Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(COC)OC>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@H](c1ccccc1)N1C(=O)N(Cc2ccccc2)[C@@H]2C(=O)OC[C@@H]21
Reaction time: 0.5 h

Procedure:
48 ml of dimethoxyethane and 0.39 g (16.2 mmol) of sodium hydride were placed in a 100-ml three-neck flask equipped with a magnetic stirrer under argon and with complete exclusion of moisture. Then 3.24 g (13.2 mmol) of (3aS, 6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo[3,4-d]-imidazol-2,4(3H, 3aH)-dione was added. After a stirring time of 10 min., 2.76 g (16.2 mmol) of benzyl bromide was added and the suspension was stirred for 30 min. Then the reaction mixture was evaporated. The residue was dissolved with 25 ml of dichloromethane and 25 ml of water. The phases were separated and the aqueous phase was washed three times, each time with 15 ml of water. The organic phases were combined, dried with 5 g of magnesium sulfate and evaporated. (3aS, 6aR)-1-[R)-(1-phenylethyl)-3-benzyl-dihydro-1H-furo-[3,4-d]-imidazol-2,4(3H, 3aH)-dione was obtained as a beige product in a yield of 3.56 g (80.5 percent). Concerning the product: Melting point: 163°-164.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:13]1=[O:30].[Br:31][CH2:32][C:33](ON1C(=O)CCC1=O)=[O:34]>C(Cl)Cl>[Br:31][CH2:32][C:33]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:34].[OH:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[C:13]1=[O:30]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(CBr)ON1C(=O)CCC1=O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)CBr)C(=O)O
Temperature: 25 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-amino-3-methylbutanoate (1.8 g) was dissolved in DCM (20 mL). 2,5-Dioxopyrrolidinyl bromoacetate (1.04 g) was added to the mixture. The mixture was stirred with a magnetic stirrer at room temperature, and reacted overnight. The solvent was stripped in vacuo. White solid (1.3 g) was obtained after purification of the crude product on silica gel column (eluted with acetic ether:petroleum ether=1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].CN([C:20]([O:24][N:25]1N=NC2C=CC=C[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.CNOC>O.CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]([N:25]([O:24][CH3:20])[CH3:26])=[O:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)O)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CON(C)C(=O)c1cc(C#C[Si](C)(C)C)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.9 %

Procedure:
2-amino-5-[2-(trimethylsilyl)ethynyl]benzoic acid (630 mg, 2.7 mmol, 1 eq.), HBTU (1.54 g, 4.0 mmol, 1.5 eq.), and 4-methylmorpholine (0.74 mL, 6.7 mmol, 2.5 eq.) were added, in order, to DMF (10 mL) and stirred at room temperature for 10 minutes. N,O-dimethylhydroxylamine hydrochloride (290 mg, 3.0 mmol, 1.1 eq.) was then added to the reaction, and the reaction was stirred at room temperature for 16 hours. Water was then added (20 mL), and the reaction was extracted three times with ethyl acetate (50 mL each). To remove residual water, saturated sodium chloride (20 mL) was added to the organic layer, and the organic layer was separated and dried over sodium sulfate. The solvent was evaporated by rotary evaporation, and the residue was purified on silica column (hexanes/ethyl acetate, 3:1) to result in 320 mg (43%) of the title compound as an orange solid. 1H NMR (500 MHz, CDCl3) δ 8.38 (d, J=1.5, 1H, Ar—H), 7.82 (dd, J=1.5, 7.5, 1H, AR—H), 7.10 (d, J=7.3, 1H, Ar—H), 5.61 (s, 2H, NH2), 4.09 (s, 3H, OCH3), 3.66 (s, 3H, NCH3), 0.22 (s, 9H, Si(CH3)3). 13C NMR (126 MHz, CDCl3) δ 169.20 (CON), 147.35 (C—Ar), 135.24 (C—Ar), 133.50 (C—Ar), 116.65 (C—Ar), 116.55 (C—Ar), 111.21 (C—Ar), 105.40 (CSi(CH3)3), 91.90 (CCSi(CH3)3), 61.44 (NOCH3), 34.53 (NCH3), 0.29 (Si(CH3)3). Exact Mass, 276.13. 277.1046 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][C:10]([NH:12][C:13]1[N:14]=[C:15]([CH2:18][NH:19][CH:20]=O)[S:16][CH:17]=1)=[O:11])[CH:7]=[CH2:8]>C1(C)C=CC=CC=1>[CH2:6]([O:9][C:10]([NH:12][C:13]1[N:14]2[CH:20]=[N:19][CH:18]=[C:15]2[S:16][CH:17]=1)=[O:11])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)Nc1csc(CNC=O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)Nc1csc2cncn12
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 75.8 %

Procedure:
A 6.4 ml portion of phosphorus oxychloride was added to a suspension obtained by adding 17 ml of dry toluene to 3.408 g of 4-allyloxycarbonylamino-2-(formylamino)methylthiazole, and the mixture was then stirred at an oil temperature of 100° C. for 45 minutes. The solvent was evaporated under reduced pressure, and to the resulting residue, 200 ml of dichloromethane and 100 ml of 0.1N sodium hydroxide were added. The solution was adjusted to pH 8.0 with a 2N aqueous sodium hydroxide solution under stirring. After the removal of insolubles by filtration, the organic layer was separated from the filtrate, and it was combined with a liquid extracted from the aqueous layer with 100 ml of dichloromethane, dried (magnesium sulfate), and then filtered. Further, the solvent was evaporated under reduced pressure to obtain an ocherous powder, and this powder was then purified by a silica gel column chromatograph to obtain 2.390 g of the title compound as a light orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[NH:5][C:6]1[NH:7][C:8](=[O:17])[C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[NH:5][C:6]1[NH:7][C:8](=[O:17])[C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2OC)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1Nc1ncc(C(=O)O)c(=O)[nH]1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Ethyl 1,6-dihydro-2-(2-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (10 g) and sodium hydroxide (4 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the precipitate is collected by filtration and recrystallized from DMF to give 1,6-dihydro-2-(2-methoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (7 g). M.p. 251°-253° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:8][CH:9]=[CH:10][C:11]=1[Br:12].[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC.O1CCCC1>[Br:12][C:11]1[CH:10]=[CH:9][O:8][C:7]=1[CH:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Brc1ccoc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1NC(=O)C(c2occc2Br)C(=O)N1
Temperature: -20 °C

Procedure:
n-Butyl lithium is reacted with 2,3-dibromofuran in ether at -70° C. according to the procedure of Zaluski et al. [Bull. soc. chim. Fr., p. 1843 (1970)] and Sornay et al. [loc. cit., p. 990 (1971)]. The reaction mixture is warmed to -20° C. and an equivalent of anhydrous alloxan in tetrahydrofuran is added dropwise. Reaction is allowed to proceed to completion by warming to room temperature for 2 hours. The product, 5-(3-bromo-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione is isolated according to the method of Example 5.
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1)#[N:2].[H-].[Na+].[CH3:18][N:19]([CH3:26])[P:20](Cl)([N:22]([CH3:24])[CH3:23])=[O:21].O>O1CCCC1>[CH3:18][N:19]([P:20]([N:22]([CH3:24])[CH3:23])([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=[C:3]1[C:1]#[N:2])=[O:21])[CH3:26]
Reactant: CN(C)P(=O)(Cl)N(C)C
Reactant: N#Cc1nc(-c2ccc(Cl)cc2Cl)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)P(=O)(N(C)C)n1cc(-c2ccc(Cl)cc2Cl)nc1C#N
Reaction time: 2 h

Procedure:
A solution of 2-cyano-4-(2,4-dichlorophenyl)imidazole (1.0 g) in tetrahydrofuran (30 ml) was treated with sodium hydride (0.16 g of 80% dispersion in oil) at 0°. A solution of tetramethylphosphorodiamidic chloride (0.89 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture stirred for 11/2 hours under nitrogen. It was then poured into water, stirred, and the precipitate filtered, dried and recrystalllsed from toluene/hexane to give 1-[bis(dimethylamino)phosphinyl]-2-cyano-4-(2,4-dichlorophenyl)imidazole, m.p. 140.5°-1°. (Compound 6).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[C:27]([C:31]([CH2:33]Br)=[O:32])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:27]([C:31]([CH2:33][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]1=[O:1])=[O:32])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (3.35 g) in dimethyl sulfoxide (30 mL), bromomethyl tert-butyl ketone (2 g), potassium carbonate (1.55 g), potassium iodide (125mg) and tetra (n-butyl) ammonium bromide (120mg) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over an hydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel colomn chromatography (ethyl acetate: n-hexane=1:3), whereby the title compound (2.3 g) was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]([C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH:15]=1)(C)[C:10]([O-])=[O:11])C>C1COCC1>[O:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([CH:9]([CH3:7])[CH2:10][OH:11])=[CH:15]1
Reactant: CCC(C)(C(=O)[O-])c1coc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(-1-benzofuran-3-yl)propanoate (1.09 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4; filtered and concentrated. The product, 2-(1-benzofuran-3-yl)-1-propanol, was obtained as white oil, was pure enough and taken to the next step without purification. Yield: 700 mg (79%); 177 (M+H).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][N:25]=1.C(N(CC)CC)C.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([NH:53][CH:54]2[CH2:56][CH2:55]2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>CN(C)C=O.C(OCC)(=O)C.O>[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([N:53]([C:28]([C:27]2[CH:26]=[N:25][C:24]([Br:23])=[CH:32][CH:31]=2)=[O:30])[CH:54]2[CH2:55][CH2:56]2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(Br)nc2)C2CC2)CC1
Reaction time: 0.5 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (2.80 g) is added to a mixture of 6-bromo-nicotinic acid (1.85 g) and triethylamine (1.28 mL) in N,N-dimethylformamide (25 mL) cooled in an ice bath. The mixture is stirred for 30 min prior to the addition of a solution of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g) in N,N-dimethylformamide (5 mL). The resulting mixture is stirred at room temperature over night. Water and ethyl acetate are added and the organic phase is separated, washed with water, 1N aqueous NaOH solution, and brine, and dried over MgSO4. The solvent is evaporated in vacuo and the residue is triturated with diisopropyl ether to yield the title compound. LC (method 5): tR=1.59 min; Mass spectrum (ESI+): m/z=424/426 (Br) [M+H]+.
Reaction SMILES: C(=O)(OC1N=CC=CN=1)N.[Cl:11][C:12]([Cl:17])([Cl:16])[C:13]([NH2:15])=[NH:14].[C:18]([O-])(=O)[CH2:19][C:20](C)=[O:21]>>[OH:21][C:20]1[CH:19]=[CH:18][N:15]=[C:13]([C:12]([Cl:17])([Cl:16])[Cl:11])[N:14]=1
Reactant: CC(=O)CC(=O)[O-]
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: NC(=O)Oc1ncccn1
Product: Oc1ccnc(C(Cl)(Cl)Cl)n1

Procedure:
The pyrimidinyl carbamate compounds of the present invention may be prepared by reacting trichloroacetamidine with the corresponding acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carbamoyl chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with methylacetoacetate to form 4-hydroxy-6-methyl-2-trichloromethylpyrimidine. In equation (B), the 4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with dimethylcarbamoyl chloride to form 6-methyl-2-trichloromethyl-4-pyrimidinyl dimethylcarbamate. ##STR3##
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C@H:10]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][O:12]2)(=O)=O.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:18]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]1[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)[O:12][CH2:11]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccncc1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4ccncc4)c3C2)cc1
Yield: 82.8 %

Procedure:
A mixture of (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (1.00 g, 2.1 mmol), pyridine-4-boronic acid (644 mg, 5.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride (256 mg, 0.3 mmol) and potassium phosphate (1.34 g, 6.3 mmol) in dioxane (15 mL) was irradiated in a microwave at 150° C. for 2.5 h. The mixture was filtered through a pad of celite and concentrated in vacuo. Purification by column chromatography, using a gradient of ethyl acetate in heptane as the eluent, gave 707 mg (83%) of the title compound: MS (ESI) m/z 407[M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=3)[S:7][C:6]=2[CH:16]=1.FC(F)(F)CO>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[S:7][C:6]=2[CH:16]=1
Reactant: Fc1ccc2cc(C3=CCNCC3)sc2c1
Agent: [Pd]
Solvent: OCC(F)(F)F
Solvent: CCO
Product: Fc1ccc2cc(C3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
Scheme IA, Step C: To a solution of 4-(6-fluorobenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.850 g, 3.64 mmol) in a 3:1 mixture of ethanol (30 mL) and 2,2,2-trifluoroethanol (10 mL) was added 10% Pd/C (0.900 g). The black slurry was stirred vigorously at room temperature under hydrogen (balloon pressure) for 1 day. The black slurry was then filtered over a pad of diatomaceous earth and washed with ethanol. The filtrate was concentrated to provide the intermediate title compound as a white solid (0.735 g, 86%). mp 115-120° C. IR (KBr) 3350 (br), 1247 cm1. Ion Spray MS 236 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7](=[O:53])[CH:8]([NH:31][C@H:32]([C@@H:35]([C@@H:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[OH:38])[OH:36])[CH2:33][OH:34])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)C>C(O)C>[OH:53][C:7](=[O:6])[CH:8]([NH:31][C@H:32]([C@@H:35]([C@@H:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[OH:38])[OH:36])[CH2:33][OH:34])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCCCCCC(N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC)C(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCCCC(N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC)C(=O)O
Reaction time: 1.5 h

Procedure:
Sodium hydroxide (0.08 ml, 6.18M) is added to a stirred solution of 58 mg of N-(α-acetoxy-tetracosanoyl) phytosphingosine in 3 ml of 96% ethanol. After 1.5 hours, additional 6.18M sodium hydroxide (0.05 ml) is added and stirring is continued for 0.5 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[CH3:50][NH:51][CH3:52]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:24])([F:25])[F:26])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:51]([CH3:52])[CH3:50])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN(C)C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 500 mg of the compound obtained in Example 219, a solution of 2 mol/L dimethylamine in THF (0.76 ml) as starting material, 300 mg of the title compound (light yellow amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:22]=[C:23]4[C:29]([CH:30]([C:51]5[C:56]([Cl:57])=[CH:55][CH:54]=[C:53]([F:58])[C:52]=5[Cl:59])[C:31]([F:50])(S(C5C=CC=CC=5)(=O)=O)S(C5C=CC=CC=5)(=O)=O)=[CH:28][NH:27][C:24]4=[N:25][CH:26]=3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.P([O-])([O-])(O)=O.[Na+].[Na+].CO.Cl.C([O-])(O)=O.[Na+]>C1COCC1.[Na].[Hg].C(Cl)Cl>[Cl:59][C:52]1[C:53]([F:58])=[CH:54][CH:55]=[C:56]([Cl:57])[C:51]=1[CH:30]([C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:18]3[CH:17]=[N:16][N:15]([C@H:12]4[CH2:13][CH2:14][C@H:9]([OH:8])[CH2:10][CH2:11]4)[C:19]=3[CH3:20])[CH:22]=2)[NH:27][CH:28]=1)[CH2:31][F:50]
Reactant: Cc1c(-c2cnc3[nH]cc(C(c4c(Cl)ccc(F)c4Cl)C(F)(S(=O)(=O)c4ccccc4)S(=O)(=O)c4ccccc4)c3c2)cnn1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1c(-c2cnc3[nH]cc(C(CF)c4c(Cl)ccc(F)c4Cl)c3c2)cnn1[C@H]1CC[C@H](O)CC1
Reaction time: 1.5 h

Procedure:
To a mixture of 5-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-methyl-1H-pyrazol-4-yl]-3-[1-(2,6-dichloro-3-fluorophenyl)-2-fluoro-2,2-bis(phenylsulfonyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (30.00 mg, 0.03333 mmol) and Disodium hydrogen phosphate (94.64 mg, 0.6667 mmol) in methanol (5.00 mL, 123 mmol) and THF (0.300 mL, 3.70 mmol) at −20° C. was added Sodium Mercury Amalgam (5% sodium; 0.28 g, 0.67 mmol). The resulting mixture was stirred between −15° C. and −5° C. for 1.5 h. The mixture was transferred into another flask by filtration to remove the inorganic insolubles. Sat. aq. solution of NH4Cl (2 ml) was added to the MeOH mixture, then the solvent was removed under reduced pressure to give a residue, which was diluted by DCM and extracted by DCM (20 mL×3). The organic phase were combined, dried and concentrated to give a desulfonylated intermediate [MS (ES+): m/z 619.23, 621.23 [MH+]. HPLC: tR=2.02 min (polar—3 min, TOF)]. This intermediate was dissolved in THF (0.3 mL) at 0° C., 2.0 M aq. HCl (0.50 mL, 1.0 mmol) was added, and the resulting mixture was stirred at rt for 30 min. NaHCO3 (112.0 mg, 1.333 mmol) was added to the mixture slowly to adjust pH=≈9. Then the solvent was removed under reduced pressure to give a residue, which was diluted by DCM and extracted by DCM (20 mL×3). The organic phase were combined, dried and concentrated to give a crude residue which was purified by silica gel chromatography (eluent: 5% MeOH in DCM) to give the title compound. 1H NMR (400 MHz, CD3OD): δ=1.48-1.60 (m, 2H), 1.94-2.16 (m, 6H), 2.26 (s, 3H), 3.63-3.77 (m, 1H), 4.15-4.28 (m, 1H), 5.20-5.54 (m, 2H), 5.62-5.75 (m, 1H), 7.28 (t, J=8.6 Hz, 1H), 7.35-7.64 (m, 4H), 8.20 (d, J=2.0 Hz, 1H). MS (ES+): m/z 505.06, 507.07 [MH+]. HPLC: tR=1.33 min (polar—3 min, TOF).
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].O1CCCC1.Br[CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH2:24]([CH:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)[CH3:25]
Reactant: CC(=O)C1=CNCCC1
Reactant: CCCCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC)CN1C=C(C(C)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-acetyl-1,4,5,6-tetrahydropyridine (20.0 g, 0.16 mole) was added under nitrogen to a mixture of sodium hydride (5.76 g, 0.24 mole) and dry tetrahydrofuran (50 ml) stirring at room temperature. After one hour, 1-bromo-2-ethyl hexane (33.8 g, 0.175 mole) was added dropwise over 15 minutes and the mixture stirred overnight at room temperature. The reaction mixture was cautiously added to iced water (100 g) under nitrogen and extracted with diethyl ether (3×100 ml). The combined organic phase was dried over magnesium sulphate, concentrated under reduced pressure and the residue distilled to give methyl 1-(2-ethylhexyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (5) as a pale yellow oil (b.pt 140-142°C./0.1 mm Hg).