Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.C[O-].[Na+].P([O-])([O-])([O-])=O>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: COC(=O)CCS
Reactant: CC1OC1(Cn1cncn1)c1ccc(F)cc1F
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of (2RS,3SR)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (7.0 g), methyl 3-mercaptopropionate (30.8 ml) and 28% sodium methylate-methanol solution (19.6 ml) in methanol (210 ml) was refluxed for 2 hours. 28% Sodium methylate methanolic solution (9.8 ml) was added to the resultant solution and refluxed for 1 hour. Thereafter, methyl 3-mercaptopropionate (4 ml) was added to the resultant solution and refluxed for 2 hours. After ice-cooling, the reaction mixture was diluted with water (100 ml) and neutralized with 5% aqueous phosphate solution, and extracted with methylene chloride (200 ml×2). The extract was dried over anhydrous sodium sulfate and distilled off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (4×50cm), eluting with ethyl acetate-hexane (3:1). The collected fractions of the object compound were concentrated and ethyl ether was added to the residue to obtain (2RS,3 RS)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2butanol (5.5 g) as colorless needles.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1[C:40]2[CH:39]([CH2:41][O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH:47]=O)[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:37]1[C:38]2[CH:39]([CH2:41][O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH2:47][N:21]([CH:18]([C:9]3[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:13](=[O:14])[C:12]4=[CH:15][CH:16]=[CH:17][N:11]4[N:10]=3)[CH2:19][CH3:20])[CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:40]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: O=CCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
A mixture of 3-benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 150 mg, 0.41 mmol), (3-oxo-propyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (Org. Lett. 2002, 4, 3001–3003, 184 mg, 0.62 mmol), acetic acetic (1.5 eq), 4 Å molecular sieves (100 mg), and 1,2-dichloroethane (10 mL) was stirred at room temperature for 30 min, then treated with sodium triacetoxyborohydride (130 mg, 0.62 mmol). After 3 h, the mixture was filtered and the filtrate washed with saturated sodium bicarbonate and water, dried (MgSO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/hexanes to give the title compound as a white solid (115 mg, 44%): MS (ESI+) 644.44 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:38][CH:39]([Cl:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:38][CH:39]([Cl:43])[C:40]([N:20]([CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:15]=1)=[O:41]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCOP(=O)(CCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylphosphonate (660 mg, 1.4 mmol) was dissolved in anhydrous methylene chloride (10 mL) with triethylamine (0.28 mL, 1.7 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (161 μL, 1.7 mmol) in anhydrous dichloromethane (0.5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate:hexanes followed by 98:2 methylene chloride:methanol to give diethyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylphosphonate (Cpd. No. 1) as a white solid. 1H NMR (CDCl3): 7.94 (m, 1H), 7.79 (m, 1H), 7.64 (m, 1H), 7.46-7.40 (m, 2H), 7.43-7.36 (m, 2H), 6.72 (s, 1H), 5.85 (s, 1H), 4.08 (m, 6H), 2.13 (m, 2H), 1.33 ppm (m, 6H). MW=580 confirmed by LC-MS, tr=11.55 min (Method A) MH+=578-582.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].CCOCC.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C(N(CC)CC)C>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][S:14]([N:13]([CH3:18])[CH3:12])(=[O:16])=[O:15]
Reactant: CC(C)(N)CN
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NCC(C)(C)N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A mixture of 30.7 g (0.35 mol) of 1,2-diamino-2-methylpropane, 150 ml of ether and 50 ml of triethylamine was cooled to 0° C. and 20 g (0.14 mol) of dimethylsulfamoyl chloride was added slowly. The reaction mixture was stirred for 30 minutes and evaporated to dryness. The residue was mixed with water, basified with K2CO3 and evaporated to dryness. Acetone was added and the mixture was filtered. Evaporation of the filtrate gave a solid which was recrystalized from toluene to give 16.5 g (60.3%) of product, mp 77°-78° C. The NMR and IR were consistent with the assigned structure.
Reaction SMILES: [CH2:1](O)[C:2]#C.Cl[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:7][CH2:6][C:1]#[CH:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCO
Reactant: ClCOCc1ccccc1
Product: C#CCOCc1ccccc1

Procedure:
Propargyl alcohol is allowed to react with chloromethylbenzyl ether to obtain 1-benzyloxy-2-propyne (1). Then, this is allowed to react with Grignard reagent and a trifluoroacetic acid ester to obtain 5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-one (2). Then, this is allowed to react with hydride of boron or aluminum to obtain 5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-ol (3). This is acetylated or isobutylated and thereafter lipase or lipase-producing microorganism is allowed to act thereon to obtain optically active (R)-5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-ol [(R)-(3)] and optically active (S)-5-benzyloxy-1,1,1-trifluoro-2-acetoxy (or butoxy)-3-pentyne [(S)-(4)].
Reaction SMILES: ClCCl.Cl.[NH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7]O.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[C:14]1([C:13]([NH:5][C:6](=[CH2:7])[C:9]([O:11][CH3:12])=[O:10])=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(NC(=O)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To dichloromethane (400 mL) were added methyl serinate hydrochloride (45.0 g) and triethylamine (132 mL), and benzoyl chloride (77.0 mL) was added dropwise. After stirring at room temperature overnight, the reaction system was washed twice with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 mL), and 2,3,4,6,7,8,9,10-octahydroprimido[1,2-a]azepine (52.0 g) was added. The mixture was stirred at room temperature for 4 hr, and the reaction system was washed twice with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product (67.0 g) of the title compound as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.I[C:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:18]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:17]3[C:25]4[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=4)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:18]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: C=Cc1ccc(N2CCN(C)CC2)nc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Product: CN1CCN(c2ccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=O)ccc34)cn2)CC1
Temperature: 90 °C

Procedure:
The title compound was synthesized according to the method of Example A15A, utilizing 1-methyl-4-(5-vinylpyridin-2-yl)piperazine (65 mg, 0.32 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol), with heating in a sealed tube at 90° C. overnight instead of with microwave irradiation. Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange material (46 mg, 39%). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1H), 8.34 (d, J=2.26 Hz, 1.0H), 8.24-8.28 (m, 2H), 8.00 (dd, J=8.91, 2.38 Hz, 1H), 7.80 (d, J=8.78 Hz, 1H), 7.51 (d, J=16.56 Hz, 1H), 7.36 (d, J=16.56 Hz, 1H), 6.97 (d, J=9.29 Hz, 1H), 5.85 (s, 2H), 3.77-3.87 (m, 4H), 3.63 (t, J=7.91 Hz, 2H), 3.06-3.15 (m, 4H), 2.75 (s, 3H), 0.88 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 478.3 [M+H]+, calcd for [C26H35N5O2Si+H]+ 478.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH3:49][CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([CH3:49])[CH2:51]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CC1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCN(C(=O)[C@@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.018 g) in DCM (0.5 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.018 g), HOBT (0.013 g) and triethylamine (0.039 ml) and the mixture was stirred at room temperature for 75 min. 3-Methylpiperidine (0.010 ml) was added and the resultant mixture stirred at room temperature for 48 h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract concentrated under reduced pressure and the residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 2:1, 1:1; ethyl acetate; ethyl acetate:methanol 2:1, 1:1) to give the title compound (0.007 g) as a white solid.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:44]=[CH:43][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[C:24]([CH2:33][CH2:34][CH:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:23]2[CH3:42])=[CH:19][CH:18]=1.CN(P(N(C)C)(N(C)C)=[O:49])C>C1COCC1>[Br:16][C:17]1[CH:44]=[CH:43][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[C:24]([CH2:33][CH2:34][C:35]([OH:49])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:23]2[CH3:42])=[CH:19][CH:18]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CCOC(=O)C(C)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25.3 %

Procedure:
n-BuLi (1.6M in hexane, 1.5 mL, 2.4 mmol) was slowly added to 2,2,6,6-tetramethylpiperidine at 0° C. and the slurry was stirred 10 min, then cooled to -78° C. and diluted with 6 mL (oxygenated) THF. The ester from Example 3, Step 2 (880 mg, 1.92 mmol) dissolved in 3 mL THF (O2) was added and the resulting mixture was stirred-- h at -78° C. and 1 h at -45° C. HMPA (668 μL, 3.8 mmol) was added and the mixture was stirred another 2 h at -30° C., then warmed to 0° C. The reaction was quenched with aq. NaHSO3 and then partitioned between saturated NH4Cl and ethyl acetate; the organic layer was washed with water, brine and dried over MgSO4. Purification by flash chromatography (40% ethyl acetate in hexane) provided 230 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([O-:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.[Na+]>>[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: O=S([O-])c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cccc(Cl)c4)cc3c2C1
Yield: 26.8 %

Procedure:
The product of Example 29, step B (230 mg, 0.65 mmol) and sodium 3-chlorobenzenesulfinate (155 mg, 0.78 mmol) were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) provided tert-butyl 8-(3-chlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (78 mg, 26%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 1H), 7.93 (t, J=1.8 Hz, 1H), 7.86-7.83 (m, 1H), 7.83-7.81 (m, 1H), 7.56-7.48 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 4.58 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.91-2.84 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][C:22]2[N:23]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][N:26]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][CH:36]([O:40][CH3:41])N(C)C>>[CH3:34][O:35][CH:36]([O:40][CH3:41])[N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][CH2:30]1
Reactant: c1ccc(C(NCc2nccn2CC2CCNCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(Cn2ccnc2CNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]piperidine (1.45 g, 0.0033M) and dimethylformamide dimethylacetal wass heated at 100° C. for 8 hrs. After this period, the reaction was stripped to dryness to give 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-piperidine carboxaldehyde dimethylacetal. The solution of the piperidinecarboxaldehydedimethylacetal in methylene chloride (5 ml) was added to the mixture of 6-aminopenicillanic acid (0.57 g, 0.0026M) and diisopropylethylamine (0.45 ml) in methylene chloride (5 ml) at 0° C. and stirred at room temperature for 3 hrs. The solvent was removed and the residue was stirred for 2 hrs in water (20 ml) which was maintained at pH 3 with 1NHCl. The mixture was filtered and the filtrate was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[[2-(aminomethyl)-1H-imidazol-1-yl]methyl]-1-piperidinyl] methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.27 g, 24% yield).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH:1]1([NH:6][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC1CCCC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Cyclopentylamine (85.2 g, 1.0 mol) and triethylamine (101.2 g, 1.0 mol) were dissolved in tetrahydrofuran (750 mL) and cooled to 0°-5° C. by means of an ice-water bath. Ethyl bromoacetate (167 g, 1.0 mol) was added dropwise at 0°-5° C. to the solution. After addition the mixture was allowed to warm up to room temperature and then stirred over night at ambient temperature. The precipitated white triethylamine hydrochloride was filtered off and the filtrate concentrated to an oil which was purified over silica gel using hexane/ethyl acetate (8.2) as the eluent. The collected product was dissolved in ether and cooled by means of an ice water bath. Dry hydrogen chloride was bubbled into the solution whereby the HCL salt of the product precipitated. Filtration yielded 138 g of product as a white solid melting at 174°-176° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH2:23]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=1
Reactant: CCCCCCOc1ccc(B(O)O)cc1
Reactant: Cc1ccc(C)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(-c2cc(C)ccc2C)cc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
Bromo-p-xylene (8.3 g, 45 mmol) (cf. A1 a)), K2CO3 (12.4 g, 90 mmol), 70 ml of toluene and 70 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 4-hexyloxyphenylboronic acid (10 g, 45 mmol) and Pd(PPh3)4 (0.65 g, 0.56 mmol) were subsequently added under protective gas. The yellow-green, turbid mixture was stirred vigorously under a blanket of protective gas for about 20 hours at an internal temperature of 85° C. After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The crude product was purified by distillation under reduced pressure: the product was obtained as a yellow oil (boiling point: 117°-125° C./0.08 mbar): 10.3 g (81%). Purity >95% (1H-NMR).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[N:7]1.Cl.[O:15]1CCCC1>CN(C)C=O.C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:4]#[C:3][CH2:2][OH:15])[N:7]=1)([O-:13])=[O:12]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccn(CC#CCCl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccn(CC#CCO)n1
Temperature: 100 °C
Reaction time: 36 h
Yield: 61 %

Procedure:
The 1-(4-chloro-but-2-ynyl)-3-nitro-1H-pyrazole (300 mg, 1.50 mmol) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (6 mL). 1.0 M aqueous hydrochloric acid solution (8 mL) was added and the solution was heated to 100° C. while stirring for 36 h in a sealed vial. The solution was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), saturated aqueous brine solution (2×25 mL), dried over magnesium sulfate and concentrated in vacuo to give a waxy yellow solid. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 4-(3-nitro-pyrazol-1-yl)-but-2-yn-1-ol (166 mg, 61%) as an off white solid: H1-NMR (400 MHz, DMSO-d6) δ 4.12 (2H, d, J=6.0 Hz), 5.23 (2H, s), 7.06 (1H, d, J=2.8 Hz), 8.08 (2H, d, J=3.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(Cl)cc1)CC(F)(F)C(F)F
Yield: 7.5 %

Procedure:
Using 1.0 g of (4-chlorobenzyl)malononitrile, 15 ml of N,N-dimethylformamide, 0.073 g of cesium carbonate, and 1.47 g of 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(4-chlorobenzyl)-2-(2,2,3,3-tetrafluoropropyl)malononitrile (the present compound (25)).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:20]=3)[S:18][C:14]=2[C:13]=1OS(C(F)(F)F)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:20]=3)[S:18][C:14]=2[C:13]=1[C:50]1[CH:51]=[CH:52][C:47]([Cl:46])=[CH:48][CH:49]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)n3)sc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a 10 mL reaction vial, (S)-ethyl 2-tert-butoxy-2-(5-methyl-2-(6-(1-methyl-1H-indazol-5-yl)pyridin-2-yl)-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate (33 mg, 0.050 mmol) and p-chlorophenyl boronic acid (48 mg, 0.20 mmol) were dissolved in dioxane (2.5 mL) under argon atmosphere. The solution was bubbled with argon for 5 min. Then potassium carbonate (45 mg, 0.32 mmol) and Pd(PPh3)4 (10 mg, 0.0075 mmol) were added sequentially. The reaction mixture was sealed and heated in oil bath at 120° C. for 4.5 h. Reaction was then diluted with EtOAc (10 mL) and filtered to remove solid. The filtrate was concentrated and purified on silica gel column with 0-40% EtOAc/Hex to afford product. LCMS-ESI+: calc'd for: C35H33ClN4O3S: 625.2, 626.2, 627.2 (M+H+); found: 625.1, 626.2, 627.1 (M+H+).