Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][C:8]=2[F:18])=[N:4][C:3]=1[C:19]([NH2:21])=[O:20].Br[C:23]1[N:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:13][C:12]1[CH:11]=[C:10]([C:14]([OH:17])([CH3:16])[CH3:15])[CH:9]=[C:8]([F:18])[C:7]=1[C:5]1[S:6][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:27][N:28]=2)=[C:3]([C:19]([NH2:21])=[O:20])[N:4]=1
Reactant: CC(C)(O)c1ccc(Br)nc1
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(N)=O)c(N)s2)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)nc2C(N)=O)nc1

Procedure:
The title compound was prepared as described in Example 15, Step 7 using 5-amino-2-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 15, Step 5) (42 mg, 0.13 mmol), 2-(6-bromopyridin-3-yl)propan-2-ol (for preparation, see WO 2004/050024 A2 Example 120 Step A) (29 mg, 0.13 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), X-PHOS (32 mg, 0.067 mmol), potassium carbonate (19 mg, 0.13 mmol), and tert-amyl alcohol (0.27 ml) as starting materials. 1H NMR (500 MHz, d6-DMSO) δ 11.31 (s, 1H), 8.40 (d, 1H), 7.83 (dd, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 7.32 (d, 2H), 7.20 (d, 1H), 5.38 (s, 1H), 5.13 (s, 1H), 1.44 (s, 6H), 1.43 (s, 6H). LRMS (APCI) calc'd for C21H23F2N4O3S [M+H]+ 449.1, found 449.0.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:27](=[O:28])[CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
48.1 ml (77 mmole) of butyllithium (as a 1.6M solution in hexane) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 12.41 g (70 mmole) of (4S)-(-)-4-benzyl-2-oxazolidinone in 200 ml of anhydrous tetrahydrofuran, and the mixture was stirred for 30 minutes. At the end of this time, a solution of 13.0 g (77 mmole) of 3-phenylpropionyl chloride in 100 ml of anhydrous tetrahydrofuran was slowly added dropwise to the mixture, and the mixture was stirred for 1 hour. The mixture was then mixed with a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced-pressure. The residue was purified by column chromatography through silica gel (using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent) to afford 16.8 g (yield 78%) of the title compound as white crystals, melting at 92°-95° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:14]([O:16]CC3C=CC=CC=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCOCC1>[Pd].C(O)(=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:14]([OH:16])=[O:15])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
2.34 g (5.38 mmol) of benzyl 3-(1-adamantyl)-4-methoxycarbonylmethyloxybenzoate, 40 ml of dioxane, 500 μl of acetic acid and 234 mg of palladium (10%) were introduced into a reactor. The mixture was hydrogenated at 40° C. and at a pressure of 7 bar for three hours. The catalyst was filtered off and the mixture was evaporated to dryness. The solid obtained was triturated from hexane, filtered off and dried. 1.74 g (94%) of the expected acid, having a melting point of 230°-1° C., was recovered.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH2:18][CH3:19])=[CH:14][C:15](=[O:17])[CH3:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC(/C(/CC)=C/C(=O)C)=CC=2)CCCCC1>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH3:19])[CH2:14][C:15](=[O:17])[CH3:16])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=CC(C)=O)c1ccc(C2CCCCC2)cc1
Agent: CC/C(=C\C(C)=O)c1ccc(C2CCCCC2)cc1
Product: CCC(CC(C)=O)c1ccc(C2CCCCC2)cc1
Yield: 86 %

Procedure:
4-(4-Cyclohexyl-phenyl)-2-hexanone was prepared analogous to Example 66 from the mixture of isomers of 4-(4-cyclohexylphenyl)-3-hexene-2-one and 4-(4-cyclohexyl-phenyl)-3-hexene-2-one and 4-(4-cyclohexyl-phenyl)-4-hexene-2-one obtained in Example 56. Yield: 86% of theory. B.p. 137°-142°C at 0.1 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[CH:7][C:6]=1[O:16][CH3:17])[CH3:2].Cl.[Cl:20][C:21]1[C:22]([F:29])=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:24]3[C:23](=[C:22]([F:29])[C:21]([Cl:20])=[CH:26][CH:25]=3)[NH:27][C:13]=2[CH3:14])[CH:8]=[CH:7][C:6]=1[O:16][CH3:17])[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)c1cc(SCC(C)=O)ccc1OC
Agent: Cl
Product: CCOC(=O)c1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1OC

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Methoxy-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride.
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=2)[C:7]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:4])([CH3:3])[CH3:2].[CH2:39]=[NH:40]>CN(C=O)C>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]3[O:29][C:39]([NH2:40])=[N:31][N:30]=3)=[CH:32][CH:33]=2)[C:7]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(C(=O)NN)cc1
Reactant: C=N
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(-c2nnc(N)o2)cc1
Temperature: 85 °C

Procedure:
To 4-[3-tert-Butylsulfanyl-2-(2,2-dimethyl-propyl)-5-(pyridin-2-ylmethoxy)-indol-1-ylmethyl]-benzoic acid hydrazide (0.05 g, 0.10 mmol) in DMF (1 mL) was added C-Di-imidazol-1-yl)-methyleneamine (0.08 g, 0.50 mmol), and the reaction was heated at 85° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (EtOAc:hexane gradient) to give the desired product.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([NH:10][C:17](=[O:18])[C:16]2[CH:20]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 5-tert-butyl-1,3,4-thiadiazol-2-amine (1.57 g, 10 mmol) and 5-chloro-2-methoxybenzoyl chloride (2.05 g, 10 mmol) in CH2Cl2 (45 mL) at 0° C. was added dropwise triethylamine (1.7 mL, 12 mmol) and the reaction mixture was allowed to warm to ambient temperature for 12 h. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure to afford 3.2 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.43 (s, 9H), 3.88 (s, 3H), 7.22 (d, J=8.8 Hz, 1H), 7.45-7.76 (m, 2H), 12.43 (s, 1H). MS (DCI/NH3) m/z 326 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][PH:4]([CH2:6][CH2:7][CH:8]=O)=[O:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:10]([N:17]=[CH:8][CH2:7][CH2:6][PH:4]([CH2:3][O:2][CH3:1])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC[PH](=O)CCC=O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: COC[PH](=O)CCC=NCc1ccccc1
Yield: 91 %

Procedure:
Sodium sulfate anhydride (120 mg) was added to a solution obtained by dissolving 3-(methoxymethylphosphinyl)-propanal (60 mg) and benzylamine (42.8 mg) in toluene (3 ml), then the resultant solution was stirred for an hour at room temperature. Sodium sulfate was filtered out, and the resultant filtrate was concentrated to obtain N-benzyl-3-(methoxymethylphosphinyl)-propylideneamine (87 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][C:13]([CH3:18])([CH2:16][NH2:17])[CH2:14][NH2:15].C(N(CC)CC)C>C(O)CCC>[NH2:15][CH2:14][C:13]([CH3:18])([CH3:12])[CH2:16][NH:17][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: CC(C)(CN)CN
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(CN)CNc1nc(Cl)nc2[nH]ccc12
Temperature: 70 °C
Yield: 92.4 %

Procedure:
To 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.904 mmol) in solid form in a round-bottom flask, a solution of 2,2-dimethyl-1,3-propanediamine (0.325 mL, 2.71 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (4 mL) was added. The mixture was heated at 70° C. for 3 h. It was then purified by HPLC to give N-(3-amino-2,2-dimethylpropyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (212 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]([O-])=O.[Na+].[OH-].[Na+]>Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:24]=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2oc(-c3ccc4c(c3)nnn4C3CCOCC3)nc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.35 g, 1.13 mmol) in concentrated hydrochloric acid (2 mL) was added dropwise an aqueous solution containing sodium nitrite (0.09 g, 1.24 mmol) with cooling to 0° C. After stirring for 2 hours at room temperature, this was cooled to 0° C. and was made alkaline with 1N aqueous sodium hydroxide solution, then extracted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to yield the title compound (0.17 g, 46.9% yield) as dark brown crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:27](=[O:37])[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH2:26].[CH2:38]([O:45][N:46]1[C:52](=[O:53])[N:51]2[CH2:54][C@H:47]1[CH2:48][CH2:49][C@H:50]2[C:55](O)=[O:56])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:38]([O:45][N:46]1[C:52](=[O:53])[N:51]2[CH2:54][C@H:47]1[CH2:48][CH2:49][C@H:50]2[C:55]([NH:26][NH:25][C:27](=[O:37])[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:56])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
HATU (4.9 g, 12.9 mmol) and tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (2.2 g, 11.4 mmol) were added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (3 g, 10.8 mmol) in CH2Cl2 (50 mL) at 0° C. DIPEA (4.2 g, 32.6 mmol) was then added and the reaction mixture was stirred at 0° C. for 12 hrs. The reaction mixture was then washed with water, and saturated sodium chloride, dried over Na2SO4, and concentrated. The crude sample was purified by silica gel column chromatography (1 to 10% MeOH/DCM) to give tert-butyl (2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)carbamate (3.5 g, 62%) as a white solid. ESI-MS (EI+, m/z): 448.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([CH3:21])[CH:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH3:9].C(N(CC)CC)C>CCOCC>[CH3:9][CH:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C(C)N1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Methanesulfonyl chloride (9.7 mL, 56 mmol) was added to a solution of 10.5 g (48 mmol) of 2-(2-hydroxy-1-methylpropyl)-1H-isoindole-1,3(2H)-dione (JP 01242569 A2) and 8.1 mL (58 mmol) of triethylamine and the mixture was stirred at room temperature overnight. The mixture was diluted with ether and washed with water and brine. Drying (MgSO4) and removal of solvent gave an oil which slowly solidified. Trituration with hexanes gave 11.8 g of 2-[1-methyl-2-[(methylsulfonyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione as a white solid, mp 67-73° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H-].[Na+].[NH2:13]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[NH2:13][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of ethyl 1H-imidazole-2-carboxylate (2.00 g, 14.27 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (0.714 g, 17.84 mmol, 60% wt). The reaction solution was stirred at room temperature for 120 min and then was cooled to 0° C. A suspension of (aminooxy)diphenylphosphine oxide [4.66 g, 19.98 mmol, prepared from diphenylphosphinic chloride following a known procedure (Org. Lett., 351-353 (2007))], in DMF (70 ml) was added. After 10 min, the ice bath was removed. The reaction mixture became viscous and stirred at room temperature for 3 h. The reaction was quenched with water until it became a clear solution, and concentrated to dryness under reduced pressure. The crude product was suspended in EtOAc (400 ml) with stirring for 30 min and filtered. The filtrate was concentrated to give a pale yellow viscous solid, 2.6 g. The crude product was purified via silica gel column (Isco prep: 0-5% MeOH-DCM over 20 minutes) to afford ethyl 1-amino-1H-imidazole-2-carboxylate (1.99 g, 90% yield) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.35 (d, J=1.3 Hz, 1H), 7.11 (s, 1H), 4.37 (q, J=7.3 Hz, 2H), 1.50 (br. s., 9H), 1.38 (t, J=7.0 Hz, 4H). ESI-MS (analytical LCMS Method A): m/z 156.0 ([M+H]+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:8]1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[S:31][CH:32]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][S:33][C:30]2[S:31][CH:32]=[C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[N:29]=2)[CH2:8]1
Reactant: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CCOC(=O)c1csc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (776 mg) of (1-2) and the resultant product (379 mg) of (1-3) were dissolved in dimethylformamide (6 mL), potassium carbonate (829 mg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (850 mg) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[C:13]4[NH:16][C:17]([NH:19][C:20](=[O:28])[C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=5)=[N:18][C:12]4=[CH:11][C:10]=3[C:9]([CH3:30])([CH3:29])[C:8]2=[O:31])=[C:4]([O:34]C)[CH:3]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[C:13]4[NH:16][C:17]([NH:19][C:20](=[O:28])[C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=5)=[N:18][C:12]4=[CH:11][C:10]=3[C:9]([CH3:29])([CH3:30])[C:8]2=[O:31])=[C:4]([OH:34])[CH:3]=1
Reactant: COc1cc(F)ccc1CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4cccc(C)c4)[nH]c3cc21
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2nc3cc4c(cc3[nH]2)N(Cc2ccc(F)cc2O)C(=O)C4(C)C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 66 %

Procedure:
N-[5-(4-Fluoro-2-methoxy-benzyl)-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-3-methyl-benzamide (5 mg) is suspended in a BBr3 solution in CH2Cl2 (1 M; 33 μl) and stirred at RT for 10 h. After addition of hydrochloric acid (200 μl; 1 N) the mixture is stirred at RT for another 1 h and then evaporated to dryness. The crude material is purified by preparative RP-HPLC eluted with MeCN/water to yield the desired compound (3.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(Cl)cc1Cl
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Cl)cc1Cl)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.22 (d, J 8.4, 1H), 7.33 (m, 2H), 7.56 (s, 1H), 7.78 (t, J 7.8, 1H), 7.90 (d, J 6.5, 1H), 8.17 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.62 (m, 2H), 9.51 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[N:29]=[CH:28]1>>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]5=[O:32])=[CH:3][C:4]=4[F:25])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:24][CH2:23]1
Reactant: CC1(C)C=NC(=O)O1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Product: CC1(C)CN(c2ccc(C(=O)N3CCN(c4ccc(C5CC5)cn4)CC3)c(F)c2)C(=O)O1
Yield: 43.2 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl]methanone (606 mg) described in Preparation Example 188 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (284 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: Ic1ccc(OC2CCCCO2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
To a stirred solution of 4-iodophenol (11.0 g, 50 mmol) in CH2Cl2 (50 ml) cooled with an ice bath, dihydropyran (5.0 g, 60 mmol) was added dropwise over 10 min at 0-5° C. After the solution became clear, toluenesulfonic acid, TsOH, (10 mg) was added. The solution was stirred at 20° C. for 15 min. Then it was quenched by addition of NaHCO3 (1 g) and 3 drops of water, and after stirring for 5 min at 20° C., the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with petroleum ether as eluent to give 14.0 g (92%) of 1 as colorless crystal; mp 66° C.; δH(CDCl3; 300 MHz): 7.55(d, J=8.3, 2H, Ar—H), 6.83(d, J=8.4, 2H, Ar—H), 5.37(t, J=3.1, 1H, OCHO), 3.86(m, 1H, THP), 3.59(m, 1H, THP), 1.87˜1.58(m, 6H, THP).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1.N1C=CC=CC=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>ClC(Cl)C>[F:19][C:2]([F:18])([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1cccc(NCc2cccnc2)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-trifluoromethoxyphenyl)pyrid-3-ylmethylamine(0.270 g, 1 mmol) and pyridine were dissolved in dichloroethane (2 ml). The solution was cooled in an ice-bath. To the solution was added 2,2,2-trifluoroethylsulfonyl chloride (0.274 g, 1.5 mmol). The mixture was stirred at room temperature overnight. Upon removing solvent, the residue was dissolved in water and extracted with EtOAc. The organic phase was washed with brine concentrated. The residue was chromatographed to afford the title compound. 1H NMR: 8.42 (d,1H,J=6.4 Hz), 8.20 (d,1H,J=2.0 Hz), 7.57 (d,1H,J=9.8 Hz), 7.40-6.85 (m,5H), 4.81 (s,2H), 3.72 (q,2H, J=7.8 Hz). MS calcd 414.1; MS (M+1) 415.1.