Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(F)cc1
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
2.36 g of 5-(4-fluorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.34 g of 3-chloro-5-(4-fluorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xviii) of the present invention).
Reaction SMILES: [OH-].[Na+].C(O)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33](=[O:51])[N:34]([CH2:38][CH2:39][N:40]4[CH2:45][CH2:44][CH:43]([C:46]([O:48]CC)=[O:47])[CH2:42][CH2:41]4)[CH:35]=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)=[O:25])=[O:15])=[N:11][CH:12]=1.Cl>O.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[C:33](=[O:51])[N:34]([CH2:38][CH2:39][N:40]4[CH2:41][CH2:42][CH:43]([C:46]([OH:48])=[O:47])[CH2:44][CH2:45]4)[CH:35]=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)=[O:25])=[O:15])=[N:11][CH:12]=1
Reactant: CCOC(=O)C1CCN(CCn2cccc(-c3ccc(C(=O)Nc4c(O)cccc4C(=O)Nc4ccc(Cl)cn4)cc3)c2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2cccn(CCN3CCC(C(=O)O)CC3)c2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88.6 %

Procedure:
An aqueous 1 M sodium hydroxide solution (3.0 ml) was added to an ethanol (5 ml)-tetrahydrofuran (5 ml) solution of ethyl 1-{2-[3-(4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}-6-hydroxyphenyl)amino]carbonyl}phenyl)-2-oxopyridin-1(2H)-yl]ethyl}piperidine-4-carboxylate (392 mg), followed by stirring at room temperature for 19 hours. 1 M hydrochloric acid (3.0 ml) and water (50 ml) were added to the reaction mixture, followed by extraction with chloroform-isopropanol. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1-{2-[3-(4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}-6-hydroxyphenyl)amino]carbonyl}phenyl)-2-oxopyridin-1(2H)-yl]ethyl}piperidine-4-carboxylic acid (332 mg) as a pale yellow solid.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:8]1[CH:9]=[C:10]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[H-].[Na+]>CN(C)C=O>[CH:1]1([C:12]2[CH:11]=[C:10]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:9]=[CH:8][C:13]=2[O:14][CH3:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc2c(c1)ncn2-c1ccc(OC)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccc(OC)c(C2CCCC2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of (800 mg, 5.3 mmoles) cyclopentyl bromide, (1.6 g, 5.3 mmoles) methyl 1-(3-hydroxy-4-methoxyphenyl)-1H-benzimidazole-5-carboxylate and 251 mg of 50% sodium hydride in 10 ml of dimethylformamide was stirred at 100° C. for 30 minutes. The reaction was cooled, poured onto H2O and extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give 2 g of crude product. Purification on silica gel with CH2Cl2 gave 1.1 g of methyl 1-(3-cyclopentyl-4-methoxyphenyl)-1H-benzimidazole-5-carboxylate. M.P.: 129°-131°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][CH2:26][CH2:27][C:28](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.C(OCC)C.CCOC(C)=O>[CH3:24][O:25][CH2:26][CH2:27][C:28]1[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1
Reactant: COCCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 15 h
Yield: 151.6 %

Procedure:
To the product of example 1 step (iii) (1.9 g) in NMP (25 mL), 3-methoxypropanoic acid (0.678 mL, 7.21 mmol) was added followed by HATU (2.74 g) and TEA (0.837 mL) under nitrogen. The resulting solution was stirred at 60° C. for 15 h. The reaction mixture was diluted with diethyl ether (300 mL) and EtOAc (300 mL), and washed with water (300 mL), sat. NaHCO3 (200 mL), and saturated brine (200 mL). The organic was dried, filtered and evaporated to afford the subtitle product (3.5 g).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([F:33])[C:6]=1[F:34])[CH3:3].CC(C)([O-])C.[K+].[CH2:41]([O:45][C:46]1[CH:51]=[CH:50][C:49]([C@H:52]2[CH2:57][CH2:56][C@H:55]([CH:58]=O)[CH2:54][CH2:53]2)=[C:48]([F:60])[C:47]=1[F:61])[CH2:42]CC.O>C1COCC1>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12]/[CH:13]=[CH:58]/[C@H:55]2[CH2:54][CH2:53][C@H:52]([C:49]3[CH:50]=[CH:51][C:46]([O:45][CH2:41][CH3:42])=[C:47]([F:61])[C:48]=3[F:60])[CH2:57][CH2:56]2)=[C:7]([F:33])[C:6]=1[F:34])[CH3:3]
Reactant: CCCCOc1ccc([C@H]2CC[C@H](C=O)CC2)c(F)c1F
Reactant: CCOc1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(CC/C=C/[C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Well-dried 3-(4-ethoxy-2,3-difluorophenyl)propyl triphenylphosphonium bromide (s23) (6.6 g) was mixed with THF (100 ml) under an atmosphere of nitrogen, and the solution was cooled to −10° C. Potassium t-butoxide (t-BuOK; 1.4 g) was added in two portions in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., the compound (s25) (3.0 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was mixed with sodium benzenesulfonate dihydrate (6.1 g) and Solmix A-11 (100 ml). Then, 6N-hydrochloric acid (20 ml) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene (100 ml). The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (ethyl acetate:Solmix=1:4 by volume) to give (E)-1-ethoxy-2,3-difluoro-4-(4-(trans-4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl)but-3-en-1-yl)benzene (No. 82) (4.6 g). The yield based on the compound (s13) was 41.9%.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2.[C:19](O)(=[O:21])[CH3:20]>>[C:19]([O:16][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1)(=[O:21])[CH3:20]
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Reactant: CC(=O)O
Product: CCC(CCCCC1CCC2CC(OC(C)=O)CC12)OC

Procedure:
The procedure followed is the same as that described in -7- Example 24 substituting 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]-7-octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 4.0 mmoles), and glacial acetic acid (7 ml). The product is kugelrohred under reduced pressure leaving a clear, colorless oil (0.7 g, 2.5 mmoles).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([Cl:10])[CH:3]=1.[C:11]1(OB(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: OB(O)Oc1ccccc1
Reactant: OCc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCc1ccc(-c2ccccc2)cc1Cl
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a suspension of tetrakis(triphenylphosphine) palladium(0) (16 mg) in toluene (1 ml) was added 4bromo-2-chlorobenzyl alcohol (100 mg) at room temperature, and the mixture was stirred. After 10 min, to the reaction mixture were added a solution of phenylboric acid (83 mg) in ethanol (0.1 ml) and a 2M aqueous sodium carbonate solution (0.9 ml), and the mixture was refluxed under heating. After 1 hr, the reaction mixture was cooled, ethyl acetate was added, and the mixture was filtered through Celite. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated, and the residue was subjected to flash silica gel column chromatography (silica gel, 40 ml, eluent: hexane-ethyl acetate=3-1) to give crude crystals. The crystals were washed with hexane to give the objective compound (76 mg) as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14]O)[C@@H:11]([OH:12])[CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Li+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:39]([CH2:14][C@H:13]1[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([CH2:3][CH2:2][Cl:1])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10][C@@H:11]1[OH:12])=[N+:40]=[N-:41]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1CCCl
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.6 %

Procedure:
1.4 g of 5-(2-chloroethyl)-2'-deoxyuridine and 1.3 g of triphenylphosphine were dissolved in 20 ml of dimethylformamide and stirred while 1.2 g of lithium azide were added to give a solution within 5 minutes at room temperature. 1.7 g of carbon tetrabromide were added portionwise during 5 minutes to give a hazy orange colored solution which was stirred at room temperature for 17 hours. 5 ml of methanol were added to give a clear solution. After 0.5 hour, the solvents were removed by evaporation under an oil pump vacuum to give a gum which was partitioned between 30 ml of ethyl acetate and 20 ml of water. The white solid which formed was removed by filtration to give 0.64 g of crude product of melting point 179°-182° C. (decomposition). This crude product was stirred with methanol and then removed by filtration to give 0.48 g of pure 5'-azido-2',5'-dideoxy-5-(2-chloroethyl)-uridine of melting point 197°-199° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([CH:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH3:18])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:35](Cl)(Cl)=[O:36]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:35](=[O:36])[N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:17]([CH3:18])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2C(C)Nc2ccc(OC)cc2)cc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)N(c3ccc(OC)cc3)C(C)c3cnc(Cl)nc32)cc1

Procedure:
A solution of (±)-{2-chloro-5-[1-(4-methoxy-phenylamino)-ethyl]-pyrimidin-4-yl}-(4-methoxy-phenyl)-amine (49.4 mg; 0.13 mmol) (from Example 1f supra) in dichloromethane (1.5 mL) was cooled in an ice-water bath. To this solution was added triethylamine (0.18 mL; 1.29 mmol) (Aldrich), followed by phosgene solution (1.89 M, 0.34 mL; 0.64 mmol) (Fluka). After two hours in the cold, the reaction was diluted with additional dichloromethane and washed sequentially with water, dilute aqueous hydrochloric acid, dilute aqueous sodium bicarbonate, and brine. The organic layer was then dried over anhydrous sodium sulfate and concentrated. Residue was purified by flash chromatography (Biotage, 12M, 40:60 ethyl acetate-hexanes as solvent) to give (±)-7-chloro-1,3-bis-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 42.6 mg; 79.2%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3][C:4]1[CH:5]=[C:6]([CH2:22][C:23](O)=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>>[F:26][C:2]([F:1])([F:27])[S:3][C:4]1[CH:5]=[C:6]([CH2:22][C:23]([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(SC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Product: NS(=O)(=O)CC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(SC(F)(F)F)c1

Procedure:
In analogy to the procedure of Example XV, the title compound is prepared from 1.2 g (3.1 mmol) of the compound from Example XXVI, 0.38 g (4 mmol) of methanesulphonamide, 0.77 g (4 mmol) of N-ethyl-N'-dimethylaminopropyl-carbodiimide hydrochloride and 0.49 g (4 mmol) of dimethylaminopyridine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N:32]=[C:33]=[O:34].Cl>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2)=[O:34]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cc(C(F)(F)F)ccc4Cl)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-2-isocyanato-4-trifluoromethyl-benzene (0.15 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-(2-chloro-5-trifluoromethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (240 mg, 49%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=7.88 min (99%); mp. 240-242° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H, CHH), 2.39 (qd, J=4.3, 13.2 Hz, 1H, CH), 2.63 (br. s., 1H, CHH), 2.82-3.02 (m, 1H, CHH), 4.24-4.55 (m, 4H, C+C2), 5.12 (dd, J=5.0, 13.1 Hz, 1H, NCH), 7.30 (dd, J=1.6, 8.4 Hz, 1H, Ar), 7.47 (d, J=7.9 Hz, 1H, Ar), 7.55 (s, 1H, Ar), 7.69 (dd, J=8.0, 15.4 Hz, 2H, Ar), 7.78 (t, J=5.7 Hz, 1H, Ar), 8.49 (s, 1H, NH), 8.66 (s, 1H, NH), 10.99 (s, 1H, NH). 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.80, 47.13, 51.58, 116.19, 116.25, 118.54, 122.07, 123.06, 124.60, 125.64, 127.02, 127.90, 128.32, 130.23, 130.49, 137.51, 142.49, 143.95, 154.67, 167.89, 170.98, 172.85. LCMS MH=495; Anal Calcd for: C22H18ClF3N4O4+0.05 HCl: C, 53.20; H, 3.66; N, 7.49; Cl, 11.28. found: C, 53.08; H, 3.39; N, 7.64; Cl, 11.29.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)=[CH:13][CH:12]=1.C(OC1C=C(C(=O)C)C=CC=1)C1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:65][CH2:66][C:67]([N:69]1[CH2:74][CH2:73][CH:72]([O:75][C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([C:82]([F:85])([F:84])[F:83])[CH:77]=2)[CH2:71][CH2:70]1)=[O:68]>CN(C=O)C.O>[O:68]=[C:67]([N:69]1[CH2:70][CH2:71][CH:72]([O:75][C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([C:82]([F:85])([F:83])[F:84])[CH:77]=2)[CH2:73][CH2:74]1)[CH2:66][NH:65][C:22]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=2)[O:21][N:20]=1)=[O:24]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)on1
Agent: CC(=O)c1cccc(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccc(O)cc2)on1
Reaction time: 8 h
Yield: 51.4 %

Procedure:
DIPEA (133 mg, 1.03 mmol) was added to a stirred solution of 5-(4-hydroxy-phenyl)-isoxazole-3-carboxylic acid (61 mg, 0.294 mmol) (prepared by the method used for the synthesis of Intermediate 25, starting from 3′benzyloxyacetophenone) in DMF (2 mL) followed by HOBt (41.7 mg, 0.308 mmol) and EDCI.HCl (59 mg, 0.308 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (99 mg, 0.294 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from 110% EtOAc in hexane afforded 74 mg (51.3% Yield) of 5-(4-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 490, 90.53%. 1H NMR (300 MHz, DMSO-d6): δ10.2 (s, 1H), 8.6 (s, 1H), 7.78 (d, 2H), 7.5 (t, 1H), 7.3 (t, 3H), 7.16 (s, 1H), 6.9 (m, 2H), 4.7 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCCC1.N1CCCC1>C(O)C.C(O)(=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:1][C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: C1CCNC1
Product: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 79.4 %

Procedure:
3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.7 g of 5-chloro-2-oxindole and 2.7 g of piperidine (or 2.2 g of pyrrolidine) in 25 mL of ethanol was refluxed for 4 hours. Slow addition of acetic acid (8 mL) resulted in a precipitate. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed by refluxing in 30 mL of ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and dried under high vacuum to give 6.5 g (80% yield) 3-[2-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1-H-indol-3-yl]-propionic acid as an orange solid: mp 370-384° C.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[CH:19]1([NH:25][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Reactant: NC1CCCCC1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(O)(CNC2CCCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.98 g) was dissolved in acetonitrile (80 mL), and cyclohexylamine (800 mg) and lithium perchlorate (960 mg) were added. The mixture was stirred at 80° C. overnight, and cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using basic silica gel (15% ethyl acetate/hexane to 80% ethyl acetate/hexane) to give the object product (2.39 g, 96%).
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH2:14][S:13]2)=[CH:8][CH:7]=1.S(Cl)(Cl)(=O)=O>O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(c2ccc(F)cc2)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(F)cc2)c1O
Temperature: -11 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A chloroform (6.3 mL) solution of 2-(4-fluorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (0.63 g, 2.38 mmol, purity: 90%) was cooled to −12° C., and to this solution, a chloroform (1.3 mL) solution of sulfuryl chloride (0.23 mL, 1.2 equivalent amounts) was dropwise added over a period of 6 minutes, followed by stirring at −11° C. for 2 hours. The temperature of the solution was raised to 3° C., and water (1.3 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow solid (0.28 g, yield: 50%).