Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CO.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].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:21]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cccnc2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 56.1, 15 g, 33.9 mmol) (15 g, 33.9 mmol), pyridin-3-ylboronic acid (4.73 g, 37.3 mmol), PdCl2(dppf) (1.240 g, 1.695 mmol), K3PO4 (21.58 g, 102 mmol), water (4 mL) and toluene (160 mL) was stirred at 100° C. overnight. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 500 g, EtOAc/MeOH from 0 to 2% MeOH). Fractions containing the pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in MeOH (50 mL), stirred overnight with Si-Thiol (1 g), filtered and the filtrate was evaporated off under reduced pressure to give the title compound as a beige solid. UPLC-MS (Condition 7) tR=1.1 min, m/z=392 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.68 Hz, 2H) 7.60 (dd, J=7.89, 4.83 Hz, 1H) 7.88 (d, J=9.05 Hz, 2H) 8.07 (dt, J=7.82, 1.90 Hz, 1H) 8.49 (d, J=2.32 Hz, 1H) 8.71 (dd, J=4.83, 1.41 Hz, 1H) 8.81 (d, J=2.08 Hz, 1H) 9.00 (d, J=2.20 Hz, 1H) 10.68 (s, 1H).
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N+:18]([O-:20])=[O:19].OS(O)(=O)=O>>[N+:18]([C:12]1[C:11]([CH3:10])=[C:16]([CH:15]=[CH:14][C:13]=1[CH3:17])[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])([O-:20])=[O:19]
Reactant: O=C(NCO)C(F)(F)F
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(Hydroxymethyl)trifluoroacetamide (6.6 mmol; 0.946 g) is added to a mixture of 2,6-dimethyl-nitrobenzene (0.899 mL; 6.6 mmol) and conc. H2SO4 (15 mL). The mixture is stirred at rt overnight, poured into ice water and stirred for 2 h. The precipitate is collected by filtration and dried. Yield 1.5 g (84%). MS [M−H]−=275, TLC: Rf=0.67 (silica gel, DCM:EtOH 95:5)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 372) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.075 g, 17%). semi-solid; 1H NMR (300 MHz, DMSO d6) δ 2.80 (m, 4H), 3.29-3.42 (3H, obstructed by H2O), 6.96 (m, 2H), 7.14-7.28 (m, 3H), 7.46-7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 466 (M+H)+, 483 (M+NH4)+. Anal. calc. for C24H20ClN2O3S.0.25H2O: C, 61.27; H, 4.39; N, 8.93. Found: 61.18; H, 4.68; N, 8.58.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].Br[CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29]>C(#N)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][N:10]([CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])[C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNC(=O)C(F)(F)F)cc1
Reactant: OC(CBr)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(CN(CC(O)C(F)(F)F)C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
260 mg of N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-acetamide (1 mmol) were dissolved in 10 ml acetonitrile and treated with 169 mg of potassium tert-butylate (1.5 mmol). After 5 min stirring at rt, 0.125 ml of [rac]-3-bromo-1,1,1-trifluoro-propan-2-ol (1.2 mmol) were added and the reaction mixture stirred at 75° C. bath temperature for 22 h. After cooling down to rt, the reaction mixture was concentrated in vacuo, dissolved in EtOAc/water and the phases separated. The organic phase was then washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:4) to give 111 mg of N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-N-(3,3,3-trifluoro-2-hydroxy-propyl)-acetamide as a white solid (30%). MS (ISP) 301.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C.ClCCl.C(O)C>[C:1]1([N:7]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccc4)ccc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.45 g (0.84 mmol) of 2-[N-(4-amidinophenyl)aminomethyl]benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide were dissolved in 15 mL of ethanol, mixed with 2 mL of 2N sodium hydroxide solution, and stirred for 4 hours at room temperature. Then the mixture was acidified with 3 mL of 2N hydrochloric acid and the solvent was distilled off. The crude product obtained was taken up in 5 mL dichloromethane/ethanol (2:1) and filtered to remove the insoluble sodium chloride. After the distillation of the solvent, the desired compound was obtained as a yellow foam. Yield: 0.26 g (67% of theory), C25H23N5O3S (473.55); Rf value: 0.47 (silica gel; methanol/5% aqueous sodium chloride=6:4); mass spectrum: (M+H)+=474.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)(=[O:19])=[O:18])[O:13][CH:14]=1)C1C=CC=CC=1.OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1>>[Cl:26][C:22]1[CH:21]=[C:20]([S:17]([NH:16][CH2:15][C:12]2[O:13][CH:14]=[C:9]([OH:8])[C:10](=[O:27])[CH:11]=2)(=[O:19])=[O:18])[CH:25]=[CH:24][CH:23]=1
Reactant: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)occ1OCc1ccccc1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Product: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)occ1O
Yield: 71.8 %

Procedure:
3-Chloro-N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-05) (14.0 g, 71.83%) was synthesized as a brown solid from N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-3-chloro-benzenesulfonamide (7-05) (25.0 g, 61.73 mmol) following the procedure described for N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-01).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:16])[CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11](OCC)=[O:12])[CH3:3].CC(O)=O>CCO.CCOCC>[O:12]=[C:11]1[CH2:10][CH2:9][CH2:8][S:7][CH:6]1[C:5]([O:4][CH2:2][CH3:3])=[O:16]
Reactant: CCOC(=O)CCCSCC(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1SCCCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a solution of 5 g (219 mmol) of sodium in 13 mL of anhydrous EtOH and 88 mL of ether are added dropwise, at 0° C. and under argon, 20.5 g (87.5 mmol) of ethyl 4-[(2-ethoxy-2-oxoethyl)sulfanyl]butanoate. After stirring for 18 hours at room temperature, the reaction mixture is poured into a mixture of AcOH (12 mL)/ice (70 g). The medium is then concentrated under reduced pressure, and the residue obtained is taken up in 100 mL of ether, washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 10% EtOAc. 5.64 g of ethyl 3-oxotetrahydro-2H-thiopyrane-2-carboxylate are obtained in the form of a yellow oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C[N+]([O-])=O.[F:9][C:10]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:11]=1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[CH:23]=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1)=[O:13].[Cl:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)Cl.[Cl-].[NH4+]>[Cl:36][CH2:37][C:38]([C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[C:24]([F:35])=[CH:25][CH:26]=[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[C:10]=3[F:9])[CH:16]=2)[NH:21][CH:22]=1)=[O:39]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49.3 %

Procedure:
A solution of aluminum trichloride (0.266 g, 2.00 mmol) in 1:1 DCM:CH3NO2 (5 mL) was added slowly to a slurry of 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.100 g, 0.254 mmol) in 1:1 DCM:CH3NO2 (2 mL) at 0° C. The solution was stirred at 0° C. for 40 minutes. A solution of 2-chloroacetyl chloride (0.0307 mL, 0.380 mmol) in DCM (1 mL) was added, and the reaction mixture was allowed to warm to room temperature overnight. Additional 2-chloroacetyl chloride (5 eq.) was added, and the reaction mixture was warmed to 50° C. for 20 hours. The solution was cooled and diluted with saturated aqueous ammonium chloride and extracted with EtOAc (3 X). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. They were then purified via column chromatography (5% MeOH/DCM) to afford N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (59 mg, 50%) as a solid.
Reaction SMILES: C(C1CC2C(=CC=C(C3N=CC(O)=CN=3)C=2)C1)CCCCCCCCC.C(C1SC(C2C=CC(O)=CC=2)=NC=1)CCCCCCCCC.[C:49]1([CH3:68])[CH:54]=[CH:53][C:52]([S:55]([O:58][CH2:59][CH2:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1>>[C:49]1([CH3:68])[CH:50]=[CH:51][C:52]([S:55]([O:58][CH2:59][CH2:60][CH2:61][CH:62]2[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)(=[O:57])=[O:56])=[CH:53][CH:54]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2)cc1
Agent: CCCCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Agent: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)s1
Product: Cc1ccc(S(=O)(=O)OCCCC2CCCCC2)cc1
Yield: 25.6 %

Procedure:
An objective product was prepared in the same manner as in Example 2 except that 2-(2-decylindan-5-yl)pyrimidine-5-ol was changed to 4-(5-decylthiazole-2-yl)phenol and 3-phenylpropyl p-toluenesulfonate was changed to 3-cyclohexylpropyl p-toluenesulfonate (Yield: 25.6%).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=O)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=[N:6][CH:5]=1)([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH2:33])[CH3:32]>>[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH:33][C:22]([C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:14]=[C:9]([N:8]2[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][N:6]=[N:7]2)[CH:10]=1)=[O:24])[CH3:32]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3nncc3C(C)C)c2)cc1
Reactant: CC(N)c1cnccn1
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3cnccn3)cc(-n3nncc3C(C)C)c2)cc1

Procedure:
5-(5-Isopropyl-[1,2,3]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid was subject to the amide coupling reaction described in step 4 of Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-yl-ethylamine, to give 5-(5-isopropyl-[1,2,3]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=427.
Reaction SMILES: [Li]CCCC.CO[CH:8](OC)[CH2:9][NH2:10].[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]#[N:19].N>CCCCCC.C1COCC1>[NH:10]1[CH:9]=[CH:8][N:19]=[C:18]1[C:14]1[S:13][CH:17]=[CH:16][N:15]=1
Reactant: N#Cc1nccs1
Reactant: COC(CN)OC
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1c[nH]c(-c2nccs2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of nBuLi (2.0 eq) in hexane was added under argon to a solution of 2,2-dimethoxyethanamine (2.0 eq) in THF at −78° C. After stirring for 30 min, thiazole-2-carbonitrile (2-Im-2, 3.0 g, 1.0 eq) was added and the resulting solution was stirred at 0° C. for 2 h, then quenched with 20 mL of 5% MeOH in water. The volatiles were removed and 6N HCl was added to adjust to pH=1. The acidic solution was refluxed overnight, cooled to rt then poured into a mixture of ice and aqueous Na2CO3. This was extracted with EtOAc and the organic layer was concentrated to give Imadazole 2. LCMS (0.01% Ammonia): 152.1 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 13.19 (bs, 1H), 7.98 (d, 1H, J=3.0 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.36 (s, 1H), 7.14 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([N:13]1[CH2:18][CH2:17][C:16]3([CH2:23][C@@H:22]([O:24][Si](C(C)(C)C)(C)C)[C:21]4[CH:32]=[C:33]([NH:36]S(C([Si](C)(C)C)C)(=O)=O)[CH:34]=[CH:35][C:20]=4[O:19]3)[CH2:15][CH2:14]1)[CH2:7][CH2:6]2)#[N:2].[F-].[Cs+]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([N:13]1[CH2:18][CH2:17][C:16]3([CH2:23][C@@H:22]([OH:24])[C:21]4[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:20]=4[O:19]3)[CH2:15][CH2:14]1)[CH2:7][CH2:6]2)#[N:2]
Reactant: CC([Si](C)(C)C)S(=O)(=O)Nc1ccc2c(c1)[C@H](O[Si](C)(C)C(C)(C)C)CC1(CCN([C@@H]3CCc4cc(C#N)ccc4C3)CC1)O2
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CC[C@@H](N1CCC3(CC1)C[C@@H](O)c1cc(N)ccc1O3)C2
Temperature: 95 °C
Yield: 74.6 %

Procedure:
To a mixture of N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-t-butyldimethylsilyloxyspiro[2H-1-benzopyran-2,4′-piperidin]-6-yl]trimethylsilylethanesulfonamide (0.50 gm, 0.75 mmole) in dimethylformamide (5 mL) under argon was added cesium fluoride (0.34 gm, 2.25 mmole)and the mixture heated to 95° C. for 30 hrs. The reaction was cooled diluted with 10% aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts were dried over sodium sulfate concentrated in vacuo to an oil and purified by flash chromatography using 90/10 dichloromethane/methanol to give N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro-[2H-1-benzopyran-2,4′-piperidin]-6-yl]amine, (0.218 gm, 80%) as a foam. MS m/z 390 (M+), 1H NMR (CDCL3) δ 1.4-2.2 (9 H, m), 2.6-3.2 (9 H, m), 3.4 (2 H, br s), 4.82 (1 H, br t), 6.60 (1 H, dd, J=9.3 and 2.8 Hz), 6.71(1 H, d, J=9.3 Hz), 6.81 (1 H, d, J=2.8 Hz), 7.18 (1 H, d, J=9.3 Hz), 7.37 (2 H, m).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:40]([CH3:41])=[CH:39][C:13]([CH2:14][CH:15]([C:23]([NH:25][S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])=[O:24])[C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:12][C:11]=1[CH3:42])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43]C1C=CC(C(Cl)=O)=CC=1>>[CH2:21]([N:18]([CH2:19][CH3:20])[C:16](=[O:17])[CH:15]([CH2:14][C:13]1[CH:39]=[C:40]([CH3:41])[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:43])=[C:11]([CH3:42])[CH:12]=1)[C:23]([NH:25][S:26]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)(=[O:27])=[O:28])=[O:24])[CH3:22]
Reactant: CCN(CC)C(=O)C(Cc1cc(C)c(NC(=O)c2ccccc2)c(C)c1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCN(CC)C(=O)C(Cc1cc(C)c(NC(=O)c2ccccc2F)c(C)c1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
In the same manner as in Example 9, a crude product was obtained using the compound (331 mg) obtained in Example 137 (4) and 4-fluorobenzoyl chloride (82 μL). This was purified by silica gel column chromatography to give the title compound (239 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.N1C=CC(C(=O)CC(OCC)=O)=CC=1.[NH2:29][C:30]1[CH:34]([N:35]2[C:43](=[O:44])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]2=[O:45])[CH2:33][CH2:32][N:31]=1>>[O:11]=[C:9]1[N:31]2[CH2:32][CH2:33][CH:34]([N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])[C:30]2=[N:29][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[CH:8]1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: NC1=NCCC1N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)CC(=O)c1ccncc1
Product: O=C1c2ccccc2C(=O)N1C1CCn2c1nc(-c1ccncn1)cc2=O

Procedure:
By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound was obtained as a white powder.
Reaction SMILES: [F:1][C:2]([F:37])([C:33]([F:36])([F:35])[F:34])[C:3]([F:32])([F:31])[C:4]([F:30])([F:29])[C:5]([F:28])([F:27])[C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O.[BrH:38].S(=O)(=O)(O)O>O>[Br:38][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([F:21])([F:22])[C:7]([F:23])([F:24])[C:6]([F:25])([F:26])[C:5]([F:27])([F:28])[C:4]([F:29])([F:30])[C:3]([F:31])([F:32])[C:2]([F:1])([F:37])[C:33]([F:34])([F:35])[F:36]
Reactant: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 29.0 g of crude 11-(heptadecafluorooctyl)-1-undecanol and 250 mL of 48% hydrobromic acid was slowly added 25 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 18 hr and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solution was concentrated to a dark liquid, which was eluted through 3 inches of silica with hexanes. Concentration of the eluent afforded 20.2 g of crude 1-bromo-11-(heptadecafluorooctyl)undecane as a nearly white solid, which was used without further purification.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)=[O:16])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.ClCCCl>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]2[CH2:18][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[CH2:20]2)=[O:16])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
0.73 g of (2S, 4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]pyrrolidine [prepared as described in step (b) above] was dissolved in 1.53 ml of anisole, and 7.25 ml of trifluoroacetic acid and 0.25 ml of trifluoromethanesulfonic acid were added dropwise, whilst ice-cooling, to the resulting solution. The mixture was then stirred at room temperature for 90 minutes, after which 1,2-dichloroethane was added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. The resulting residue was washed by repeated decantation, in turn, with hexane and with diethyl ether. The residue was diluted with ethyl acetate and was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was washed with water and with an aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 420 mg of the title compound, in the form of an amorphous powder.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH3:7].[CH3:22][Si:23](C1NC=CN=1)([CH3:25])[CH3:24].C[Si](Cl)(C)C.N1C=CN=C1>O1CCCC1>[CH3:7][C@@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH2:5][CH2:4][CH2:3][C:2]([CH3:20])([O:1][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH3:21]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reactant: C[Si](C)(C)c1ncc[nH]1
Agent: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Temperature: 0 °C

Procedure:
A solution of 24 mg (0.08 mMol) of (4aR,5R,8aR)-5-[(R)-5-Hydroxy-1,5-dimethyl-hexyl]-4a-methyl-octahydro-naphtalen-1-one in 0.5 ml of tetrahydrofuran is cooled under stirring and Argon atmosphere to 0°. The reaction mixture is stirred for an additional hour after addition of 12 μl (0.08 mMol) of trimethylsilylimidazole, of 5.1 μl (0.04 mMol) of trimethylsilylchloride and of 2.8 mg (0.04 mMol) of imidazole. The reaction mixture is poured into ice water, extracted three times with diethylether, the combined organic extracts are washed twice with brine and dried over Na2SO4. The organic solvent is evaporated in vacuo and the residue is chromatographed over 5 g of silicagel with hexane/diethylether 9/1 to yield 25 mg of pure, oily (4aR,5R,8aR)-5-[(R)-1,5-Dimethyl-5-trimethylsilanyloxy-hexyl]-4a-methyl -octahydro-naphtalen-1-one
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[NH:16][C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:19][CH:20]1[CH2:22][CH:21]1[CH2:23]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[N:16]([CH2:19][CH:20]3[CH2:22][CH:21]3[CH3:23])[C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC1CC1CBr
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2)[nH]c1C
Product: Cc1cc(C(=O)CCc2ccc(F)cc2)n(CC2CC2C)c1C
Yield: 74.2 %

Procedure:
The title compound was prepared as a pale yellow oil in 74.20% yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(4-fluorophenyl)propionyl]-2,3-dimethylpyrrole and 2-methylcyclopropylmethyl bromide.