Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[O:14][CH2:13][CH2:12][O:11]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OCCO
Reactant: O=Cc1ccc2sccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2cc(C3OCCO3)ccc2s1
Reaction time: 7 h

Procedure:
16.5 g of 1-benzothiophene-5-carbaldehyde and 49.5 mL of ethylene glycol were dissolved in 165 mL of toluene, to which 0.30 g of para-toluenesulfonic acid monohydrate was added, and this solution was stirred for 7 hours while heating it under reflux. The reaction mixture was cooled to room temperature, to which an aqueous solution of sodium hydroxide was added, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to yield 15.8 g of 2-(1-benzothiophen-5-yl)-1,3-dioxolane as yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[S-:12][C:13]#[N:14].[K+]>Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([NH2:14])=[S:12])=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Product: NC(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
4-Trifluoromethylaniline (2.00 g; 12.4 mmol) and potassium thiocyanate (4.82 g; 49.7 mmol) was suspended in 1N aqueous HCl (20 ml). A clear solution was obtained upon heating to reflux (after 1 hour, a precipitate started to form). The mixture was refluxed overnight, then cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with brine and dried with anhydrous sodium sulphate. Solvent was removed, and the residual oil was striped twice from acetonitril, to give a quantitative yield of (4-trifluoromethylphenyl)thiourea.
Reaction SMILES: [CH:1]1([C:6]([OH:19])([CH2:9][C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=O>C(N(CC)CC)C>[CH:1]1([C:6]([OH:19])([CH2:9][C:10]([CH3:11])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:18])[CH:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(CC(O)(CO)C1CCCC1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(CC(O)(C=O)C1CCCC1)c1ccccc1

Procedure:
185 mg of 2-cyclopentyl-4-methyl-4-phenyl-1,2-pentanediol is converted with 438 mg of pyridine-sulfur trioxide complex, 2.5 ml of DMSO and 0.5 ml of triethylamine into 160 mg of aldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@H](CO)[C@H](O)C1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
(3R,4R)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (2.50 g), triphenylphosphine (5.74 g) and benzoic acid (2.55 g) were dissolved in tetrahydrofuran (60 mL). While this solution was chilled in a salt/ice bath, diethyl azodicarboxylate (40% toluene solution, 9.53 mL) was added dropwise. The mixture was stirred at 0° C. or below for 1 hour and then at room temperature for 2 hours and was subsequently concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1). The eluted pale brown tar-like material was dissolved in ethanol (60 mL). To this solution, potassium carbonate (4.07 g) in water (30 mL) was added and the mixture was refluxed for 3 hours while being stirred. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (200 mL). This solution was washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: methanol=10:1) to give (3R,4S)-[1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol as a milky white syrup (2.04 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH:22]=[CH:23][CH3:24])=[CH:17][CH:16]=1)(=[O:9])[CH3:8].CC(O)[C:28]#[N:29]>CO>[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH2:22][CH:23]([C:28]#[N:29])[CH3:24])=[CH:17][CH:16]=1)(=[O:9])[CH3:8]
Reactant: CC=CC(=O)c1ccc(CCCCNC(C)=O)cc1
Reactant: CC(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCCCCc1ccc(C(=O)CC(C)C#N)cc1
Yield: 79.9 %

Procedure:
1.1 ml of a 10% sodium carbonate aqueous solution was added to 15 ml of a methanol solution containing 510 mg of 4-[4-(acetylamino)butyl]-1-(2-butenoyl)benzene and 1.69 g of acetocyanhydrin, and the mixture was refluxed under heating for 2 hours. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol (40:1)) to obtain 450 mg of 4-[4-(acetylamino)butyl]-1-(3-cyanobutanoyl)benzene.
Reaction SMILES: [C:1]([NH:11][C:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([NH:11][C:12]1([CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:13][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1(CO)CC1)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-CBZ-amino-1-(hydroxymethyl)cyclopropane (similarly prepared according to JMC 31, 2004, 1998) (250 mg) was dissolved into DCM (25 ml) with DIPEA (250 l) and stirred at 0° C. for 15 minutes. To the reaction was added MsCl (1.1 eq) and stirred for 30 minutes. The reaction was washed with NaHCO3 solution, water, brine and dried with Na2SO4. The solution was evaporated to give N-CBZ-amino-1-(methylsulfonyloxymethyl)cyclopropane as an off white solid. This solid was mixed with above 6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and Cs2CO3 (250 mg) in DMA (4 ml). The reaction was heated at 100° C. for 10 hours and mixed with EtOAc and water, then filtered, further extracted with EtOAc. The combined organic layer was evaporated and purified with silica gel column to give the titled product. Mass: (M+1), 578
Reaction SMILES: [F:1][C:2]1[C:3](O)=[N:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(Cc2ccc(F)cc2)ncc1F
Product: Fc1ccc(Cc2ncc(F)c(Cl)n2)cc1
Yield: 90 %

Procedure:
A mixture of 1.93 g (8.7 mmol) of 5-fluoro-2-(4-fluorobenzyl)-4-hydroxypyrimidine, from Step 1, and 15 mL of phosphorus oxychloride was heated in an oil bath at 90° C. for 1.5 hours and then concentrated in vacuo. The residue was triturated with 75 mL of ice water and the aqueous mixture was adjusted to pH 8-9 by the addition of solid sodium bicarbonate. The mixture was extracted with 3 X 70 mL of methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a light brown residue. The residue was purified by flash chromatography on a 230-400 mesh silica gel column (4.8 X 14.6 cm) eluted with hexane:methylene chloride (1:1 v/v) to afford 1.94 g (90% yield) of the title compound; MS DCI-NH3M/Z: 241 (M+H)+ ; 1H NMR (CDCl3) d 4.22 (s, 2H), 7.00 (m, 2H), 7.30 (m, 2H), 8.48 (s, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[CH2:43][CH2:42][C:20]2[N:21]([CH2:29][CH:30](OS(C)(=O)=O)[C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=3[C:19]=2[CH2:18]1>CN(C=O)C.O>[CH3:16][N:17]1[CH2:43][CH2:42][C:20]2[N:21]([CH2:29][CH:30]([O:8][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=3[C:19]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: O=C(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)c2ccncc2)c2ccncc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of isonicotinic acid (200 mg, 1.626 mmol) in DMF (10 mL) was added potassium carbonate (560 mg, 4.065 mmol) and stirred the solution at 80° C. for 30 min. Methanesulfonic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl ester (455 mg, 1.138 mmol) was added portionwise into the reaction mixture, which was stirred at 80° C. 30 min. The progress of reaction was monitored by LCMS and TLC. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (4×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield isonicotinic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (30 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.79 (d, 2H), 8.58 (d, 2H), 7.77 (d, 2H), 7.23 (d, 1H), 7.18 (s 1H), 7.12 (d, 2H), 7.0 (d, 1H), 6.24 (t, 1H), 4.54 (dd, 1H), 4.35 (dd, 1H), 3.68 (s, 2H), 2.76 (t, 2H), 2.61 (m, 1H), 2.51 (s, 3H), 2.43 (s, 3H), 2.43 (m, 1H). Separation by chiral HPLC provided enantiomers 147a and 147b.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:4]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:26]([NH:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=3)=[O:27])=[CH:12][CH:11]=2)[CH:4]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CSc1cc(Oc2ccc(N)cc2)ncn1
Solvent: C1CCOC1
Product: CSc1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of 4-(6-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine (1.3 g, 5.5 mmol) in THF (24 ml) is cooled to 0° C. A solution of 3-(trifluoromethyl)phenyl isocyanate (790 μl, 5.5 mmol) in THF (24 ml) is added and stirring is continued overnight at r.t. The solvent is evaporated and the crude product is purified by silica gel chromatography using an ethyl acetate/heptane eluent (1:1) to give 1.76 g (75%) of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C:9](=[O:11])[CH2:8][CH2:7][C@@H:6]1[C:12]([OH:14])=O)=[O:4].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[C:53]1([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)C(C)C)(C)C>>[O:11]=[C:9]1[CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:12]([N:62]2[CH2:63][CH2:64][N:59]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:60][CH2:61]2)=[O:14])[CH2:7][CH2:8]1
Reactant: COC(=O)[C@H]1CC(=O)CC[C@@H]1C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CC(=O)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.5 %

Procedure:
To a stirred solution of (1S,2S)-2-(methoxycarbonyl)-4-oxocyclohexanecarboxylic acid (1.014 g, 0.005065 mol) in anhydrous N,N-dimethylformamide (20.0 mL, 0.258 mol) at rt was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.989 g, 0.005572 mol), 1-phenylpiperazine (1.17 mL, 0.00760 mol), followed by N,N-diisopropylethylamine (2.66 mL, 0.0152 mol). The reaction mixture was stirred at rt for 15 h. The reaction was quenched with water (40 mL), extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 40-70% EtOAc/Hex. to give the product as a colorless solid (1.299 g, 74% in yield). MS (ESI): (M+H)+=345.1.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1.Br[CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:32]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=3)=[CH:12][N:11]=2)=[C:2]([F:1])[C:7]=1[F:8])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Reactant: CCCCBr
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCC)c(F)c3F)nc2)cn1
Yield: 69 %

Procedure:
The etherification of 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine using 2.7 mmol of 1-bromobutane is carried out analogously to the procedure indicated for Example 3. Corresponding purification gives 0.76 g (69%) of colorless crystals, X 85 SC 156 SA 180 I.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1.C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)C(=O)N(CC2CCCO2)c2cc([N+](=O)[O-])c(N)cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated using 2-bromomethyl-tetrahydro-furan (1.7 ml; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 30° C. for 3 days. After aqueous work-up the crude material is de-acetylated in MeOH (150 ml) using DBU (2,3 ml) at reflux. After aqueous work-up and purification by RP chromatography 5-amino-3,3-dimethyl-6-nitro-1-(tetrahydro-furan-2-ylmethyl)-1,3-dihydro-indol-2-one (1.88 g) is obtained.
Reaction SMILES: [CH:1]1([O:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:31][CH2:32][N:33]([C:12](=[O:14])[CH2:11][NH:10][C:8](=[O:9])[O:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:34][CH2:35]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)OC1CCCCC1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)OC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
86.1 mg (0.428 mmol) of {[(cyclohexyloxy)carbonyl]amino}acetic acid, 176 mg (0.642 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine and 98.5 mg (0.514 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were suspended in 10 ml of dichloromethane. 0.086 ml (0.617 mmol) of triethylamine was added to the obtained suspension, and they were stirred at room temperature for 3 hours. The resultant mixture was concentrated under reduced pressure and then ethyl acetate was added to the residue. The resultant mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by the silica gel chromatography (hexane:ethyl acetate=95:5 to 1:4) to obtain the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19]>CN(C=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([O:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[N:9][CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Potassium t-butoxide was added to a DMF solution of 2,5-dibromopyridine and 2-(dimethylamino)ethanol, and the whole was stirred at an oil bath temperature of 100° C. for 3 hours to obtain N-{2-[(5-bromopyridin-2-yl)oxy]ethyl}—N,N-dimethylamine, which was further treated in a similar manner to Reference Examples 11 and 12 to obtain an objective compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[F:23])[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>>[Br:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[F:23])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 4 (2.15 g, 5.3 mmol) and N-methyl-2-pyrrolidine (15 mL). After cooling to 0 C, a solution of N-bromo succinimide (1.03 g, 5.8 mmol) in 10 mL of N-methyl-2-pyrrolidine was added over 15 minutes. After 15 additional minutes, the reaction mixture was warmed to room temperature and was stirred for 1 hour. The mixture was then poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The residue was triturated with acetonitrile and filtered to give the title compound as a white powder (1.5 g, 59%). 1H NMR (400 MHz, CD3OD) δ 8.00 (dd, J=2.0 and 8.4 Hz, 1H), 7.95 (dd, J=1.7 and 10 Hz, 1H), 7.64 (q, J=8.8 and 14.4 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.66 (s, 1H), 5.36 (s, 2H), 3.95 (s, 3H), 2.01 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.50 (1F), −115.97 (1F), −123.01 (1F) ppm. ES-HRMS m/z 484.0169 (M+H calcd for C21H16BrF3NO4 requires 484.0192).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]([CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9][CH2:10][CH2:11][C:12]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:13])=[O:7])=[CH:29][CH:30]=1
Reactant: O=C(O)CCCN(C(=O)c1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-[(1,2-diphenylethyl)amino]butyric acid and ethyl 3-aminopropionate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-(1,2-diphenylethylamino)butyryl]-3-aminopropionic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=2[OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1O
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1c(-c2ccnc(Cl)n2)cccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A vial was charged with 2,4-dichloropyrimidine (362 mg, 2.43 mmol), 2-hydroxy-3-trifluoromethylphenylboronic acid (250 mg, 1.21 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (42.6 mg, 0.061 mmol). Acetonitrile (6 mL) and sodium carbonate (3.0 mL, 1.0 M aqueous, 3.0 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 6 h, then was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 275.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 13.43 (s, 1H), 8.74 (d, J=5.5 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.76 (app d, J=5.5 Hz, 2H), 7.06 (t, J=8.0 Hz, 1H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCSCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a solution of 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (599 g, 2.50 mmol) (obtained as described in Reference Example 25(2)) in methylene chloride (30 ml) were added methanesulfonyl chloride (0.49 ml, 6.30 mmol) and triethylamine (0.88 ml, 6.30 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 40 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate as the eluant to afford 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (709 mg, yield 93%) as a pale yellow solid.