Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[N+:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][S:44](Cl)(=[O:46])=[O:45])([O-:36])=[O:35].N1C=CC=CC=1>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[S:44]([CH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N+:34]([O-:36])=[O:35])(=[O:45])=[O:46])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)Cc1ccccc1[N+](=O)[O-])[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reaction time: 2 h
Yield: 109.1 %

Procedure:
A solution of 0.689 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS) -pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 8 ml of dichloromethane was treated with 0.236 g of 2-nitro-α-toluenesulphonyl chloride and 0.152 ml of pyridine at room temperature and under a nitrogen atmosphere. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in ethyl acetate and washed in sequence with water, 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulphate. Evaporation and trituration of the residue with diethyl ether gave 0.72 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(2-nitrobenzylsulphonyl)valerohydrazide in the form of a white solid.
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:20][C@@H:21]3[O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(=O)CC>[CH3:33][N:31]([CH3:32])[C:30]([O:29][C@@H:21]1[C@@:22]2([CH3:23])[C:17](=[CH:16][CH:15]=[C:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])[CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:20]1)=[O:34]
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)Nc5ccccc5)C[C@H](OC(=O)N(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCC(C)=O
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)Nc5ccccc5)C[C@H](OC(=O)N(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 10 h
Yield: 55 %

Procedure:
In 10 ml of 2-butanone was dissolved 95 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxypregna-5,7-diene, followed by addition of 50 mg of pyridinium p-toluenesulfonate, and the mixture was stirred in an atmosphere of argon gas at a temperature of 50° C. for 10 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 45 mg of 1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties. 1H-NMR spectrum (90 MHz) δTMSCDCl 3: 0.66 (s, 3H), 1.02 (s, 3H), 1.15 (d, J=6.2 Hz, 3H), 2.78 & 2.81 (each s, 6H), 4.65-5.15 (2H), 5.36 (m, 1H), 5.70 (m, 1H), 6.80 (hr. s, 1H), 7.1-7.7 (5H), 9.60 (d, J= 3.5 Hz, 1H) IR spectrum (KBr): 1725, 1720, 1695 cm-1
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[C:8]1([C@@H:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1C=CCCC1
Solvent: O
Product: O=C1CCC[C@@H](c2ccccc2)C1
Yield: 80 %

Procedure:
Cyclohexenone (30 mg, 0.312 mmol), a rhodium complex of Rh(acac) (C2H4)2 (5.2 mg, 0.02 mmol), 50 mg of the polymer having the (R)-BINAP group (17) obtained in Preparation Example 1 and a phenylboronic acid (244 mg, 2.0 mmol) were reacted in 4 mL of water at 100° C. for 13 hours. The reaction mixture was filtered out to recover the polymer having the (R)-BINAP group. Meanwhile, the filtrate was extracted with ether and washed with saturated sodium hydrogen carbonate aqueous solution and saturated saline. It was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative chromatography (hexyane:ethyl acetate=3:1) to obtain 43.5 mg of (R)-3-phenylcyclohexanone with optical purity of 97% ee in 80% yield.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[S:21]1[CH2:25][CH:24]([C:26]([NH2:28])=[O:27])[NH:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH:24]([C:26]([NH2:28])=[O:27])[CH2:25][S:21][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)C1CSCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: NC(=O)C1CSCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with and 4-thiazolidinecarboxamide (CAN 103749-87-7) in the presence of TBTU and DIEA. The mixture of enantiomers was separated by chiral HPLC (Reprosil Chiral NR). The (−) enantiomer was isolated as white solid; MS (EI): m/e=399.4 [MH+]; αD20 (DMSO)=−547.6°.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:3]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Yield: 5.4 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid methyl ester (275 mg, 0.89 mmol) and methyl urea (165 mg, 2.22 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 5.5 mL, 2.67 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 3 d. The reaction mixture was allowed to cool to 25° C. and then partitioned between water and ethyl acetate. The layers were separated, and the aqueous layer was further extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionyl]-3-methyl-urea (17 mg, 6%) as a white solid: mp 158-160° C.; FAB-HRMS m/e calcd for C21H25N3O2 (M+H)+ 352.2025, found 352.2028.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.CS(O[CH2:17][CH:18]1[CH2:20][CH:19]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)=O.O>CN(C=O)C>[N:3]1([CH2:17][C@@H:18]2[CH2:20][C@H:19]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C1CC1COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H]1Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
To a suspension of sodium hydride (60%, 55 mg, 1.4 mmol) in DMF (5 mL) was added indole (135 mg, 1.2 mmol). After stirring at room temperature for 10 min, ethyl 2-(((methylsulfonyl)oxy)methyl)cyclopropanecarboxylate (307 mg, 1.4 mmol) was added. After stirring at room temperature for 6 h, the mixture was poured into water, and the aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1-5:1) to give 153 mg (54%) of the title compound as a pale brown oil;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:32]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=C(Cl)c1cccs1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)c3cccs3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 11 μL (0.11 mmol) 2-thiophenecarbonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH2:17]C)([CH2:15]C)[CH2:14][C:4]=12)[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:23]([NH:25][NH2:26])=O>>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]2[O:10][C:8]([C:6]3[S:7][C:3]([CH2:1][CH3:2])=[C:4]4[CH2:14][C:13]([CH3:15])([CH3:17])[CH2:12][CH2:11][C:5]=34)=[N:26][N:25]=2)[CH:27]=[C:28]([CH3:30])[N:29]=1
Reactant: CCc1sc(C(=O)O)c2c1CC(CC)(CC)CC2
Reactant: Cc1cc(C(=O)NN)cc(Cl)n1
Product: CCc1sc(-c2nnc(-c3cc(C)nc(Cl)c3)o2)c2c1CC(C)(C)CC2

Procedure:
2-Chloro-4-[5-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-pyridine is synthesized from 3,5,5-triethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid and 2-chloro-6-methyl-isonicotinic acid hydrazide in analogy to Example 9; LC-MS: tR=1.22 min, [M+1]=388.25.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc([N+](=O)[O-])cc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethanol (367 mg, 0.943 mmol) in DMF (3 ml) at room temperature under nitrogen was added 4-nitrophenol (144 mg, 1.037 mmol), followed by cesium carbonate (614 mg, 1.886 mmol) and the resulting mixture stirred at room temperature overnight. Ethyl acetate (50 mL) was added and washed with water followed by brine. The organic layer was then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to afford the crude product which was used for the next reaction without further purification. LCMS: retention 1.24 min/2.0 minute run: (ESI) m/z 401 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH:15]=2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)cc1F
Yield: 52.2 %

Procedure:
The product was synthesized according to General Procedure 1, described in Example 1, starting with 4-bromo-2-fluorobenzene sulfonyl chloride (17.8 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) affording 10.4 mg (52%) of the title compound. MS (ESI+) calcd for C13H9BrFN5O2S 396.964436, found 396.963956.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:13]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[NH:11][C:12]=1[C:19]([F:22])([F:20])[F:21]
Reactant: BrBr
Reactant: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Bromine (2.3 mL, 43.7 mmol) is added to a solution of methyl 2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carboxylate (8.44 g, 29.2 mmol) and sodium acetate (3.6 g, 43.7 mmol) in acetic acid. The reaction mixture is stirred for 30 minutes, diluted with a 0.4 wt/wt % sodium sulfite solution and extracted with diethyl ether. The organic extracts are combined, washed with saturated sodium hydrogen carbonate solution, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain an oil which solidifies to give the title product as a solid (9.2 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O>[C:35]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2)(=[O:37])[CH3:36]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(NC(C)=O)cc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (0.035 g, 0.103 mmol) in dimethylformamide (0.7 mL) was treated with N,N-diisopropylethylamine (0.018 mL, 0.103 mmol) followed by acetyl chloride (0.011 g, 0.134 mmol) and the reaction solution was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 8.52 (s, 1H), 8.25 (t, J=5.7 Hz, 1H), 7.74-7.78 (m, 2H), 7.65-7.67 (m, 1H), 7.62-7.67 (m, 2H), 7.43 (dd, J=8.2, 1.9 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 4.71-4.76 (m, 4H), 3.16-3.21 (m, 2H), 2.04 (s, 3H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 381 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21](=[O:26])C(F)(F)F)=[CH:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:30]>CN(C)C=O>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21]([OH:26])=[O:30])=[CH:12]1)=[O:27])([CH3:3])([CH3:4])[CH3:2]
Reactant: O
Reactant: CN(CCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCn1cc(C(=O)O)c2ccc(Cl)cc21)C(=O)OC(C)(C)C

Procedure:
To a solution of 15.4 g (38.0 mmol) crude {2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-methyl-carbamic acid tert-butyl ester in 380 ml N,N-dimethylformamide were slowly added 11.0 g (228 mmol) sodium hydride (50%, dispersion in oil) followed by 3.40 ml (190 mmol) water at 15-22° C. After stirring for 1 h at room temperature 500 ml water were added slowly. The mixture was washed with two 300-ml portions of tert-butyl methyl ether. The combined organic layers were extracted with 300 ml of a 0.5 M aqueous solution of sodium hydroxide. The combined aqueous layers were acidified to pH 2 with an ice-cold 4 M aqueous solution of hydrochloric acid at 0-5° C. and extracted with two 400-ml portions of ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)([CH3:11])[CH2:9][OH:10])[C:5](O)=[C:4]([CH3:22])[C:3]=1[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]([CH3:22])[C:5]2[O:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)([CH3:11])[C:6]=2[CH:7]=1
Reactant: Cc1c(Br)cc(C(C)(CO)c2ccc(C(C)C)cc2)c(O)c1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Br)cc2c(c1C)OCC2(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-2,3-dimethylphenol obtained in Reference Example 22 (830 mg, 2.21 mmol) and triphenylphosphine (638 mg, 2.43 mmol) in THF (60 mL) was added diethylazodicarboxylate (a 40% toluene solution, 1.06 g, 2.43 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain oily 5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran 660 mg. To a solution of said compound (660 mg, 1.84 mmol) and benzylamine (0.24 mL, 2.21 mmol) in toluene (10 mL) were added palladium acetate (4 mg, 0.02 mmol) and BINAP (34 mg, 0.6 mmol) at room temperature, and the mixture was stirred under argon stream for 15 minutes. Sodium tert-butoxide (248 mg, 2.58 mmol) was added to the reaction solution at room temperature, and the mixture was heated under argon stream for 18 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, the organic layer was washed with water and a saturated brine and then was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1), to obtain 660 mg (yield 77%) of the title compound as an oily matter.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)=[O:25]
Reactant: CSc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (ice/water) solution of 1.1 g. of 2-methylthio-4,5-diphenyl-thiazole pre-dissolved in 15 ml. of methylene chloride is added in portions over 5 minutes, 0.8 g. of m-chloro-peroxybenzoic acid. Examination by TLC after 30 minutes indicates the presence of essentially all of the sulfinyl compound (reaction complete). The precipitated m-chloro-benzoic acid is filtered off and the methylene chloride solution is washed successively with a 10% solution of sodium bisulfite and with saturated sodium bicarbonate solution, dried, evaporated in vacuo to dryness and the residue further dried overnight in vacuo to yield 2-methylsulfinyl- 4,5-diphenyl-thiazole, m.p. 102°-103° C.
Reaction SMILES: [C:1]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:7][CH:6]=1)#[N:2].O.N>C(O)=O>[NH2:28][C:22]1([C:20]([NH:19][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=3)=[CH:9][CH:10]=2)=[O:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3cccc(C#N)c3)cc2)CCOCC1
Agent: N
Solvent: O=CO
Solvent: O
Product: N#Cc1cccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)c1
Temperature: 36 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
(S)-tert-butyl 4-(1-cyano-2-(3′-cyanobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 8, step (ii), 282 mg) in formic acid (1.5 mL) was stirred at room temperature for 5 h, warmed at 36° C. for 30 mins then stirred at room temperature overnight. Water was added and the cooled solution was made basic with 0.880 ammonia and then extracted (×3) with dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered and the solvent was evaporated to yield an oil which was purified by chromatography on silica using 80% ethyl acetate in isohexane as eluent and then crystallised from isopropanol to yield a solid. The solid was washed with diethyl ether and dried to afford the titled compound (89 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 67 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.25 mmol), 3-(trifluoromethyl)benzoic acid (57 mg, 0.25 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 318, the title compound (83 mg, 63%) was obtained as a white powder.
Reaction SMILES: [C:1]1([CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C>O1CCOCC1>[OH:19][N:18]([CH:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[CH:15][CH:14]=1)[CH3:17])[C:25]([NH2:24])=[O:26]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(NO)c1ccc(OC(C)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(Oc1ccc(C(C)N(O)C(N)=O)cc1)c1ccccc1

Procedure:
N-hydroxy-N-(1-(4-(1-phenylethoxy)phenyl)ethyl)urea was prepared using Scheme 2 by refluxing 1-(4-(1-phenylethoxy)phenyl)ethylhydroxylamine (2.22 g 8.64 mmole) for thirty minutes with trimethylsilylisocyanate (1.19 gr, 10.4 mole) in dioxane (30 ml). The reaction mixture was then washed with saturated NH4Cl solution, dried with MgSO4, and evaporated. The residue was washed with ether to give a white solid (1.3 g).