Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([C:17]#[N:18])[S:15][CH:16]=3)[CH:10]=[CH:11][C:6]=2[NH:5][CH:4]([C:19]([F:22])([F:21])[F:20])[O:3]1.[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>CN(C=O)C.[Cl-].[Na+].O>[C:26]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([C:17]#[N:18])[S:15][CH:16]=3)=[CH:8][C:7]=2[C:2]([CH3:23])([CH3:1])[O:3][CH:4]1[C:19]([F:22])([F:20])[F:21])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(-c3csc(C#N)c3)cc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3csc(C#N)c3)cc2C(C)(C)OC1C(F)(F)F
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.25 g, 0.74 mmol) was dissolved in DMF (10 mL), NaH (0.09 g, 2.22 mmol) was added and the mixture was stirred for 30 minutes prior to the addition of acetyl chloride (0.079 mL, 1.11 mmol). Upon disappearance of the starting material the reaction mixture was poured into brine (100 mL) and the product extracted with ether (150 mL), dried over sodium sulfate and concentrated. The residue was purified by a flash column chromatography (silica gel, 25% ethyl acetate/hexane) to yield 4-[1-acetyl-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.1 g, 36%) as an amorphous solid: 1H-NMR (DMSO-d6) δ 8.58 (s, 1H), 8.5 (s, 1H), 7.83-7.80 (m, 2H), 7.64 (d, 1H, J=8.74 Hz), 6.42 (q, 1H, J=10 Hz), 2.24 (s, 3H), 1.73 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([CH2:15][CH2:16][NH2:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][CH2:15][C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: NCCC1=CCCCC1
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(NCCC2=CCCCC2)cc1
Yield: 95.2 %

Procedure:
Using the general procedure, 4-bromotoluene (172 mg, 1.0 mmol) was coupled with 2-(1-cyclohexenyl)ethylamine (209 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent afforded the desired product as a colorless oil (205 mg, 95% yield). Rf=0.6 (hexane/ethyl acetate=10:1).
Reaction SMILES: [CH2:1]([C:3]1[S:25][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1)[CH3:2].[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[CH2:1]([C:3]1[S:25][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:26](=[O:28])[CH3:27])[CH2:20]4)=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(N3CCN(C(=O)C4CCCNC4)CC3)ncnc2s1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2c(N3CCN(C(=O)C4CCCN(C(C)=O)C4)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
[4-(6-Ethyl-thieno[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-piperidin-3-yl-methanone (Example 294, 17.0 mg) was dissolved in methylene chloride (1.00 mL) and diisopropylethylamine (12.4 μL). Acetylchloride (3.7 μL) was added and the reaction was stirred at room temperature for 30 minutes. The reaction was applied to silica gel and the product was isolated by eluting from 0% to 4% methanol/methylene chloride over 45 minutes then 10% methanol/methylene chloride for 15 minutes. Yield=53%, ES-MS: (M+H)+ 402
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26](=[O:28])[CH3:27])=[CH:23][C:22]=2[CH:29]=1>>[C:26]([C:24]1[O:25][C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:2]3[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:29][C:22]=2[CH:23]=1)(=[O:28])[CH3:27]
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Product: CC(=O)c1cc2cc(NC3=C(c4ccccc4)S(=O)(=O)N(C)C3=O)ccc2o1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(5-amino-1-benzofuran-2-yl)ethanone in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 7.89 (bs, 1H), 7.38-7.37 (m, 1H), 7.25 (d, 1H), 7.16-7.10 (m, 4H), 7.09-7.03 (m, 3H), 3.22 (s, 3H), 2.50 (s, 3H); Mass Spectrum: M+H+ 397.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=1.Cl>C(OCC)(=O)C.O.CN(C)C=O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC(F)(F)F)s1
Reaction time: 4 h
Yield: 18.3 %

Procedure:
To an N,N-dimethylformamide solution (30 mL) of 2,2,2-trifluoroethanol (1.50 g, 15.0 mmol), sodium hydride (655 mg, 15.0 mmol) and ethyl 5-chlorothiophene-2-carboxylate (1.91 g, 10.0 mmol) were added and the resultant mixture was stirred at 65° C. for 6 hours, at room temperature for 15.5 hours, and at 65° C. for 4 hours. After completion of the reaction, water and 1 M hydrochloric acid were added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (464 mg, yield 18%).
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@@:6]([OH:24])([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:5](=[O:25])[CH2:4]2)[CH3:2].[CH3:26][Li].[I-].[Li+]>O1CCCC1>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([OH:24])[C@:5]([CH3:26])([OH:25])[CH2:4]2)[CH3:2]
Reactant: [Li]C
Reactant: CC[C@@]12CC(=O)[C@](O)(c3cccnc3)C[C@H]1CCc1cc(O)ccc12
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3cccnc3)C[C@H]1CCc1cc(O)ccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 6.3 %

Procedure:
A solution of (2R,4aR,10aR)-4a-Ethyl-2,7-dihydroxy-2-pyridin-3-yl-1,4,4a,9,10,10a-hexahydro-2H-phenanthren-3-one (30 mg, 0.09 mmol) in tetrahydrofuran (8 mL) was cooled to 0° C. A 1.0 M solution of methyllithium/lithium iodide complex in tetrahydrofuran (0.43 mL, 0.43 mmol) was added and the mixture was allowed to stir from 0° C. to room temperature over 5 hours. The solution was cooled to 0° C. and additional 1.0 M methyllithium/lithium iodide solution (0.2 mL, 0.2 mmol) was added. After the mixture was allowed to stir overnight at room temperature, it was again cooled to 0° C. and more methyllithium/lithium iodide solution (0.3 mL, 0.3 mmol) was added. After stirring the mixture for a further 4 hours at room temperature, it was quenched with water and saturated aqueous ammonium chloride solution. The mixture was extracted six times with ethyl acetate, and the combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The title compound (2 mg, 6%) was isolated by chromatography on silica gel eluting with a gradient of 2% to 10% methanol in chloroform. Mass spectrum (m/e) 354 (M++1).
Reaction SMILES: [H][H].[C:3]([OH:10])(=O)[CH2:4][CH2:5][C:6]([CH3:8])=O.[NH2:11][C:12]1[CH:13]=[C:14]([C:16]([CH3:20])=[CH:17][C:18]=1[CH3:19])[NH2:15]>C(O)C.[Pt]=O>[NH2:11][C:12]1[CH:13]=[C:14]([N:15]2[CH:6]([CH3:8])[CH2:5][CH2:4][C:3]2=[O:10])[C:16]([CH3:20])=[CH:17][C:18]=1[CH3:19]
Reactant: [H][H]
Reactant: Cc1cc(C)c(N)cc1N
Reactant: CC(=O)CCC(=O)O
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cc(C)c(N2C(=O)CCC2C)cc1N
Yield: 80 %

Procedure:
A suspension of 0.2 g of platinum oxide in 25 ml of ethanol is treated with hydrogen and a solution of 34.8 g (0.3 mol) of levulinic acid and 85 g (0.62 mol) of 3-amino-4,6-dimethylaniline in 300 ml of ethanol is then added. The hydrogenation is carried out at room temperature. The desired pyrrolidinone derivative is obtained in a yield of about 80%.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12](Cl)=[O:13].Cl.[CH2:21]1COCC1>>[F:8][C:9]1[CH:10]=[C:11]([C:12]([O:13][CH3:21])=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: N#CCC#N
Reactant: C1CCOC1
Reactant: COc1cc(F)cc(C(=O)Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=C(C#N)C#N)c1cc(F)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of malononitrile (2.87 g, 0.044 mmol) in dry THF (50 ml) was stirred at 0° C. under an argon atmosphere. NaH in paraffin oil (4.64 g, 0.116 mol) was added piece-wise to solution. 3-fluoro-5-methoxybenzoyl chloride (BA67, 0.029 mol) was dissolved in 50 ml dry THF and added slowly to reaction. Reaction was warmed to room temperature and stirred under argon for 24 hours. 1N HCl (200 ml) was slowly added, then reaction mixture was extracted with EtOAc. Organic phases were combined, dried with magnesium sulfate, then concentrated in vacuo to yield 2-((3-fluoro-5-methoxyphenyl)(methoxy)methylene)malononitrile (BA69).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:23][C:24]1([CH3:37])[O:28][CH:27]([C:29]2[CH:30]=[CH:31][C:32]([CH:35]=[O:36])=[N:33][CH:34]=2)[CH2:26][O:25]1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:37])[O:28][CH:27]([C:29]2[CH:30]=[CH:31][C:32]([C:35](=[O:36])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:33][CH:34]=2)[CH2:26][O:25]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: CC1(C)OCC(c2ccc(C=O)nc2)O1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)OCC(c2ccc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)nc2)O1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
To a solution (10 mL) of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (500 mg) in ethanol were added 5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-2-carbaldehyde (350 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (45.0 mg) and triethylamine (93 μL), and the mixture was stirred with heating under reflux for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (232 mg, yield 28%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 530 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[CH:10][N:11](C)[C:7]=2[CH:6]=[C:5]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:14]=2)[N:4]=1)#[N:2].[CH3:35][NH2:36]>CO.O>[CH3:35][NH:36][C:25]([C:23]1[N:24]=[C:19]([CH2:18][O:17][C:16]2[CH:29]=[CH:30][C:13]([C:5]3[N:4]=[C:3]([C:1]#[N:2])[C:8]4[N:9]=[CH:10][NH:11][C:7]=4[CH:6]=3)=[CH:14][C:15]=2[C:31]([F:33])([F:32])[F:34])[CH:20]=[CH:21][CH:22]=1)=[O:27]
Reactant: COC(=O)c1cccc(COc2ccc(-c3cc4c(ncn4C)c(C#N)n3)cc2C(F)(F)F)n1
Reactant: CN
Solvent: O
Solvent: CO
Product: CNC(=O)c1cccc(COc2ccc(-c3cc4[nH]cnc4c(C#N)n3)cc2C(F)(F)F)n1
Temperature: 120 °C

Procedure:
The mixture of methyl 6-((4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)methyl)picolinate (0.064 mmol, 30 mg) and methylamine in methanol (2M, 1 ml) was heated with microwaves at 120° C. for 10 minutes, then diluted with water (3 ml). The product was collected by filtration and washed with cold methanol (3 ml) to give 6-(4-((6-(methylaminocarbonyl)pyridin-2-yl)methoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (22 mg). 1H NMR (DMSO) δ: 8.80 (s, 1H), 8.77 (m, 1H, NH), 8.76 (s, 1H), 8.54 (m, 2H), 8.16 (m, 1H), 8.06 (d, 1H), 7.76 (d, 1H), 7.59 (d, 1H), 5.58 (s, 2H), 4.04 (s, 3H). MS m/z 467 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.I[C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1>>[OH:25][C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:3]=2)=[CH:17][CH:18]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(O)c1ccc(I)cc1
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Product: CC(C)(O)c1ccc(Nc2nn(-c3ccccc3)cc2C#N)cc1

Procedure:
3-{[4-(1-hydroxy-1-methylethyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carbonitrile was prepared according to the general procedure in Example 11 Step 1 using 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (70 mg, 0.380 mmol) and 2-(4-iodophenyl)propan-2-ol (100 mg, 0.380 mmol) as the starting materials.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[N:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:2].[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C.[Na:42].[OH-].[Na+]>C(Cl)Cl.C(O)C>[Na:42].[C:28]([NH:23][S:20]([C:17]1[CH:18]=[N:19][C:14]([N:6]2[C:7]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:3]([C:1]#[N:2])[C:4]([C:24]([F:26])([F:27])[F:25])=[N:5]2)=[CH:15][CH:16]=1)(=[O:21])=[O:22])(=[O:30])[CH3:29]
Reactant: CC(C)(C)CNc1c(C#N)c(C(F)(F)F)nn1-c1ccc(S(N)(=O)=O)cn1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2NCC(C)(C)C)nc1
Yield: 80 %

Procedure:
6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid amide (166.3 mg, 0.413 mMol), was dissolved in methylene chloride (10 ml) and stirred under nitrogen. Acetic anhydride (126.5 mg, 1.239 mMol), triethylamine (49.3 mg, 0.49 mMol) and N,N-dimethylaminopyridine (25.2 mg, 0.5 mMol) were added into the methylene chloride solution, and stirred for 18 hours. The reaction mixture was washed with water and brine, dried with magnesium sulfate, filtered, and evaporated. The residue was chromatographed on silica, eluting with 0.75% methanol/methylene chloride, to give a free acid in 80% yield. The free acid was converted to the sodium salt by reacting the free acid with one equivalent of sodium hydroxide in ethanol, evaporation, and drying under high vacuum. The desired product was isolated by chromatography on silica gel column. MS: 443.5 ES, r.t.: 3.0 minutes.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([CH3:28])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[F:26])[C:18]2=[O:27])=[CH:12][CH:11]=1)[C:5]([O:7]CC)=[O:6].CO.[OH-].[Na+].Cl>C1COCC1.O>[F:30][C:2]([F:1])([F:29])[CH:3]([CH3:28])[CH:4]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[F:26])[C:18]2=[O:27])=[CH:14][CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C(C(=O)O)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
855 mg (2.02 mmol) of ethyl 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoate were dissolved in 5.7 ml each of THF, methanol and water, and 16.2 ml (40.39 mmol) of 10% strength aqueous sodium hydroxide solution were added. The mixture was stirred at RT overnight. The reaction mixture was then diluted with water, acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 457.2 mg (58.2% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Br.[C:15]([O:19][C:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]1[CH2:31][NH:32][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:34])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[C:15]([O:19][C:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][N:32]([CH2:12][C:5]1[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:34])=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: CC(NCC1Nc2ccccc2N1C(=O)OC(C)(C)C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C(C)c1ccccn1

Procedure:
Using General Procedure A: Reaction of 2-bromomethyl-5-cyano-benzoic acid methyl ester and 2-[(1-pyridin-2-yl-ethylamino)-methyl]-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester in CH3CN with DIPEA, KI, and DMAP gave 2-{[(4-cyano-2-methoxycarbonyl-benzyl)-(1-pyridin-2-yl-ethyl)amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a light yellow solid. 1H NMR (CDCl3) δ 1.56-1.59 (m, 3H), 1.71 (s, 9H), 3.86 (s, 3H), 4.23 (s, 1H), 4.28-4.30 (m, 2H), 4.40-4.47 (m, 2H), 7.10-7.16 (m, 1H), 7.24-7.32 (m, 3H), 7.42-7.46 (m, 1H), 7.51-7.66 (m, 2H), 7.71-7.76 (m, 1H), 7.82 (d, 1H, J=1.7 Hz), 7.92 (d, 1H, J=8.0 Hz), 8.53 (d, 1H, J=4.8 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH2:18][CH2:19]Cl)(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=[O:6])=[O:5].C(N(CC)CC)C.C1(C=CC(O)=CC=1)O>C(OCC)(=O)C.CN(C)C=O>[CH:18]([S:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])=[CH:9][CH:10]=1)(=[O:17])=[O:16])=[CH2:19]
Reactant: O=S(=O)(CCCl)Cc1ccc(CS(=O)(=O)CCCl)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Cc1ccc(CS(=O)(=O)C=C)cc1

Procedure:
A suspension consisting of 21.2 g. of α,α'-bis(2-chloroethylsulfonyl)-p-xylene (prepared from p-xylylene dichloride as in Example 1), 25 ml. of triethylamine, 0.05 g. of hydroquinone and 400 ml. of ethyl acetate-N,N-dimethylformamide (1:1 v./v.) were stirred at 25° C. for 20 hours and filtered. The filtrate was evaporated to 150 ml. volume, poured into water and the white solid isolated and recrystallized from methanol and ethyl acetate; m.p. 207°-212° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:16](OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:15]([CH2:28][OH:29])[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CS(C)=O.CCOCC>[CH2:1]([O:8][C@@H:9]1[CH2:16][C@@H:15]([CH2:28][OH:29])[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](CO)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CO[C@@H]1C[C@H](OCc2ccccc2)C[C@@H](CO)O1
Temperature: 80 °C
Yield: 81.3 %

Procedure:
Methyl 3-O-benzyl-4-O-tosyl-2-deoxy-α-D-ribo-hexopyranoside (6.55 g, 15.50 mmoles) is dissolved in dry DMSO (50 ml). Sodium borohydride (2.35 g; 62.01 mmoles) is added and the reaction is stirred under nitrogen in a bath maintained at 80° C. for four days. The reaction is cooled to room temperature and diluted with ether and extracted with water. The aqueous extract is then extracted four times with ether. The combined ether extracts are dried (MgSO4), filtered, and the solvent evaporated in vacuo to give crude product. This crude product is purified by flash chromatography on a 60 mm×150 mm column eluting with 15% (by volume) acetone in methylene chloride. A small portion (0.9 g) containing an impurity is rechromatographed on a 30 mm×130 mm column with the same eluant to give a combined total of 3.18 g of methyl 3O-benzyl-2,4-dideoxy-α-D-erythro-hexopyranoside as a gum, [α]D25 +58.56 (c, 0.7, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]2)[CH2:6]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH:27][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.030 g (0.06 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-aminopropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine, 0.02 mL (0.24 mmol) of methanesulfonyl chloride, and 0.03 mL (0.15 mmol) of diisopropylethyl amine in 0.5 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, CH2Cl2:methanol, 95:5) to give the title compound. Mass Spectrum (ESI) m/e=574 (M+1 35Cl, 35Cl), 576 (M+1 35Cl, 37Cl), and 578 (M+1 37Cl, 37Cl). [a]D=+11.0 (c=0.815, CHCl3).
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[N:7]2[C:8]=1[C:9]([O:11]CC=C)=[O:10])=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[K+:50].C(OCC)(=O)C>C(OCC)C.C(Cl)Cl.C(OCC)(=O)C>[N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10])=[N+:2]=[N-:3].[K+:50]
Reactant: C=CCOC(=O)C1=C(N=[N+]=[N-])C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(N=[N+]=[N-])C[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of allyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (42 mg, 0.15 mmol) and triphenylphosphine (12 mg, 0.045 mmol) in 1:1 methylene chloride-ethyl acetate (2.7 ml) is treated with 0.5M potassium 2-ethylhexanoate in ethyl acetate (0.3 ml, 0.15 mmol) and tetrakis(triphenylphoshine)palladium (O) (13.8 mg, 0.012 mmol). The mixture is stirred 15 minutes at ambient temperature under a nitrogen atmosphere, diluted with diethyl ether, and centrifuged. The insoluble pellet is washed with ether and dried under vacuum to afford potassium (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:23]2([C:26]#[N:27])[CH2:25][CH2:24]2)[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:23]2([C:26]#[N:27])[CH2:24][CH2:25]2)[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: N#CC1(c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CO
Product: N#CC1(c2ccc(O)c(O)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
To a solution of 1-(3,4-bis-benzyloxy-phenyl)-cyclopropanecarbonitrile (10 g, 28 mmol) in MeOH (50 mL) was added Pd/C (0.5 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 4 h. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give 1-(3,4-dihydroxy-phenyl)-cyclopropanecarbonitrile (4.5 g, 92%). 1H NMR (DMSO 400 MHz) δ 9.06 (br s, 2 H), 6.67-6.71 (m, 2 H), 6.54 (dd, J=2.4, 8.4 Hz, 1 H), 1.60-1.57 (m, 2 H), 1.30-1.27 (m, 2 H).