Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N+:20]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([NH2:20])=[CH:14][C:15]([F:19])=[C:16]([F:18])[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCCNc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNc1cc(F)c(F)cc1N
Reaction time: 2 h

Procedure:
To a stirred solution of N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-difluoro-2-nitroaniline (37) in methanol (5 ml) was added 10% palladium on carbon (catalytic amount) portion wise at room temperature. The reaction mixture was allowed to stir under the atmosphere of hydrogen gas supplied by balloon at room temperature for 2 h. The reaction mixture was filtered through celite and filtrate was concentrated to afford the desired product N1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-difluorobenzene-1,2-diamine (0.09 g; crude). LCMS (M+1=303).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][CH:7]=1.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11]>>[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:25]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11]
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Reactant: Fc1cccc(Br)c1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3cccc(F)c3)CC2)CC1

Procedure:
3-[Trans-4'-(trans-4"-propylcyclohexylethyl)cyclohexyl]fluorobenzene (C-N point: 48.4° C., N-I point: 79.4° C.) (50 g) obtained from 3-fluorobromobenzene and 4-(trans-4'-propylcyclohexylethyl)cyclohexanone in the same manner as in Example 1, was dissolved in nitrobenzene (100 cc), followed by adding anhydrous aluminum chloride (50.5 g) to the solution, agitating it, dropwise adding acetyl chloride (29 g) to the mixture, heating the resulting mixture on a water bath at 40° C. for 2 hours after completion of heat generation to complete reaction, adding the reaction material to a mixture of ice (500 g) with conc. hydrochloric acid (100 cc), vigorously agitating the mixture to decompose the resulting aluminum chloride complex, extracting the freed oily substance with toluene (200 cc), washing the extract solution with water until the wash water became neutral, drying it over anhydrous sodium sulfate, filtering off the drying agent, distilling off toluene and nitrobenzene and recrystallizing a remaining oily substance from ethyl acetate to obtain 2-fluoro-4-[trans-4'-(trans-4"-propylcyclohexylethyl)cyclohexyl]acetophenone (20.2 g). This product exhibited a liquid crystal phase over 62.1° C. (C-N point) to 161.4° C. (N-I point).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=3[O:11][C:10]=2[CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[O:11][C:10]=1[CH3:20]
Reactant: COc1ccc2c(C(O)C3CCCCC3)c(C)oc2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(C(Cl)C3CCCCC3)c(C)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution (10 mL) of cyclohexyl(6-methoxy-2-methyl-1-benzofuran-3-yl)methanol (499 mg) synthesized above in toluene was added thionyl chloride (159 μL), and the mixture was stirred at room temperature for 1 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 object compound (530 mg, 99%) as a pale-yellow oil.
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].[S:9]1C=C[C:11](C=O)=[CH:10]1>>[O:8]=[C:7]1[C:3]2[CH:11]=[CH:10][S:9][C:4]=2[CH:5]=[CH:6][NH:2]1
Reactant: Cn1cccc1C=O
Reactant: O=Cc1ccsc1
Product: O=c1[nH]ccc2sccc12

Procedure:
The synthesis of this compound was accomplished with the same sequence of reactions as used to prepare IIIc, except that the starting material (X) is 3-thiophenecarboxaldehyde. The multiple step preparation of the positional isomer IIIc' was complicated, however, in that the Curtius-type rearrangement reaction (Example 4) gave the desired VI intermediate compound in low yield as the major product of this reaction was a sym-triazine by-product which resulted from trimerization of the isocyanate intermediate. Nonetheless, application of the reactions outlined in Scheme 1 resulted in production of the IIIc' product, which was a brown gum and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:38]([O:37][C:35](=[O:36])[CH2:34][N:13]1[C:14](=[O:16])[C:15]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)=[N:9][C:10]=2[N:11]([CH3:18])[C:12]1=[O:17])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
Step 1 7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (1.0 g, 2.14 mmol, intermediate 9), tert-butyl 2-bromoacetate (0.34 mL, 2.36 mmol), and potassium carbonate (0.45 g, 3.21 mmol) were combined in DMF (20 mL) and heated at 50° C. for 2 h. The reaction was cooled to room temperature diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with 1N lithium chloride (2×100 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to give tert-butyl-2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate (1.24 g, 100% yield) as a clear oil. LCMS retention time=4.817 minutes and 97% purity, LCMS MH+ 581.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[Cl:18][C:19]1[CH:26]=[C:25]([CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])[O:27][CH:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=1)[C:36]([O:38][CH3:39])=[O:37]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)C(Oc1ccc(C=O)c(Cl)c1)c1ccccc1
Yield: 76.3 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 4, 1.00 g (6.41 mmol) of 2-chloro-4-hydroxybenzaldehyde was alkylated with 1.61 g (7.05 mmol) of methyl 2-bromophenylacetate to afford 1.49 g (76%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH2:18][CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:37]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH:38]([CH3:40])[CH3:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:44]2[CH2:45][CH2:46][N:41]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]2)=[O:15])=[CH:11][C:10]=1[CH2:18][CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CN1CCNCC1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccccc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccccc1
Reaction time: 0.67 h
Yield: 100.2 %

Procedure:
4-benzyloxy-3-isobutylbenzoic acid (4.94 g) was dissolved in a mixture of chloroform (60 ml) and triethylamine (4.83 ml). To this mixture, diphenylphosphinic chloride (3.66 ml) was added while being cooled with ice. After being stirred for 40 minutes, the mixture, with 1-isobutylpiperazine (2.48 g) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained residue was purified by silica gel column chromatography (chloroform: methanol=50:1), thereby yielding 7.11 g of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14]
Reactant: Nc1cc(Cl)ccc1S
Reactant: CCN(CC)C(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCSc1ccc(Cl)cc1N
Yield: 84.4 %

Procedure:
Following General Procedure A, the title compound (1.0 g, 88%) was prepared from 2-amino-4-chlorobenzenethiol (660 mg, 4.13 mmol), crude 3-bromo-N,N-diethylpropanamide (860 mg, 6.60 mmol) and K2CO3 (2.9 g, 20.67 mmol) in DMF (20 ml).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([C:21]([N:15]2[CH2:16][CH2:17][C:12]([NH:11][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:19])([CH3:18])[CH2:13][CH2:14]2)=[O:22])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCC(C)(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dichloromethane (3 mL) at room temperature was added methyl 4-chlorocarbonylbenzoate (0.125 g, 0.62 mmol) and triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane (2×). The combined organic layers were washed with 10% KHSO4, sat. NaHCO3, brine, dried (MgSO4), and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 411 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.07 (d, 2H), 7.46 (d, 2H), 7.33 (m, 5H), 5.06 (s, 2H), 4.63 (m, 1H—NH), 4.18-4.13 (m, 2H), 3.95 (s, 3H), 3.36 (m, 2H), 2.09 (m, 2H), 1.78-1.42 (m, 2H), 1.41 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+:16]([O-])=O)[CH:7]=1>CO.[Pd]>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[NH2:16]
Reactant: CN(C)CCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1cc(N)cc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 90 %

Procedure:
A suspension of N,N-dimethyl-2-(3-nitro-5-(trifluoromethyl)phenoxy)ethanamine (75 mg, 0.270 mmol) in MeOH (5 mL) was added to a solution of Pd/C (57.4 mg, 0.539 mmol) in MeOH (5 mL). The mixture was hydrogenated at 26° C. for 3 h under a H2 atmosphere. Then the solution was filtered and concentrated to afford 3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)aniline (60.3 mg, 0.243 mmol, 90% yield). TLC (PE/EA=1:1, Rf=0.5): 1H NMR (400 MHz, CD3OD) δ 6.56 (s, 1H), 6.48 (s, 2H), 4.24-4.17 (m, 2H), 3.18 (t, J=5.1 Hz, 2H), 2.67 (s, 6H). ES-LCMS m/z 249 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1ccncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccncc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 3-bromo-4-pyridinecarboxaldehyde 3 (3.0 g, 16.2 mmol) in absolute methanol (40 mL) was added NaBH4 (0.736 g 19.5 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours under nitrogen. The solvent was then removed under vacuum. Water and ethyl acetate were added and the organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to afford the compound 4 (3.021 g, 100%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccccc2Cl)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:42])[CH2:41][O:40][CH2:39]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:39][O:40][CH2:41]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2ccccn2)COC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)COC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.045 g, 0.107 mmol, 1.0 eq) and 3-(pyridin-2-yl)oxetan-3-amine.2HCl (0.025 g, 0.112 mmol, 1.05 eq) in DMF at 0° C. was added TEA (0.15 ml, 1.08 mmol, 10 eq) and BOP reagent (0.06 g, 0.136 mmol, 1.3 eq). The reaction mixture was stirred as rt overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC. Yield: 0.015 g (25.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[N:22]#[C:23]Cl.C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:21][C:15]1[CH:14]=[C:13]([C:10]([C:4]2[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:23]#[N:22])=[C:6]([CH3:9])[CH:5]=2)([CH3:12])[CH3:11])[CH:18]=[C:17]([CH3:19])[C:16]=1[OH:20]
Reactant: N#CCl
Reactant: Cc1cc(C(C)(C)c2cc(C)c(O)c(C)c2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(C)(C)c2cc(C)c(OC#N)c(C)c2)cc(C)c1O
Temperature: 0 °C
Yield: 99.5 %

Procedure:
28.4 g (0.1 mol) of 2,2-bis-(3,5-dimethyl-4-hydroxyphenyl)-propane are suspended in 500 ml of water and 300 ml of dichloromethine. After cooling to 0° C, 15 ml (0.3 mol) of cyanogen chloride are added. 10.6 g (0.1 mol) of Na2CO3, dissolved in 50 ml of water, are then added dropwise over the course of 2 hours, with vigorous stirring, in such a way that a pH value of between 7.5 and 8.5 is maintained constantly in the reaction mixture. At the same time, the reaction temperature is kept at about 0° C by cooling. Thereafter, the reaction is terminated by slow addition of 1 N NaOH, the 1 N NaOH being added in such a way that a pH value of 7.5 to 8.0 is constantly maintained in the reaction mixture and persists as the final value. After the end of the reaction, the organic phase is separated off, washed with 50 ml of water and concentrated at room temperature. 30.8 g (99% of theory) of 2-(3,5-dimethyl-4-hydroxyphenyl)-2-(3,5-dimethyl-4-cyanatophenyl)-propane are obtained as the residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)ccc1Oc1ccccc1
Yield: 93.9 %

Procedure:
A mixture of phenol (5.64 g, 60 mmol) and potassium t-butoxide (6.74 g, 60 mmol) in 50 mL 1,4-dioxane was stirred at room temperature for 0.5 h. To the mixture was added 2-chloro-5-nitro-benzoic acid methyl ester (10.78 g, 50 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was purified by chromatography with EtOAc:hexanes, 1:4, as eluant, yielding (11.739 g, 86%) 5-nitro-2-phenoxy-benzoic acid methyl ester. A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (2.0 g, 7.32 mmol) in 30 mL ethanol and Pd/C (200 mg) were hydrogenated at 40 psi overnight to yield 5-amino-2-phenoxy-benzoic acid methyl ester (1.672 g, 94%). A mixture of 5-amino-2-phenoxy-benzoic acid methyl ester (0.95 g, 3.9 mmol) and hydrazine (4 mL, 80%) was refluxed for 4 h to yield 5-amino-2-phenoxy-benzoic acid hydrazide (0.722 g, 76%). The title compound was prepared from 5-amino-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (CDCl3): 10.81 (s, 1H), 8.15 (s, 1H), 8.0 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.40 (m, 2H), 7.19 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.8, 2H), 6.80 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.[CH2:13](Br)[C:14]#[CH:15]>C1(C)C=CC=CC=1>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([NH:1][CH2:15][C:14]#[CH:13])=[CH:3][C:4]=2[O:8]1
Reactant: C#CCBr
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Solvent: Cc1ccccc1
Product: C#CCNc1ccc2c(c1)OC(F)(F)O2
Temperature: 80 °C

Procedure:
To a stirred solution of 5-amino-2,2-difluorobenzo-1,3-dioxole (2.8 g, 16.17 mmmol) in 25 mL of anhydrous toluene was dropwise added propargyl bromide (0.99 mL, 11 mmol). The mixture was heated to 80° C. overnight after which it was allowed to cool to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography using DCM as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 2.22 (1H), 3.85 (2H), 6.30-6.85 (3H); MS (ESI) 212 (M+H).
Reaction SMILES: [Na+].[C:2]([CH:7]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)[C:8]([NH:10][CH:11]1[C:18](=[O:19])[N:17]2[CH:12]1[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1)=[C:16]2[C:20]([O-:22])=[O:21])=[O:9])([O:4][CH2:5][CH3:6])=[O:3].Cl[CH2:41][O:42][C:43](=[O:56])[C@H:44]([CH:53]([CH3:55])[CH3:54])[NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[C:49]([O:48][C:46]([NH:45][CH:44]([CH:53]([CH3:55])[CH3:54])[C:43]([O:42][CH2:41][O:21][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[CH2:23][S:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1)[CH:11]([NH:10][C:8](=[O:9])[CH:7]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:31]1[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32]1)[C:18]2=[O:19])=[O:22])=[O:56])=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nnc(C)s3)CSC12)n1ccc2ccccc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)=C(CSc3nnc(C)s3)CSC12)n1ccc2ccccc21
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 7-[[2-carbethoxy-2-(1H-indol-1-yl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared by the general procedure described in W. German Offen. No. 2,236,620 are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 7-[[2-carbethoxy-2-(1H-indol-1-yl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedure to give the title compound.