Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([CH:8]=[CH:9][CH3:10])[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>O>[F:1][C:2]([F:11])([CH2:8][CH:9]=[CH2:10])[C:3]([OH:5])=[O:4]
Reactant: CC=CC(F)(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=CCC(F)(F)C(=O)O
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of ethyl α,α-difluoropentenoate 8b (80 g, 0.49 mol, U.S. Pat. No. 4,847,401, issued Jul. 11, 1989) in H2O (80 mL) is added LiOH (20.9 g, 0.5 mol) over 5 min at 0°-5° C. The reaction mixture is allowed to warm to room temperature for 3 h, then heated at 45°-50° C. for 3 h. Ethanol and H2O are removed (60 torr, 45° C.) from the reaction mixture. The resulting orange oil is dried (1 torr, room temperature) for 2 h to obtain an oily solid. The oily solid is diluted in H2O (75 mL) and acidified to pH 1 using conc HCl. The reaction mixture is extracted with diethyl ether (3×150 mL). Conc HCl is added to the aqueous layer until it is pH 1 and the aqueous layer is extracted again with diethyl ether (3×100 mL). The combined organic layers are dried (MgSO4), concentrated to an oil and distilled (140°-170° C.) to obtain 58.8 g, 432 mmol of the title compound 8c as an oil in 88% yield. 19F NMR (CDCl3) δ -106.8 (t)(CFCl3 as ref); 13C NMR (CDCl3) δ 168.3 (t, CO2H), 126.4 (s, C=C), 122.3 (s, C=C), 115.0 (t, CF2), 38.9 (t, CH2); 1H NMR (CDCl3) δ 2.88 (m, CH2, 2H), 5.28 (m, 1H), 5.32 (s, 1H), 5.76 (m, 1H), 8.74 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:27])=[CH:15]/[C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:27])=[CH:15]/[C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:37])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCOc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Solvent: ClC(Cl)Cl
Product: C/C(=C\c1ccc(OCCS(C)=O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
2.1 g of the compound obtained in Example 5 are dissolved in 50 ml of chloroform and treated slowly at 0° with a solution of 1.2 g of m-chloroperbenzoic acid (90%) in 10 ml of chloroform. After stirring at 0° for 20 hours the mixture is washed with dilute soda solution and water, dried and evaporated. The thus-obtained yellow oil is filtered over a small silica gel column (eluting agent hexane/ethyl acetate=1:2) and recrystallized from ethyl acetate. There are obtained 1.7 g of methyl 2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl sulphoxide, melting point 134°-136°.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([NH2:33])=[O:32])[N:26]=1.CC(C)([O-])C.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([O:22][C:25]5[N:26]=[C:27]([C:31]([NH2:33])=[O:32])[CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: NC(=O)c1cccc(F)n1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cccc(C(N)=O)n5)cc43)sc2C(=O)N1
Temperature: 145 °C
Yield: 11.7 %

Procedure:
To a solution of Example 57 (75 mg, 0.227 mmol) in THF (4 mL) was added 2-fluoro-6-pyridinecarboxamide (64 mg, 0.453 mmol) and sodium tert-butoxide (87 mg, 0.906 mmol). The reaction was heated to 145° C. under microwave irradiation for 50 minutes then cooled to r.t. The mixture was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to give the title compound (12 mg, 12%) as a white solid. δH (CDCl3) 8.02 (1H, d, J 2.6 Hz), 7.91 (1H, dd, J 7.2 and 0.9 Hz), 7.85 (1H, t, J 7.9 Hz), 7.08 (1H, dd, J 7.9 and 0.9 Hz), 6.98 (1H, d, J 8.9 Hz), 6.85 (1H, dd, J 8.9 and 2.6 Hz), 4.27-4.43 (2H, m), 4.05-4.17 (2H, m), 2.83 (2H, s), 1.37 (6H, s). LCMS (ES+) 452.0 (M+H)+, RT 2.85 minutes (Method 1).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([N:5]1[CH2:12][CH2:11][C@:10]2([CH3:16])[C:13]([CH3:15])([CH3:14])[C@H:6]1[CH2:7][C:8]1[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([N+:24]([O-])=O)=[CH:17][C:9]=12)=[O:4]>[Pd].CO>[NH2:24][C:18]1[C:19]([NH2:21])=[CH:20][C:8]2[CH2:7][C@@H:6]3[C:13]([CH3:14])([CH3:15])[C@:10]([CH3:16])([C:9]=2[CH:17]=1)[CH2:11][CH2:12][N:5]3[C:3](=[O:4])[C:2]([F:28])([F:1])[F:27]
Reactant: CC1(C)[C@H]2Cc3cc([N+](=O)[O-])c([N+](=O)[O-])cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10% palladium on carbon (300 mg) and 2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-8,9-dinitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (330 mg) in methanol (5 mL) is shaken under hydrogen atmosphere at room temperature for 2 h. Then, the catalyst is separated by filtration and the solvent is removed under reduced pressure to give the crude title compound that is used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[CH:27]OS(C)(=O)=O)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>CN(C=O)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[CH:27][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)N1CCC(=COS(C)(=O)=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(=Cn2ccc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of indole (0.53 g, 4.5 mmol) in dry DMF (15 mL) was added potassium t-butoxide (580 mg, 5.2 mmol) at ambient temperature. After stirring for 30 minutes, 4-(methanesulfonyloxymethylene)-piperidine-1-carboxylic acid ethyl ester (1.2 g, 4.5 mmol) was added. After 8 hours, the reaction mixture was quenched with water and extracted with t-butyl methyl ether (2×50 mL). The combined organic phases were washed with water (2×), dried, evaporated, and purified by column chromatography on silica gel eluting with toluene/acetone 96:4. Evaporation of the eluting solvent gave 0.92 g (71% of theory) of a slightly bluish oil.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[C:12]([F:18])=[N:13][CH:14]=[CH:15][C:16]=1I.[O:19]=[C:20]([CH2:25][CH3:26])[C:21]([O:23][CH3:24])=[O:22].O.C1COCC1>CCCCCC.C1COCC1>[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[C:12]([F:18])=[N:13][CH:14]=[CH:15][C:16]=1[C:20]([OH:19])([CH2:25][CH3:26])[C:21]([O:23][CH3:24])=[O:22]
Reactant: Fc1nccc(I)c1C1OCCO1
Reactant: CCC(=O)C(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)(C(=O)OC)c1ccnc(F)c1C1OCCO1

Procedure:
6.9 ml (11 mmol) of 1.6M butyllithium in hexane are added dropwise to a solution, stirred at −78° C. under an argon atmosphere, of 3.1 g (11 mmol) of 3-(1,3-dioxolan-2-yl)-2-fluoro-4-iodopyridine in 100 ml of THF. The reaction mixture is then stirred for 10 minutes at −78° C. before the dropwise addition of a solution of 1.5 g (13 mmol) of methyl 2-oxo-butyrate in 20 ml of THF. The mixture is stirred for 3 hours at −78° C., hydrolysed with a mixture of water/THF, and decanted. The aqueous phase is extracted 3 times with 50 ml of ethyl acetate each time, and the combined organic phases are dried over magnesium sulphate and then concentrated. The expected product is obtained by purification of the residue by chromatography over silica (eluant:dichloromethane/acetone 95/5).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)N1CCOCC1.[C-:18]#[N:19].[K+].[OH-].[Na+]>O>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([CH:3]([CH:2]([CH3:1])[CH3:17])[C:18]#[N:19])=[CH:15][CH:14]=1
Reactant: [C-]#N
Reactant: CC(C)C(c1ccc(O)cc1)N1CCOCC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(C#N)c1ccc(O)cc1
Yield: 97 %

Procedure:
A mixture of 4-(2-methyl-1-morpholinopropyl) phenol (2.35 g; 0.01 mol), potassium cyanide (1.6 g; 0.024 mol) and water (2.5 ml) is heated at 95°-100° C. for 17 hours. The reaction mixture is then cooled down, and added to about 35 ml of 5% sodium hydroxide. The aqueous solution is washed with ether (2×, 20 ml), and then its pH is adjusted to ~2 with 6 N hydrochloric acid. The acidified aqueous solution is extracted with ether (2×, 30 ml), the ethereal extracts are combined, washed with water, dried over magnesium sulfate, and concentrated to afford 1.7 g of title product, a viscous, almost colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:20]#[N:21])=[CH:10][CH:9]=2)[C:4](=[O:22])[NH:3]1.[Br:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32]Br>>[Br:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][N:3]1[C:2]([CH3:23])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:20]#[N:21])=[CH:10][CH:9]=2)[C:4]1=[O:22]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(-c3ccccc3)c2)C1=O
Reactant: Fc1ccc(CBr)c(Br)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(-c3ccccc3)c2)C(=O)N1Cc1ccc(F)cc1Br

Procedure:
Under conditions as described for the preparation of 1.2, compound 223.1 was reacted with 2-bromo-1-bromomethyl-4-fluorobenzene and afforded 223.2. Molecular weight 491.06 (C25H19BrFN3O2); retention time Rt=2.68 min. [B]; MS (ESI): 492.31 (MH+).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([Br:19])=[N:17][CH:18]=2)[CH2:9]1.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:10]2[CH2:11][N:8]([CH3:2])[CH2:9]2)=[CH:18][N:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1ccc(OC2CNC2)cn1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC(Oc2ccc(Br)nc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.2 %

Procedure:
In a solution of 5-(Azetidin-3-yloxy)-2-bromo-pyridine trifluoro-acetic acid salt (0.5 g, 1.46 mmol) in dichloromethane (20 mL), add formaldehyde aqueous solution (37%, 0.58 mL, 7.29 mmol). Then add Na(OAc)3BH (0.774 g, 3.65 mmo) carefully. The reaction was stirred at room temperature under argon for 45 min. The reaction was quenched with water (30 mL), and then extracted with dichloromethane (3×20 mL). The combined organic phase was washed thoroughly with brine and water. Evaporation of solvent afford 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine (0.37 g, yield 98%), which was pure enough for next step.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(C(F)(F)F)c2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc(C(F)(F)F)c3)cc2=O)n1
Yield: 5 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-[6-oxo-4-(3-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 22) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(3-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (13.7 mg, 5%); ES+-HRMS m/e calcd for C26H30F3N5O4 [M+H+] 534.2323 found 534.2323. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.27-1.77 (m, 8H), 1.92 (m, 1H), 2.25 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.48 (dd, J=4.4, J=11.0 Hz, 1H), 5.86 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.65 (m, 1H), 7.70-7.83 (m, 3H), 8.16 (d, J=2.8 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]=[CH:5][C:6]1([C:30]([CH3:38])([CH3:37])[O:31][SiH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:7]1>CO>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1([C:30]([CH3:38])([CH3:37])[O:31][SiH2:32][C:33]([CH3:35])([CH3:34])[CH3:36])[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:7]1
Reactant: COC(=O)C=CC1(C(C)(C)O[SiH2]C(C)(C)C)CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Solvent: CO
Product: COC(=O)CCC1(C(C)(C)O[SiH2]C(C)(C)C)CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 2 h

Procedure:
The product from step 24d (0.24 g, 0.44 mmol) was dissolved in methanol (15 mL), degassed by bubbling nitrogen through the solution, charged with Rh/C and hydrogen gas (40 PSI), and shaken for 2 h. The reaction was filtered and concentrated to give 3-{5-(tert-butyl-dimethyl-silanyloxymethyl)-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester as a crude oil. MS found: (M+H)+=549.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:14]([C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)[C:15]([CH3:17])=[O:16]>>[NH:14]([C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)[C:15]([CH3:17])=[O:16]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(=O)Nc1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Product: CC(=O)Nc1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 454 was prepared from 4-morpholinoaniline and 4-(5-acetamino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C26H25N5O3: 456.20; found: 455.95.
Reaction SMILES: N([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[CH3:8])=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C(O)(=O)C>O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]([CH:7]2[CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]2)[OH:15])[CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC1(C)CCCN1N=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CCC(C(O)c2cccc(Cl)c2)N1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
35.4 ml (0.24 mols) of diisopropylamine are dissolved in 350 ml of tetrahydrofuran and cooled to −75° C. under nitrogen with a bath of dry ice and acetone. At this temperature, 180 ml (0.29 mols) of an approximately 1.6 molar solution of butyl lithium in hexane are added dropwise. By removing the cooling bath, the temperature is allowed to rise to −10° C. The solution of lithium-diisopropylamine thus obtained is again cooled to −78° C. This solution is mixed over the course of 20 minutes with 32 g (0.25 mols) of 1-nitroso-2,2-dimethylpyrrolidine and stirred for a further 10 minutes. Then, 35.2 g (0.25 mols) of 3-chlorobenzaldehyde are added dropwise over the course of 15 minutes, and the mixture is stirred for a further 3 hours at −75° C. To the resulting orange-coloured solution is then added dropwise, over the course of 20 minutes, a solution of 40 ml (0.7 mols) of glacial acetic acid in 80 ml of tetrahydrofuran. The reaction mixture which is now light yellow is warmed to room temperature by removing the cooling bath, and is then poured onto a mixture of 1 liter each of saturated sodium chloride solution and methyl chloride. After shaking out, the aqueous phase is separated and washed twice, each time with 200 ml of methylene chloride. The combined organic phases are washed with 200 ml of water, dried over sodium sulphate and the solvent residues are removed in a vacuum. The crystalline residue is dissolved whilst hot in a mixture of 180 ml of toluene and 270 ml of hexane. Upon cooling, the title substance is obtained in the form of white crystals having a m.p. of 143-144° C.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])#[N:2].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl.C(N(CC)CC)C.CCCCCC>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])#[N:2]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: N#CCNC(=O)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: N#CCN(SC(Cl)(Cl)Cl)C(=O)c1ccccc1Cl
Reaction time: 0.42 h

Procedure:
To a stirred mixture of 5.0 g (0.026 mole) N-Cyanomethyl-2-chlorobenzamide (the product of Example 8) and 5.3 g (0.029 mole) trichloromethylsulfenyl chloride in 125 ml methylene chloride, 3.2 g (0.032 mole) triethylamine in 25 ml methylene chloride were dropped in over 35 minutes. The reaction mixture was stirred about 25 minutes. The reaction mixture was washed three times with 75 ml water, dried over magnesium sulfate and stripped to give a brown oil. Hexane (25 ml) was added to the oil which crystallized when cooled in an ice bath.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.[OH-].[NH4+]>>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([NH2:21])=[O:2])[CH3:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(N)=O
Yield: 46.6 %

Procedure:
The process was carried out as was Example 45, starting with 2.8 g of the compound of Example 25, 2.5 g of carbonyldiimidazole and 4 ml of ammonium hydroxide. The product was recrystallized from toluene and then from ethanol to obtain 1.3 g of the desired product, m.p. 143°-145°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[N:28]=[C:27]([S:29][CH3:30])[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[C:27]([S:29][CH3:30])[N:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSc1nc(N)n[nH]1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: CSc1nc2ncc3c(n2n1)CC1CCCC3N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-5-methylthio-1,2,4-triazole.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:4]=2[NH:3]1.CC(C[AlH]CC(C)C)C>C1COCC1>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(CO)cc2[nH]1

Procedure:
24.6 g (0.128 mol) of 20a are suspended in THF and stirred with 624.8 ml (0.768 mol) of DIBAL (20% strength solution in toluene) at -70° C. overnight in analogy to Example 1a.
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24]C(C)(C)O[C:27](=[O:29])[CH:28]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[H][H].[OH-].[Na+]>O.[OH-].[OH-].[Pd+2].C(O)(=O)C>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]4)=[C:11]([F:21])[CH:10]=3)[CH2:22][C:23](=[O:24])[CH2:28][C:27](=[O:29])[O:32]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCC1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of 1-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile (6.0 g, 13.7 mmol) from step 3 below was added Pd(OH)2/C (2.0 g) and ethanol (100 mL). The reaction was placed under a nitrogen atmosphere using a balloon filled with hydrogen. The slurry was stirred vigorously for 18 hours. The reaction was filtered to remove all of the solids, and the liquid was concentrated to an oil. The oil was dissolved in methanol (100 mL), and solution of NaOH (1.64 g, 41 mmol) dissolved in water (30 mL). The reaction was stirred for 18 hours, and then acetic acid (1 mL) was added. The liquid was concentrated to an oil, then redissolved in CH2Cl2, and washed with 1 N HCl. The organic layer was dried over MgSO4, filtered, and then concentrated to give the desired product (4.338 g, 83%). MS (ESI): 382 (M−H+).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].S(O[CH2:15][C@H:16]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)(=O)C.C(OCC)(=O)C>C1COCC1>[CH3:1][Si:2]([CH2:3][CH2:4][S:5][CH2:15][C@@H:16]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)COS(C)(=O)=O
Reactant: C[Si](C)(C)CCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)CSCC[Si](C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 2-trimethylsilylethanethiol (0.86 g, 6.41 mmol), synthesis described by Anderson, Ranasinghe, Palmer, and Fuchs, above) in THF (10 mL) was added sodium hydride (0.256 g, 6.41 mmol as a 60% mineral oil dispersion). The mixture was stirred for 10 minutes. Boc-homophenylalaninol mesylate (2.00 g, 5.82 mmol, synthesis described in Example 13, above) was added. The solution was stirred for 2 hours. Ethyl acetate (50 mL) was added. The solution was washed with 30 mL each of 1M HCl, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure, giving the intermediate (S)-2-tert-butoxycarbonylamino-4-phenylbutyl trimethylsilylethyl sulfide. TLC: (5% ethyl acetate/hexane) Rf =0.22. This material was dissolved in CH2Cl2 (50 mL), cooled to -10° C., and treated with 4-chloroperbenzoic acid (3.24 g, 12.22 mmol, estimated 65% peracid content). The mixture was stirred overnight. The suspension was filtered, and saturated aqueous NaHSO3 (40 mL) and saturated aqueous sodium bicarbonate (50 mL) were carefully added to the filtrate. The organic phase was separated, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the product, Boc-Hph-β-SO2CH2CH2TMS in quantitative mass recovery from the mesylate. TLC: (30% ethyl acetate/hexane) Rf =0.49.