Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:14])=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[C:6]([O:8][CH3:9])=[O:7].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Cl:14][C:4]1[C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:12]([F:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(F)c(CN)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(CNC(=O)C(C)(C)C)c1Cl
Yield: 81.7 %

Procedure:
The title compound was prepared following the procedure described in step-2 of Intermediate-2 using methyl 3-(aminomethyl)-2-chloro-4-fluorobenzoate (340 mg, 1.42 mmol), DIPEA (550 mg, 4.27 mmol) and pivaloyl chloride (204 mg, 1.7 mmol) in CH2Cl2 (5 mL) to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 7.81-7.74 (m, 2H), 7.36-7.30 (t, J=9.0 Hz, 1H), 4.39-4.37 (d, J=4.5 Hz, 2H), 3.85 (s, 3H), 1.06 (s, 9H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)CCC>>[N:28]1[CH:29]=[CH:30][C:25]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[N:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(-c2ccncc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from 3′-(5-bromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-(tri-n-butylstannyl)pyridine. The title compound (52 mg) was obtained as a pale solid, m/z 343 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=CC=2OC)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].NC1N(C2CCC2)N=CC=1C#N>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16]
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Agent: N#Cc1cnn(C2CCC2)c1N
Product: NC(=O)c1cnn(C2CCC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-cyclobutyl-1H-pyrazole-4-carbonitrile provided the title compound. 400 MHz 1H NMR (CD3OD) δ 7.71 (s, 1H), 4.71-4.55 (m, 1H), 2.61-2.50 (m,2H), 2.46-2.31 (m, 2H), 1.89-1.83 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH:8]=O)[CH:6]=O)[CH3:2].Cl.[NH:12]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=[O:18])[NH2:13]>CCO>[CH2:1]([O:3][C:4]([C:5]1[CH:8]=[N:13][N:12]([C:14]2[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:6]=1)=[O:10])[CH3:2]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: Cc1ccc(C(=O)O)cc1NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2C)c1
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A solution of 2-formyl-3-oxo-propionic acid ethyl ester (Bertz, S. H.; Dabbagh, G.; Cotte, P. J. Org. Chem. 1982, 47, 2216) (1.44 g, 10 mmol) in EtOH (10 mL) was cooled in an ice bath. A slurry of 3-hydrazino-4-methyl-benzoic acid hydrochloride (2.02 g, 10 mmol) in EtOH (50 mL) was added and the reaction stirred overnight. The EtOH was removed under reduced pressure and the residue partitioned between water and CH2Cl2. The layers were separated and the organic layer washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Hexanes were added and the solution concentrated. The resulting solid was collected by vacuum filtration, washed with hexanes and dried under vacuum to provide 1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.86 g, 68%) as a yellow solid: ESI MS m/z 275 [C14H14N2O4+H]+.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:3][CH:2]1[N:11]1[CH2:27][CH2:26][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH:15]2[OH:25])[CH2:13][CH2:12]1.[C:28]([O-:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([O-:33])=[O:32].C(O)(=O)/C=C/C(O)=O>C(OCC)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]1[CH:10]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:3][CH:2]1[N:11]1[CH2:27][CH2:26][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][C:15]2=[O:25])[CH2:13][CH2:12]1
Reactant: OC1CCN(c2ccccc2)C12CCN(C1CC3CCCCCC3C1)CC2
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CCN(c2ccccc2)C12CCN(C1CC3CCCCCC3C1)CC2

Procedure:
Oxidation of 8-(decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture of diastereoisomers) according to the general method of example 20 and formation of the fumarate with fumaric acid in diethyl ether yielded the title compound, pale brown solid, m.p. 219° C. and MS: m/e=367.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16]CC)=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19].[OH-].[Na+]>C(O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][C:3]3[CH:20]=[CH:21][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[CH:23][C:2]=3[Cl:1])[C:9]=2[CH:10]=1)([OH:16])=[O:15]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(-c4cccs4)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(-c2cccs2)cc1Cl
Temperature: 25 °C
Yield: 37.2 %

Procedure:
1-(2-chloro-4-(thiophen-2-yl)benzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole (0.60 g), a 10% aqueous solution of sodium hydroxide (2 ml), and ethanol (5 ml) were mixed and refluxed for 15 minutes under heating. After allowing the solution to cool to room temperature. insoluble matter was removed by filtration with celite. The filtrate was adjusted to pH 6 with 1N hydrochloric acid (about 4 ml). The deposited crystals were collected by filtration, washed with 50% aqueous ethanol, and dried under reduced pressure to obtain the desired compound, 6-carboxy-1-(2-chloro-4-(thiophen-2-yl) benzyl)-2-methylbenzimidazole (0.208 g).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:11][C:10]=2[CH3:24])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:27][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:11][C:10]=1[CH3:24]
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cyclohexyl{2-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methanol (1.20 g) synthesized above in toluene (20 mL) was added thionyl chloride (297 μL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.27 g, quantitative) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH2:31][C:32]#[N:33])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:40][CH2:39][CH2:38][CH2:37]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([C:31](=[CH:37][CH:38]4[CH2:40][CH2:39]4)[C:32]#[N:33])=[O:34])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: C1CCNCC1
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (120 mg, 0.26 mmol, 1.00 equiv), piperidine (27 mg, 0.28 mmol, 1.07 equiv) and cyclopropanecarbaldehyde (28 mg, 0.40 mmol, 1.51 equiv) in methanol (8 mL) was stirred in sealed tube at room temperature for 24 h. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 85.4 mg (64%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 506 (M+1). 1HNMR (300 MHz, CDCl3, ppm) 8.392 (1H, s), 7.676˜7.581 (2H, t), 7.445˜7.393 (2H, t), 7.202˜7.097 (5H, m), 6.601˜6.566 (1H, d, J=10.5), 5.737 (2H, s), 5.010˜4.912 (1H, m), 4.691˜3.185 (4H, m), 2.464˜2.035 (5H, m), 1.275˜0.876 (4H, m).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.C(O[CH:24](OCC)[CH2:25][CH2:26][CH2:27][NH:28][CH3:29])C>O.Cl>[CH:1]1([CH2:7][CH2:8][N:9]2[C:11]3[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:25]([CH2:26][CH2:27][NH:28][CH3:29])=[CH:24]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(CCCNC)OCC
Reactant: Cc1ccc(N(N)CCC2CCCCC2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCCc1cn(CCC2CCCCC2)c2ccc(C)cc12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
The title compound was prepared by General Method 3. A solution of 1-(2-cyclohexylethyl)-1-p-tolylhydrazine (0.15 g) in water (1 mL) and conc. HCl (0.18 mL) was heated to 60° C. EtOH (1 mL) was added followed by 4,4-diethoxy-N-methylbutan-1-amine (0.12 g) and the temperature was raised to 90° C. Conc. HCl (0.1 mL) was added and the heating was continued for an additional 6 h after which the reaction mixture was cooled and stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 9/1/0.1) to obtain 79 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:13][CH2:14]Br.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#CCc1cc(F)cc(F)c1
Reactant: BrCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2cc(F)cc(F)c2)CC1
Reaction time: 8 h

Procedure:
To a mixture of 3,5-difluoro-phenylacetonitrile (11.48 g), 1,2-dibromoethane (42.2 ml) and benzyltriethylammonium chloride (0.68 g) was added sodium hydroxide solution (50% in water, 30 ml) at room temperature. The mixture was vigorously stirred overnight. Water was added and the aqueous phase was extracted twice with diethyl ether. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (SiO2; heptane/EtOAc) to give 1-(3,5-difluoro-phenyl)-cyclopropanecarbonitrile as a light pink solid (8.23 g). 1H-NMR (300 MHz, CDCl3, δ): 1.40-1.44, (m, 2H), 1.78-1.82 (m, 2H), 6.70-6.85 (m, 3H).
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[CH:2].C#CCCCCCC.[Br:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:14]([O:13][C:12](=[O:18])[NH:11][C:3]1([C:1]#[C:2][C:31]2[CH:32]=[CH:33][C:28]([Br:27])=[CH:29][CH:30]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: Brc1ccc(I)cc1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(Br)cc2)COC(C)(C)OC1
Yield: 63 %

Procedure:
When tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and 4-bromo-iodobenzene was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 63% yield, as a pale paste, which solidified on standing. 1H-NMR (CDCl3) 1.43 (s, 2H); 1.46 (s, 9H); 1.48 (s, 3H); 4.00 (d, 2H, J=11.35 Hz); 4.08 (d, 2H, J=11.41 Hz); 5.19 (s, 1H); 7.26 (d, 2H, J=6.74 Hz); 7.41 (d, 2H, J=6.67 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](COCC[Si](C)(C)C)[C:11]([C:21]([F:24])([F:23])[F:22])=[N:10][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:21]([F:23])([F:22])[F:24])=[N:10][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(C(F)(F)F)nc(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Yield: 38.9 %

Procedure:
A solution of protected sulfonamide from step 2 (500 mg, 1 mmol) in a solution of 3 N HCl (5 ml) in EtOH (4 ml) was heated to reflux for 1 hour, cooled and diluted with water (20 ml). The resulting mixture was extracted with methylene chloride, dried (Na2SO4) and the solvent was evaporated. The residue was recrystallized from toluene containing a small amount of ethyl acetate to give the title product (150 mg, 40%): m.p. 259-260° C. Anal. Calc'd. for C16H11N3O2F4S: C, 49.87; H, 2.88; N, 10.90; S, 8.32. Found: C, 50.30; H, 3.10; N, 10.55; S, 8.73.
Reaction SMILES: [C:1]1([C:6](Cl)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][C:25]1=[O:33])[CH3:23]>O>[CH2:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:6](=[O:7])[C:1]3[S:5][CH:4]=[CH:3][CH:2]=3)=[CH:30][CH:31]=2)[CH2:26][C:25]1=[O:33])[CH3:23]
Reactant: O=C(Cl)c1cccs1
Reactant: CCN1C(=O)Cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCN1C(=O)Cc2cc(C(=O)c3cccs3)ccc21
Temperature: 100 °C
Yield: 47.7 %

Procedure:
To a mixture of 27.3 g. (19.9 mmoles) of 2-thenoyl chloride, 30 ml. of nitrobenzene and 32.95 g. of aluminum chloride was gradually added 10 g. (62 mmoles) of 1-ethyloxindole, and the resulting reaction mixture heated at 100° C. for 75 minutes. The reaction was cooled to room temperature and poured into 2 l. of ice and water. The product was extracted with methylene chloride and the dried extract concentrated to dryness, 11.05 g. The product was recrystallized from methylene chloride-hexane, 8.03 g. (47.7% yield)m, m.p. 158°-160° C.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:11]([N:13]1[CH2:34][CH2:33][CH2:32][C@H:14]1[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:30]([Cl:31])=[N:29][S:28][N:27]=1)=[O:16])=[O:12])=O)(C)(C)C>>[ClH:25].[NH2:9][C@H:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:11]([N:13]1[CH2:34][CH2:33][CH2:32][C@H:14]1[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:30]([Cl:31])=[N:29][S:28][N:27]=1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1nsnc1Cl)C1CCCCC1
Agent: Cl
Product: N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1nsnc1Cl)C1CCCCC1

Procedure:
HCl gas was bubbled through a stirred 0° C. solution of 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide (41.1 mg, 0.07 mmol) CH2Cl2 (1.0 mL) for 15 min. The solution was reduced in vacuo. 1-[(2R)-2-amino-2-cyclohexylethanoyl]-N-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide hydrochloride was isolated as a solid. LCMS m/z=496.5.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: ClCCl
Product: CC(=O)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To 1.0 q (3.4 mmole) of 2-(4 mercaptophenyl)-(4 pyridyl)-6,7-dihydro [5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 in 50 ml methylene chloride at 0° C. was added a solution of 0.3 g (3.7 mmole, 0.26 ml) acetyl chloride in 10 ml CH2Cl2 over a period of 10 minutes. The reaction was allowed to come to room temperature and was stirred for 30 minutes. The mixture was then diluted with methylene chloride and washed with 3N NaHCO3, saturated NaCl, treated with Na2SO4, stripped, then flash chromatographed on silica with methylene chloride containing 1% to 5% MeOH. The isolated material was recrystallized twice from ethyl acetate to give 0.20 g of the titled compound. 17.6% yield, mp 216-217.5 152°-154° C. C19H17N3OS, Calculated, C: 68.03, H: 5.11, N: 12.53; Found, C: 68.25, H: 5.40, N: 12.14.
Reaction SMILES: [CH3:1][C@H:2]([CH:9]=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH:12](Cl)[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[Li+].[I-]>C1COCC1>[CH3:1][C@H:2](/[CH:9]=[CH:12]/[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Reactant: CCOC(=O)C[C@H](C)C=O
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](C)/C=C/B1OC(C)(C)C(C)(C)O1

Procedure:
Following the same procedure for the preparation of pinacol boronates, the reaction of ethyl (S)-3-methyl-4-oxobutanoate (S)-3 (0.057 g, 0.40 mmol) with CrCl2 (0.39 g, 3.18 mmol), 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 5 (0.168 g, 0.80 mmol) and LiI (0.21 g, 1.59 mmol) in THF (6 mL) afforded, after purification by column chromatography (silica gel, 97:3 hexane/ethyl acetate), 69 mg (65%) of a colourless oil identified as ethyl (3S,4E)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoate (S)-4.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[N:6]=1>O1CCOCC1.O.CCOCC>[CH:11]([C:9]1[CH:10]=[C:5]([CH3:4])[N:6]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]([O:16][CH3:17])=[O:15])[N:8]=1)=[O:2]
Reactant: O=[Se]=O
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(C)n1)C(OC)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: COC(=O)[C@@H](Oc1nc(C)cc(C=O)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Selenium dioxide (8.5 g, 76 mmol) is dissolved in a solution of dioxane (238 mL) and water (40 mL) at 55-60° C. To the solution of selenium dioxide, the compound of Example 9 (20 g, 51 mmol) is added and then the reaction mixture is heated at reflux for 10 hr. The reaction mixture is cooled to room temperature, diluted with ether (200 mL) and filtered. The filtrate is concentrated at reduced pressure on a rotary evaporator and then extracted with ethyl acetate (2×100 mL) to yield the crude title compound. MS m/z 406.9 (M+.+1).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:9])#[N:4].[F:24][C:25]([F:34])([F:33])[C:26](I)([F:31])[C:27]([F:30])([F:29])[F:28]>CN(C)C=O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:26]([F:31])([C:27]([F:30])([F:29])[F:28])[C:25]([F:34])([F:33])[F:24])=[CH:13][C:12]=1[C:17]([F:19])([F:18])[F:20])=[O:9])#[N:4]
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2C(F)(F)F)c1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
1.1 g (29 mmol) of powdery sodium hydroxide and 1.3 g (4.8 mmol) of iron(II) sulfate heptahydrate were stirred in an ice bath, until the color of the mixture changed to black. Immediately after the discoloration, 5 g of N,N-dimethylformamide were added thereto, and then, a solution obtained by dissolving 1.0 g (3.5 mmol) of 3-cyano-N-(2-(trifluoromethyl)phenyl)benzamide and 1.4 g (4.8 mmol) of heptafluoroisopropyl iodide in 5 g of N,N-dimethylformamide was added thereto, followed by stirring at room temperature for 3 hours. The obtained reaction liquid was filtered through cerite and the residue was washed with 50 mL of ethyl acetate. Then, 40 g of water were added to the resulting reaction liquid, and after performing extraction, the organic layer was dried over magnesium sulfate. Then, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. Thereafter, the condensed residue was purified by silica gel chromatography, to obtain 0.93 g (yield 59%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>CN(C)C=O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH2:8])[N:7]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: Nc1cncc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2cncc(N)n2)CC1
Temperature: 100 °C

Procedure:
4-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamine was prepared from 6-chloro-pyrazin-2-ylamine (1.00 g, 7.72 mmol) and 1-methylpiperazine (942 L, 8.49 mmol) combined in N,N-dimethylformamide (35 mL) and heated at 100° C. overnight. The reaction was poured into water and extracted with 3 portions of dichloromethane. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield an off-white solid. This solid was purified via chromatography (silica gel 40 g methanol in dichloromethane). Product isolated as a tan oil that solidified upon standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm):7.33 (s, 1H), 7.16 (s, 1H), 5.93 (s, 2H), 3.40 (s, 4H), 2.36 (s, 4H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>C1COCC1>[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[N:29]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:8][CH2:9][CH3:10]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCC[C@@H](C)CCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 25 °C

Procedure:
To (R)-4-methyl-heptanoic acid (19 g, 0.132 mol) and triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0° C. was added trimethylacetylchloride (20 g, 0.17 mol). After 1 hour LiCl (7.1 g, 0.17 mol) was added followed by (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone) 3 (30 g, 0.17 mol). The mixture was warmed to room temperature and after 16 hours the filtrate was removed by filtration and the solution concentrated under reduced pressure. Flash chromatography (7:1 hexane/EtOAc) gave (4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one as an oil. 31.5 g; 79%. [α]D=+5.5 (c 1 in CHCl3). MS, m/z (relative intensity): 304 [M+H, 100%]; 1H NMR (400 MHz; CDCl3) δ 7.4–7.2 (m, 5H), 5.6 (d, J=7.32 Hz, 1H), 4.75 (m, 1H), 2.96 (m, 1H), 2.86 (m, 1H), 1.62 (m, 1H), 1.43 (m, 1H), 1.25 (m, 4H), 1.12 (m, 1H), 0.85 (m, 9H); 13C NMR (100 MHz; CDCl3) δ 173.70, 153.23, 133.81, 133.59, 128.92, 128.88, 128.92, 128.88, 125.83, 79.12, 54.93, 39.24, 33.66, 32.32, 31.47, 27.18, 26.52, 20.25, 19.57, 14.75, 14.52.