Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)(=[O:43])=[O:44])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 92 %

Procedure:
Methyl 4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoic acid (off-white solid) in 92% yield. HRMS calc for [C39H35ClN2O6S2—H] 725.15523 found 725.15437.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12](=[O:22])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[C:12](=[O:22])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCC(=O)N2CCN2CCOCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCC(c2ccc(O)cc2)N1CCN1CCOCC1
Temperature: 100 °C
Yield: 73.7 %

Procedure:
To a suspension of pentane washed sodium hydride (80% oil dispersion, 5.18 g) in dry dimethylformamide (275 ml) was added 5-(4-methoxyphenyl)pyrrolidin-2-one (16.0 g) followed by N-(2-chloroethyl)morpholine hydrochloride (15.5 g) and potassium iodide (0.05 g) at ambient temperature. The solution was heated at 110° C. for 1.5 hrs, cooled to ambient temperature, and quenched with saturated aqueous ammonium chloride solution. The mixture was concentrated in a Kugelrohr apparatus. The residue was diluted with water and ethyl acetate, the layers were separated, and the aqueous phase was extracted with ethyl acetate (4 times). The combined organic extracts were washed with brine, dried over anhydrous potassium carbonate, filtered, and the filtrate was concentrated. The residue was purified by preparative high performance liquid chromatography (silica gel, 1% triethylamine/1% methanol/ethyl acetate). The appropriate fractions were collected and concentrated to afford 18.2 g (72.8%) of 5-(4-methoxyphenyl)-1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinone. 5-(4-Methoxyphenyl)-1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinone (8.82 g) was dissolved in 48% hydrobromic acid (50 ml) and warmed at 100° C. for 5 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane (6 times). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Dilution of the residue with dichloromethane and ether gave the analytical sample (1.99 g), mp 143°-144° C. The mother liquor was concentrated to give a total of 6.20 g (74.0%) of product.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[C:3]1=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:21]
Reactant: C[C@@H]1OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1OC[C@@H](c2ccccc2)NC1=O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2S,5R)-2-methyl-3-oxo-5-phenylmorpholine-4-carboxylate from Step D (160 mg, 0.55 mmol) in CH2Cl2 (2 mL) at ambient temperature was added TFA (0.41 mL, 5.5 mmol). After stirring for 1 h, the reaction mixture was concentrated in vacuo to give the title compound. MS: m/z=192 (M+1).
Reaction SMILES: COC(=O)C1C=CC(N[C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=CC=1Cl.[OH-:43].[Na+]>CO.O1CCCC1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:15]3([CH:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[CH:13]([C:11]([OH:43])=[O:12])[NH:17][CH:16]3[CH2:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:30]2=[CH:29][CH:28]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 66 %

Procedure:
In a manner similar to the methods described in Example 16 and Example 22, rac-2-chloro-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 24 (78 mg, 0.12 mmol) was hydrolyzed with aqueous NaOH in methanol and tetrahydrofuran at 78° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (50 mg, 66%), then rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (30 mg, 0.049 mmol) was reacted with EDCI (19 mg, 0.097 mmol), HOBt (13 mg, 0.097 mmol), triethyamine (9.8 mg, 0.097 mmol), and NH4Cl (26 mg, 0.49 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-3-chloro-phenyl)-amide as a off white solid (Yield, 35 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:20]=1
Reactant: Cc1cc(N2CCC(C)C2=O)ccc1-c1ccc(C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(-c2ccc(N3CCC(C)C3=O)cc2C)cc1
Reaction time: 3 h
Yield: 98.4 %

Procedure:
A stirred solution of 2'-methyl-4'-(3-methyl-2-oxopyrrolidin-1-yl)biphenyl-4-carboxylic acid (D21, 0.35 g, 0.0011 mole) in DMF (5 ml) at 25° C. was treated with anhydrous potassium carbonate (0.27 g, 0.0020 mole) and iodomethane (0.08 ml, 0.0014 mole). The mixture was stirred for 3 hours, then diluted with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extract was washed with water (2×100 ml), then dried (Na2SO4) and concentrated in vacuo to afford the title compound as a beige solid (0.35 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([N:9]=[C:10]=[O:11])=[O:8])([O-:3])=[O:2].[C:15]([CH:17]1[CH2:19][NH:18]1)#[N:16]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([NH:9][C:10]([N:18]1[CH2:19][CH:17]1[C:15]#[N:16])=[O:11])=[O:8])([O-:3])=[O:2]
Reactant: N#CC1CN1
Reactant: O=C=NC(=O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 5.8 g. m-nitrobenzoyl isocyanate in 100 ml. toluene is added dropwise, while stirring, in the course of about 10 minutes to 2.04 g. 2-cyanoaziridine in 50 ml. anhydrous toluene. The reaction mixture is stirred for 30 minutes at ambient temperature and the precipitated solid product is filtered off with suction, washed with toluene and triturated with diethyl ether. There are thus obtained 4.8 g. white 1-(N-3-nitrobenzoyl-carbamoyl)-2-cyanoaziridine; m.p. 156°-158° C. (after drying for 1.5 hours in a vacuum at 70° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([CH:14]([C:22]([OH:24])=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:22]([OH:24])=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(C(C(=O)O)c2ccc(F)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(C(=O)O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.6 %

Procedure:
5.0 g of 1-t-Butoxycarbonyl-4-[carboxy-(4-fluorophenyl)methyl]-3,6-dihydro-2H-pyridine was dissolved in 50 ml of methanol, and 0.50 g of palladium hydroxide/carbon was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 days. After removal of the catalyst by Celite filtration, the filtrate was concentrated under reduced pressure to give 3.6 g of a crude 1-t-butoxycarbonyl-4-[carboxy-(4-fluorophenyl)methyl]piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][CH:14](OC)OC)=[S:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][N:12]=[C:10]2[SH:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=S)NCC(OC)OC)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(-n2ccnc2S)cc1

Procedure:
A solution of 10 g (0.06 mole) of p-methoxyphenyl isothiocyanate in 100 ml of chloroform was treated with 6.3 g (0.06 mole) of aminoacetaldehyde dimethyl acetal. The solvent was evaporated and the residue was recrystallized from ethanol to yield N-(p-methoxyphenyl)-N'-(β,β-dimethoxyethyl)thiourea, 9.2 g (57%). A suspension of this thiourea in a solution of 5 ml of concentrated sulfuric acid and 20 ml of water was refluxed for 3 hours. The mixture was cooled and a solid was filtered, washed with water, and dried. Recrystallization from ethanol gave 1-(4-methoxyphenyl)-2-mercaptoimidazole, 4.9 g (70%), mp 215°-217° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](N1C2C=CC=CC=2OCC1)=[O:4].C(Cl)Cl.ICl.S(=O)(O)[O-].[Na+].[OH2:27]>C(O)(=O)C>[F:16][C:2]([F:1])([F:15])[C:3]([O:4][C:3](=[O:4])[C:2]([F:16])([F:15])[F:1])=[O:27]
Reactant: O
Reactant: O=C(N1CCOc2ccccc21)C(F)(F)F
Agent: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reaction time: 0.75 h

Procedure:
A mixture of 0.5 g (2.16 mmol) of this 4-(trifluoroacetyl)-3,4-dihydro-2H-1,4-benzoxazine, 20 ml of glacial acetic acid and 5 ml of methylene chloride was cooled to 10° in an ice bath. A solution of 1 ml of iodine monochloride in 1 ml of acetic acid was added slowly over a period of 5 minutes Following the addition, the mixture was stirred for 45 minutes and was then diluted with water and a aqueous solution of sodium bisulfite. The product was extracted with ether. The extracts were washed with water, dried and evaporated. Crystallization of the residue from hexane yielded colorless crystals with m.p. 78°-80°.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O)([O-:33])=[O:32].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1.C1C=CC=CC=1.O>[C:3]([C:2](=[CH:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)[C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1)=[O:6])(=[O:4])[CH3:5]
Reactant: CC(=O)CC(=O)OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
4.1 g of 2-[2-(4,4-diphenylpiperid-1-yl)-ethoxy]-ethyl acetoacetate, 15 g of 3-nitrobenzaldehyde, 8 ml of acetic acid and 0.5 ml of piperidine are heated at the boiling point in 300 ml of toluene using a water separator. After 1.9 ml of water have been separated off, the cooled solution is washed with saturated sodium bicarbonate solution and then with water. After the organic phase has been dried with sodium sulfate, the clear reddish-brown solution is concentrated under a high vacuum. The resulting viscous residue is used for the condensation reaction, without further purification. Yield: 53 g of crude product as a cis/trans-isomer mixture. Other entraining agents which are suitable are: benzene and chlorinated hydrocarbons. The yield of crude product is 95-100% of theory.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([C:19]2[CH:32]=[CH:31][C:22]3[C@H:23]4[C@H:28]([CH2:29][CH2:30][C:21]=3[CH:20]=2)[NH:27][CH2:26][CH2:25][CH2:24]4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:27]3[C@@H:28]4[C@H:23]([C:22]5[CH:31]=[CH:32][C:19]([C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=6)=[CH:20][C:21]=5[CH2:30][CH2:29]4)[CH2:24][CH2:25][CH2:26]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc(-c2ccc3c(c2)CC[C@@H]2NCCC[C@@H]32)cc1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3ccc(-c4ccccc4)cc3CC[C@@H]21
Yield: 19 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-8-phenyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 19% of theory; TLC: rf=0.43 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7](C(C)(C)C)=[CH:6][C:5]([C:12](C)(C)C)=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1.OC1C(C(C)(C)C)=CC(C)=CC=1N1N=C2C=CC=CC2=N1.OC1C(C(C)(C)C)=CC(C(C)(C)C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C(C(C)(C)C)=CC(C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C=C(O)C=CC=1C(C1C=CC=CC=1)=O.OC1C=C(OC)C=CC=1C(C1C=CC=CC=1O)=O.OC1C=C(OC)C(S(O)(=O)=O)=CC=1C(C1C=CC=CC=1)=O.C(SC1N=C(SCCCCCCCC)N=C(NC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)N=1)CCCCCCC>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1
Reactant: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CCCCCCCCSc1nc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc(SCCCCCCCC)n1
Agent: COc1cc(O)c(C(=O)c2ccccc2)cc1S(=O)(=O)O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
2-(2′-hydroxy-3′,5′-di-tert-butylphenyl) benzotriazol; 2-(2′-hydroxy-3′-tert-butyl-5′-methylphenyl) benzotriazol; 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)-5-chlorobenzotriazol; 2-(2′-hydroxy-3′-(3″,4″,5″,6″-tetrahydrophthalimidomethyl)-5′-methylphenyl) benzotriazol; 2,2-methylene bis(4-(1,1,3,3-tetramethylbutyl)-6-(2H-benzotriazol-2-yl) phenol); 2-(2′-hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazol; 2,4-dihydroxybenzophenone; 2,2′-dihydroxy-4-methoxybenzophenone; 2-hydroxy-4-methoxy-5-sulfobenzophenone; bis(2-methoxy-4-hydroxy-5-benzoylphenylmethane); (2,4-bis-(n-octylthio)-6-(4-hydroxy-3,5-di-tert-butylanilino)-1,3,5-triazine;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][N+:11]([O-:13])=[O:12]
Reactant: COc1ccccc1C=O
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C=C[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Using the same reaction procedure and workup as described in Example 1, step 1, 2-methoxy-benzaldehyde (5 g, 36.7242 mmol) in ethanol (166 mL) was reacted with nitro methane (1.98 mL, 36.7242 mmol) and 10N NaOH (1.39 g, 34.9602 mmol). The resulting mixture was stirred at 0° C. for 1 hr to afford 4.5 g of the product (83.89% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].[CH3:14]O>OS(O)(=O)=O>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Br:1]
Reactant: COc1ccc(CC(=O)O)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)cc1Br
Reaction time: 18 h

Procedure:
To a solution of (2-bromo-4-methoxy-phenyl)-acetic acid (1.07 g, 4.37 mmol) in 25 mL MeOH was added two drops of concentrated H2SO4 and the reaction was heated to reflux. After 18 hours, the solvent was removed in vacuo to give 920 mg of (2-bromo-4-methoxy-phenyl)-acetic acid methyl ester. This material was used directly in the next step without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21](Cl)=[C:20](Cl)[N:19]=[C:18](Cl)[C:17]=2Cl)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+]>CO.C1COCC1.[Pd]>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)CC1
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccncc2)CC1
Reaction time: 30 h
Yield: 58.9 %

Procedure:
To a stirred solution of 1-Boc-4-[(2,3,5,6-tetrachloropyrid-4-ylamino)methyl]piperidine (2.5 g, 5.83 mmol) in a mixture of methanol (23 mL) and THF (23 mL) was added sodium methoxide (1.89 g, 35 mmol) and 5% palladium on carbon (1.24 g). The mixture was hydrogenated for 30 h and the cataylst was filtered off and the solution concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water and satd sodium bicarbonate. The aqueous washes were back extracted with ethyl acetate, and the combined organics dried (MgSO4) and concentrated in vacuo to give the product (1.0 g, 59%).
Reaction SMILES: I[C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6]([S:12][CH3:13])=[N:5][C:4](=[O:14])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6]([S:12][CH3:13])=[N:5][C:4](=[O:14])[CH:3]=1
Reactant: COCCn1c(I)cc(=O)nc1SC
Reactant: COc1ccc(OC)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: COCCn1c(-c2cc(OC)ccc2OC)cc(=O)nc1SC

Procedure:
To a mixture of 6-iodo-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one (100 mg, 0.31 mmol), (2,5-dimethoxyphenyl)boronic acid (0.37 mmol, 1.2 equiv.) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (14 mg, 0.017 mmol, 0.05 equiv) was added degassed 1,4-dioxane (2 mL), followed by a degassed solution of sodium carbonate (65 mg, 0.61 mmol) in water (0.7 mL). This reaction mixture was subjected to microwave irradiation at 120° C. for 30 minutes and the crude reaction mixture was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1O[C:10](=[O:12])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)(=O)C>[CH3:1][C:2]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:10](=[O:12])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1ccccc1N
Reactant: Cc1nc2cnccc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(C)nc2cnccc2c1=O

Procedure:
2-Methyl-3-oxa-1,7-diaza-naphthalen-4-one (1.95 g, 12.0 mmol) was dissolved in acetic acid (30 mL) and o-toluidine (1.92 mL, 18 mmol) was added. The reaction was refluxed 7 hours, cooled and concentrated. The residue was taken up in ethyl acetate and extracted with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (2×4 inches, packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (500 mL); 25% ethyl acetate/hexane (800 mL); 25% ethyl acetate/hexane (200 mL) and 40% ethyl acetate/hexane (200 mL), unweighed recovered 2-methyl-3-oxa-1,7-diaza-naphthalen-4-one; 40% ethyl acetate/hexane (300 mL), unweighed mixed fraction; 40% ethyl acetate/hexane (3000 mL), 2-methyl-3-o-tolyl-3H-pyrido[3,4-d]pyrimidin-4-one (2.47 g, 81%) of as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=[O:21])[CH:11]([CH3:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:25]=1[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:26]([C:25]2[C:24]([F:23])=[CH:30][CH:29]=[CH:28][C:27]=2[F:31])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([CH3:20])[C:10](=[O:21])[CH:9]=1
Reactant: Nc1c(F)cccc1F
Reactant: CC(C(=O)CC(=O)c1ccccc1Cl)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2c(F)cccc2F)c(-c2ccccc2Cl)cc1=O
Yield: 24.5 %

Procedure:
In 200 ml of xylene were dissolved 6.3 g (0.020 mole) of 5-(2-chlorophenyl)-2-methyl-1-phenyl-1,3,5-pentanetrione, 20.0 g (0.155 mole) of 2,6-difluoroaniline, 4.6 g (0.024 mole) of para-toluenesulfonic acid and 50.0 g of Molecular Sieves 5A, followed by reflux for 8 hours. Solid matter was filtered off from the reaction mixture and 300 ml of chloroform was added to the filtrate. The mixture obtained was washed first with 50 ml of 10% hydrochloric acid and then with 50 ml of a 10% aqueous solution of sodium hydroxide. After washing the chloroform layer further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium solfate, the solvent was distilled off and the residue was subjected to column chromatography (eluent: ethyl acetate) to afford crystals. The crystals were recrystallized from a 2:1 mixed solvent of acetone and hexane, thereby yielding 2.0 g of 6-(2-chlorophenyl)-1-(2,6-difluorophenyl)-3-methyl-2-phenyl-4(1H)-pyridinone having a melting point of 213°-215° C.
Reaction SMILES: N[C:2]1([NH2:16])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]1=[N:4][CH:5]=[N:6]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>CN(C=O)C>[NH2:16][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]
Reactant: O=C(CBr)c1ccccc1
Reactant: COCCOC1=NC(N)(N)C2=NC=NC2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(CC(=O)c3ccccc3)c2n1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-amino-2-(2-methoxyethoxy)adenine (500 mg, 2.39 mmol) in DMF (5 ml) was added K2CO3 (330 mg, 2.39 mmol). Then 2-bromoacetophenone was added and the reaction mixture was heated to 70° C. with stirring for 30 min. The solvent was removed under vacuum and the residue was washed with brine. The aqueous phase was extracted with DCM and the organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography using linear gradient of MeOH in DCM as eluent. 1H NMR (CDCl3) δ 3.40 (s, 3H), δ 3.72 (t, 2H), δ 4.45 (t, 2H), δ 5.58 (s, 2H), δ 5.67 (bs, 2H), δ 7.53-7.74 (m, 4H), δ 8.03 (s, 1H), δ 8.06 (s, 1H); MS: 328.2 (M+1), 326.0 (M−1).