Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[ClH:14].[H][H]>C(O)C.[Pd]>[ClH:14].[NH2:2][CH2:1][C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(C#N)nc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(CN)nc1
Reaction time: 12 h

Procedure:
To a solution of ethyl 6-cyano-3-pyridinecarboxylate (3.75 g) and cone. HCl (7.5 mL) in 225 mL ethanol was added 10% Pd/C (wet, 375 mg) and the reaction mixture was hydrogenated using hydrogen balloon and stirred for 12 h. Solution was filtered through celite and ethanol was evaporated to give ethyl 6-(aminomethyl)-3-pyridinecarboxylate HCl as a white solid, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17]>CCO.C1COCC1>[CH2:16]([O:18][C:19]([C:20]1[S:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]=1[NH2:9])=[O:22])[CH3:17]
Reactant: N#CC1=C(Cl)CCCC1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1sc2c(c1N)CCCC2
Temperature: 90 °C
Yield: 101.4 %

Procedure:
A 250 mL flask was charged with 2-chloro-cyclohex-1-enecarbonitrile (3.0 g, 21 mmol) in a 6:1 mixture of EtOH/THF (42 mL), K2CO3 (2.9 g, 21 mmol), and mercapto-acetic acid ethyl ester (3.5 mL, 32 mmol), after which it was fitted with a reflux condenser under N2 atmosphere and heated to 90° C. for 24 h. The mixture was filtered through a pad of diatomaceous earth, such as celite®, rinsing thoroughly with MeOH (400 mL). After concentration, the title compound was purified by FCC (60% ethyl acetate (EtOAc)/hexanes) to give an amber-colored oil (4.8 g). MS: 226.1. 1H NMR (400 MHz, CDCl3) δ ppm 5.35 (s, 2H), 2.71-2.64 (m, 2H), 2.36-2.26 (m, 2H), 1.87-1.77 (m, 4H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[C:4](=[O:6])[CH3:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:5][C:4](=[O:6])[C:3]([O:8][CH3:9])([O:2][CH3:1])[CH3:7]
Reactant: COC(OC)N(C)C
Reactant: COC(C)(OC)C(C)=O
Product: COC(C)(OC)C(=O)C=CN(C)C
Temperature: 100 °C
Reaction time: 42 h
Yield: 99.5 %

Procedure:
A mixture of 100 g of 3,3-dimethoxy-2-butanone and 99.2 g of N,N-dimethylformamide dimethylacetal was stirred at 100° C. for 42 hours. After cooling the reaction mixture, the mixture was concentrated under reduced pressure to give 141 g of 1-dimethylamino-4,4-dimethoxy-1-penten-3-one.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>>[C:28]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([OH:30])=[O:29]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1c[nH]c2ccccc12)C(=O)O
Yield: 42 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-tryptophan to provide the title compound in 42% yield as yellow needles (recrystallization from isopropanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:21]1[N:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21]2[N:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])=[C:4]([F:9])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 4-bromo-2-fluorophenylamine (10.4 g, 54.7 mmol) in THF (25 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (83.3 mL, 83.3 mmol, 1 M solution in hexanes) dropwise over 15 minutes. The reaction mixture was stirred for one hour at −78° C. 2,6-Dichloro-nicotinic acid (5.00 g, 26.0 mmol) was then added dropwise as a solution in THF (15 mL) and the reaction mixture was allowed to warm from −78° C. to room temperature and stir for 16 hours. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to 0-2 with 6 N HCl and then diluted with EtOAc. The organic layer was separated and washed with H2O, saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated several times with ethyl acetate and the resulting solid was collected, washed with dichloromethane and dried under vacuum to yield 7.50 g (83%) pure desired product as a dark pink solid.
Reaction SMILES: [H-].[Na+].O1CCCC1.F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>O>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH:14]=1
Reactant: Oc1ccccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Oc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With cooling with ice, 377 mg of sodium hydride (30% liquid paraffin added) was added to a tetrahydrofuran solution of 2,4-difluoro-1-nitrobenzene (1 g), and then o-fluorophenol (775 mg) was added, and stirred at room temperature for 2 hours. Water was added, then extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the entitled compound.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1)=[N+:2]=[N-:3].[H-].[Na+].I[CH3:24].O>CN(C=O)C>[N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([O:20][CH3:24])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(N=[N+]=[N-])CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CC(N=[N+]=[N-])CCN(c2c([N+](=O)[O-])cnn2C)C1
Reaction time: 0.17 h

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol, Intermediate 18 (0.85 g, 3.0 mmol) in DMF (5 mL) cooled to 0° C. under nitrogen, was added sodium hydride (60% in mineral oil, 133 mg, 3.3 mmol) and the resulting mixture was stirred for 10 min. Iodomethane (0.37 mL, 6.0 mmol) was added and the mixture stirred at room temperature for 16 hr. Water (200 mL) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave 5-azido-3-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as an oil (0.76 g). This azide (0.76 g, 2.6 mmol) in THF (15 mL) and water (3 mL) was treated with triphenylphosphine (0.71 g, 2.7 mmol). The mixture was heated at 65° C. for 16 hr and the solvents were removed under reduced pressure to afford 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was suspended in DCM (40 mL) and di-tert-butyl dicarbonate (1.13 g, 5.2 mmol) and DIPEA (1.36 mL, 7.8 mmol) were added. After stirring at room temperature for 16 hr the solvent was removed under reduced pressure and the residue dissolved in DCM (40 mL). Water (20 ml) was added and the organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave tert-butyl 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.84 g, 74% over three steps) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=4.3 Hz, 1H), 5.39 (d, J=7.9 Hz, 1H), 4.21-3.94 (m, 1H), 3.84 (s, 3H), 3.56-3.42 (m, 2H), 3.35-3.03 (m, 6H), 2.28-1.89 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:50])[C@@H:5]([O:47][CH2:48][CH3:49])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26]/[CH:27]=[CH:28]/[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:39]([C@@H:38]([O:44][CH2:45][CH3:46])[CH2:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29]/[CH:28]=[CH:27]/[C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:47][CH2:48][CH3:49])[C:4]([OH:50])=[O:3])=[CH:12][CH:11]=3)=[CH:20][CH:21]=2)=[CH:36][CH:35]=1)([OH:41])=[O:40]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)O)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)(E)(S)(S) 2-ethoxy-3-{4-[5-(4-{5-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-pent-3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-propionic acid ethyl ester (example 1) (88 mg 0.13 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (2 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a crystalline product. The product was recrystallised from ethyl acetate and petroleum ether to give 35 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:19](=[O:20])[C:18]1[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=1[C:16]([NH:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NCCc1ccccc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(NCCc1ccccc1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
N-(2Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), β-phenylethylamine (0.333 g, 2.75 mmol), and benzene (8 ml)/hexane (12 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred for 30 minutes at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-phenylethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.840 g, 2.9% yield).
Reaction SMILES: [NH3:1].[CH2:2]([NH:9][C:10](=[O:25])[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][C:17]([CH3:23])([CH3:22])[CH:16]3[O:24][CH:15]3[C:14]=2[CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>C(O)C>[NH2:1][CH:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([CH2:11][C:10]([NH:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:25])[CH:13]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH:16]1[OH:24]
Reactant: N
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C2OC21
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C(N)C1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
250 ml of a 25%-strength aqueous ammonia solution was added to a solution of 35 g of the N-benzyl-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)acetamide obtained above in 250 ml ethanol, and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into 500 ml water and extracted with 250 ml dichloromethane. The organic phase was separated, dried over sodium sulfate and largely evaporated under reduced pressure. 200 ml diethyl ether was added to the remaining residue. The crystals produced after a while were removed by suction and dried on a rotary evaporator at 60° C. and 20 bar. 11 g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-benzylacetamide was obtained as grey solid, which was used without further purification or characterization for the subsequent reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Sc2cccc3ccccc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2cccc3ccccc23)cc1
Yield: 0.1 %

Procedure:
1-(4--Nitrophenylthio)naphthalene (39.0 moles, 11.0 g) was dissolved in 200 ml ethyl acetate and hydrogenated over 8 g of 5% Pd/C at 40 psi for 1 hr at room temperature. The solution was filtered through celite and the solvent removed to yield 1-(4-aminophenylthio)naphthalene 9.0 g, 92%. Mass spec (FD) 251. Calculated for C15H17NS: C, 76.46; H, 5.21, N, 5.57 Found: C, 76.71; H, 5.39; N, 5.47.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.C([O-])(=O)C.[NH4+:29]>C(O)C>[CH3:17][C:4]1[C:3](=[CH:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:2](=[O:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[N:5]=1.[NH4+:29]
Reactant: Cc1cc(O)n(-c2ccc(S(=O)(=O)O)cc2)n1
Reactant: O=Cc1cccs1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1=Cc1cccs1
Reaction time: 4 h

Procedure:
12.75 g of 5-hydroxy-3-methyl-1-(4-sulfophenyl)-1H-pyrazole, 6.2 g of thiophene-2-carboxaldehyde and 3.85 g of ammonium acetate in 100 mL of ethanol were heated at 80° C. After 4 hours, the mixture was cooled and filtered. The crude product was allowed to reflux in 250 mL of methanol for 30 min and the mixture was then cooled and filtered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[BH4-].[Na+].O.[OH-].[Na+].[C:44](O)(=O)[CH3:45]>>[CH2:44]([N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:12]=[C:11]([CH3:13])[O:10][N:9]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1)[CH3:45]
Reactant: CC(=O)O
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)no1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4noc(C)n4)cc2C)cc1)CC3
Yield: 52 %

Procedure:
A stirred solution of 5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E3, 100 mg, 0.20 mmole) in glacial acetic acid (2 ml) at room temperature under argon was carefully treated with sodium borohydride pellets (50 mg, 1.3 mmole) and stirred for 24 H. Additional sodium borohydride pellets were added (50 mg, 1.3 mmole) and reaction mixture stirred at room temperature for a further 72 h. The reaction mixture was then treated with water (20 ml), basified with 10% NaOH solution (20 ml) and extracted with dichloromethane. The extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 3% MeOH/CHCl3. Crystallisation of the product form ethyl acetate/60-80 petrol afforded the title compound as a white solid (55 mg, 52%) mp 202-204° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CC(=O)CCCCCl
Product: CC(=O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Yield: 90.4 %

Procedure:
The compound was also accessible, inter alia, by first reacting 7-benzyl-3-methylxanthine with 1-chloro-5-hexanone under the reaction conditions described above to give 7-benzyl-3-methyl-1-(5-oxohexyl)-xanthine (yield 90.4% of theory, melting point: 82°-84° C.) and then reductively methylating the oxohexyl side chain with methylmagnesium chloride in anhydrous ether analogously to Example 9 (yield: 60.2% of theory; melting point: 108°-110° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26]CC3C=CC(OC)=CC=3OC)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nc(C)cc(NCC3CCN(C(=O)OCc4ccccc4)CC3)n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 4-{[2-(2,4-dimethoxy-benzylamino)-6-methyl-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylic acid benzyl ester from Step 1 above (0.4 g, 0.79 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL). The resulting reaction solution was stirred at rt for 1 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1-10 (10% NH4OH in MeOH)/99-90 CH2Cl2) to give 4-[(2-amino-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):356.36
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[C:19]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[C:19]=3[CH3:28])[C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: O=[N+]([O-])c1cc(Br)c2nc(CF)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(CF)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Into a 250 ml of round bottom flask with 4-bromo-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (3 g, 10.95 mmol) in N,N-Dimethylformamide (DMF) (50 mL) was added 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (4.16 g, 16.42 mmol) and potassium carbonate (4.54 g, 32.8 mmol). The resulting reaction mixture was stirred 1 h at 80° C., cooled to room temperature and poured into water, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The expected compound was collected and evaporated to yield 4-bromo-2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (3.05 g, 6.84 mmol, 62.4% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.56 (s, 3H) 5.54-5.78 (m, 4H) 6.51 (d, J=7.83 Hz, 1H) 7.18 (t, J=7.83 Hz, 1H) 7.64 (d, J=7.83 Hz, 1H) 8.13 (d, J=1.77 Hz, 1H) 8.44 (d, 1H); LC/MS: MS (ES+) m/e 447 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:20][C:19]=1[F:33])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH2:5]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([Cl:3])=[O:31])=[CH:26][CH:25]=2)=[CH:20][C:19]=1[F:33])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1F

Procedure:
Thionyl chloride (8.5 g) was added to 4.0 g of the 4'-dodecyloxy-3'-fluorobiphenyl-4-carboxylic acid synthesized by the method shown in Example 1, and one drop of pyridine was added. The mixture was refluxed for 6 hours. After the reaction, the reaction mixture was concentrated to obtain 4'-dodecyloxy-3'-fluorobiphenyl-4-carbonyl chloride. To the product was added 2.15 g of 4-hydroxyphenyl (s)-2-ethoxypropionate. Furthermore, 10 ml of dry pyridine was added, and the mixture was stirred at room temperature for 20 hours. After the reaction, the reaction mixture was poured into a large amount of ethyl acetate, and the mixture was washed twice with a dilute aqueous solution of hydrochloric acid, and three times with water. The ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated to give 6.05 g of crude crystals. The desired product was separated by silica gel chromatography using ethyl acetate/hexane as an eluent. Recrystallization from ethanol gave 4.01 g (yield 67%) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[N:7]1)C.Cl>C1COCC1.[OH-].[Li+]>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH:10]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2nn(CC(=O)O)cc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
To a solution of ethyl[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl]acetate from Step 1 (1.05 g, 2.6 mmol) in THF (20 mL) was added 3.0 mL of aqueous in lithium hydroxide at 25° C. under nitrogen and the mixture stirred at 25° C. for 24 hours. The mixture was acidified with 2N HCl, extracted with two portions ethyl acetate and the organic layer separated, washed with brine, dried over MgSO4 and concentrated in vacuo. Chromatographic purification on silica gel using 20% ethanol/79% chloroform/1% acetic acid as the eluant gave [4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl]acetic acid as a white solid (0.58 g, 60%). Elemental analysis for C18H15N2FSO4 +0.8 CH3CO2H Calc'd: C, 55.73, H, 4.34, N, 6.63, S, 7.59. Found: C, 55.72, H, 4.35, N, 6.74, S, 7.72.