Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][C:48](Cl)=[O:49].C(N(C(C)C)CC)(C)C>ClCCl>[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][C:48]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2)=[O:49]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)Cc5cccs5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40 mg of product obtained in stage 4 are mixed with 11.4 mg of 2-thiopheneacetyl chloride, 25 μl of diisopropylethylamine and 2 ml of dichloromethane. The mixture is stirred for 1 hour at ambient temperature, and then washing with brine, drying over magnesium sulfate and evaporation to dryness are carried out.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17].[C:19](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:19][O:17][C:16](=[O:18])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Br:8]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.349 mL, 0.698 mmol) was added to a solution of (2-bromo-phenyl)acetic acid (50 mg, 0.233 mmol) in methanol (0.4 mL) and toluene (2 mL), and the mixture was stirred at room temperature for five minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (53 mg, 99%).
Reaction SMILES: C([Li])CCC.[CH:6]1[N:7]=[CH:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=12.[CH2:15]=[O:16].Cl>CCCCCC.CCOCC>[OH:16][CH2:15][C:8]1[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[CH:6][N:7]=1
Reactant: c1ncn2c1CCCC2
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OCc1ncc2n1CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.58 molar n-butyl lithium in n-hexane (49 ml.) was added over 0.5 hour to a stirred solution of 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (8.9 g.) in dry ether at -60° under nitrogen. After 3 hours, gaseous formaldehyde generated by the thermal condensation of paraformaldehyde (6.9 g.) was passed into the red solution. The mixture was allowed to warm to room temperature overnight, acidified with hydrochloric acid and extracted with chloroform. The aqueous layer was basified with an excess of saturated sodium carbonate solution and extracted with chloroform. Concentration and recrystallisation of the residue from ethanol-ethyl acetate-petroleum ether afforded 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (7.7 g.), m.p. 188°-199°.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][C:7]3[CH:9]=[C:10]([OH:14])[CH:11]=[C:12]([CH3:13])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([O:14][C:10]2[CH:11]=[C:12]([CH3:13])[C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[NH:8][C:7]=3[CH:9]=2)[CH:21]=1
Reactant: Cc1cc(O)cc2[nH]c(C3CC3)nc12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CC3)nc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
90 mg (0.48 mmol) 2-cyclopropyl-4-methyl-1H-benzo[d]imidazol-6-ol and 77 mg (0.50 mmol) 4,6-dichloropyrimidine in 2.0 mL DMF were combined with 70 mg (0.50 mmol) potassium carbonate and stirred for 8 h at 50° C. Then ice water was added and the substance was extracted with ethyl acetate and concentrated by rotary evaporation i.vac.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+].Cl>CN1CCCC1=O>[CH3:32][C:31]1[O:30][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:28][C:27]=1[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:1]/[N:2]=[C:3](/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:40][CH:39]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: O=C(O)CCCCCC/C(=N\O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
(E)-8-(Hydroxyimino)-8-phenyloctanoic acid (1.0 g) and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (1.26 g) were dissolved in 1-methyl-2-pyrrolidone (10 ml), and the solution was ice-cooled. Sodium tert-butoxide (0.85 g) was added to the reaction mixture at not higher than −5° C. and the mixture was stirred at the same temperature for 30 min, and then at room temperature for 4 hr. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate (20 ml). The organic layer was washed with 10% brine (20 ml) and dried over anhydrous sodium sulfate. The organic layer was concentrated and acetone/water (1/1) (20 ml) was added to the obtained residue (brown oil). The mixture was dissolved under reflux and allowed to cool for crystallization. The crystals were collected by filtration, washed with H2O (5 ml) and dried in vacuo at 50° C. for 4 hr. Acetone/water (2/1) (30 ml) was added to the obtained crystals, the mixture was dissolved under reflux, and allowed to cool for crystallization. The crystals were collected by filtration and washed with water (5 ml). The crystals were dried in vacuo at 0° C. for 4 hr, and the objective product was obtained as white crystals (1.55 g, yield 86%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: O=Cc1ccnc(-c2ccccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with [2,2′-bipyridine]-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 403.97 g/mol.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH3:24])=[CH:8]2)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:25])[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([CH3:24])[C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(C)c2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3,8-dimethyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (145 mg, 0.43 mmol), glycine (3.22 g, 43 mmol) and NaOMe solution (68 mL, 34 mmol, 0.5M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 108 mg of the title compound as a white solid. MS: (+) m/z 382.08 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:20])[CH:7]=1)=O)C.O.[NH2:22][NH2:23]>C(O)C>[O:20]=[C:8]1[CH:7]=[C:6]([C:4]([NH:22][NH2:23])=[O:3])[CH:11]=[CH:10][N:9]1[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1ccn(COCC[Si](C)(C)C)c(=O)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(C(=O)NN)cc1=O
Temperature: 78 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
The title compound of example 19.1 (9.5 g, 32 mmol) was stirred in ethanol (100 mL) at 78° C. Hydrazine hydrate (7.8 mL, 159.7 mmol) was added and the reaction mixture was stirred at 78° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was stirred in diethyl ether and filtered to give a yellow solid (8.5 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([O:12]C)=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15].C>CO.C(O)C>[OH:15][CH2:14][CH2:16][NH:17][C:10](=[O:12])[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: NCCO
Reactant: COC(=O)Cn1ccnc1[N+](=O)[O-]
Solvent: CCO
Solvent: CO
Product: O=C(Cn1ccnc1[N+](=O)[O-])NCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
A mixture of 2.50 g (13.5 mmol) of methyl 2-nitroimidazole-1-acetate and 3.0 ml (50.0 mmol) of ethanolamine in 15.0 ml methanol was stirred 20 hr at room temperature. The mixture was diluted with 45 ml ethanol and heated on a stream bath to effect solution. The hot solution was decolorized with charcoal, filtered and evaporated to dryness. The residue was recrystallized from a solution of 150 ml ethyl acetate and 10 ml of methanol to afford 1.81 g (62.4%) of SR-2508 as a white powder, mp 164.5-165.0° C., that was homogeneous by thin layer chromatography on silica gel with 10% methanol in ethyl acetate (Rf 0.16). The solubility of SR-2508 in 0.9% saline solution was approximately 200 mg/ml.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15]>>[C:1]1([CH2:7][C:8]([OH:12])([C:9]([OH:11])=[O:10])[CH2:16][C:14](=[O:15])[C:13]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: CC(=O)C(=O)O
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O

Procedure:
According to the study by the present inventors, it has been found that PtALD can catalyze the aldol condensation reaction of indolepyruvic acid with pyruvic acid (or oxalacetic acid) to yield 4-(indol-3-ylmethyl)-4-hydroxy-2-oxoglutaric acid (IHOG), and the reaction of phenylpyruvic acid with pyruvic acid to yield 4-phenylmethyl-4-hydroxy-2-oxoglutaric acid (PHOG).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1cc(-c2cc(F)c(CC(=O)OC(C)(C)C)cc2C)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(F)c(CC(=O)O)cc2C)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of tert-butyl 2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetate 191-5 (80 mg, 0.37 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 2 hours. The solvent and TFA was removed by rotary evaporation to give 2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetic acid 191-6. The product was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[CH3:22]O>>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:22])=[O:9]
Reactant: CO
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Product: COC(=O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 50 °C
Yield: 98 %

Procedure:
To a 300 ml, 3-necked flask equipped with a stirrer, gas bubbling tube, condenser, thermometer and drying tube is charged anhydrous methanol (100 ml) and 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (12 g., 0.038 mole). Anhydrous hydrogen chloride gas is bubbled into the reaction mixture until the reaction temperature (exotherm) rises to 50° C. The reaction mixture is then maintained at 50° C. with external heating for 4 hours, then cooled, the solvent removed in vacuo and the residue dissolved in CCl4 (200 ml) and triturated with water (50 ml). The decanted and dried (anh. MgSO4) CCl4 layer is reduced in vacuo to give 12.2 g. of methyl 3-(2-chloro-4-trifluoromethylphenoxy)benzoate (98% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].CO[CH:30](OC)[CH:31](Br)[CH3:32].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][C:31]([CH3:32])=[CH:30][N:26]=1
Reactant: COC(OC)C(C)Br
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
A mixture of 1.50 g (3.90 mmol) of starting material I, 3.57 g (19.50 mmol) of 2-bromopropionaldehyde dimethyl acetal and 15 ml of dimethylformamide was stirred at 90° C. for 1.5 h. Then the reaction mixture was diluted with water and the crude product obtained was purified by column chromatography using silica gel (MN Kieselgel 60; Macherey-Nagel, Düren, Germany) as adsorbent and a mixture of toluene-ethyl acetate (16:1) as eluent to yield 1.08 g (66%) of the title compound; Mp.: 193-195° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.CC(C)=O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1/[CH:14]=[CH:13]/[CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)C(=O)c1ccc(OC/C=C/c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OC/C=C/c2ccc3ccccc3c2)cc1
Yield: 92 %

Procedure:
A mixture of (E)-4-[[3-(2-naphthalenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.85 g) in methanol (20 mL), acetone (5 mL), and 0.5N sodium hydroxide (6 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from dichloromethane-hexane to give 0.75 g of colorless (E)-4-[[3-(2-naphthalenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid, mp 142°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH:24]=2)[C:10]1=[O:42].[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[NH:43]([C:14]1[N:13]=[C:12]2[N:11]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]4[C:32](=[O:41])[C:33]5=[CH:40][CH:39]=[CH:38][CH:37]=[C:34]5[C:35]4=[O:36])[CH:24]=3)[C:10](=[O:42])[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: Nc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 180 °C
Yield: 29 %

Procedure:
A mixture of 200 mg (0.52 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 3 ml of aniline was heated at 180° C. for 40 minutes and then cooled. The mixture was partitioned between 40 ml of dichloromethane and 40 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel using diethyl ether/hexane (1:1) for the elution. The product-containing fractions were combined and evaporated to give 30 mg (29%) of 7-anilino3-(2,6-dichlorophenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 142° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15].C(OCC)(=O)C.[ClH:22]>O.[Cu]Cl>[Cl:22][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(O)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A saturated solution of sodium nitrite (1.8 g, 26.0 mmol) in water (12 mL) was added dropwise to a suspension of 2-amino-5-nitro-phenol (2.0 g, 13.0 mmol) in concentrated hydrochloric acid (10 mL) at 0° C. and stirred for 30 min. In another flask, copper (I) chloride (5.15 g, 52.0 mmol) and concentrated hydrochloric acid (20 mL) were heated to between 60 and 70° C. and the diazonium salt solution was added dropwise to this over a period of 30 min. The reaction mixture was heated to 80° C. and stirred for 15 min. It was then cooled to room temperature and ethyl acetate (50 mL) was added and stirred for 5 min. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with water (4×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent to afford 2-chloro-5-nitro-phenol (2.08 g, 92%) as a crystalline yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)cc(O)c1
Yield: 91.9 %

Procedure:
To a solution of 3,5-dihydroxybenzoic acid (50.0 g, 320 mmol) in methanol (310 ml) was added concentrated sulfuric acid (7.7 ml) and the resultant solution heated at reflux for 16 hrs. It was then cooled and approximately 200 ml of methanol removed under reduced pressure. To the remaining solution was added water (300 ml) and the mixture extracted with ether (4×50 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (50 ml), dried, and evaporated to dryness. The resultant solid was recrystallized from 50 ml of methanol/125 ml of water to give methyl 3,5-dihydroxybenzoate as off-white crystals (50.1 g, 91.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH2:1][Br:25])=[CH:17][CH:16]=2)=[O:7])=[CH:9][CH:10]=1)#[N:13]
Reactant: Cc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Heat a mixture of 4-(4-methyl-benzoyl)-benzonitrile (300 mg, 1.356 mmol), NBS (386 mg, 2.169 mmol), and AIBN (22 mg, 0.136 mmol) in carbon tetrachloride (10 mL) for 14 h at reflux. Add additional NBS (121 mg) and AIBN (11 mg) and reflux the mixture for 3 h. Cool the reaction mixture to ambient temperature and filter the mixture. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1) to provide the title compound as a solid (286 mg, 70%) GC-MS m/z: 300 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][N:14]([CH3:29])[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>O.ClCCCl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][CH2:21][CH:18]2[CH2:17][CH2:16][C:15]([N:14]([CH3:13])[CH3:29])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(CNCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tryptamine (2-(1H-indol-3-yl)ethylamine, 321 mg, 2 mmol.) was dissolved in abs. 1,2-dichloroethane. After the addition of 4-dimethylamino-4-phenylcyclohexanecarbaldehyde (463 mg, 2 mmol.), the mixture was stirred for 1 h at RT. Sodium triacetoxyborohydride (660 mg, 3 mmol.) was then added, and stirring was carried out for 3 d at RT. For working up, 1,2-dichloroethane (10 ml), water (15 ml) and 2M HCl (3 ml) were added to the reaction mixture. After stirring vigorously for 15 min., the phases were separated and the aqueous phase (pH 3) was extracted again with 1,2-dichloroethane (10 ml). 5M NaOH was then added to the aqueous phase (pH 11), followed by extraction with EE (5×20 ml). The combined EE phases were dried, filtered and concentrated. The residue was the still impure diastereoisomeric mixture of the bases of the target product (690 mg, m.p. 56–64° C.), which was purified by flash chromatography on silica gel (70 g) and separated (eluant: 1200 ml of methanol/conc. ammonia solution 99.5:0.5). 220 mg (0.59 mmol.) of the non-polar diastereoisomer of (4-{[2-(1H-Indol-3-yl)ethylamino]methyl}-1-phenylcyclohexyl)dimethylamine (m.p. 78–83° C.) were obtained and were dissolved in 2-butanone; chlorotrimethylsilane (222 μl, 1.8 mmol.) was added at RT, and stirring was carried out for 2 h. The suspension was cooled for 1 h in an ice bath, and the solid was filtered off. The hygroscopic dihydrochloride was washed with cold ether and dried in vacuo. The dihydrochloride of the non-polar diastereoisomer of (4-{[2-(1H-Indol-3-yl)ethylamino]methyl}-1-phenylcyclohexyl)dimethylamine was thus obtained in a yield of 205 mg (white solid, m.p. 170–180° C. with decomposition, rearrangements at only 105° C.).