Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:19](O)[CH3:20].C(Cl)CCl>ClCCl>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH2:19][CH3:20])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCO
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylacetic acid (24.65 g, 91 mmol) in dichloromethane (150 mL), was added 200 proof ethanol (10.63 mL, 181 mmol), EDC (34.7 g, 181 mmol) and 4-(N,N-dimethylaminopyridine (DMAP, 14.39 g, 118 mmol) at room temperature. The solution was stirred at RT over night, washed with 2 N HCl and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4, and the solvent was removed under vacuum to provide 26 g (96%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:3]=1[F:20].[CH3:21]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]2[O:11][CH:21]=[N:1][C:2]=2[C:3]=1[F:20]
Reactant: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2Cl)c1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1Cl
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 4-amino-2-((2-chlorophenyl)amino)-3-fluoro-5-hydroxybenzoic acid in trimethyl orthoformate (100 mL) was added p-TsOH (0.42 g, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (300 mL). The precipitate was filtered off and the filter cake was washed with water to afford a yellow solid (12.31 g, 87.9% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 13.9 (s, 1H), 9.05 (s, 1H), 8.8 (s, 1H), 8.23 (s, 1H), 7.43 (m, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 6.74 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)=[CH2:2].[Br-:11]>CN(C)C=O>[Br:11]/[CH:2]=[CH:1]/[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: C=Cc1c[nH]c(=O)[nH]c1=O
Reactant: [Br-]
Solvent: CN(C)C=O
Product: O=c1[nH]cc(/C=C/Br)c(=O)[nH]1
Yield: 83.4 %

Procedure:
5-vinyluracil (2.75 g, 20 mmoles) was dissolved in dry dimethylformamide (250 ml). To this solution was added a solution of bromide (3.2 g, 20 mmoles) in dry dimethylformamide (30 ml). The reaction mixture was shaken until colourless and then heated at 100° for 1 hour. The solution was then evaporated under reduced pressure to a brown oil to which was added water (30 ml). The resulting pink suspension was filtered and the pale pink solid recrystallised from methanol to give E-5-(2-bromovinyl)uracil (3.62 g, 84% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]23[CH2:19][N:16]([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.ClCCl>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]34[CH2:19][N:16]([CH2:15][CH2:14]3)[CH2:17][CH2:18]4)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Clc1ccc(C23CCN(CC2)C3)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1cc(N2CCCC2)ncc1C12CCN(CC1)C2
Temperature: 130 °C
Yield: 41.1 %

Procedure:
0.852 g (11.98 mmol) of pyrrolidine is added to a sealed tube comprising 0.060 g (0.29 mmol) of 4-(6-chloropyridin-3-yl)-1-azabicyclo[2.2.1]heptane obtained in stage 5.1 of Example 5. The mixture is heated at 130° C. for 3 hours, cooled to ambient temperature and diluted with 40 ml of toluene and the combined mixture is concentrated under reduced pressure. The residue thus obtained is diluted with 50 ml of dichloromethane and poured into 300 ml of a saturated aqueous sodium carbonate solution. The aqueous phase is extracted twice with 100 ml of dichloromethane, and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 85/15/1.5. 0.029 g of the expected product is obtained in the form of a brown powder.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[CH3:22][NH2:23]>C1COCC1>[CH3:22][NH:23][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: O=C(O)c1cccc2cc(Oc3ccnc(F)n3)ccc12
Solvent: C1CCOC1
Product: CNc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(2-Fluoropyrimidin-4-yloxy)-1-naphthoic acid (step a, 1 g, 3.53 mmol) was suspended in THF (10 mL) and warmed to partially dissolve. The mixture was cooled to RT and N-methylamine (2 M in THF, 8.9 mL, 17.7 mmol) was added. After 2 h, the solvent was concentrated in-vacuo. The residue was diluted with H2O and made pH 7 using 1 N HCl. The solid was filtered and rinsed with water and Et2O to yield the title compound as a pink solid.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][O:7][C:8](=[O:10])[CH3:9])[CH:3]=[O:4].CO.N1C2C(=CC=CC=2)C=C[CH:14]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:8]([O:7][CH:6]=[CH:5][C:2]([CH3:1])=[CH:3][O:4][CH3:14])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC=C(C)C=O
Reactant: c1ccc2ncccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC=C(C)C=COC(C)=O
Yield: 990.3 %

Procedure:
28.4 g (0.2 mole) of 2-methyl-4-acetoxy-2-butenal is dripped into a mixture of 23.3 g (0.22 mole) of o-formic acid methyl ester, 12.8 g (0.4 mole) of methanol and 0.35 g (2millimoles) of p-toluene-sulfonic acid. Acetalization takes place while the temperature rises. After 1 hour 2 g (15 millimoles) of quinoline is added and the whole is heated at 185° to 190° C (internal temperature) and at a pressure of 200 mm Hg for 20 minutes The methanol which is eliminated is distilled off in a 20-cm column. Then the pressure is adjusted to 20 mm Hg with the result that 23.2 g of 1-acetoxy-3-methyl-4-methoxy-1,3-butadiene in the form of a mixture of two geometric iosmers is obtained. The yield is 75% of the theory.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:23][CH2:22][CH:21]([NH:20][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:26][CH2:25]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 75 %

Procedure:
Method 1 was followed using 4-chloro-3-nitroanisole (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 60° C. for 72 hours yielding tert-butyl 1-(4-methoxy-2-nitrophenyl)piperidin-4-ylcarbamate (75%). LCMS (m/z): 352.1 (MH+); LC Rt=3.22 min.
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:10]=2)[C:5]1=O)([CH3:3])[CH3:2].Cl.O1CCOCC1>O>[CH:1]([CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=2)[CH2:12]1)([CH3:3])[CH3:2]
Reactant: CC(C(=O)O)c1ccc2c(c1)C(=O)C(C(C)C)C2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc2c(c1)CC(C(C)C)C2

Procedure:
A mixture of 15g. of 2-(2-isopropyl-1 -oxoindan-6-yl)propionic acid, 40g. of zinc amalgam, 50 ml. of conc. hydrochloride acid, 200 ml. of dioxane and 30 ml. of water was heated under reflux for 15 hours. After completion of the reaction, the reaction mixture was extracted with ether and the ether extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and the residue was recrystallized from n-hexane to give 9.5g. of the desired product as colorless crystals of m.p. 90° - 91.5° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[OH:15]>CC#N>[C:13]([C:11]1[CH:10]=[CH:9][C:8]([OH:15])=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:12]=1)#[N:14]
Reactant: CCN=C=O
Reactant: N#Cc1ccc(O)c(N)c1
Solvent: CC#N
Product: CCNC(=O)Nc1cc(C#N)ccc1O
Yield: 70 %

Procedure:
Ethyl isocyanate (7.1 g; 100 mmol) was added to a stirred solution of 2-amino-4-cyanophenol (13.4 g; 100 mmol) in MeCN (250 mL), and the resultant solution was stirred for 12 h. The precipitate was filtered off and dried (vacuum) to give the sub-title compound in a 70% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:17]=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>>[CH3:47][O:48][CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:17]=[N:18][N:19]([C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:20]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[2-(triphenylmethyl)(1,2,3,4-tetrazol-5-yl)]-1H-indazol-3-yl}phenylamine (0.246 g, 0.407 mmol) in tetrahydrofiran (4 mL) was added 2-methoxyacetyl chloride (0.056 mL, 0.61 mmol) and triethyl amine (0.284 mL, 2.035 mmol). The reaction mixture was stirred overnight at room temperature before being partitioned between ethyl acetate and water. The product was purified by column chromatography (40% ethyl acetate in hexanes) (0.104 g, 38% yield): ES-MS (m/z) M+ was not detected.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[N:10][C:11](=[O:14])[NH:12][CH:13]=1.Br[CH2:16][S:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:18]>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:17]([CH2:16][N:10]2[CH:9]=[C:8]([Cl:7])[CH:13]=[N:12][C:11]2=[O:14])=[O:18])=[CH:20][CH:21]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=S(CBr)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CS(=O)c1ccc(Cl)cc1

Procedure:
Potassium tert-butoxide (4 mmol) in DMF (10 ml) was added to a solution of 5-chloropyrimidin-2-one (4 mmol) in DMF (40 ml). The mixture was stirred at room temperature for 10 min before 1-bromomethylsulfinyl-4-chlorobenzene (see Preparation 5) (4 mmol) was added. The resultant mixture was stirred at 60° C. for 2 days, the solvent distilled off at reduced pressure, the residue triturated with water, the insoluble material dried and washed with a little chloroform before recrystallization from DMSO; the crystalline material was also washed with a little methanol and finally with water; yield 0.30 g (25%), m.p. 262° C. (Found: C43.63; H2.68. Calc. for C11H8Cl2N2O2S: C43.59; H2.67)1H NMR (DMSO-d6): δ 5.12 (CH2), 7.60 (Ph, b.s.), 8.19 and 8.62 (H-4, H-6, d, J 4 Hz). IR (KBr): 1660 (CO), 1060 cm-1 (SO) MS (70 eV; m/e (rel int. %): 302 (0.5, M), 159 (6), 145 (33), 143 (100).
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:25]2[C:2]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Yield: 42.7 %

Procedure:
Distilled THF (50 mL) was added to 3-chloro-3-(4-chlorophenyl)isobenzofuran-1(3H)-one (1.50 g, 5.76 mmol) followed by 4-chlorobenzylamine (0.77 mL, 6.34 mmol) and triethylamine (0.96 mL, 6.91 mmol) as for general procedure A and recrystallised in acetonitrile to give pure white solid 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (945 mg, 2.46 mmol. 43%). Rf 0.54 (40:60 EtOAc:petrol). Mp. 156.5-157.4° C. λmax (CH3OH)/nm 221.0, Abs 0.850. IR: 3159, 1659, 1487, 1468 cm−1. 1H NMR (300 Hz, CDCl3); δ 3.07 (s, br, 1H, OH), 4.01 (d, 1H, J=15.0 Hz, N—CH2), 4.52 (d, 1H, J=15.0 Hz, N—CH2), 7.05 (m, 4H, Ar—H), 7.16-7.21 (m, 5H, Ar—H), 7.42 (m, 2H, Ar—H), 7.73 (m, 1H, Ar—H). 13C NMR (75 Hz, DMSO); δ 42.6 (N—CH2), 91.5 (Ar2(O)CN), 123.1, 124.0, 128.2, 128.7, 129.1, 130.4, 130.6, 133.4, 133.5, 135.0, 136.8, 137.0, 148.8 (Ar), 168.0 (C═O). LC/MS-ES+ m/z 406.1, 366.0, 244.9, 242.9, 161.0. Anal. Calcd. for C21H15Cl2NO2.0.2H2O: C, 65.03; H, 4.00; N, 3.61%. Found C, 65.08; H, 4.06; N, 3.88%. HRMS (EI) m/z: 244.0291. Found 244.0299.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][NH:5][NH:6]C(OCC1C=CC=CC=1)=O.[ClH:19]>CCO.[Pd]>[ClH:19].[ClH:19].[F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][NH:5][NH2:6]
Reactant: O=C(NNCCC(F)(F)F)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NNCCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To benzyl 2-(3,3,3-trifluoropropyl)hydrazinecarboxylate (1.7 g, 6.49 mmol, 1 eq.) in a mixture of EtOH (30 mL) were added Pd/C (1.0 g) and HCl (12 N, 2.0 mL). The mixture was charged with H2 (60 psi), stirred at RT for 1 h, filtered, and concentrated to give (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.07 g) as a yellow solid. MS (ESI) m/z 129.1 [M+H]+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1>C1CCCCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Solvent: C1CCCCC1
Product: O=C(O)CC(Sc1ccccc1)c1ccc(Cl)cc1

Procedure:
3-(4-Chlorophenyl)-3-(phenylthio)propionic acid, m.pt. 99°-102° (ex cyclohexane) was prepared from benzenethiol and p-chlorocinnamic acid by a method exactly analogous to that used in Example 1(a)
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][C:12]2[S:13][C:14]([S:17][CH3:18])=[N:15][N:16]=2)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])[CH3:3].B(O[O-])=[O:25].[Na+]>C(O)(=O)C.CCOCC>[CH3:20][C:19]([C:7]1[CH:8]=[C:9]([S:11][C:12]2[S:13][C:14]([S:17]([CH3:18])=[O:25])=[N:15][N:16]=2)[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:23])([CH3:22])[CH3:21]
Reactant: O=BO[O-]
Reactant: CSc1nnc(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CS(=O)c1nnc(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A solution of 2,6-bis(1,1-dimethylethyl)-4-[[5-(methylthio)-1,3,4-thiadiazol-2-yl]thio]phenol (0.25 g, 0.68 mmol) and sodium perborate (0.11 g, 0.71 mmol) in acetic acid (20 mL) is stirred at room temperature for 7 hours then stored at 0° C. overnight. The reaction mixture is diluted with ether and washed three times with water, then with a saturated solution of sodium bicarbonate and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a white solid which is chromatographed on silica gel eluting with a gradient of ethyl acetate:hexane (1:9, 2:8, 3:7, then 1:1) yielding 0.16 g (61%) of 2,6-bis(1,1-dimethylethyl)-4-[[5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl]thio]-phenol; mp 162.0°-163.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH3:11][N:12]([CH3:39])[C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:35])=[C:23]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:24]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH3:39][N:12]([CH3:11])[C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:35])=[C:23]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[CH:29][CH:28]=2)[CH:24]=1)=[O:17]
Reactant: ClCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(OCCCN2CCOCC2)cc1
Temperature: 60 °C
Yield: 78.5 %

Procedure:
4-(3-Chloropropyl)morpholine (0.1 g) was added to a stirred mixture of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide (0.195 g), potassium carbonate (0.21 g) and DMA (5 ml). The mixture was then heated to 60° C. for 36 hours. The mixture was poured into water (150 ml) and the resultant solid was collected, washed with water and with diethyl ether. The product was dried under vacuum. There was thus obtained the title compound (0.203 g) as a colourless solid; NMR Spectrum: (DMSOd6) 1.88 (m, 2H), 2.18 (s, 3H), 2.36 (t, 4H), 2.41 (t, 2H), 2.96 (s, 6H), 3.58 (t, 4H), 4.08 (t, 2H), 6.9 (m, 1H), 7.01 (d, 2H), 7.19 (m, 3H), 7.26 (t, 1H), 7.58 (d, 1H), 7.78 (s, 1H), 7.98 (d, 2H), 9.72 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M+H+ 517.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[C:10](=[O:15])[CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1ccc(C)c(C2CCCCC2=O)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)c(C2CCCC(Br)C2=O)c1
Temperature: 25 °C
Yield: 115.2 %

Procedure:
2-(2,5-Dimethyl-phenyl)-cyclohexanone (51 mg, 0.25 mmol) was dissolved in chloroform (1 mL). To this solution bromine (42.3 mg, 0.27 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (81 mg) which was used directly in the next step without further purification.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:11][OH:12]>>[C:1]1(=[N:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCc2ccccc21
Product: ON=C1CCc2ccccc21

Procedure:
In Step 1 a 1-indanone is treated with a hydroxylamine and a base to produce a 1-indanone oxime. In Step 2 the oxime is hydrogenated to produce a corresponding primary amine, both R and S forms. In Step 3 the primary amine is then added to D-N-acetyl-3,4-dimethoxyphenylalanine in alcohol to produce the (R,R) and (R,S) salts of the primary amine. The (R,S) salt crystallizes first and the (R,R) salt is soluble. These are separated by filtration. The mother liquor, on concentrating and cooling precipitates the desired R,R isomer in high yield and optical purity. In Step 4 a solution of R,R isomer is treated with a base to produce the R form of the primary amine. In Step 5 the R primary amine is reacted with a tertiary amine and 6-chloropurineriboside to produce the adenosine compounds of Formula I of the present invention, for example, N6 -[1-(R)-indanyl]adenosine. ##STR4##
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.Cl.[NH2:10][OH:11].C(=O)(O)[O-].[Na+]>C(O)C>[OH:11][N:10]=[CH:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1ccnc1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cn1ccnc1C=NO
Yield: 55.7 %

Procedure:
A mixture consisting of 118.4 grams of 1-methylimidazole-2-carboxaldehyde, 82.5 grams of hydroxylamine hydrochloride, 113.9 grams of sodium bicarbonate and 1300 ml of absolute ethanol was heated under reflux for 2 hours and then filtered while still hot. The filtrate was concentrated to give a colorless residue which was recrystallized from 2-propanol to give 75 grams of 2-(hydroxyimino)methyl-1-methylimidazole as colorless crystals melting at 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32](=[O:38])[N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:39][CH2:40][CH3:41])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:44][S:45]([CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:47])=[O:46]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:53]3[CH2:52][CH2:51][N:50]([CH2:49][CH2:48][S:45]([CH3:44])(=[O:46])=[O:47])[CH2:55][CH2:54]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:38])=[CH:25][C:24]=3[O:39][CH2:40][CH3:41])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1
Yield: 87.2 %

Procedure:
cis-4,5-Bis-(4-chloro-phenyl)-2-[4-(1-diethylcarbamoyl-1-methyl-ethyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (27 mg, 0.0439 mmol) was reacted with 1-(2-methanesulfonyl-ethyl)piperazine dihydrochloride (17.5 mg, 0.0659 mmol, example 17) using the procedure described in example 25 to give cis-2-(4-{4,5-bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-N,N-diethyl-isobutyramide (29.5 mg, 87% yield) as white solids. HR-MS (ES, m/z): observed 770.2909, calculated for C39H50Cl2N5O5S [(M+H)+] 770.2904.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:13]2[CH:14]=[C:15]([NH2:16])[CH:17]=[CH:18][CH:19]=2)=[CH:5][N:4]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ncc(B(O)O)cn1
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: [Na+]
Solvent: COCCOC
Product: COc1ncc(-c2cccc(N)c2)cn1
Temperature: 25 °C
Yield: 83 %

Procedure:
2-methoxypyrimidine-5-boronic acid (0.134 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.097 g in 83% yield.