Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:15]1([N:14]2[C:13]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[(S)-1-[1-Cyclohexyl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (0.55 g, 1.52 mmol) was dissolved in DCM (10 mL) and TFA (4 mL) added. The reaction mixture was stirred at RT for 30 minutes. The resultant mixture was concentrated in vacuo and the residue was dissolved in DCM (40 mL) and stirred vigorously with saturated aqueous NaHCO3 for 10 minutes. The layers were separated and the organic fraction was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a dark yellow gum which solidified on standing (0.41 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 7.63 (1H, s), 7.22 (1H, s), 7.01-6.89 (1H, m), 4.43-4.21 (2H, m), 2.29-2.09 (2H, m), 2.06-1.66 (5H, m), 1.57 (3H, s), 1.51-1.23 (3H, m)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH-].[Na+].Cl>O1CCCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of Example 1C (180 mg) in tetrahydrofuran (4 mL) and methanol (2 mL) was added 2N NaOH (2 mL). The mixture was stirred at 50° C. for 4 hours, cooled and neutralized by the slow addition of 5% aqueous HCl. The precipitates were collected by filtration and dried to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=O)[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].C[N:33](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([NH2:33])=[O:30])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10]
Reactant: CN(C)C=O
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Yield: 57 %

Procedure:
To a mixture of (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.25 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (0.13 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.16 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=10:0-8:2), and the obtained pale-brown solid was washed with ethyl acetate-hexane to give the title compound (143 mg, yield 57%) as pale-brown crystals. MS: 459 (MH+). melting point 227-228° C.
Reaction SMILES: [C:1]12([O:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[C:4]1=[O:12])[CH2:3][CH2:2]2.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:1]3([C:4](=[O:12])[C:5]=2[CH:11]=1)[CH2:3][CH2:2]3)([O-:15])=[O:14]
Reactant: O=C1c2ccccc2OC12CC2
Reactant: O=[N+]([O-])O
Product: O=C1c2cc([N+](=O)[O-])ccc2OC12CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Spiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (7.0 g.) was added in small portions to fuming nitric acid (70 ml.) previously cooled to -50° C. to -60° C. After stirring for 20 minutes, the reaction mixture was poured into ice-water and the precipitated crystals were collected by filtration, washed with water and recrystallized from ethanol. By the above procedure there was obtained 5-nitrospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as colorless prisms, m.p. 107°-110° C. Yield 7.3 g. This product was in good agreement with the crystals obtained in Example 18.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:32])[C:16](=[O:31])[CH2:17][N:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:19][CH2:20][O:21][CH3:22])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:35])[CH3:34].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([N:15]([CH3:32])[C:16](=[O:31])[CH2:17][N:18]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:19][CH2:20][O:21][CH3:22])[CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:6][CH:7]=2)=[CH:39][CH:38]=1)(=[O:35])[CH3:34]
Reactant: COCCN(CC(=O)N(C)C(CN1CCCC1)c1ccc(Br)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: O
Product: COCCN(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccc(NC(C)=O)cc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 28.9 %

Procedure:
N1-[1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(3,4-dichlorophenyl)-N1-methyl-N2-[2-(methyloxy)ethyl]glycinamide (150 mg, 0.276 mmol) was dissolved in 1 mL of 1,4-dioxane and combined with [4-(acetylamino)phenyl]boronic acid (74 mg, 0.413 mmol), Pd(dppf)2Cl2 (6.8 mg, 0.008 mmol), and 825 uL of 1M Na2CO3 in water in a glass reaction tube (0.5-2.0 mL Smith Process Vial) that was equipped with a magnetic stir bar. The tube was fitted with a rubber septum and hermetically sealed with a crimped metal foil seal. Using a Personal Chemistry Emrys Optimizer microwave unit, the reaction mixture was magnetically stirred and irradiated with microwave energy of dynamically adjusted power in order to maintain a temperature of 160° C. for 360 seconds. The reaction mixture was diluted with 2 mL of DMSO and filtered through a 0.2 micron PTFE filter and purified by preparative HPLC (Waters C18RP Xterra 5 micron 50×100 mm column, 45 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 95% over 20 min, UV detection at 215 nm) to give 47.7 mg (19%) of the title compound as a brown solid. MS (ES) m/e 598, 600 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Br:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Br:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Br:20]
Reactant: Nc1c(Br)cc(C(=CC(=O)O)c2ccc(Br)cc2)cc1Br
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Br)cc(C(=CC(=O)N2CCOCC2)c2ccc(Br)cc2)cc1Br

Procedure:
This compound was prepared from 4-amino-β-(4'-bromophenyl)-3,5-dibromo-cinnamic acid (isomer ratio A:B=1.5:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][C:67]1=[O:72].C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:9]1[N:8]=[C:7]([S:22][CH3:23])[C:6]2[C:11](=[C:2]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C:67]3=[O:72])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C1COCCN1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(N3CCOCC3=O)cccc12
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (336 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (144 mg, 0.25 mmol), morpholin-3-one (102 mg, 1 mmol) and Cs2CO3 (383 mg, 1.18 mmol) was added dioxane (5 mL). The reaction vessel was evacuated and flushed with argon (3×), and the mixture was heated at 100° C. overnight. The mixture was diluted with MeOH and DCM and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to afford 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)morpholin-3-one (203 mg, 57%) as a mixture which was used without further purification. LC-MS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[C:10]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>ClCCl>[CH3:31][S:32]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[C:10]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(-c2cccc(N3CCCNCC3)c2)nc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(-c2cccc(N3CCCN(S(C)(=O)=O)CC3)c2)nc2ccccc21
Yield: 56.5 %

Procedure:
To a solution of 2-(3-[1,4]Diazepan-1-ylphenyl)-1-methyl-1H-benzoimidazole (0.18 g, 0.46 mmol) and triethylamine (0.32 mL, 2.30 mmol) in dichloromethane (4 mL), was added methanesulfonyl chloride (0.04 mL, 0.55 mmol). After 16 h stirring at room temperature water (1 mL) was added, the organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude was purified by flash chromatography (eluent:EtOAc) to obtain 0.10 g (54%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][CH2:14]Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][S:9]2(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCCCl)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=S1(=O)CCCN1c1ccc(Br)cc1
Reaction time: 3 h
Yield: 73.6 %

Procedure:
N-(4-Bromophenyl)-3-chloropropane-1-sulfonamide (1.0 g, 3.2 mmol) was dissolved in DMF, Cs2CO3 (1.56 g, 4.8 mmol) was added, and the mixture was stirred for 3 hours. The mixture was then diluted with ether, washed with water, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-60% ethyl acetate in hexane) to afford 0.65 g (74%) 2-(4-bromophenyl)isothiazolidine 1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)=O)=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:29][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC(c2ncc(-c3ccc(F)cc3)o2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To benzyl 4-{[2-(4-fluorophenyl)-2-oxoethyl]carbamoyl}piperidine-1-carboxylate (5.5 g) was added phosphorous oxychloride (20 mL), followed by stirring at 80° C. for 3 hours. After leaving to be cooled, the reaction liquid was concentrated under reduced pressure, and the residue was azeotroped with toluene three times. To the residue were added ethyl acetate and water, and the organic phase was separated. The organic phase was washed with a saturated aqueous sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 30/70) to obtain benzyl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate (1.84 g) as a colorless oily substance.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:5]1)(=[O:3])[CH3:2].[Cl-:21].[Na+]>C(#N)C.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([Cl:21])[CH:11]=2)[CH:6]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [Cl-]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CN2C(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)N(C(C)=O)CC2CCNC(C)=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of N-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide (0.29 mmol) in acetonitrile (1.5 ml) is added bis(trifluoroacetoxyiodobenzene) (PIFA 1.2 eq) and the medium is left stirring for 1 min at room temperature. Saturated sodium chloride solution (0.5 ml) is next added and, after 15 min, the mixture is diluted with dichloromethane (10 ml) and dried over magnesium sulphate. The crude product obtained after evaporation is chromatographed on a column of flash silica (5/95 methanol/dichloromethane) and N-[2-(l-acetyl-6-chloro-5-methoxyindolin-3-yl)ethyl]acetamide (70 mg) is thus obtained.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:20]N1C(=O)CCC1=O>CN(C=O)C>[Br:20][C:16]1[S:17][CH:18]=[CH:19][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1
Reactant: CCCCCCCCc1ccc(-c2ccsc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2ccsc2Br)cc1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
In a three necked flask under argon, 1.40 g (5.14 mmol) of YKP67 in 40 mL of DMF are cooled to 0° C. 915 mg (5.14 mmol, 1 eq.) of N-bromosuccinimide are solubilised in 20 mL of mixture [DMF/MeOH:1/1]. This solution of NBS (protected from light) is then added drop by drop (30 min) into the reaction medium. The temperature of the medium is then left to rise to ambient temperature over 2 h. The medium is hydrolysed with a 1 mol·L−1 HCL solution and extracted with ethyl ether. The combined organic phases are washed with a saturated NaCl solution then dried on anhydrous Na2SO4. After drying on Na2SO4, filtration and evaporation of the solvent, the purification is carried out on silica column with cyclohexane. 1.58 g of final compound YKP69 in the form of a translucent oil (yield of 85.7%) are obtained.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:10]=[CH:11][C:12]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:13]([CH:28]=2)[C:14](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:38]([O:42][C:43](=[O:50])[C@H:44]([CH2:46][CH2:47][S:48][CH3:49])[NH2:45])([CH3:41])([CH3:40])[CH3:39].ON1C2N=CC=CC=2N=N1>CN(C=O)C>[N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:10]=[CH:11][C:12]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:13]([CH:28]=2)[C:14]([NH:45][C@@H:44]([CH2:46][CH2:47][S:48][CH3:49])[C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:50])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(/C=C/Cn2ccnc2)ccc1CCc1ccc(F)cc1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)c1cc(/C=C/Cn2ccnc2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 50 %

Procedure:
A solution of pentafluorophenyl 5-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate (0.36 g, 0.7 mmol), L-methionine-tert-butyl ester(0.173 g, 0.84 mmol) and 1-hydroxy-7-azabenzotriazole (0.1 g, 0.73 mmol) in DMF (2 ml) was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was taken up in ethyl acetate, washed with 5% sodium hydrogen carbonate solution and saturated brine and evaporated to dryness. The residue was then purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give the title compound. Yield: 50%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][CH:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=2[N:37]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=2[N:37]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C#N)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(C#N)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (3S)-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[F:19][C:20]([F:27])([F:26])[C:21]1[N:22]=[CH:23][NH:24][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:24]2[CH:25]=[C:21]([C:20]([F:27])([F:26])[F:19])[N:22]=[CH:23]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(-n2cnc(C(F)(F)F)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 64.9 %

Procedure:
In a similar way a solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 5.62 mmol), 4-trifluoromethyl-imidazole (0.945, 6.74 mmol) and ethyl-diisopropyl-amine (3.94 ml, 22.5 mmol) in 10 ml of dioxane is heated to reflux for 48 hours. After a similar workup procedure 1.4 g (3.65 mmol, 65%) of amorphous 5-(4-trifluoromethyl-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester are obtained, ES-MS: m/z 384 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)(C)CC(CCCCN=[N+]=[N-])CCCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)CC(CCCCN)CCCc1cccnc1
Reaction time: 14 h

Procedure:
The crude azide (1.29 g) is dissolved in 7 ml dry tetrahydrofuran, and 0.82 g (3.1 mmol) triphenylphosphine is added followed by two boiling stones and 0.08 ml (4.4 mmol) water. The solution is stirred for 14 h. An additional 0.82 g triphenylphosphine and 0.08 ml water are added and the mixture is stirred for another 5 h. The reaction mixture is concentrated under vacuum and then purified by silica gel chromatography using first ethyl acetate to remove nonpolar impurities and triphenylphosphine oxide. Then the eluent is changed to 9:1 methanol/triethylamine to obtain methyl 8-amino-2,2-dimethyl-4-(3-[3-pyridyl)propyl]-octanoate as an oil; NMR (CDCl3): delta 3.59 (s,3H), 2.67 (t,2H), 2.54 (t,2H), 1.13 (s,6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11]([C@H:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=2)[C:14]([OH:16])=[O:15])[C:10]1=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]1([C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N+]=[N-])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(Cl)Cl.CO>O1CCOCC1.CC(O)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11]([C@H:13]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=2)[C:14]([O:16][CH:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:15])[C:10]1=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN([C@@H](C(=O)O)c2ccc(OC(=O)OC(C)(C)C)cc2)C1=O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CN([C@@H](C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(OC(=O)OC(C)(C)C)cc2)C1=O
Yield: 88.7 %

Procedure:
2 g (4.49 mmols) of (3S)-3-tert.-butoxycarbonylamino-(αR)-α-(4-tert.-butoxycarbonyloxyphenyl)-2-oxo-1-azetidineacetic acid are dissolved in 50 ml of dioxan and 1 g (5.2 mmols) of diphenyldiazomethane is added all at once to this solution. After 4 hours no further starting material can be seen in the TLC (CHCl3 : MeOH:HOAc, 85:12:3). The red colour is removed by adding two drops of glacial acetic acid and the mixture is evaporated in vacuo at a bath temperature of 25°. The colourless foam is dissolved in 20 ml of absolute ethanol and the product starts to crystallise out. 2.4 g (87% of theory) of pure diphenylmethyl (3S)-3-tert.-butoxycarbonylamino-(αR)-α-(4-tert.-butoxycarbonyloxyphenyl)-2-oxo-1-azetidineacetate with a melting point of 155°-157° are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.Cl.[NH2:14][OH:15]>C(N(CC)CC)C>[OH:15][NH:14][C:11]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:12]
Reactant: O=C=NC1CCCc2sccc21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NO)NC1CCCc2sccc21

Procedure:
The above compound is prepared in the manner described in Example 6, by allowing 4,5,6,7-tetrahydrobenzo-[b]thien-4-yl isocyanate to react with hydroxylamine hydrochloride in the presence of triethylamine. The product melts at 158.5° C. to 160.5° C.