Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[CH3:8][O:9][C:10](=[O:29])[CH:11]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20](N)[CH:19]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.ClC1C=CC=CC=1Cl>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:29])[CH:11]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:1])[CH:19]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: F[B-](F)(F)F
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(N)c1
Agent: N#[O+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of nitrosonium tetrafluoroborate (215 mg, 1.84 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated dropwise with a solution of 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (500 mg, 1.54 mmol) in a small amount of methylene chloride. The resulting reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then allowed to warm to 25° C. and was treated with 1,2-dichlorobenzene (6 mL). The resulting reaction mixture was heated at 100° C. for 1 h, during which time, the methylene chloride was distilled off. After 1 h at 100° C., the reaction mixture was allowed to cool to 25° C. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate to elute 1,2-dichlorobenzene then 2/1 hexanes/ethyl acetate) to afford impure 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester as a yellow oil. Repurification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded pure 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester (214 mg, 42%) as a pale yellow oil which solidified upon sitting at 25° C. to a pale yellow solid: mp 66-68° C.; EI-HRMS m/e calcd for C16H21FO4S (M+) 328.1144, found 328.1148.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C[CH2:25][N:26](C(C)C)C(C)C.N#CBr>CN(C=O)C.O>[C:25]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)#[N:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Agent: N#CBr
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C#N)C4)cc2)C(=O)O1
Temperature: 100 °C
Yield: 25.8 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (0.2 g, 0.57 mmol) in DMF (5 mL) were added DIPEA (0.3 mL, 1.7 mmol) and cyanogen bromide (0.18 g, 1.1 mmol) at r.t. The reaction mixture was stirred at 100° C. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 0.2:9.8 MeOH:CHCl3) to provide the title compound (0.05 g, 26%) as white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].C(O[CH:10](OCC)[N:11]([CH3:13])[CH3:12])C>>[CH3:10][N:11]([CH3:13])[CH:12]=[CH:4][C:3](=[O:5])[CH:2]([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)C
Reactant: CCOC(OCC)N(C)C
Product: CC(C)C(=O)C=CN(C)C
Yield: 80 %

Procedure:
3-Methylbutan-2-one (2.5 g, 1 eq.) and dimethylformamide diethylacetal (7.46 mL, 1.5 eq.) were heated at 100° C. for 4 days to give compound 232 as yellow viscous oil in 80% yield, which was used directly without further purification in the next step. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.94 (s, 3H), 0.95 (s, 3H), 2.52 (s, 1H), 2.74 (brs, 3H), 3.01 (brs, 3H), 4.96 (d, J=12.97 Hz, 1H), 7.45 (d, J=12.97 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:28]1[NH:29][CH2:30][CH2:31][N:32]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[NH:32]1[CH2:31][CH2:30][N:29]=[C:28]1[N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:20][CH2:21]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21
Reactant: CSC1=NCCN1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCN(C4=NCCN4)CC3)cccc21
Temperature: 50 °C

Procedure:
A solution of 1-(phenylsulfonyl)-4-piperzin-1-yl-1H-indole (71 mg, 0.18 mmol) in dioxane is treated with 2-methylthio-2-imidazoline hydroiodide (52.7 mg, 0.22 mmol) and N,N-diisopropylethylamine (62 μl, 0.36 mmol), heated at 50° C. for 16 hr., cooled and concentrated in vacuo to give a residue. The residue is purified by HPLC to give the title product, 15 mg, identified by HPLC and mass spectral analyses (2.57 min; 410 M+H) using the LCMS conditions described in Table I.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>ClCCl>[CH3:56][S:57]([O:39][C@H:36]1[CH2:37][CH2:38][C@@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[O:59])=[O:58]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](OS(C)(=O)=O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (250 mg) and triethylamine (240 μL) are dissolved in dichloromethane (2 mL), treated with methanesulfonyl chloride (40 μL) and stirred for 12 hours at room temperature. The mixture is partitioned between ethylacetate and water. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is used directly in the next step. LC (method 5): tR=1.19 min; Mass spectrum (ESI+): m/z=794 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]([CH3:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([F:21])[F:20])[CH:14]=3)[C:9](=[O:22])[C:8]([C:23](O)=[O:24])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][C:60]1[O:64][C:63]([CH2:65][NH2:66])=[N:62][N:61]=1>CN(C=O)C>[CH3:59][C:60]1[O:64][C:63]([CH2:65][NH:66][C:23]([C:8]2[C:9](=[O:22])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([F:20])[F:21])[CH:14]=3)=[C:11]([CH3:12])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:24])=[N:62][N:61]=1
Reactant: Cc1nnc(CN)o1
Reactant: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)O)cn1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(CNC(=O)c2cn(C3CCCC3)c(C)c(-c3cccc(C(F)F)c3)c2=O)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-cyclopentyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 9, 116 mg, 0.334 mmol), HBTU (140 mg, 0.369 mmol), DIPEA (116 μL, 0.668 mmol) in DMF (1 mL) is stirred for 15 min at room temperature. C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine (46 mg, 0.407 mmol) is added and the reaction mixture is stirred for 72 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 67 mg (45% of theory); ESI mass spectrum: [M+H]+=443; Retention time HPLC: 0.98 min (Z003_001).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8](=[O:24])[N:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:10]=1)=[O:5])C.O.O.[OH-].[Li+]>O1CCCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]2=[O:24])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)[nH]c2=O)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
tert-Butyl 4-(4-(ethoxycarbonyl)-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (400 mg, 1.179 mmol) was dissolved in tetrahydrofuran (10 mL). Water (10 mL) was added to the mixture followed by lithium hydroxide hydrate (180 mg, 4.29 mmol). Mixture was warmed to 70° C. and held with stirring for 16 hours. Mixture was cooled to room temperature. Reaction was quenched with 4.5 mL 1N hydrochloric acid. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 98% yield. MS (M−H)−=310.2.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][C@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]1[OH:42]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)N[C@H]2CCCC[C@@H]2O)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (1S,2S)-2-aminocyclohexanol, the title compound was obtained in 61% purity by HPLC. MS(ESI+): m/z=472.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([OH:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl>[OH:18][C:4]1([CH2:3][CH2:2][NH:1][C:27](=[O:28])[O:29][CH2:30][CH3:31])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:14][CH2:15][CH2:16][CH2:17]2
Reactant: CCOC(=O)Cl
Reactant: NCCC1(O)CCc2ccccc2C12CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCC1(O)CCc2ccccc2C12CCCC2
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of the product from Example 9 (1.05 g, 4.28 mmol) and triethylamine (0.44 g, 4.35 mmol) in 10 mL of CH2Cl2 was cooled to 0° C. and ethyl chloroformate (0.47 g, 4.33 mmol) in 5 mL CH2Cl2 was added dropwise. The reaction was warmed to room temperature and washed with water. The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 1:1 heptane/ethyl acetate) to give the title compound (1.33 g, 98%) as an oil.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C1(C)C=CC=CC=1>[I:1][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:5]([O:4][CH3:3])=[O:6])=[CH:10][CH:11]=1
Reactant: II
Reactant: COC(=O)COc1ccc(CCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(CCI)cc1
Reaction time: 1 h

Procedure:
5.5 g (21.6 mmol) of iodine are added to a solution of 4.16 g (19.6 mmol) of 2-(4-methoxycarbonylmethyloxyphenyl)-ethanol, 5.7 g (21.6 mmol) of triphenylphosphine and 1.84 g (29.3 mmol) of imidazole in 200 ml of toluene at room temperature, while stirring, and stirring is continued at room temperature for one hour. A precipitate separates out and is filtered off with suction and discarded. The mother liquor is concentrated to dryness under reduced pressure and the residue is heated with petroleum ether. The triphenyl oxide which has precipitated out is filtered off with suction and the mother liquor is concentrated to dryness again. A crude oil remains.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([NH:29][C:30](=[O:40])[C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37]CO)=[O:32])[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:1][CH2:37][CH2:36][CH2:35][CH2:34][NH:33][C:31](=[O:32])[C:30]([NH:29][CH2:25][CH2:26][CH2:27][CH3:28])=[O:40]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCNC(=O)C(=O)NCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCNC(=O)C(=O)NCCCCCBr
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of carbon tetrabromide (51 mg, 0.15 mmol) in CH2Cl2 (5 mL) was stirred into a 0° C. solution of triphenylphosphine (48 mg, 0.18 mmol) and N1-n-butyl-N2(5-hydroxypentyl)oxalamide (30 mg, 0.130 mmol) in dry CH2Cl2 (5 mL) under an argon atmosphere. After 2 h, the reaction mixture was washed with water (5 mL), brine (10 mL), dried over anhydrous Na2SO4, and all volatiles were removed under reduced pressure. The residue was purified by SiO2 column chromatography using EtOAc/hexane (1:4) to give compound the title compound (32 mg, 84%) as a colorless solid, mp 109-110° C. TLC: 50% EtOAc/hexanes, Rf˜0.50; 1H NMR (300 MHz) δ 7.55 (br s, NH, 1H), 7.50 (br s, —NH, 1H), 3.40 (t, J=6.0 Hz, 2H), 3.25-3.35 (m, 4H), 1.80-1.85 (m, 2H), 1.40-1.60 (m, 6H), 1.25-1.35 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz) δ 160.30, 160.15, 39.65, 33.65, 32.45, 31.40, 28.60, 25.60, 20.20, 13.90. HRMS calcd for C11H22BrN2O2 [M+1]+ 293.0865, found 293.0870.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:10][CH2:11][C:12](Br)=O.[Al+3].[Cl-].[Cl-].[Cl-].FC(F)(F)C(O)=O>C(Cl)Cl.C([SiH](CC)CC)C>[Br:10][CH2:11][CH2:12][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2
Reactant: O=C(Br)CBr
Reactant: c1ccc2c(c1)CCC2
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: BrCCc1ccc2c(c1)CCC2
Reaction time: 2 h

Procedure:
2 ml (0.016 mol) of indan in 33 ml of methylene chloride and 1.6 ml (0.019 mol) of bromoacetyl bromide are mixed at 0° C. 2.27 g (0.017 mol) of AlCl3 are slowly added and the medium is allowed to return to room temperature and stirred for 2 hours. The mixture is poured into water/ice and extracted with methylene chloride. The organic phase is dried, filtered and the solvent is evaporated off under reduced pressure. The crude reaction product is crystallized from hexane. A white solid is separated (m.p. 57.8-58.1° C.) corresponding to the acylation product. 1.67 g (7 mmol) of this product are dissolved in 3.9 ml of triethylsilane and 3.9 ml of trifluoroacetic acid and the medium is heated at 80° C. for two hours. The medium is poured into an ice/NaOH mixture and extracted with ethyl acetate. The title compound is obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)CCCCC.Cl>>[OH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:13](=[O:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC(=O)Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCC(=O)c1ccccc1O
Temperature: 120 °C

Procedure:
24 g (0.18 mole) of powdered aluminium trichloride were carefully added to 31 g (0.16 mole) of phenyl hexanoate and the mixture was slowly heated with occassional stirring to 120° C and was held there for 11/2 hours. The residue was ground into a powder and was poured into iced dilute hydrochloric acid with stirring. The mixture was extracted with ether and the ether extracts were washed with dilute sodium hydroxide solution, then with water, dried over magnesium sulfate and evaporated to dryness to obtain 14.2 g of (1-(2'-hydroxyphenyl)-hexan-1-one as a pale yellow oil. IR spectrum showed o-hydroxyphenylcarbonyl at 1650cm-1.
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C1COCC1>[N:1]1([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:25]4[NH:26][C:27]3=[O:28])=[CH:17][CH:18]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: Nc1cccnc1Nc1ccc(N2CCn3c2nc2ccccc23)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of N2-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]pyridine-2,3-diamine (20 mg) and 1,1′-carbonyldiimidazole (19 mg) in THF (5 mL) was stirred at ambient temperature overnight. After this time, the solids that formed were collected by filtration to afford 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 mg) as off-white crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[CH:12][C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]1.C([BH3-])#N.[Na+]>CO.CS(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:19][N:24]5[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]5)=[CH:21][CH:22]=4)=[CH:12][C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(-c2cc3cc(-c4ccccc4)ccc3o2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(-c5ccccc5)ccc4o3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
A mixture of 4-(5-phenylbenzofuran-2-yl)benzaldehyde (49 mg, 0.14 mmol) and azetidine-3-carboxylic acid (30 mg, 0.28 mmol) in MeOH (1 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (60 mg, 0.28 mmol) was added in two portions and the reaction mixture was stirred for 16 h. Concentration of the solvent under reduced pressure yielded a yellow solid that was dissolved in DMSO (3 mL) and filtered to give a yellow solution that was purified by HPLC to yield 3 mg of desired product [hS1P1 EC50=1200 nM]: 1H NMR (400 MHz, CD3OD) δ 8.03 (d, 2H), 7.84 (br s, 1H), 7.66-7.58 (m, 6H), 7.45 (t, 2H), 7.36-7.32 (m, 2H), 4.47 (s, 2H), 4.40-4.32 (m, 4H), 3.72 (m, 1H). MS (ESI) m/z: Calculated: 383.15; Observed: 383.9 (M++1).
Reaction SMILES: Cl.[CH2:2]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]([OH:24])=[O:23])[CH:19]=2)[NH:14]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].[CH3:27]I>C(O)(=O)C.O.C(O)C>[CH3:27][N:14]1[C:15]2[C:20](=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH2:21][CH:13]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CI
Reactant: CCCCCCCCCCCC1Cc2cc(C(=O)O)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCCCCCC1Cc2cc(C(=O)O)ccc2N1C

Procedure:
A mixture of (RS)-2-(n-undecyl)indoline-5-carboxylic acid hydrochloride (6.8 g), sodium hydroxide (6.8 g), water (25 ml), ethanol (75 ml) and methyl iodide (10 ml) was heated under reflux for 1 hour. Methyl iodide (5 ml) was added and the mixture was heated for 30 minutes, then poured into water and acidified with acetic acid. The product was collected and recrystallised from methanol to give (RS)-1-methyl-2-(n-undecyl)indoline-5-carboxylic acid (3.0 g), in the form of white needles, m.p. 102°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(O)(=O)C.C(#N)[CH:14]([CH2:16][C:17]#[N:18])O>C(O)C.C(Cl)Cl>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:14]1[CH2:16][C:17]#[N:18]
Reactant: N#CCC(O)C#N
Reactant: Nc1ccccc1O
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CCc1nc2ccccc2o1
Yield: 71.8 %

Procedure:
To a solution of 2-aminophenol (5.0 g, 45.8 mmol) dissolved in 115 mL of anhydrous ethanol and 8 mL of glacial acetic acid was added malonitrile (9.08 g, 140 mmol) at 100° C. The resulting homogeneous solution was refluxed for 24 hours and the solvent was removed in vacuo to yield a red/brown oil. The oil was diluted with CH2Cl2 (100 mL) and any remaining solids were then removed by filtration. The mother liquor was washed twice with a saturated sodium bicarbonate solution and twice with water, dried over magnesium sulfate, filtered and evaporated to yield 5.2 g (71%) of the product as a yellow oil. This material was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:24]=[N:25][C:26](SC)=[N:27][CH:28]=3)[CH2:13][CH2:12]2)=[O:10])[N:3]=1.O[O:32][S:33]([O-:35])=O.[K+].[CH2:37]1COCC1>O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:24]=[N:25][C:26]([S:33]([CH3:37])(=[O:35])=[O:32])=[N:27][CH:28]=3)[CH2:13][CH2:12]2)=[O:10])[N:3]=1
Reactant: CSc1ncc(-c2ccccc2N2CCN(C(=O)Cn3nc(C)cc3C)CC2)cn1
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3-c3cnc(S(C)(=O)=O)nc3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(3,5-dimethyl-pyrazol-1-yl)-1-{4-[2-(2-methylsulfanyl-pyrimidin-5-yl)-phenyl]-piperazin-1-yl}-ethanone (210 mg, 0.497 mmol) in THF (5 mL) is added a solution of oxone (611 mg, 0.994 mmol) in water (5 mL). The mixture is allowed to stir at room temperature for 4 h. Water (10 mL) is added and the mixture is extracted with EtOAc 3×. The organic extracts are washed with water, brine, dried (Na2SO4) and concentrated. The residue is re-dissolved in dichloromethane (3 mL) and loaded on a 10 g Biotage SNAP column and eluted with 100% EtOAc to provide 2-(3,5-dimethyl-pyrazol-1-yl)-1-{4-[2-(2-methanesulfonyl-pyrimidin-5-yl)-phenyl]-piperazin-1-yl}-ethanone (102 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:19]=[CH:18][C:16]([NH2:17])=[N:15][C:13]1=[O:14]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:17][C:16]1[CH:18]=[CH:19][NH:12][C:13](=[O:14])[N:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Over a period of about 1 h, benzyloxycarbonyl chloride (52 mL, 0.36 mol) was added dropwise to a suspension of cytosine (8, 20 g, 0.18 mol) in dry pyridine (1000 mL) at 0° C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 mL) and 4N hydrochloric acid were added to reach pH~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The moist precipitate was refluxed with absolute ethanol (500 mL) for 10 minutes, cooled to 0° C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250° C. Anal. for C12H11N3O3. Found(calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.