Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([CH2:17][C@H:18]3[CH2:23][N:22]([S:24]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)(=[O:26])=[O:25])[CH2:21][CH2:20][N:19]3[C:32]3[N:37]=[CH:36][C:35]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:34][N:33]=3)[CH:10]1[CH2:11][O:12][CH2:13]2)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[S:24]([N:22]1[CH2:21][CH2:20][N:19]([C:32]2[N:33]=[CH:34][C:35]([C:38]([OH:44])([CH3:43])[C:39]([F:41])([F:40])[F:42])=[CH:36][N:37]=2)[C@@H:18]([CH2:17][N:16]2[CH:10]3[CH:9]([OH:8])[CH2:15][CH:14]2[CH2:13][O:12][CH2:11]3)[CH2:23]1)(=[O:25])=[O:26]
Reactant: CC(O)(c1cnc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(OCc2ccccc2)C3)nc1)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(O)(c1cnc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(O)C3)nc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 2-(2-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (endo) (170 mg, 0.26 mmol) and CH2Cl2 (5 mL). BCl3 (1M in CH2Cl2, 4.20 mL, 4.20 mmol) was added slowly. After 15 min at 0° C., the reaction was carefully quenched with MeOH and concentrated. The resultant foam was then recrystallized from MeOH/ether to yield an off-white solid which was purified via column chromatography (12 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (120 mg) (endo) as a mixture of four isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[C:10]3[CH:16]=[CH:15][N:14](S(C4C=CC=CC=4)(=O)=O)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.CO.[Li+].[OH-]>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([N:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
tert-Butyl 4-(5-(3-fluorophenyl)-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.220 g, 0.410 mmol) was placed in 1:1 THF:MeOH (6 mL). 3M LiOH (0.683 mL, 2.05 mmol) was then added, and the reaction was stirred at 50° C. for 1 hour. The reaction was then cooled, added to water and extracted with DCM. The organic fractions were dried, filtered and concentrated to give the crude product tert-butyl 4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.150 g, 92.29% yield), which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([C:16]2[N:17]=[C:18]3[N:23]([CH:24]=2)[N:22]=[C:21](Cl)[CH:20]=[CH:19]3)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]([C:16]2[N:17]=[C:18]3[CH:19]=[CH:20][C:21]([O:3][CH2:2][CH3:1])=[N:22][N:23]3[CH:24]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CC[O-]
Reactant: FC(F)(F)c1ccc(-c2cn3nc(Cl)ccc3n2)cc1Br
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(Br)c3)cn2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
NaOEt (21% in EtOH, 2.97 mL) is added to a mixture of 2-[3-bromo-4-(trifluoromethyl)phenyl]-6-chloro-imidazo[2,1-f]pyridazine (1.5 g, 3.98 mmol) in THF (50 mL). The mixture is stirred for 4 hours at 50° C., then the THF solution is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (1.36 g, 88.8% yield). LCMS (m/z)=386.3, 388.3 [M+H]+, tR=3.34 min. (compound same as Example 204)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28](OC)=[O:29])[C:15](=[O:27])[N:16]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28]([NH:33][CH2:34][CH2:35][OH:36])=[O:29])[C:15](=[O:27])[N:16]3[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Reactant: NCCO
Product: COc1ccc(-n2c(=O)c(C(=O)NCCO)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1
Yield: 89 %

Procedure:
In a similar manner to that described in example 196, from methyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.115 mmol) and 2-aminoethanol (0.03 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (47 mg, 89% yield) as a white solid. 1H NMR (CDCl3) δ 10.18 (s, 1 H), 8.44 (s, 1 H), 7.08-7.02 (m, 4 H), 6.98-6.94 (m, 2 H), 6.91-6.87 (m, 2 H), 6.74 (s, 1 H), 3.90 (s, 2 H), 3.85 (s, 3 H), 3.71 (m, 2 H), 3.53 (m, 2 H); HRMS m/z calcd for C25H23FN3O5: 464.1616 Found: 464.1617.
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH3:13][N:14]([CH3:40])[C:15]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)(O)[CH2:17][CH2:16]1>ClCCl>[CH3:13][N:14]([CH3:40])[C:15]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:20][CH2:19][C:18]2([C:26]3[NH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]=3[CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: CN(C)C1(c2ccccc2)CCC(O)(CCCc2c[nH]c3ccccc23)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC2(CCCc3c2[nH]c2ccccc32)CC1
Temperature: 25 °C
Reaction time: 336 h

Procedure:
Trifluoromethane sulphonic acid trimethylsilyl ester (755 mg, 617 μL, 3.4 mmol) was added to a suspension of 4-dimethylamino-1-[3-(1H-indol-3-yl)propyl]-4-phenylcyclohexanol (320 mg, 0.85 mmol) in absolute dichloromethane (20 mL), wherein a clear brown solution formed that was stirred for 14 d at room temperature. The reaction solution was then diluted with dichloromethane (10 mL), washed with 1 N sodium carbonate solution (2×10 mL), water and saturated sodium chloride solution (10 mL each), dried with sodium sulphate and concentrated to low volume in a vacuum. The residue (270 mg) was mixed with methanol (30 mL) and stirred overnight at room temperature, wherein a light-coloured solid formed, which was filtered off and washed with a little methanol (2 mL).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:12]2[C:13](=[O:17])[CH2:14][CH2:15][CH2:16][C@@H:11]2[O:10][N:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Cl:22])(=O)C>CO>[CH2:1]([C@@H:8]1[C@@H:12]2[C:13](=[O:17])[CH2:14][CH2:15][CH2:16][C@@H:11]2[O:10][N:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[ClH:22]
Reactant: CC(=O)Cl
Agent: CN1O[C@H]2CCCC(=O)[C@H]2[C@H]1Cc1ccccc1
Solvent: CO
Product: Cl

Procedure:
rel-(3R*,3aS*,7aS*)-3-Benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one [2.51 g, 102 mMol; prepared as described under (A)] in methanol was stirred at 0° C. and treated dropwise with acetyl chloride (0.73 ml, 102 mMol). The solvents were removed in vacuo to yield an oil which became a white foam under high vacuum (0.01 mm Hg). This crude product was recrystallised from acetone to give the unsubstituted title compound hydrochloride as a white crystalline solid, m.p. 154°-156° C. (decomposition) in quantitative yield.
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: NCCCCCCCCCCN
Reactant: O=P(O)(O)CCl
Solvent: O
Product: NCCCCCCCCCCNCP(=O)(O)O

Procedure:
Chloromethanephosphonic acid (5.5 g, 42 mmoles) and 1.10-diaminodecane (44 g, 255 mmoles) were heated under reflux in water (200 cm3) for 20 hours. The water was removed and ethanol (400 cm3) added to the solid residue. The phosphonic acid was filtered off and dried. The crude yield was 11.4 g (87%). A sample was purified by recrystallization from water/ethanol to give N-(10-aminodecyl)-aminomethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 238° C.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]([B:11]1[O:19][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:12]1)=[CH2:10]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:7]([O:6][C:4]([CH:3]1[CH2:10][CH:9]1[B:11]1[O:19][C:16]([CH3:18])([CH3:17])[C:13]([CH3:14])([CH3:15])[O:12]1)=[O:5])[CH3:8]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1CC1B1OC(C)(C)C(C)(C)O1
Reaction time: 2 h
Yield: 104.6 %

Procedure:
Ethyl diazoacetate (3.49 g, 61.3 mmol) was added over 20 minutes to a stirred suspension of palladium (II) acetate (61 mmol) and vinylboronic acid pinacol ester (1.9 g, 12.26 mmol) in diethyl ether (30 mL) and stirred for 2 hours. The reaction was concentrated in vacuo and the residues distilled under vacuum (100-140° C. at 0.5-1 mbar) to afford 2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopropanecarboxylic acid ethyl ester (3.08 g, quant.) as a 4:6 mix of products, cis/trans isomers. 1H NMR 300 MHz (CHCl3-d): δ 4.26-4.25 (0.8H, m), 4.12-4.12 (1.2H, m), 1.83-1.82 (0.4H, m), 1.76-1.75 (0.6H, m), 1.28-1.27 (6H, m), 1.26 (6H, m), 1.22 (3H, m), 1.16-1.05 (0.8H, m), 1.01-1.00 (1.2H, m), 0.58 (0.6H, ddd, J=10.25, 7.44, 5.18 Hz), 0.41-0.41 (0.4H, m)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]=[CH:13][CH2:14][C@@H:15]([CH2:19][C@H:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[OH:21])[C:16]([OH:18])=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:29]I>C1COCC1>[CH2:3]([O:10][CH2:11][CH:12]=[CH:13][CH2:14][C@@H:15]([CH2:19][C@H:20]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[O:21][CH3:29])[C:16]([OH:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: O=C(O)[C@@H](CC=CCOCc1ccccc1)C[C@@H](O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](C[C@H](CC=CCOCc1ccccc1)C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of NaH (605 mg, 60% oil dispersion) in 30 mL THF was slowly added at room temperature the crude (S)-6-(benzyloxy)-2-((R)-2-(4-fluorophenyl)-2-hydroxyethyl)hex-4-enoic acid isolated above as a solution in 5 mL THF. To this mixture was added dropwise methyl iodide (732 μL, 1.7 g, 11.3 mmol) and the resulting stirred for 3 h at room temperature. The reaction was quenched by the slow addition of 20 mL 1M aqueous HCl and the mixture extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×30 mL) and dried over sodium sulfate. Evaporation of solvent afforded the product as an oil which was used directly in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[N:10]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[N:10]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:42][CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]4[C:47](=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:46]3=[O:55])[CH:26]=2)[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cn1cc(-c2c(C#N)n(C(=O)OC(C)(C)C)c(=O)n2-c2c[nH]c3ccccc23)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2c(C#N)n(C(=O)OC(C)(C)C)c(=O)n2-c2cn(CCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a suspension of 0.12 g (0.28 mmol) of the product from step c) and 0.15 g (1.1 mmol) of K2CO3 in dry 5 ml of DMF was added 0.083 g (0.30 mmol) of N-(3-bromopropyl)-phthalimide. The mixture was stirred at room temperature overnight and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water, brine, dried over Na2SO4 and evaporated. Chromatography on SiO2 (heptan-ethyl acetate) gave the title compound (152 mg, 86%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5](O)[C:4]1=[O:14].[BrH:15]>>[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:15])[CH:10]=2)[NH:5][C:4]1=[O:14]
Reactant: NC1Cc2ccccc2N(O)C1=O
Reactant: Br
Agent: Cl
Product: NC1Cc2cc(Br)ccc2NC1=O
Temperature: 25 °C

Procedure:
The title compound was prepared from 3-amino-1-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline hydrochloride (Davis, A. L., et al., J. Med. Chem., 7, 632 (1964)) according to procedures similar to those described in McCord, T. J., et al., J. Het. Chem., 9, 119 (1972), as follows. To 48% aqueous HBr solution (70 mL) was added 3-amino-1-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline hydrochloride (2.0 g, 9.3 mmol). The resulting mixture was stirred at reflux for 2 h. HPLC/MS indicated a nearly 1:1 mixture of desired product and its 8-bromo isomer plus a small amount of dibromo product. After cooling to RT, precipitate was filtered and treated with excess saturated aqueous Na2CO3 solution to make a basic (pH=10) mixture. This heterogenous mixture was extracted repeatedly with CH2Cl2. During these extractions, a substantial amount of solid remained undissolved and suspended in the aqueous layer. The combined organic extracts were dried over Na2SO4 and evaporated under vacuum. The resulting residue was chromatographed on silica gel eluted with 10% MeOH in CH2Cl2 to obtain the title compound (0.15 g). Additional title compound (0.56 g) was obtained by filtering the heterogenous aqueous layer and washing the filtered solid with water, then Et2O, and then 10% MeOH in Et2O before drying under vacuum.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:53][CH:54]1[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH2:55]1.Br[C:68]1[CH:69]=[C:70]([CH:73]=[CH:74][CH:75]=1)[C:71]#[N:72]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:71]([C:70]1[CH:69]=[C:68]([NH:53][CH:54]2[CH2:55][CH2:56][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:58][CH2:59]2)[CH:75]=[CH:74][CH:73]=1)#[N:72]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C#N)c2)CC1
Temperature: 105 °C
Yield: 82.4 %

Procedure:
A mixture of BINAP (560 mg, 0.9 mmol), palladium acetate (135 mg, 0.6 mmol) and cesium carbonate (2.932 g, 9 mmol) in 1,4-dioxane (10 ml) was sonicated for 50 minutes. 1,1-Dimethylethyl 4-amino-1-piperidinecarboxylate (1.2 g, 6 mmol) and 3-bromobenzonitrile (1.638 g, 9 mmol) were added and the mixture heated to 105° C. overnight under an argon atmosphere. On cooling, the solvent was removed in vacuo and the residue partitioned between water (100 ml) and EtOAc (100 ml). The organic layer was separated, dried and concentrated and the crude product purified by column chromatography. Elution with a 0-50% Et2O/petroleum ether gradient gave the title compound as a white solid (1.49 g). δH (CDCl3, 250 MHz) 7.22 (1H, t), 6.95 (1H, dd), 6.77 (2H, m), 4.07 (2H, m), 3.77 (1H, m), 3.41 (1H, m), 2.93 (2H, m), 2.03 (2H, m), 1.47 (9H, s), 1.34 (2H, m). MS (ES): MH+ 302.
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.[H][H]>CO.[Rh]>[CH:17]1([C:6]2([OH:5])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:7]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O)(C2CCCCC2)C1
Temperature: 85 °C
Yield: 100 %

Procedure:
0.5 ml of acetic acid and 40 mg of rhodium on alumina 5% are added to a solution containing 117 mg (0.470 mmol) of 3-hydroxy-3-phenyl-1-(tert-butoxy-carbonyl)azetidine (cf. procedure 1-2-1) dissolved in 4 ml of methanol. The reaction medium is placed at 4 bar of hydrogen and heated at 85° C. for 4 hours. The catalyst is filtered off and washed with methanol and the solvents are evaporated off. 120 mg in the form of a beige powder are obtained with a yield of 100%.
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23](OC(C)(C)C)=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:46]([C:48](C)([CH:52]=[CH2:53])[C:49](O)=O)#[N:47].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(#N)C>[Cl:1][C:2]([Cl:32])([Cl:33])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23](=[O:24])[C:48]([C:46]#[N:47])([CH3:49])[CH:52]=[CH2:53])[CH:19]([CH3:20])[CH3:21])[CH3:15])[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: C=CC(C)(C#N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: C=CC(C)(C#N)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)C(C)C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
A stirred solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (692 mg, 1.3 mmol) in dry dichlormethane (39 mL) was cooled to 0° C. under nitrogen and then trimethylsilyl trifluoromethanesulfonate (578 mg, 471 μL, 2.6 mmol) was added. The reaction was stirred for 1 h and then quenched with saturated sodium bicarbonate solution. The organic layer was separated and washed with further saturated sodium bicarbonate solution (2×), dried over anhydrous sodium sulfate, filtered and evaporated. To the residue was added 4 Å molecular sieves (powdered, 1.3 g) and a solution of the crude 2-cyano-2-methyl-but-3-enoic acid (2 mmol) in dry acetonitrile (39 mL) followed by 1-hydroxybenzotriazole (containing 20% H2O) (307 mg, 1.82 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (349 mg, 1.82 mmol). The mixture was stirred for 3.5 h, filtered through Celite, washing with extra dichloromethane and the filtrate washed with saturated ammonium chloride solution, water then saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 1:3 to afford the title compound (356 mg, 51%) as a white solid as a mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3) δ 0.90-0.97 (m, 3H), 0.99 (d, J=6.9 Hz, 3H), 1.33 (app t, J=7.1 Hz, 3H), 1.54-1.61 (m, 1H), 1.70-1.79 (m, 1H), 1.71 (s, 1.5H), 1.72 (s, 1.5H), 1.89-2.00 (m, 1H), 2.09-2.25 (m, 2H), 2.91-3.02 (m, 1H), 3.65-3.76 (m, 1H), 3.84 (d, J=11.2 Hz, 1H), 4.22-4.36 2H), 4.72 (d, J=12.1 Hz, 1H), 4.97 (dd, J=12.1 Hz, 2.5 Hz, 1H), 5.31-5.38 (m, 1H), 5.44 (t, J=9.8 Hz, 1H), 5.70 (dd, J=17.2, 10.3 Hz, 1H), 5.87-6.02 (m, 1H), 6.53-6.60 (m, 1H), 6.73-6.87 (m, 1H). LCMS (m/z) 538.0, 540.0, 542.0 [M+H], Tr=2.68 min.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][S:8]([CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[O:9].C(O)(C(F)(F)F)=O.O.CCCCCC>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:19][C:13]([F:18])([C:14]([F:15])([F:16])[F:17])[CH2:12][CH2:11][CH2:10][S:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[O:2])=[O:9]
Reactant: COC(CCCCS(=O)CCCC(F)(F)C(F)(F)F)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
5,5-Dimethoxy-1-(4,4,5,5,5-pentafluoropentylsulfinyl)pentane (355 mg, 0.10 mmol) was dissolved in chloroform (2 ml), 50% TFA aqueous solution (2 ml) was added thereto at room temperature, and the resulting mixture was then stirred for 2 hours. After the reaction was completed, the reaction solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1-ethyl acetate) to give 5-(4,4,5,5,5-pentafluoropentylsulfinyl)pentanal (28 mg, yield 93%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][CH:35]1[CH2:40][NH:39][C:38](=[O:41])[CH2:37][NH:36]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH3:34][CH:35]1[CH2:40][NH:39][C:38](=[O:41])[CH2:37][N:36]1[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:29])([F:31])[F:30])=[CH:23][CH:22]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: CC1CNC(=O)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1CNC(=O)CN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 120 °C
Yield: 7.7 %

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (350 mg, 0.662 mmol, Intermediate B) was combined with 5-methylpiperazin-2-one (79 mg, 0.695 mmol, Anichem, North Brunswick, N.J.), potassium carbonate (275 mg, 1.99 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (4.41 mL) was heated at 120° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). The filtrate was concentrated and purified by reverse-phase HPLC (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH, to give the title compound (28 mg) as a mixture of four diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]1=[O:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:28]=[CH:27][C:26](=[O:40])[N:25]([CH3:24])[CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Product: Cn1cc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)ccc1=O

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one following a procedure analogous to that described in Example 28. LC (method 10): tR=1.59 min; Mass spectrum (ESI+): m/z=412 [M+H]+.