Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6]S[CH2:4][C:3]1([CH3:9])[C:7]#[N:8].C1C=C(Cl)C=C(C(OO)=O)C=1.[S:21]([O-:25])([O-])(=[O:23])=S.[Na+].[Na+]>C(Cl)Cl>[OH:1][CH:2]1[CH2:6][S:21](=[O:25])(=[O:23])[CH2:4][C:3]1([CH3:9])[C:7]#[N:8]
Reactant: CC1(C#N)CSCC1O
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C#N)CS(=O)(=O)CC1O
Temperature: 25 °C

Procedure:
(3R,4S and 3S,4R)-4-Hydroxy-3-methyltetrahydrothiophene-3-carbonitrile (140 mg, 0.98 mmol) was dissolved in DCM (4.9 mL) and was stirred vigorously at ambient temperature. m-CPBA (340 mg, 2.0 mmol) was added in three portions and the resulting mixture was maintained at ambient temperature for 18 hours. The mixture was then diluted with 1M aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was again washed with 1M aqueous sodium thiosulfate, saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100% EtOAc/hexanes) to afford the title compound. 1H NMR (600 MHz, CD3OD): δ 4.40 (t, J=6.5 Hz, 1H); 3.70 (d, J=13.6 Hz, 1H); 3.56 (dd, J=13.8, 6.2 Hz, 1H); 3.29-3.30 (m, 1H); 3.23 (dd, J=13.7, 6.8 Hz, 1H); 1.60 (s, 3H).
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:14]=[C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[C:33]2[CH:38]=[CH:37][C:36]([S:39][CH3:40])=[CH:35][CH:34]=2)\[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[CH3:40][S:39]([C:36]1[CH:35]=[CH:34][C:33](/[C:18](/[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:21][CH:20]=2)=[CH:17]/[CH2:16][O:15][C:13]2[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:3])[CH:14]=2)=[CH:38][CH:37]=1)=[O:1]
Reactant: CSc1ccc(/C(=C/COc2ccc(OCC(=O)O)c(C)c2)c2ccc(C#CCn3cccn3)cc2)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2ccc(S(C)=O)cc2)ccc1OCC(=O)O

Procedure:
30% Aqueous hydrogen peroxide (0.0618 mL, 0.6 mmol) was added to a solution of (E)-[4-[3-[4-(methylsulfanyl)phenyl]-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetic acid (262 mg, 0.5 mmol; example 48) in glacial acetic acid (7 mL) at 5° C. under stirring. The mixture was left to stand over night at ambient temperature, diluted with water (40 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were alkalized with 15% aqueous solution of ammonium hydroxide; the solution was washed with water (10 mL) and brine (10 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was triturated with hexanes (3×15 mL) to yield the title compound as pale solid.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:14]=1[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=[O:12])C1C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC>[OH:8][C:9]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:14]=1[C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)=[O:12]
Reactant: CCCOc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)c2ccc(OC)cc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)c2ccc(OC)cc2O)c1
Reaction time: 24 h
Yield: 74 %

Procedure:
To a solution of 1-(2-benzyloxy-4-methoxybenzoyl)-2-(3,4-methylenedioxybenzoyl)-5-prop-1-yloxybenzene (0.437 g, 0.84 mmol) in a mixture 1:1 ethyl acetate:hexane (20 ml) was added 10% Pd/C (0.040 g) and the mixture was shaken under hydrogen atmosphere at 60 psi for 24 h. The reaction mixture was filtered through a pad of celite and the filtrate dried (MgSO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, 3:7 ethyl acetate:hexane) afforded the title compound as a pale yellow oil (0.270 g, 72%).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]2[C@@H:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C:32]4=[O:37])=[CH:27][CH:26]=3)=[O:23])[CH2:20]S[CH2:18]2)=[O:16])=[CH:10][CH:9]=1>O.CO>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]2[C@@H:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C:32]4=[O:37])=[CH:27][CH:26]=3)=[O:23])[CH2:20][S:3](=[O:5])(=[O:2])[CH2:18]2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CSCN1C(=O)Nc1ccc(Cl)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CS(=O)(=O)CN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.1 A solution of 4.54 g (54.0 mmol) of sodium hydrogencarbonate and 3.60 g (27.0 mmol) of 2-(S)-thiazolidine-4-carboxylic acid in 50 ml of water is heated to 80° C., and 8.46 g (54.0 mmol) of 4-chlorophenyl isocyanate are added. The reaction mixture is stirred at this temperature for 1 hour. The mixture is allowed to cool, and the precipitate formed is filtered off. The filtrate is acidified using 1N HCl, and the precipitate formed is filtered off and dried, giving (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid as a colourless solid; ESI 287. 3.2 498 mg (2.60 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 573 mg (2.00 mmol) of (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid and 384 mg (2.00 mmol) of 4-(4-aminophenyl)morpholin-3-one in 4 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. The reaction mixture is added to saturated sodium hydrogencarbonate solution, and the precipitate formed is filtered off, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)-thiazolidine-3,4-dicarboxamide (“A3”) as a colourless solid; ESI 461. 3.3 A solution of 1.9 g of oxone in 30 ml of water is added to a suspension of 450 mg (0.976 mmol) of “A3” in 50 ml of methanol, and the reaction mixture is stirred at room temperature for 24 hours. The reaction mixture is added to water, and the precipitate formed is filtered off and dried, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)-1,1-dioxo-1λ6-thiazolidine-3,4-dicarboxamide (“A4”) as a colourless solid; ESI 493.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[C:29]([O:30][CH3:31])=[N:28][C:27]2[C:26]([C:32](Cl)=[O:33])=[C:25]([CH3:35])[C:24]([N+:36]([O-:38])=[O:37])=[CH:23][C:22]=2[N:21]=1>O1CCCC1>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:32]([C:26]1[C:27]2[N:28]=[C:29]([O:30][CH3:31])[C:20]([O:19][CH3:18])=[N:21][C:22]=2[CH:23]=[C:24]([N+:36]([O-:38])=[O:37])[C:25]=1[CH3:35])=[O:33])([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCC(=O)OC(C)(C)C)c2nc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of glycine tert-butyl ester hydrochloride 104 mg (0.67 mmol) and triethylamine in 3 mL anhydrous tetrahydrofuran 0.26 mL (1.69 mmol) under an atmosphere of nitrogen was added dropwise a solution of 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) in 7 mL anhydrous tetrahydrofuran at 0° C. After the addition was complete (approximately 5 minutes), the reaction mixture was stirred at room temperature for 24 hours, filtered, and concentrated. The residue was taken up in ethyl acetate and the organic solution was washed with water, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude product was purified by elution through a flash column (silica gel 60, 230-400 mesh, 3:2 hexanes/ethyl acetate) to give a yellow oil which crystallized on standing, 200 mg (77%), mp 125-126° C.; 1H NMR (CDCl3): δ 8.32 (s, 1H, 8-H), 6.32 (br s, 1H, amide NH), 4.14 (d, 2H, J=5.1 Hz), 4.09 (s, 3H), 3.99 (s, 3H), 2.54 (s, 3H), 1.47 (s, 9H, tert-butyl protons); MS (APCI): m/z 407 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-])=O)=[C:14]([F:19])[CH:13]=[C:12]([F:20])[C:11]=1[F:21].[Cl-].[NH4+].CCOC(C)=O>CCO.[Fe]>[F:21][C:11]1[C:12]([F:20])=[CH:13][C:14]([F:19])=[C:15]([NH2:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Yield: 66.4 %

Procedure:
To the stirred solution of (2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine 3 (5.2 gm, 12.62 mmol) in EtOH (200 ml), ammonium chloride (10.12 gm, 189.3 mmol) and iron powder (10.57 gm, 189.3 mmol) was added. This reaction mixture was kept stirring at reflux for 16 hours. Reaction mixture was allowed to cool and was filtered over celite and concentrated to dryness. The residue obtained was taken into EtOAc and was washed with water. The EtOAc layer was dried over sodium sulfate and further purified by crystallization from EtOH to provide off-white solid (3.2 gm, yield: 66.39%). M−H+: 381.1. 1H NMR (DMSO, 300 MHz): 5.0 (s, 2H); 6.2 (t, 1H); 7.2-7.3 (m, 2H); 7.45 (s, 1H); 7.5 (d, 1H).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=1[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: Cc1ccc(C)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1ccc(C)c(C(O)C(=O)c2ccccc2)c1

Procedure:
Phenylglyoxal monohydrate (500 mg, 3.29 mM) and p-xylene (0.56 ml, 4.79 mM) were dissolved in dichloroethane (5 ml), titanium tetrachloride (0.9 ml, 8.2 mM) was added, and reacted at room temperature for 30 minutes. Using the same procedure as in Example 1, 2',5'-dimethylbenzoin was obtained as crystal (587.7 mg, 73.9% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36].C(OCC)(=O)C>ClCCl>[C:35]([NH:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Yield: 95.4 %

Procedure:
In a solution of 0.20 g of 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoic acid amide and 0.12 g of triethylamine in 5 mL of dichloromethane, 0.05 g of acetyl chloride was added under cooling with ice and with stirring, and stirred at room temperature for 40 minutes. After the completion of the reaction, 10 mL of ethyl acetate was added in the reaction mixture, and washed with 10 mL of water, 10 mL of saturated sodium hydrogen carbonate aqueous solution, and then 10 mL of saturated ammonium chloride aqueous solution in that order. The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.21 g of the crude aimed product as yellow crystal. The resulting product was used as such without purification for the next step.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2.[N+:16]([O-])([OH:18])=[O:17]>FC(F)(F)C(O)=O>[N+:16]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][C:2]1([CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[CH2:1]2)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCC2(CC1)Cc1ccccc1C2
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC2(CC1)Cc1ccc([N+](=O)[O-])cc1C2

Procedure:
A spiro(cyclohexane-1,2'-indan)-4-one [11] [prepared as above in step (10) of the first process for producing the compounds of Process B] in the cold (at about 0° C.) in trifluoroacetic acid, has nitric acid added thereto and the low temperature maintained for from about 1 to about 4 hours, to yield a corresponding 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one [29] .
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C[O:6][C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][C:20](=O)[CH2:21][C:22](OCC)=[O:23])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:8].[Li+].[OH-]>C(O)(C)(C)C.[OH-].[Na+].CCOC(C)=O>[O:23]=[C:22]1[NH:4][C:2](=[S:3])[NH:1][C:20]([CH2:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:9]([C:7]([OH:8])=[O:6])=[CH:10][CH:11]=[CH:12]3)=[CH:21]1
Reactant: CCOC(=O)CC(=O)Cc1ccc2c(C(=O)OC)cccc2c1
Reactant: NC(N)=S
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: O=C(O)c1cccc2cc(Cc3cc(=O)[nH]c(=S)[nH]3)ccc12
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
3.46 g (45.4 mMol) thiourea are added to a solution of 29.7 mMol 6-(3-ethoxycarbonyl-2-oxo-propyl)-naphthalene-1-carboxylic acid methyl ester in 25 ml tert-butanol. Then 13.3 g (119 mMol) potassium tert-butyrate are added (exothermic). After 50 min, the mixture is heated for 4.5 h in an oil bath of 100° C. Cooling to rt gives an almost solid mixture, which is redissolved by addition of 59 ml of a 1 M aq. solution of LiOH and stirring during 40 min. This solution is diluted with 500 ml of a 0.33 M solution of NaOH and EtOAc. The organic phase is separated off, washed with 300 ml of a 0.33 M solution of NaOH and discarded. The aq. phases are acidified by addition of 2 N HCl (pH=3), the precipitated product filtered off, washed with 0.001 N HCl and dried in vacuo at 80° C. The crude material is stirred in a boiling mixture of 0.6 l CH3CN, 60 ml EtOAc, 120 ml MeOH and 120 ml THF. Filtration of the hot suspension then leads to the title compound: m.p.: 334-337° C.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]1=[O:7].[CH2:8]1[O:10][CH:9]1[CH2:11]O.[H-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[O:10]1[CH2:8][CH:9]1[CH2:11][O:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=c1nccc[nH]1
Reactant: OCC1CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cnc(OCC2CO2)nc1
Yield: 30 %

Procedure:
A solution of 2 (1H)-pyrimidinone (0.61 g, 4 mmol) and glycidol (0.30 g, 4 mmol) in DMF (10 mL) was added dropwise to a stirred suspension of NaH (0.14 g, 6 mmol) in DMF (5 mL). The reaction mixture is stirred at r. t. until the reagents disappeared (TLC). The reaction mixture is taken up with brine and extracted with EtOAc (3×20 mL). The organic phases are separated, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (Petroleum ether/AcOEt, 1:1, as eluent) to afford pure compound in 30% yield. 1H NMR (CDCl3): δ 2.60-2.70 (m, 2H), 3.16 (m, 1H), 3.89-4.04 (m, 2H), 4.17-4.28 (m, 1H), 4.50-4.65 (m, 1H), 7.00 (t, 1H, J=7.4 Hz), 8.56 (d, 2H, J=4.9 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][CH:8](Cl)[C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH3:15][C:16](=[CH:18][CH3:19])[CH3:17].C(O)(C)(C)C>CCOCC>[Cl:7][C:8]1([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:18]([CH3:19])[C:16]1([CH3:17])[CH3:15]
Reactant: ClC(Cl)c1ccsc1
Reactant: CC=C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC1C(C)(C)C1(Cl)c1ccsc1
Reaction time: 1 h
Yield: 40 %

Procedure:
Potassium-t-butoxide (2.0 g, 18 mmol) was added over 5 min to a rapidly stirred solution of 3-dichloromethylthiophene produced as in a) (1.00 g 6.0 mmol) in dry ether (10-20 ml) at 0° C., containing 2-methylbut-2-ene (>8 equiv.). After 1 h at 20° C., the products were worked up as in Example 3a) to give oils which contained no starting material, although traces of t-butanol were present. The product was a mixture of geometrical isomers (anti/syn=1.31) (0.7 g, 59%). Kugelrohr distillation (oven temperature 80° C. at 0.1mmHg) afforded the product as a colourless oil (0.47 g, 40%) with no change in the isomer ratio (Found M+ 200.0431. C10H13SCl requires M, 200.0426). Chromatography on silica with petroleum as eluent resulted in decomposition of the minor (syn) isomer affording pure major anti-isomer (27%) (Found M+ 200.0437. C10H13SCl requires M, 200.0426) which showed νmax (film) 752s, 773s, 838s, 1453m, 2927s, 2950s and 2996 m cm-1 ; δH (200 MHz; CDCl3) 0.85 (3H, s), 1.22 (3H, s), 1.24 (4H, m), 7.11 (2H, m), 7.24 (1H, q, J 3, 5 Hz); m/z 200 (M+), 185 (M -CH3), 165 (M+ -Cl). From the 1H n.m.r. of the mixture, the minor (syn) isomer showed δH (200 Mz; CDCl3) 0.94 (3H, s), 1.05 (3H, d, J 6.5 Hz), 1.35 (1H, q, J 6.5 Hz), 1.48 (3H, s), 7.05 (1H, dd, J 1.5, 5.0 Hz) and 7.25 (2H,m); m/z 200 (M+), 185 (M+ -CH3), 165 (M+ -Cl).
Reaction SMILES: C(OC[N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[C:6]1[S:24][CH3:25])C.Cl>C(O)C>[OH:21][C@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][N:11]1[C:12](=[O:14])[C:13]2[NH:5][C:6]([S:24][CH3:25])=[N:7][C:8]=2[N:9]([CH3:23])[C:10]1=[O:22]
Reactant: CCOCn1c(SC)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Agent: Cl
Solvent: CCO
Product: CSc1nc2c([nH]1)c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of (R)-7-ethoxymethyl-1-(5-hydroxyhexyl)-3-methyl-8-methylsulfanylxanthine (20 mg, 0.054 mmol) in ethanol (1.9 ml) was added concentrated hydrochloric acid (0.10 ml). The reaction mixture was stirred at 80° C. for 24 hours. After evaporation of the solvent under reduced pressure, the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-hydroxyhexyl)-3-methyl-8-methylsulfanylxanthine (12 mg, 70% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:6]
Reactant: C1CCNC1
Reactant: Cc1cc(F)cc(C(=O)O)c1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(F)cc(C(=O)N2CCCC2)c1Br
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-fluoro-3-methylbenzoic acid (140 mg, 0.60 mmol), pyrrolidine (99 μL, 1.20 mmol) and Hunig's base (210 μL, 1.20 mmol) in DMF (2 mL) at RT was added HATU (457 mg, 1.20 mmol) and the reaction stirred at this temp overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-60% Hex/EtOAC) to yield (2-bromo-5-fluoro-3-methylphenyl)(pyrrolidin-1-yl)methanone as a clear oil.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1>>[F:35][C:36]1([F:40])[CH2:39][N:38]([C:2]2[CH:34]=[CH:33][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=2)[CH2:37]1
Reactant: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Reactant: FC1(F)CNC1
Product: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CC(F)(F)C5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions to Example 152 using 3,3-difluoroazetidine. MS (ESI): mass calcd. for C29H31F2N5O3, 535.24; m/z found, 536.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.52 (d, J=9.6, 2H), 7.04 (d, J=8.2, 2H), 6.96 (s, 1H), 6.91 (d, J=8.8, 1H), 6.52 (d, J=8.3, 2H), 6.26 (s, 1H), 5.44 (d, J=16.5, 1H), 5.38 (d, J=16.4, 1H), 4.99 (s, 2H), 4.17 (t, J=11.9, 4H), 3.83 (s, 3H), 3.59-3.53 (m, 1H), 2.88-2.78 (m, 1H), 2.41-2.29 (m, 1H), 1.98 (s, 1H), 1.79 (t, J=27.9, 5H), 1.53-1.38 (m, 1H).
Reaction SMILES: [NH:1]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[C@H:2]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][CH2:54][C:55]([O:57]C)=[O:56])=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:33])[C@@H:22]([CH3:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[OH-].[Na+]>CN(C=O)C.CO>[NH:1]([C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])[C@H:2]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][CH2:54][C:55]([OH:57])=[O:56])=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])=[O:33])[C@@H:22]([CH3:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of compound (v) (0.92 g, 0.001 M) in 50% DMF/methanol was treated with 1 N NaOH solution (2.5 ml) and stirred at R.T. for 1 hour. Upon acidification the precipitated product (0.45 g) was recrystallised from methanol in 49% yield. M.P. 171°-173°. T.L.C. 2:1 CHCl3 :MeOH (t.butyl chloroformate/NaI-starch spray) showed one spot at Rf 0.50 [α]D25° =-5.4° (C=1, AcOH). The F.T. 13C NMR was consistent with structure.