystals were filtered and recrystallized from a mixed solvent of dimethylformamide and ethanol to give the title compound (3.54 g, 60.6%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]=1[C:34](=[O:36])[CH3:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.Cl>C(OCC)(=O)C>[OH:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[CH:35][C:34]([C:11]2[C:12]([O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][C:14]([O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:10]=2[O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:36])=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)c1c(OC(=O)c2ccccc2)cc(OC(=O)c2ccccc2)cc1OC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Oc1cc(OC(=O)c2ccccc2)c(C(=O)C=Cc2ccc(O)cc2)c(OC(=O)c2ccccc2)c1)c1ccccc1
Reaction time: 96 h

Procedure:
2',4',6'-tribenzoyloxyacetophenone (83.5 g) and 4-hydroxybenzaldehyde are dissolved in 850 ml of ethyl acetate. Hydrogen chloride is led in at a temperature of 0° for 6 hours. The reaction mixture is then kept at about 5° for 4 days and then freed from most of the hydrogen chloride with nitrogen passed through the solution. The ethyl acetate is evaporated and the residue mixed with 300 ml benzene and evaporated to remove the remaining hydrogen chloride. The residue is mixed with abs. ethanol (460 ml). A crystalline solid is formed, collected by filtration and then suspended in ether and refluxed with stirring for 2 hours. After cooling, filtration and washing with ether there is obtained 41 g of 4-hydroxy-2',4',6'-tribenzoyloxy-chalcone with m.p. 198°-200°. This compound is dissolved in 1400 ml dioxane and hydrogenated at room temperature and atmospheric pressure with 4 g of 10% Pd/C as catalyst. When the theoretical amount of hydrogen has been absorbed the reaction is stopped, the catalyst removed by filtration and the dioxane evaporated in vacuo. The residue is recrystallized twice from abs. ethanol and 28 g of 3-(4-hydroxyphenyl)-2',4',6'-tribenzoyloxypropiophenone is obtained with a m.p. of 156°-8°.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:31]([NH:35][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)\[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Reactant: CCCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: CCCCNc1ccc2c(c1)c1c(n2/C=C(\C)c2ccncc2)CCN(C)C1
Temperature: 100 °C
Yield: 99.2 %

Procedure:
8-Chloro-2-methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.100 g, 0.245 mmol), sodium tertbutoxide (0.283 g, 2.948 mmol), palladium acetate (0.010 g, 0.049 mmol) and 2-di-tertbutylphosphino-2′-4′-6′-triisopropylbiphenyl (0.031 g, 0.0735 mmol) were charged in a reaction bottle which were evacuated and back filled with nitrogen for 5 min. Dry toluene (2 mL) was added under nitrogen atmosphere. Finally, N-butyl amine (0.034 mL, 0.343 mmol) was added to the reaction mixture and contents heated at 100° C. overnight. The reaction mixture was filtered and precipitate washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and purified by reverse phase chromatography to yield 91 mg of desired compound as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.82 (d, 2H), 8.24 (d, 2H), 7.74 (d, 2H), 7.50 (d, 1H), 7.38 (d, 1H), 4.50 (m, 2H), 3.90 (m, 1H), 3.70 (m, 1H), 3.42 (m, 2H), 3.26 (m, 2H), 3.18 (s, 3H), 2.10 (s, 3H), 1.76 (m, 2H), 1.46 (m, 2H), 1.0 (t, 3H).