Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[NH:20][CH:21]=O)([OH:3])=[O:2].C(O)C>ClC1C=CC=CC=1Cl>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:21]=[N:20][C:11]2[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]1=2)([OH:3])=[O:2]
Reactant: Cn1c(NCCCCCC(=O)O)c(NC=O)c(=O)n(C)c1=O
Solvent: Clc1ccccc1Cl
Solvent: CCO
Product: Cn1c(=O)c2ncn(CCCCCC(=O)O)c2n(C)c1=O
Yield: 65.7 %

Procedure:
9.3 Grams (0.03 mol) of the formamido derivative (IV) was suspended in 500 ml of o-dichlorobenzene and stirred at reflux under an inert atmosphere for 4 hours. It was cooled and the solvent removed on a rotary evaporator attached to a vacuum pump. The crystalline residue was partitioned between 200 ml of ether and 100 ml of 5% aqueous sodium bicarbonate solution. The aqueous phase was separated, washed with 100 ml of ether, and acidified to pH 3.2 with 5N HCl. The precipitate was recrystallized first from aqueous methanol, then from absolute ethanol to give 5.8 g (66% yield) of the xanthine (V) as fine white crystals, mp 177° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1)#[N:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[N:27][CH:28]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C#N)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-cyanopyridine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as a brown solid. (HPLC: tR 2.42 min (Method A); M+H=396 MS-ES)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH2:23])[CH3:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH:23][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[S:9]([CH3:12])(=[O:11])=[O:10])[CH3:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(F)ccc1S(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Yield: 9 %

Procedure:
2,4-Difluoro-1-(methylsulfonyl)benzene (3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (3.13 mmol) and N,N-diisopropylethylamine (6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (9% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[N:19][N:18]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[C:7]=2[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C3CC3)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 3-cyclopropyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (12.9 g), 3,4-dihydro-2H-pyran (5.26 g) and p-toluenesulfonic acid monohydrate (2.38 g) in THF (300 mL) was stirred at r.t. until the reaction was complete. Water was added and the mixture was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed over a short path column (heptane/ethyl acetate gradient). 11.4 g (70%) of the title compound were obtained.
Reaction SMILES: [Li+].[Cl-].C([Mg]Cl)(C)C.[Cl:8][C:9]1[N:10]=[C:11]([Cl:27])[C:12]2[C:17](I)=[CH:16][N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[N:14]=1.S([C:38]#[N:39])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([Cl:27])[C:12]2[C:17]([C:38]#[N:39])=[CH:16][N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[N:14]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 776.8 %

Procedure:
To a solution of LiCl (dry, 5.3 g, 126 mmol) in THF (150 mL) was added iPrMgCl (63 mL of 2 M in THF, 126 mmol). After stirring for 15 min, the mixture was cooled to −78° C. and 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (31 g, 4.5 mmol) was added dropwise as a solution in THF (50 mL). After stirring for 20 min, a solution of tosyl cyanide (19.8 g, 100 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min. The reaction was quenched with HOAc (20 mL) and after stirring at −78° C. for 15 min, water (200 mL) and EtOAc (200 mL) were added. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (two×150 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. After sitting as a concentrate in EtOAc overnight, crystals formed which were collected to afford 3.8 grams 90% purity by 1H NMR. The filtrate was purified via flash chromatography to afford the title compound (12 g). The combined yield was 15.8 grams (66% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) 0.00 (s, 9H), 0.91-1.01 (m, 2H), 3.53-3.66 (m, 2H), 5.65 (s, 2H), 7.94 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:43]=[N:42][N:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.01 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.55 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:4), and was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 143) (794.5 mg) as yellow crystals.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[C:8]#[N:9].[OH2:18].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[F:17])[C:8]([NH2:9])=[O:18]
Reactant: O
Reactant: N#CC(N)c1ccc(Cl)cc1F
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1ccc(Cl)cc1F
Reaction time: 3 h
Yield: 82 %

Procedure:
Then, 20 g of concentrated sulfuric acid was added to 1.03 g of water, to which 17 g of 2-amino-2-(4-chloro-2-fluorophenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 100 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 15.3 g (yield, 82%) of 2-amino-2-(4-chloro-2-fluorophenyl)acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:17]([CH:14]1[CH2:16][CH2:15]1)[CH2:12]2
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccc(Br)cc2CN1C1CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.13 g, 0.42 mmol), cyclopropylamine (0.034 mL, 0.49 mmol) and potassium carbonate (0.090 g, 0.65 mmol) in ethanol (0.9 mL) was stirred at 40° C. for 3 h. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with 30% EtOAc in hexanes to afford the desired product (0.10 g, 94%). LCMS (M+H)+: m/z=252.0/254.0.
Reaction SMILES: [OH-].[K+].Br[CH:4]([C:6]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)OCC(C)(C)CO1)C.Cl.[C:22]([O-])([OH:24])=[O:23].[Na+]>O>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([CH:6]([CH3:4])[C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: CC(Br)C1(c2ccc(O)cc2)OCC(C)(C)CO1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(C(=O)O)c1ccc(O)cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of potassium hydroxide (0.185 g; 0.0039 mole) in water (18 ml), 2-(1'-bromoethyl)-5,5-dimethyl-2-(4'-hydroxyphenyl)-1,3-dioxane (1 g, 0.0031 mole) is added, and the mixture is kept under a nitrogen atmosphere at room temperature for 30 minutes. After this time, potassium hydroxide (0.5 g; 0.089 mole) is added, and the mixture is refluxed for 1 hour. The reaction mixture is then submitted to successive treatments with HCl, with NaHCO3 and once again with HCl as described in Example 1c. 2-(4'-Hydroxyphenyl)-propionic acid is obtained (0.385 g; 0.0023 mole; yield of 75%). Its characteristics are identical to those given for the product of Example 1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@H:13]([C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][N:23]2C(OC(C)(C)C)=O)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:21]12[CH2:26][C@H:24]([NH:23][CH2:22]1)[CH2:25][N:20]2[C:18]([C@@H:13]([NH:12][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](NC(=O)c1cc2ccccc2[nH]1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl (1S,4S)-5-[N-(1H-indol-2-ylcarbonyl)-3-methyl-L-valyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (40.5 g, 89.2 mmol) in CH2Cl2 (300 mL) was added TFA (75 mL) at 0° C. The mixture was stirred at room temperature for 18 h. The reaction was quenched with 1N NaOH while adjusting the pH of the solution to 8-9. The reaction was then extracted with CH2Cl2 (3×500 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. LCMS (m/z): 355.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[N:15][CH:16]=[C:17]([C:20]#[N:21])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[NH:22]1C=N[N:24]=[N:23]1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[N:15][CH:16]=[C:17]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: c1nnn[nH]1
Reactant: COc1cc2c(cc1OC)-c1ncc(C#N)c(=O)n1CC2
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)-c1ncc(-c3nnn[nH]3)c(=O)n1CC2
Yield: 57 %

Procedure:
In a manner similar to that described in Example 23C, 6,7-dihydro-9,10-dimethoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carbonitrile was converted to the corresponding tetrazole in 57% yield, m.p. 286°-288° (decomp) from acetic acid.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O.CO>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: OCc1ccc(N2CCOCC2)cc1
Reaction time: 0.25 h
Yield: 17.6 %

Procedure:
A solution of 4-(4-morpholinyl)benzoic acid (1.00 g, 4.83 mmol) and 4-methylmorpholine (0.53 mL, 4.8 mmol) in tetrahydrofuran (25 mL) at −10° C. was treated with ethyl chloroformate (0.46 mL, 4.8 mmol). After 0.25 h, the mixture was treated with sodium borohydride (550 mg, 14.5 mmol) followed by MeOH (50 mL) slowly. The mixture was then treated with 5% HOAC in water and the mixture was concentrated. The residue was purified by chromatography (SiO2, EtOAc:hexanes) yielding 164 mg (18%) of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[C:10]=1[N+:19]([O-:21])=[O:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:8]1([C:9]2[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[C:10]=2[N+:19]([O-:21])=[O:20])[CH2:6][CH2:7]1
Reactant: Cn1c(NCCOS(C)(=O)=O)c([N+](=O)[O-])c(=O)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1c(N2CC2)c([N+](=O)[O-])c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.6 %

Procedure:
6-(2-methanesulfonyloxyethylamino)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione (5.8 g) was dissolved in 70 ml of acetonitrile and added with 3.8 g of potassium carbonate. The reaction was carried out under heating with reflux for 3 hours. The reaction mixture as cooled down to room temperature; insoluble materials were removed by filtration. The filtrate was concentrated to a volume of 20 ml, added with 100 ml of ether and then stored refrigerated for 2 days. Crystals formed were collected by filtration and washed with hexane; thus 1.0 g of a powdery compound, 6-aziridin-1-yl)-1,3-dimethyl-5-nitro-2,4(1H,3)-pyrimidinedione, was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:20]([O-])=[O:21].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CCCN(C(=O)N(CCCl)N=O)C1OC[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 37.5 %

Procedure:
9.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-xylopyranosylurea are dissolved in 25 ml of formic acid, and 6.0 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is stirred at the same temperature for 30 minutes. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 3.7 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-xylopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: Fc1ccc(OCCCCl)cc1
Product: Fc1ccc(OCCCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 53 %

Procedure:
Following the combined procedures of Examples 14 and 16, 4-[bis(4-fluorophenyl)methyl]piperidine and 4-(3-chloropropoxy)-1-fluorobenzene were reacted and worked up by chromatography in Example 16, to give the free base in 53% yield as a yellow oil after drying in vacuo at 80° C. overnight.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[OH2:15]>O1CCOCC1>[O:12]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=1)[CH:11]=[O:15]
Reactant: O
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Solvent: C1COCCO1
Product: O=CC(=O)c1cccc(OC(F)(F)F)c1
Yield: 98 %

Procedure:
To a solution of 1-(3-(trifluoromethoxy)phenyl)ethanone (5.0 g, 24.6 mmol) dissolved in 1,4-dioxane (75 mL) and water (4 mL) was added SeO2 (4.38 g, 39.4 mmol) in one portion. The mixture was refluxed overnight. The mixture was filtered to remove the black precipitate. The filtrate was concentrated and purified by column chromatography (1:5 Ethyl Acetate/Pentane) to give 2-oxo-2-(3-(trifluoromethoxy)phenyl)acetaldehyde as a yellow oil (5.3 g, 98% yield).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].I[CH2:21][CH2:22][CH3:23]>>[CH2:21]([N:15]1[CH2:14][CH:13]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([C:2]([F:1])([F:18])[F:19])(=[O:5])=[O:4])[CH:7]=2)[CH2:17][CH2:16]1)[CH2:22][CH3:23]
Reactant: O=S(=O)(c1cccc(-c2ccncc2)c1)C(F)(F)F
Reactant: CCCI
Product: CCCN1CC=C(c2cccc(S(=O)(=O)C(F)(F)F)c2)CC1
Temperature: 100 °C

Procedure:
4-(3-Trifluoromethylsulfonylphenyl)-Pyridine (0.3 g) was dissolved in 1-iodo-propane (2 ml) and heated to 100° C. for 2 h. Then the voilatiles were evaporated and the residue redissolved in abs EtOH (20 ml) and NaBH4 (340 mg) was added portions wise at −20° C. The mixture was then allowed to reach r.t. and stirred over night. To the mixture was added 10% Na2CO3 solution (20 ml). The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash chromatography (MeOH:CH2Cl2 (1:9 (v/v)). Collection of the fractions containing pure product and evaporation of the solvent afforded pure 1-propyl-4-(3-trifluoromethylsulfonylphenyl)-1,2,3,6-tetrahydropyridine (150 mg). MS m/z (rel. intensity, 70 eV) 333 (M+, 21), 305 (16), 304 (bp), 171 (14), 128 (14). Rf 0.55 (MeOH)
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:32][C:28]1[CH:27]=[C:26]([CH2:25][S:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=3[CH3:15])[CH2:17][CH2:18]2)(=[O:24])=[O:23])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3cccc(Cl)c3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)Cc2cccc(Cl)c2)CC1
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution {4-[1-(3-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (52.4 mg, 0.104 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (49.8 mg, 2.08 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight under a nitrogen atmosphere. The solvent was evaporated. Water (˜25 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (2.1 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum. This crude product was further purified using preparative reverse-phase HPLC to give {4-[1-(3-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (9 mg, 18%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.44 (br. s, 1H), 7.95-8.12 (m, 1H), 7.90 (dd, J=9.03, 6.53 Hz, 1H), 7.65-7.74 (m, 2H), 7.55 (s, 1H), 7.46 (d, J=1.00 Hz, 2H), 7.36 (t, J=9.00 Hz, 1H), 4.54 (br. s., 2H), 4.13 (dd, J=5.52, 3.51 Hz, 1H), 3.78 (br. s., 4H), 3.48-3.65 (m, 1H), 2.91-3.22 (m, 3H), 2.42 (br. s., 5H), 1.69 (m, 2H). MS cald. for C25H26ClFNO4S [(M+H)+]: 490, obsd. 490.2.
Reaction SMILES: Cl[Sn]Cl.[CH3:4][C:5]1([CH3:45])[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:8](=[O:30])[N:7]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:32]=2)[C:6]1=[O:44].C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:37][C:34]1[CH:35]=[CH:36][C:31]([N:7]2[C:6](=[O:44])[C:5]([CH3:45])([CH3:4])[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[C:8]2=[O:30])=[CH:32][C:33]=1[C:40]([F:43])([F:42])[F:41]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Yield: 84 %

Procedure:
SnCl2, 2H2O (3.84 g, 17 mmoles) is added to the compound of Example 1 (1.08 g, 1.7 mmole) dissolved in AcOEt (30 ml). The reaction mixture is heated under reflux until the starting compound disappears (5 h 30) and then cooled down using an ice bath. After dilution with AcOEt (30 ml), the mixture is poured onto a 1M aqueous solution of NaHCO3 (120 ml). The mixture is stirred for a few hours during which time a white precipitate forms. This precipitate is eliminated by filtration on celite. The filtrate is decanted and the organic solution is dried over Na2SO4, filtered and concentrated to dryness under vacuum. The expected compound is obtained in the form of a yellow oil with a yield of 84% (868 mg).