Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:16][CH:17]=1.COC(=O)[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([F:32])[CH:26]=1>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:19](=[O:21])[CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)=[CH:26][C:27]=1[F:32]
Reactant: COC(=O)c1ccc(Cl)c(F)c1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)c(F)c1
Temperature: -78 °C

Procedure:
Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 4 L, 4000 mmol) was added over 1 hour to a solution of 3-chlorophenyl acetic acid (250.0 g, 1465 mmol) in anhydrous tetrahydrofuran (1.75 L) at −78° C. under nitrogen. The resulting reaction mixture was stirred for an additional hour at −78° C. Then, a solution of methyl-4-chloro-3-fluorobenzoate (221.0 g, 1175 mmol, Example 4, Step A) in tetrahydrofuran (500 mL) was added over 1 hour at −78° C., and the resulting reaction mixture was stirred at the same temperature for 2 hours. The reaction was monitored by TLC. On completion, reaction mixture was quenched with 2 N hydrochloric acid (2.5 L) and aqueous phase was extracted with ethyl acetate (2×2.5 L). The combined organic layer was washed with brine (2.5 L), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude material which was purified by flash column chromatography (silica gel: 100 to 200 mesh, product eluted in 2% ethyl acetate in hexane) to afford the title compound as a white solid.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Na].O.[CH2:17]([O:19][C:20](=[O:32])[CH:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20](=[O:32])[CH:21]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:13][CH:12]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:18]
Reactant: CCCCCCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc(C2=CCCCCC2)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 g of p-(1-cycloheptenyl)-phenol in a little absolute ethanol are first added to a solution of 1.6 g of sodium in 100 ml of absolute ethanol, which is stirred at room temperature whilst excluding water; 25.2 g of α-bromo-undecanoic acid ethyl ester are then added dropwise, the mixture is left at 50°C for 24 hours, the ethanol is removed in vacuo and the residue is partitioned between ether and ice-cold 1 N sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and concentrated by evaporation in vacuo. Crude α-[p-(1-cycloheptenyl)-phenoxy]-undecanoic acid ethyl ester boiling at 160° C/0.06 mm Hg is obtained in the evaporation residue.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CN1CC[CH2:16][C:15]1=O.[CH2:20]([Mg]Br)[CH3:21]>O1CCCC1>[CH2:15]([C:2]1[CH:11]=[C:10]([CH2:20][CH3:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:16]
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: CN1CCCC1=O
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)OC)c(CC)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 32 %

Procedure:
To a mixture of Fe(acac)3 (0.34 g, 0.96 mmol), methyl 2,4-dichlorobenzoate (4.0 g, 19.6 mmol), and N-methyl-2-pyrrolidinone (8 mL) in THF (100 mL) at −20° C. under nitrogen was added a tetrahydrofuran (THF) solution (1.0 M) of ethylmagnesium bromide (40.0 mL, 40.0 mmol) over a period of −5 min. The resulting mixture was stirred while gradually warming to ambient temperature. Stirring was continued for an additional 17 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was separated, washed with brine, dried (MgSO4), and pumped to dryness under reduced pressure. The brown residue was purified by column chromatography (SiO2, 20% EtOAc/heptane) to give 1.2 g of the desired product as a clear oil (yield of 32%), along with 1.1 g of methyl 4-ethylbenzoate. 1H NMR (300 MHz, DMSO-d6) δ 1.15 (t, 3H), 1.20 (t, 3H), 2.66 (q, 2H), 2.92 (q, 2H), 3.82 (s, 3H), 7.15 (d, 1H), 7.23 (s, 1H), 7.76 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=[O:23].OS(O)(=O)=O.O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:21]2[CH:20]=[CH:19][C:18](=[O:23])[NH:17][CH:22]=2)=[CH:4][CH:3]=1
Reactant: O=c1cccc[nH]1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(c2ccc(C)cc2)c2ccc(=O)[nH]c2)cc1
Temperature: 180 °C
Yield: 13.8 %

Procedure:
A mixture of bis(4-methylphenyl)methanol (5 g), and pyridin-2(1H)-one (6.72 g) was stirred at 180° C. To the solution was added concentrated H2SO4 (0.07 mL), and the mixture was stirred at 250° C. for 2 hours. Water (15 mL) and DCM (15 mL) were poured into the reaction mixture. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc). The desired fractions were collected and evaporated in vacuo, and the residue was washed with MeCN and dried in vacuo to give 5-[bis(4-methylphenyl)methyl]pyridin-2(1H)-one (0.94 g) as white crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=2[C:17]#[N:18])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2C#N)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77.7 %

Procedure:
To a solution of N-Boc-piperazine (2.02 g, 11.0 mmol) in DMSO (20 mL) was added 2-fluoro-6-chlorobenzonitrile (1.55 g, 10 mmol) and potassium carbonate (1.52 g, 11 mmol). The mixture was stirred at 80° C. for about 48 hours. The mixture was cooled to r.t. and diluted with diethyl ether (200 mL). The solution was washed with 1N HCl (2×20 mL), H2O (3×20 mL) and brine (20 mL) and then dried over sodium sulfate and concentrated to a yellow oil. Purification by flash chromatography (4:1 hexanes/ethyl acetate) gave the title compound (2.5 g, 86%) as a colorless oil.
Reaction SMILES: [N+](C1C=CC(CNC(N)=O)=CC=1)([O-])=[O:2].[NH2:15][C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[C:20](=[O:32])[N:19]([CH3:33])[C:18](=[O:34])[CH:17]=1.[Cl-].[Ca+2].[Cl-]>O.C(O)(=O)C.[Zn]>[C:18]([OH:34])(=[O:2])[CH3:17].[NH2:15][C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[C:20](=[O:32])[N:19]([CH3:33])[C:18](=[O:34])[CH:17]=1
Reactant: NC(=O)NCc1ccc([N+](=O)[O-])cc1
Reactant: Cn1c(=O)cc(N)n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)cc(N)n(Cc2ccc(N)cc2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Using the general procedure for Intermediate 1, (4-nitro-benzyl)-urea [J. Med. Chem. 1996, 39, 1924] is converted into 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidin-2,4-dione, [MH]+ 277. A solution of calcium chloride (4.94 g, 45 mmol) in water (100 ml) is added to a solution of 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione (19.08 g, 69.0 mmol) in acetic acid (300 ml). Zinc dust (58.8 g, 900 mmol) is then added portionwise with external cooling. The reaction is stirred at room temperature for 1.5 hours, filtered through a celite plug and washed successively with ethanol and acetic acid. Evaporation of the combined filtrate and washings affords 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidin-2,4-dione acetic acid salt, [M-3H]− 243. Acetic anhydride (7.2 ml, 76.0 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (17.0 g, 69.0mmol) in pyridine (260 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[4-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 289. Using the general procedure for Intermediate 1, this compound is converted into N-[4-(5,6-diamino-3-methyl-2,4-dioxo-3,4dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 304.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][Si](C(C)(C)C)(C)C)[CH:13]=[CH:12][C:11]=2[F:24])[OH:9])=[C:4]([Cl:25])[CH:3]=1.C(#N)C.C[N+]1([O-])CCOCC1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[F:24])=[O:9])=[C:4]([Cl:25])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C(O)c2ccc(Br)cc2Cl)c1
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1cc(O)ccc1F)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Compound 510 (15.9 g, 35.6 mmol) was dissolved in dry DCM (80 mL) and dry acetonitrile (10 mL) under an argon atmosphere. The mixture was cooled to 0° C. and added 4-methyl-morpholine 4-oxide (6.27 g, 53.5 mmol), grinded molecular sieve (4 Å, 17.8 g). Tetra-N-propylammonium perruthenate (VII) (250 mg, 0.71 mmol) was added in 5 portions (5×50 mg) and the reaction mixture was stirred for 10 min. at 0° C., evaporated to ⅓ volume and filtered through silica. The silica was washed with EtOAc (300 mL). The organic phase was concentrated in vacuo affording the crude product. Purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:80 to 1:10) as the eluent, affording the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH2:4].Cl.[CH2:8]([N:10]([CH2:32][CH3:33])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28](=[NH:31])OC)[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH3:9].C(OCC)(=O)C>CO>[CH2:8]([N:10]([CH2:32][CH3:33])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28]([NH:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH3:6])=[NH:31])[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH3:9]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Reactant: CCC(C)CN
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)CNC(=N)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of (2RS)-2-methylbutylamine (3.18 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate hydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is taken up with ethyl acetate (50 cc). The solution is washed with distilled water (50 cc) alkalinized to pH 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on a column of neutral alumina (height: 23 cm; diameter: 2.1 cm), eluting with mixtures of ethyl acetate and cyclohexane in proportions (by volume) of 20:80 (850 cc) and 10:90 (500 cc), then with pure ethyl acetate (500 cc) and finally with mixtures of ethyl acetate and methanol in proportions (by volume) of 95:5 (500 cc), 90:10 (500 cc) and 80:20 (500 cc and collecting 50-cc fractions. The first litre is discarded and fractions 40 to 56 are then combined, concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-[ (2RS)-2-methylbutyl]-2-phenothiazinecarboxamidine (1.33 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30](=[O:31])[C:29]3[CH:32]=[CH:33][CH:34]=[C:27]4[C:28]=3[C:23](=[CH:24][CH:25]=[CH:26]4)[C:22]2=[O:35])[CH2:15][CH2:14]1)(O)=[O:2].CS([O-])(=O)=O.ClC1C=CC=C[N+:43]=1C.N>CN1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30](=[O:31])[C:29]3[CH:32]=[CH:33][CH:34]=[C:27]4[C:28]=3[C:23](=[CH:24][CH:25]=[CH:26]4)[C:22]2=[O:35])[CH2:15][CH2:14]1)(=[O:2])[NH2:43]
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)c1ccc2[nH]cc(C3CCN(CCN4C(=O)c5cccc6cccc(c56)C4=O)CC3)c2c1
Agent: CN1CCCC1
Agent: CS(=O)(=O)[O-]
Agent: N
Product: NC(=O)c1ccc2[nH]cc(C3CCN(CCN4C(=O)c5cccc6cccc(c56)C4=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.1 g of 2-[2-(4-(5-carboxy-3-indolyl)piperidino)ethyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione are suspended in 100 ml of N-methylpyrrolidine. 3.2 g of 2-chloro-1-methylpyridinium methanesulfonate are then added and the mixture is stirred at room temperature for 12 hours. Dried NH3 gas is passed into the resulting solution until it is saturated and the mixture is stirred again for 10 hours. Customary working up gives 2-[2-(4-(5-carbamoyl-3-indolyl)piperidino)ethyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])[CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)Cl>[C:16]([C:10]1[NH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:15])=[C:12]([C:13]#[N:14])[CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)cc1-c1[nH]ccc1C#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C#N)c(-c2cc(Cl)ccc2C)[nH]1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a mixture of 2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carbonitrile (1.80 g, 8.28 mmol) in DCM (40 mL) was added acetyl chloride (0.936 mL, 13.14 mmol) at room temperature, under nitrogen. The resultant mixture was cooled to 0° C. and anhydrous aluminum trichloride (2.62 g, 19.8 mmol) was added in small portions during a period of 10 min, keeping the internal temperature below 5° C. Upon complete addition, the mixture was brought to room temperature and allowed to stir for 30 min. Then, the mixture was slowly poured in a solution of ice-cooled 1 M HCl (18 mL). The aqueous layer was separated and extracted twice with DCM (40 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (10 to 20% EtOAc/hexane) to afford the title compound (2.0 g, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:14]([O-])([O:16]C(C)C)=[O:15].S(=O)(=O)(O)O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CC(C)O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(O)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41.9 %

Procedure:
To a solution of ethyl 3,4-dihydroxybenzoate (9.5 g, 52.2 mmol), isopropyl nitrate (13.5 g, 130.5 mmol), and tetrabutylammonium hydrogensulfate (0.884 g, 2.61 mmol) in DCM (100 mL), was added sulfuric acid (14.25 g, 145.6 mmol) slowly at 0° C. The reaction mixture was warmed to room temperature and stirred for 45 min, then quenched with ice/water (150 mL), and extracted with DCM (150 mL×2). The extracts were combined, and the solvent removed under vacuum. The product was purified by silica gel column (20% v/v EtOAc in PE) to give ethyl 3,4-dihydroxy-2-nitrobenzoate (4.97 g, 40% yield). ESI MS: m/z 228 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:7].[CH:8]1[N:13]=[C:12](Cl)[C:11]2[N:15]=[CH:16][N:17]([C@@H:18]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@H:19]3[OH:26])[C:10]=2[N:9]=1.C(N(CC)CC)C>O1CCOCC1>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:12]1[C:11]2[N:15]=[CH:16][N:17]([C:10]=2[N:9]=[CH:8][N:13]=1)[C@@H:18]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@H:19]1[OH:26]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: N[C@@H]1CCC[C@H]1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@H](O)[C@@H]1O
Temperature: 100 °C
Yield: 18.4 %

Procedure:
Trans-2-hydroxycyclopentylamine (0.35 g, 3.46 mmol)(prepared by reaction of cyclopentene oxide with ammonia in a sealed vessel: see example 11) was reacted with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-9H-purine) (0.5 g, 1.7 mmol) in dioxan (30 ml) in the presence of triethylamine (0.93 g, 9 mmol). The reaction mixture was heated at 100° C. for 70 h, cooled and evaporated. The resultant residue was purified by flash chromatography eluting with a mixture of ethyl acetate and methanol (19:1). The fractions found to contain the highest amounts of N-[(1R, trans)-2-hydroxycyclopentyl]adenosine following HPLC examination, were combined and evaporated to a solid (0.17 g). Recrystallisation from methanol provided the pure N-[(1R, trans)-2-hydroxycyclopentyl]adenosine (0.11 g, 18%) mp 233°-235° C. 1H NMR (DMSO-d6)δ 1.43-2.12 (6H, 4m, --CH2CH2CH2 --), 3.52-3.59 (1H, m, H-5'a), 3.54-3.71 (1H, m, H-5'b), 3.97 (1H, q, H-4'), 4.07 (1H, br, --C HOH) 4.15 (1H, q, H-3'), 4.61 (1H, q, H-2'), 4.87, 5.21, 5.41-5.47 (4H, d & 3m, OH groups), 5.89 (1H, d, H-1'), 7.75 (1H, br d, --NH), 8.21 and 8.37 (H-2 and H-8).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH2:37]C)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.[C:41](O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([C:32]1[CH:31]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:39])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:17])([F:18])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:35]=[C:34]([CH3:36])[N:33]=1)[CH3:41]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M229) (292 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (188 mg, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:29]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.22 g, 0.5 mmol) and commercially available 3-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.154 g, 69%). MS (ISP) 446.3 [(M+H)+]; mp 194° C.
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10][N:9]2[C:4](=[N:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.[C:22](OCC)(=[O:24])C>C(#N)C>[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][C:22]([NH:5][C:4]2[CH:3]=[CH:2][CH:1]=[C:11]3[C:6]=2[CH:7]=[CH:8][N:9]=[CH:10]3)=[O:24])[CH:16]=[CH:17][CH:18]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(C)=O
Reactant: NCCc1cccc(F)c1
Solvent: CC#N
Product: O=C(NCCc1cccc(F)c1)Nc1cccc2cnccc12
Yield: 65 %

Procedure:
The product from Example 1A (0.65 g, 2.25 mmol), DBU (0.85 g, 5.6 mmol) and 2-(3-fluorophenyl)ethylamine (0.35 g, 2.5 mmol) in acetonitrile (50 mL) were refluxed for 10 hours. The mixture was cooled, concentrated, diluted with ethyl acetate, washed twice with aqueous ammonium chloride and concentrated to dryness. The solid obtained was suspended in ethyl acetate and filtered to obtain 0.45 g (65%) of the title compound as a tan solid. 1H NMR (300 MHz, d6-DMSO) δ 9.27 (s, 1H), 8.63 (s, 1H), 8.51 (d, 1H), 8.26 (d, 1H), 7.89 (d, 1H), 7.71 (d, 1H), 7.59 (m, 1H), 7.35 (m, 1H), 7.18-7.0 (m, 3H), 6.60 (t, 1H), 3.42 (m, 2H), 2.72 (m, 2H); MS (DCI/NH3) m/z 310 (M+H)+; Anal. Calcd. For C18H16N3FO. 0.1H2O: C, 69.48; H, 5.25; N, 13.51. Found: C, 69.31; H, 5.25; N, 13.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:38][C:37]2[CH:39]=[CH:40][C:34]([C:33]([F:41])([F:42])[F:32])=[CH:35][CH:36]=2)=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(Cc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (82 mg, 0.1933 mmol) in methylene chloride (10 ml) were added 4-trifluoromethylaniline (47 mg, 0.2919 mmol), triethylamine (39 mg, 0.3861 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (98 mg, 0.5798 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (58 mg, 0.1024 mmol, 53%).
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][CH:4]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[CH2:26]([N:25]([CH2:23][CH:2]([OH:1])[CH2:3][CH:4]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC1CO1
Solvent: CO
Product: CN(Cc1ccccc1)CC(O)CC(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Yield: 94.4 %

Procedure:
2.39 g (7.65 mmole) of t-butyl 4,5-epoxy-2-(1-naphthylmethyl)pentanoate (prepared as described in Preparation 11) were reacted with 1.39 g (11.5 mmole) of N-methylbenzylamine in 20 ml of methanol for 2 days. At the end of this time, the reaction mixture was concentrated by evaporation underreduced pressure, and the residue was purified by column chromatography through silica gel (eluent: a 5: 95 by volume mixture of methanol and methylene chloride), to afford 3.13 g of the title compound as a pale brown oil.