Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CC/C=C/c1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC/C=C/c1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 0.26 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-(1-trans-butenyl)-4-chloroimidazole-5-carboxaldehyde in 10 mL of methanol at 0° C. was added 0.24 g of sodium borohydride portionwise over 0.5 hours. The mixture was stirred for an additional 0.5 hours at 0° C. and then poured into a solution at 10% sodium hydroxide in water. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (elution:ethyl acetate/benzene) provided 0.23 g of 1-[2'-carbomethoxybiphenyl-4-yl)methyl-2-(1-transbutenyl)-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDCl3) δ7.84 (d, 1H); 7.53 (t, 1H); 7.40 (t, 1H); 7.29 (m, 3H); 7.08 (d, 2H); 6.86 (d of t, 1H); 6.17 (d, 1H); 5.30 (s, 2H); 4.54 (br s, 2H); 3.63 (s, 3H); 2.23 (quint., 2H); 1.04 (t, 3H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:40]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CS(=O)(=O)CCOC(=O)Cl
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccn1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-ethoxycarbonylmethylamide hydrochloride and 2-(methylsulfonyl)ethyl chloroformate. Yield: 72% of theory, C30H33N7O7S (635.7); Rf value: 0.23 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=636; (M+H+Na)++=329.8.
Reaction SMILES: O[N:2]=[CH:3][C@:4]1([CH2:18][OH:19])[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][CH2:5]1.[CH3:20][C:21]([O-])=[O:22].[Na+]>C(OC(=O)C)(=O)C>[C:3]([C@:4]1([CH2:18][O:19][C:21](=[O:22])[CH3:20])[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][CH2:5]1)#[N:2]
Reactant: CC(=O)[O-]
Reactant: Cc1cn([C@H]2CC[C@@](C=NO)(CO)O2)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@]1(C#N)CC[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 100 °C
Reaction time: 24 h
Yield: 149.2 %

Procedure:
To a solution of the 4'-α and 4'-β isomers of 3'-deoxy-4'-hydroxyiminomethylthymidine (40 mg, 0.15 mM) (Formula 24) in 0.5 ml acetic anhydride, was added NaOAc (6 mg, 0.07 mM) and stir at 100° C. for 24 hours. The solvent was removed by evaporation and the residue chromatographed on silica gel using 4% CH3OH/CH2Cl2, affording the 4'-α and 4'-β isomers of 3'-deoxy-4'-cyano-5'-O-acetylthymidine (32 mg, 0.11 mM).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:11])[CH:3]=1.[N:12]([O-])=O.[Na+]>Cl.O>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH:6][NH2:12])=[C:4]([F:11])[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc(N)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of 48.0 g (0.27 mole) of 4-chloro-2-fluoro-5-methoxyaniline in 50 mL of concentrated hydrochloric acid was cooled to -5° C., and 23.5 g (0.34 mole) of sodium nitrite in 100 mL of water was added dropwise. Upon complete addition, the reaction mixture was stirred at 0° C. for one hour. A solution of 154.0 g (0.68 mole) of stannous chloride in 225 mL of concentrated hydrochloric acid was cooled to 0° C., and the cold solution prepared above was slowly added to it. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature, then was filtered to collect a solid. The solid was made basic and extracted with toluene. The toluene layer was separated and dried over magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure to give 22.4 g of 4-chloro-2-fluoro-5-methoxyphenylhdrazine as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[C:14](OCC)=[O:15])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.CCCCCC>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][OH:15])[CH3:2]
Reactant: CCOC(=O)c1c(CC)nc2c(C)cc(C)nn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nn2c1CO
Yield: 84.2 %

Procedure:
To a solution of 2.702 g (10.9 mmol) of the product of Step A dissolved in 21 mL of anhydrous THF was added 6.0 mL of a 1.0M solution of lithium aluminum hydride in THF at 0° C., and the reaction mixture was stirred under a nitrogen atmosphere. After 1 hour TLC analysis (75% EtOAc-hexane) indicated complete reduction of the ester, and the reaction mixture was quenched by stepwise addition of 0.23 mL water, 0.23 mL of 15% sodium hydroxide solution, and finally 0.69 mL of water. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residual oil was redissolved in EtOAc and dried (MgSO4), filtered, evaporated and dried in vacuo to afford 1.884 g (84%) of a tan solid which was used in the next step without further purification.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(O)C>[CH2:30]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1OC
Temperature: 80 °C

Procedure:
Vanillin (100 g; 0.657 mol) is dissolved in ethanol (500 ml), and dried K2CO3 (101.5 g; 0.73 mol) is added. Heating to 80° C. is then carried out and 1-bromododecane is added dropwise under a protective gas atmosphere. The suspension is heated at reflux for a further 16 hours. After cooling to 25° C., filtration is carried out, the residue is then washed several times with ethanol and the combined filtrates are concentrated to dryness by evaporation. The residue is dissolved in tert-butyl methyl ether. Washing is then carried out with 1M aqueous sodium hydroxide solution (3×200 ml) and water (1×200 ml), and the organic phase is dried over Na2SO4, filtered off and concentrated to dryness by evaporation.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:44])([CH3:43])[CH2:6][NH:7][C:8](=[O:42])[C@H:9]([N:17]([C:19](=[O:41])[C@H:20]([N:32](C(OC(C)(C)C)=O)[CH3:33])[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]([CH3:44])([CH3:43])[CH2:6][NH:7][C:8](=[O:42])[C@H:9]([N:17]([CH3:18])[C:19](=[O:41])[C@H:20]([NH:32][CH3:33])[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
2-((2R)-2-(N-((2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl) propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethyl acetate (511 mg, 0.85 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0° C. Trifluoroacetic acid (2 ml) was added, and the solution was stirred for 15 min at 0° C. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (50 ml), and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatogrpahy on silica (30 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 160 mg of 1,1-dimethyl-2-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenyl propionylamino)ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C1C(=CC=CC=1)O.C1(C)C(C)=CC=CC=1.[OH-].[Ca+2:45].[OH-]>O.CO>[CH3:12][CH:11]([C:8]1[CH:7]=[C:3]([C:4]([O-:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Ca+2:45].[CH3:12][CH:11]([C:8]1[CH:7]=[C:3]([C:4]([O-:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCC(C)c1ccc(O)c(C(=O)O)c1
Agent: O=C(O)c1ccccc1O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCCC(C)c1ccc(O)c(C(=O)[O-])c1

Procedure:
The title compound in 4 g of base oil XOMAPE 150 (9.12 g, Basicity Index 1.21) was prepared as outlined in Example 4 by employing 5-(pentadecy-2-yl)salicylic acid (Example 9, 3.33 g), a commercial lower alkyl (i.e. less than C20) salicylic acid (Infineum M7103, obtainable from Infineum UK Limited, 3.70 g), xylene (203.33 g), calcium hydroxide (1.56 g), and a promoter (methanol:water (97%:3%), 23.37 ml).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]2[C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[CH3:15])[CH3:2]>CO.O1CCOCC1.[C].[Pd]>[NH2:12][C:8]1[C:6]2[O:7][C:3]([CH2:1][CH3:2])=[C:4]([CH3:15])[C:5]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCc1oc2c([N+](=O)[O-])cccc2c1C
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: CCc1oc2c(N)cccc2c1C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a solution of 2-ethyl-3-methyl-7-nitrobenzo[b]furan (1.00 g) in a mixture of methanol (15 ml) and dioxane (10 ml) was added 10% palladium carbon (100 mg) and the above mixture was hydrogenated at 3 atom for 1 hour. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 7-amino-2-ethyl-3-methylbenzo[b]furan (858 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:28](I)[CH2:29][CH3:30]>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:28][CH2:29][CH3:30])[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Product: Cl
Yield: 112 %

Procedure:
A mixture of 9.28 g of 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (prepared by the process of Belgium Pat. No. 858,101), 140 ml of dimethylformamide, 8.48 g of sodium carbonate and 4.67 g of propyl iodide was stirred for 5 hours at room temperature under an inert atmosphere and was then poured with stirring into 1.4 liters of water after which crystallization occured. The mixture was filtered and the recovered product was rinsed with water and dried under reduced pressure in the presence of a dehydrating agent. The product was crystallized from ethanol to obtain 6.95 g of 5-chloro-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole hydrochloride melting at 229°-230° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[S:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].B1(C=C)OB([CH:24]=[CH2:25])OB(C=C)O1.C1C=CN=CC=1.O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]([C:2]1[N:7]=[N:6][C:5]2[S:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1)=[CH2:25]
Reactant: Clc1cc2c(nn1)SCCO2
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: O
Product: C=Cc1cc2c(nn1)SCCO2
Temperature: 96 °C
Yield: 71.2 %

Procedure:
A solution of 3-chloro-6,7-dihydro[1,4]oxathiino[3,2-c]pyridazine (450 mg, 2.4 mmol) in dimethoxyethane (12 ml) was treated with tetrakis(triphenylphosphine)palladium (0) (61 mg), potassium carbonate (313 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (375 mg) and water (1.5 ml). The mixture was heated at 96° C., overnight. The mixture was evaporated to dryness, treated with aqueous sodium bicarbonate solution, extracted (4×) with DCM, dried (sodium sulphate), evaporated and chromatographed on silica gel (50 g), eluting with 1:1 ethyl acetate-hexane, affording a solid (200 mg, 46%), containing slightly impure product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH2:15]([O:22]CC1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na]>CS(C)=O.C(O)C1C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: [Na]
Solvent: OCc1ccccc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 866.3 %

Procedure:
To a solution containing 45.1 g (0.02 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of DMSO was added dropwise at ambient temperature a solution containing 26 g (0.2 mole) of sodium benzyloxide in 75 ml of benzyl alcohol causing the temperature to rise 40° C. After 48 hours at ambient temperature, the reaction mixture was poured into ice water and extracted with ether, and the extract was dried and concentrated to about 200 ml. To the concentrated solution was added 200 ml of hexane and the resulting solution was cooled. Filtration gave 51.5 g (87%) of colorless crystalline solid; m.p. 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([OH:19])[CH:16]=[CH:15]2)=[C:7]([NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:6]=1)=[O:4].N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([O:19][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:16]=[CH:15]2)=[C:7]([NH:20][CH2:21][CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(2,2-Diphenyl-ethylamino)-9-((1R,4S)-4-hydroxy-cyclopent-2-enyl)-9H-purine-2-carboxylic acid methyl ester (2.80 g, 6.14 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry tetrahydrofuran (30 ml) is added followed by dry pyridine (0.97 g, 12.3 mmol). Ethyl chloroformate (2.66 g, 24.6 mmol) is added slowly and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 ml) and 1M HCl (2×200 ml). The organic layer is washed with saturated sodium bicarbonate solution (2×200 ml), water (2×100 ml), brine (2×100 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, 4% MeOH in dichloromethane). MS (ES+) m/e 528.3 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH2:10])=[N:2]1.[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+].BrC[C:19]([Cl:21])=O.O>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11](=[O:14])[CH2:19][Cl:21])=[N:2]1
Reactant: Nc1noc2ccccc12
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)CBr
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCl)Nc1noc2ccccc12
Temperature: 25 °C

Procedure:
To a mixture of benzo[d]isoxazol-3-ylamine (1 g) and cesium carbonate (2.42 g) in dry DMF (20 mL), stirred at rt, was added bromoacetyl chloride (0.62 mL) by dropwise addition. After stirring the mixture for 8 hours, the reaction was poured into water (100 mL) and the products extracted into ether (2×200 mL). The combined extracts were dried over magnesium sulfate and concentrated to dryness. The crude product was purified on silica gel using ether/isohexane (4/6) to afford the sub-titled compound as a colourless solid (0.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25]Cl)[C:3]=1[F:28].Cl.[CH3:30][NH:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25][N:31]([CH3:32])[CH3:30])[C:3]=1[F:28]
Reactant: CNC
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
1.50 g (3.63 mmol) of Compound 159 obtained in EXAMPLE 159 was dissolved in 30 mL of dimethylformamide, 1.48 g (18.2 mmol) of dimethylamine hydrochloride and 2.50 g (18.2 mmol) of potassium carbonate were added, and the mixture was stirred at 50° C. for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane, to give 1.18 g of Compound 161 (yield: 77%). This compound was dissolved in ethyl acetate, 3 mL of a 1N hydrochloric acid/2-propanol solution was added, and the precipitated crystals were collected by filtration, to give a hydrochloride of Compound 161.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][CH2:18][O:19][C:20]1[CH:30]=[CH:29][C:23]([CH:24](O)[C:25]([OH:27])=O)=[CH:22][CH:21]=1.Cl.[C:32](Cl)(=[O:34])[CH3:33]>C(O)(=O)C>[C:32]([O:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]2[C:7]3[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=3[O:15][C:25]2=[O:27])=[CH:29][CH:30]=1)(=[O:34])[CH3:33]
Reactant: O=C(O)C(O)c1ccc(OCCO)cc1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)OCCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Temperature: 120 °C
Yield: 197.8 %

Procedure:
A suspension of 154.7 g (0.75 mol) of 2,4-di-tert-butylphenol and 106.1 g (0.50 mol) of 4-(2-hydroxyethoxy)mandelic acid (compound (201), Example 10, Table 2) in 200 ml of acetic acid saturated with hydrogen chloride gas stirred under a nitrogen atmosphere is refluxed for 8 hours. The acetic acid is then distilled off on a vacuum rotary evaporator, 15 ml (0.21 mol) of acetyl chloride are added to the residue, and the mixture is maintained at 120° C. for 20 minutes. The reaction mixture is again concentrated on a vacuum rotary evaporator, 400 ml of methanol are added to the residue, and the mixture is allowed to stand at about -8° C. The precipitated crystals are filtered off, washed with 250 ml of cold methanol and dried to give 176.3 g (83%) of 3-[4-(2-acetoxyethoxy)phenyl]-5,7-di-tert-butylbenzofuran -2-one, m.p. 93°-96° C. (compound (101), Table 1). Recrystallization from ligroin yields the compound (101) in two crystal forms. Crystal form A: m.p. 75°-78° C., enthalpy of fusion 62.4 Joule/g. Crystal form B: m.p. 93°-96° C., enthalpy of fusion 118.2 Joule/g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[O:16])=[C:11]([OH:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[OH:16])=[C:11]([OH:31])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cc(OCc2ccccc2)ccc1C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of (4-benzyloxy-2-hydroxy-phenyl)-(4-benzyloxy-phenyl)-methanone (T1) (1.6 g, 4 mmol) in 40 mL of THF:MeOH (1:1) was added sodium borohydride (0.160 g, 4 mmol) and solution stirred at 40° C. for 4 hours. After complete consumption of starting material (TLC) the solvents were evaporated, till about 5 mL remaining in the flask. The residue was carefully neutralized with 1 N H2SO4, till pH dropped to 6 and yellow solution turned colorless. This was extracted with 50 mL (4×EtOAc:water, 1:1). The organic layers were combined and dried over sodium sulfate and evaporated to give (1.12 g, 68%) of T2 as pinkish white solid. 1H NMR (400 MHz, DMSO-d6) δ, 9.42(s, 1H, OH-Ph), 7.30(m, 13H, Ar—H2′/6′, 2×C6H5), 6.89 (d, 2H, Ar—H3′/5′), 6.44 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5), 6.38 (d, 1H, J=2.4 Hz, Ar—H3), 5.51 (d, 1H, CH—OH), 5.04 (s, 2H, PhCH2), 4.99 (s, 2H, PhCH2).