Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3](=O)/[CH:4]=[C:5](\O)/[C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:9][CH:10]=1.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[NH:34][NH2:35].C(O)(=O)C>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[N:34]1[C:5]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)=[CH:9][CH:10]=2)=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[N:35]1
Reactant: NNc1cc(Cl)ccc1Cl
Reactant: CS(=O)(=O)c1cccc(-c2ccc(/C(O)=C/C(=O)C(F)(F)F)s2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cc(Cl)ccc3Cl)s2)c1
Temperature: 102.5 °C
Reaction time: 3 h

Procedure:
Into an 8 mL vial was weighed 202.7 mg (539 μmol) of (Z)-1,1,1-trifluoro-4-hydroxy-4-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)but-3-en-2-one, 117.4 mg (550 μmol) of 2,5-dichlorophenylhydrazine hydrochloride, 3 mL of acetic acid, and 1 mL of DMF. The resulting reaction was stirred at 100-105° C. for 3 h then was concentrated to dryness in vacuo. The residue was purified by silica gel flash chromatography (3×23 cm, 1:1 ethyl acetate-hexanes) and was dried affording the product as a faintly yellow solid, yield: 89 mg (55%). 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.87 (d, J=9 Hz, 1H), 7.75 (d, J=9 Hz, 1H), 7.6 (m, 2H), 7.5 (m, 2H), 7.27 (d, J=4 Hz, 1H), 6.90 (s, 1H), 6.87 (d, J=4 Hz, 1H), 3.09 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]>O1CCCC1.C(O)(=O)C.O>[F:1][C:2]([F:30])([F:31])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][OH:22])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CC(C)(C)[Si](C)(C)OCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCO)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.9 %

Procedure:
The 9-[2-(Tert-butyldimethylsilanyloxy)ethyl]-9H-fluoren-9-carboxylic acid (2,2,2-trifluoroethyl)amide (6.00 g) obtained in Example 6c) was dissolved in tetrahydrofuran (13 mL)—acetic acid (39 mL)—water (13 mL). The solution was stirred at room temperature for 20 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate:hexane=1:1 to give the title compound (3.80 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:39])([F:38])[S:22]([O:25][C:26]1[C:35]([CH2:36]O)=[CH:34][C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH:27]=1)(=[O:24])=[O:23].C(Br)(Br)(Br)[Br:41]>C(Cl)Cl>[F:20][C:21]([F:39])([F:38])[S:22]([O:25][C:26]1[C:35]([CH2:36][Br:41])=[CH:34][C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH:27]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Oc1cc2c(cc1CO)CCCC2)C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(Oc1cc2c(cc1CBr)CCCC2)C(F)(F)F

Procedure:
Triphenylphosphine (46.8 mg, 0.178 mmol) was added to a stirred solution of 3-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (46.1 mg, 0.149 mmol) and carbon tetrabromide (59.2 mg, 0.178 mmol) in dry CH2Cl2 (1 mL) at 0° C. under N2. The reaction mixture was loaded directly onto a column and purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford 3-(bromomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate, as a colorless solid. Rf=0.95 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.21 (s, 1H); 7.01 (s, 1H); 4.48 (s, 2H); 2.81-2.74 (m, 4H); 1.83-1.78 (m, 4H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>CN(C=O)C>[CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:22][CH2:23][N:24]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH2:25][CH2:26]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCNCC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Solvent: CN(C)C=O
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCN(CC(F)(F)F)CC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one: 3.78 (94 mg, 0.19 mmol) in DMF was added TEA (117 mg, 1.1 mmol), then followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (45 mg, 0.19 mmol). Reaction mixture was stirred at r.t. overnight, and LC-MS showed reaction was complete. The reaction mixture was filtered and purified by prep HPLC (MeCN:water gradient, TFA modified) to provide 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(2,2,2-trifluoroethyl)spiro[indoline-3,4′-piperidin]-2-one: 3.80 as its TFA salt.
Reaction SMILES: C[Si](C)(C)[N-:3][Si](C)(C)C.[K+].[C:11]1(C)C=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:18](S([O-])(=O)=O)([CH3:20])[CH3:19]>O1CCCC1>[NH:3]1[C:15]2[C:20](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:18]=[CH:19]1
Reactant: CC(C)S(=O)(=O)[O-]
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of potassium N,N-bis(trimethylsilyl)amide in toluene (0.50 M, 24.7 mL, 12.3 mmol, 1.1 equiv) was added dropwise via syringe to a stirred solution of the enone 5 (4.24 g, 11.2 mmol, 1 equiv, dried by azeotropic distillation with toluene, 3 mL) in tetrahydrofuran (31.3 mL) at −78° C. and the reaction solution was stirred at −78° C. for 30 min. A solution of the isopropyl sulfonate ester 6 (4.99 g, 16.2 mmol, 1.45 equiv, prepared immediately prior to use, dried by azeotropic distillation with toluene, 3 mL) in tetrahydrofuran (3.0 mL) was then added dropwise via cannula to the cold reaction solution. The flask containing the sulfonate ester 6 was rinsed with two 3.0-mL portions of tetrahydrofuran, which were transferred to the reaction flask via cannula. Upon completion of the addition, the reaction flask was immersed in a −35° C. bath and the reaction solution was stirred at this temperature 30 h. The product solution was then partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium chloride solution (100 ml). The washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography on silica gel (deactivated with 10% triethylamine-ethyl acetate, eluting with 10% ethyl ether-hexanes initially, grading to 20% ethyl ether-hexanes, 5%-steps) to furnish the alkylation product 7 as a white foam (4.37 g, 70%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[N:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4cnc5ccccc5n4)cc3CC[C@@H]12
Yield: 55.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloroquinoxaline (76 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 82 mg (55%) of the title compound as an amorphous foam. FDMS: m/e=389. α[D]589 =+68.96 (c=0.81, chloroform).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>CN(C)C=O.ClCCl>[F:37][C:25]([F:24])([F:36])[C:26]1[CH:27]=[C:28]([S:32]([NH:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]3[CH2:3]2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](N)C[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (7S,8aS)-tert-butyl 7-aminohexahydropyrrolo[1,2-a]-pyrazine-2(1H)-carboxylate (0.22 g, 0.92 mmol) in dimethylformamide/dichloromethane (1:5, 5 mL) was added sodium carbonate (0.166 g, 1.56 mmol) and 3-(trifluoromethyl)-benzene-1-sulfonyl chloride (0.315 g, 1.29 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (m, 1H), 1.38 (s, 9H), 1.40 (m, 2H), 1.70 (m, 1H), 1.84 (m, 1H), 2.00 (m, 1H), 2.18 (m, 1H), 2.64 (m, 1H), 2.79 (m, 1H), 3.70 (m, 1H), 3.80-3.95 (m, 2H), 7.83 (m, 1H), 8.05 (m, 1H), 8.11 (m, 2H), 8.15 (m, 1H); MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:33]=[CH:32][C:11]([O:12][C:13]2[C:14]([C:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]=3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1.C(Cl)[Cl:35].[ClH:37]>O1CCOCC1>[ClH:35].[ClH:37].[NH:22]1[CH2:21][CH2:20][CH:19]([C:14]2[C:13]([O:12][C:11]3[CH:32]=[CH:33][C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:9][CH:10]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Nc2ccc(Oc3nccnc3C3CCNCC3)cc2)nc1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.2 g, 11.67 mmol) and DCM (100 mL) was added 4M HCl in dioxane (12 mL, 48.0 mmol). After 4 hours, another 5 mL of 4M HCl in dioxane was added. After a further 16 hours, the precipitates had clung to the walls of the flask and the clear stirring solution was decanted away. The precipitates were washed with another 50 mL of DCM and the solution again decanted away. The flask was placed under vacuum for 30 minutes to give N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine dihydrochloride as a hydroscopic yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29]([OH:31])=O)(=[O:12])=[O:11].[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[N:33]1([CH2:38][CH2:39][NH:40][C:29]([C:28]2[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=2/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=3)=[O:31])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Reactant: NCCN1CCCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1

Procedure:
2-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid was coupled with 2-pyrrolidin-1-yl-ethylamine to give the titled compound.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH2:10]1)C1C=CC=CC=1.[ClH:25].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:25].[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:11]2[CH2:12][CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10]2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(C2CCCC(NCc3ccccc3)C2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCCC(N)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Benzyl-N-[3-(3,4-dimethoxyphenyl)cyclohexyl]amine (3.16 g) was dissolved in ethyl acetate, 4 N HCl-ethyl acetate solution was added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the solvent under reduced pressure, it was dissolved in acetic acid (100 ml), and 10% palladium-carbon (640 mg) was added thereto. After substituting the reaction vessel with hydrogen gas, hydrogen addition was effected for 3 hours at normal pressure, at 80° C. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to produce crude crystals which were then washed with diethyl ether to give 2.80 g of 3-(3,4-dimethoxyphenyl)cyclohexylamine hydrochloride (quantitative yield).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[CH:41]1[CH2:46][CH2:45][CH2:44][O:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:41]4[CH2:46][CH2:45][CH2:44][O:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCCOC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCCOC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.057 g, 18%).
Reaction SMILES: C(N[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)C.[CH2:30]([O:32]C1N=C(C(O)=O)C=C(C)N=1)[CH3:31]>>[CH2:30]([O:32][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:31]
Reactant: CCOc1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Product: CCOc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{4-[5-(2-Ethoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-ethoxy-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.81 min*; [M+H]+=401.07.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1[C:35]2[NH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C([N:38]1[C:50]2[CH:49]=[CH:48][C:47](Br)=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[C:42](Br)[CH:43]=2)C>>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([N:34]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:35]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([N:38]1[C:50]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[C:44]3[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2Cc1ccccc1
Product: c1ccc(Cn2c3ccc(-n4c5ccccc5c5ccccc54)cc3c3cc(-n4c5ccccc5c5ccccc54)ccc32)cc1
Yield: 70 %

Procedure:
The obtained N-benzyl-3,6-dibromocarbazole was allowed to couple with carbazole in the same manner as described in synthesis of N-ethyl-3,6-dibromocarbazole (Embodiment 1) to give N-benzyl-3,6-di(N-carbazolyl)carbazole. The yield was 70%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([CH:15]1[CH2:17][O:16]1)([CH3:14])([CH3:13])[CH3:12]>>[CH3:12][C:11]([CH3:14])([CH3:13])[CH:15]([OH:16])[CH2:17][O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8]
Reactant: CC(C)(C)C1CO1
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Product: CC(C)(C)C(O)COc1c(Cl)nc(Cl)nc1Cl
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of 2,4,6-trichloro-pyrimidin-5-ol (400 mg, 2.01 mmol) and 2-tert-butyl oxirane (3 mL) was heated at 100° C. for 3 hours before being cooled and concentrated in vacuo. The resultant residue was triturated in hot methanol and the insoluble material removed. The filtrate was concentrated in vacuo and the resultant residue was purified by column chromatography (SiO2, 0-15% ethyl acetate in cyclohexane) to give 3,3-Dimethyl-1-(2,4,6-trichloro-pyrimidin-5-yloxy)-butan-2-ol as a white solid (275 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 4.28 (1H, dd, J=9.38, 2.19 Hz), 4.00 (1H, t, J=9.19 Hz), 3.76-3.69 (1H, m), 2.53 (1H, d, J=3.48 Hz), 0.95 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=O)[CH:21]=[CH:22][O:23][C:24]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.[Pt]=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(=O)ccoc4c3O2)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1

Procedure:
[(2R)-7-Oxo-2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-2-yl]methyl 4-methylbenzenesulfonate (1.0 g, 2.6 mmole) dissolved in acetic acid (50 mL) was hydrogenated at 40 psi in the presence of 0.30 g platinum oxide on a Parr shaker for 5 hours. The catalyst was filtered through celite and the filter cake washed with water. The filtrate was then extracted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate until neutral. The organic extracts were dried over magnesium sulfate, filtered and evaporated to give 0.78 g (81%) of the (R)-enantiomer of the title compound as a clear oil. 1H (CDCl3) doublet 7.8 δ (2 H); doublet 7.4 δ (2 H); singlet 6.5 δ (1 H); singlet 6.4 δ (1 H); multiplet 4.2 δ (1 H); multiplet 4.1-4.3 δ (5 H); multiplet 4.0 δ (1 H); triplet 2.7 δ (2 H); singlet 2.4 δ (3 H); triplet 2.0 δ (2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].FC(F)(F)S(O[CH2:19][C:20]([F:23])([F:22])[CH3:21])(=O)=O.CCCCCCCCCCN>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:19][C:20]([F:23])([F:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(F)(F)COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CCCCCCCCCCN
Product: COC(=O)c1ccc(OCC(C)(F)F)c(Cl)c1
Yield: 54 %

Procedure:
The title compound is prepared in 54% yield (1.54 g, white solid) from methyl 3-chloro-4-hydroxybenzoate (2.00 g, 10.7 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.11 g, 26.8 mmol) in a similar manner to Step-1 of Amine-10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B(O)O)[CH:8]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[N:23]=3)=[CH:15][CH:14]=2)[CH:8]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: COc1cncc(B(O)O)c1
Product: COc1cncc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3-Methoxypyridine-5-boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 364.2 (M+1)
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@@:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31]C)=[O:30])([CH3:25])[CH2:23][OH:24])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@@:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])([CH3:25])[CH2:23][OH:24])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc([C@](C)(CO)NC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@](C)(CO)c1cccc(C(=O)O)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a mixture of 86 mg of methyl 3-[(2R)-2-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-1-hydroxypropan-2-yl]benzoate, 1.9 ml of methanol, and 1.9 ml of THF was added 0.36 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 40° C. for 16 hours. The reaction mixture was left to be cooled to room temperature and 1 M hydrochloric acid was then added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 52 mg of 3-[(2R)-2-({ [8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-1-hydroxypropan-2-yl]benzoic acid.