Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14]Br>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.5 %

Procedure:
To a suspension of 1.53 g (63.8 mmol) of sodium hydride in 50 ml of dry dimethylformamide was added over thirty minutes a solution of 8.23 g (63.8 mmol) of 4-chlorophenol. After stirring for one hour at room temperature, 16 g (77 mmol) of 1,3-dibromopropane was added in one portion. The mixture was stirred for 68 hours, and the solvent removed under reduced pressure. The residue was dissolved in diethyl ether and washed with water. The aqueous layer was then extracted twice with ether. The combined organic extracts were washed three times with water, once with brine, then dried (MgSO4). After filtration, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, using 10% methylene chloride/hexane as the eluent and produced 710 mg of the title compound, which was homogeneous by thin layer chromatography (10% by volume of methylene chloride/hexane on silica gel plates).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)[C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=1.[Li]C(C)(C)C.[NH4+].[Cl-]>C1COCC1>[OH:30][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([C:3]2[C@@H:4]([CH2:7][CH2:8][CH2:9][C:10]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=3)[CH2:5][CH2:6][CH:2]=2)=[CH:19][CH:20]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(O)c1ccc(C2=C(Br)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A −78° C. solution of 9 (10 mg, 0.02 mmol) in THF (0.4 mL) was treated with tert-BuLi (60 μL, 0.01 mmol, 1.7 M/pentane). After 30 min., 2 mL saturated NH4Cl solution was added and the resulting mixture was extracted with dichloromethane (3×20 mL). The combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. The crude product still contained vinyl bromide 9 and so was resubmitted to the reaction conditions: THF (0.2 mL) and tert-BuLi (100 mL,) were added and the reaction was stirred for 3 h at −40° C. and then worked up as above. Purification by flash chromatography on silica gel (0%→30% MeOH/CH2Cl2) gave compound 11 (4 mg, 0.01 mmol, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:19]([C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
1-[5-Bromo-2-hydroxyphenyl]ethanone (13.4 g) was dissolved in N,N-dimethylformamide (300 mL). To the reaction mixture were added potassium carbonate (25.8 g) and 2-bromo-1-cyclohexylethanone (19.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was filtered through celite, water (200 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (150 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.3 mL) was added to the solution at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (70 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitate was washed with diisopropyl ether to give the title object compound (15.4 g, 77%) as a pale-yellow solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH3:25])[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:33][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[CH3:25])=[O:32]
Reactant: CN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCCC1
Reaction time: 2 h

Procedure:
A solution of {2-[3-chloro-5-(cyclohexyl-methyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.036 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.024 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]([O:24]CC)=[O:23])[N:10]2[CH3:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]>Cl>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH:21]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:22]([OH:24])=[O:23])[N:10]2[CH3:13])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)C(c1ccccc1)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1C
Agent: Cl
Product: Cn1c(CC[C@@H]2CCCN2C(C(=O)O)c2ccccc2)cc2ccc(C(=N)N)cc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
13 g of ethyl 2-[(S)-2-[2-(6-amidino-1-methylindol-2-yl)ethyl]-pyrrolidinyl]-2-phenylacetate obtained in Example 2 was dissolved in 5 ml of 35% hydrochloric acid solution, and the resulting solution was heated to 60° C. and stirred for 1.5 hours, and then stirred at room temperature overnight. The reaction solvent was removed by distillation under reduced pressure. The residue was purified with column chromatography [eluent: dichloromethane/methanol(2:3)] on NH-DM1020 silica. The fractions containing the desired product were combined and then distilled under reduced pressure to obtain 6.2 mg of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6](N)[C:7]=1[Cl:8].C(N=C=S)(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CC[N:37]=[C:38]=[N:39][CH:40]2[CH2:45]CCC[CH2:41]2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:10][C:38]([NH:39][CH:40]([CH3:45])[CH3:41])=[N:37][C:4]=2[CH:3]=1
Reactant: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Reactant: Nc1ccc(Cl)c(Cl)c1N
Agent: CC(C)N=C=S
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Yield: 66.7 %

Procedure:
5,6-Dichloro-1,2-phenylenediamine (200.0 g, 1.13 mol), isopropyl isothiocyanate (122.0 g, 1.21 mol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (622.0 g, 1.47 mol) and pyridine (4 L) were used according to general procedure I. The product was recrystallized from acetonitrile to give 184 g (67%) of a brown solid. Analytical data were consistent with those reported above.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([O:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:9][C:8]([CH3:17])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[O:29][CH3:30])[N:6]=1>CO.CN1C(=O)CCC1.CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:5]1[C:10]([O:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:9][C:8]([CH3:17])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[O:29][CH3:30])[N:6]=1
Reactant: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Temperature: 100 °C

Procedure:
Sodium methoxide in methanol (25 w/w %, 0.5 ml) is added to a solution of compound 45 (50 mg, 0.124 mmol) in NMP (0.5 ml). The resulting mixture is heated to 100° C. overnight, then cooled to room temperature, diluted with 50% EtOAc in hexane, washed with water, brine, dried, filtered and evaporated. The crude product is purified by chromatography (eluted with 6% EtOAc in hexane) to give the product as colorless oil. 1H NMR (CDCl3) δ 1.00 (t, J=7.6 Hz, 6H), 1.75 (m, 4H), 2.04 (s, 3H), 3.80 (s, 3H), 3.94 (s, 3H), 4.12 (m. 1H), 6.78 (s, 1H), 6.89 (dd, 1H), 6.92 (s, 1H), 7.30 (d, J=8.4 Hz, 1H). LCMS 400.4 (M+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:25][C@H:26]1[C:34]2[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:32][CH:31]=[N:30][C:29]=2[C@H:28]([OH:41])[CH2:27]1.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([CH2:53][NH:54][CH2:55][C:56]([OH:59])([CH3:58])[CH3:57])[C:50](O)=[O:51])=[CH:45][CH:44]=1.C(Cl)Cl>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([C@@H:49]([CH2:53][NH:54][CH2:55][C:56]([OH:59])([CH3:57])[CH3:58])[C:50]([N:38]2[CH2:37][CH2:36][N:35]([C:33]3[C:34]4[C@H:26]([CH3:25])[CH2:27][C@@H:28]([OH:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:40][CH2:39]2)=[O:51])=[CH:47][CH:48]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(O)CNC[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@H](CNCC(C)(C)O)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.100 g, 0.265 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (31 mg, 0.13 mmol), N,N-diisopropylethylanine (0.231 mL, 1.32 mmol) and (S)-2-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropylamino)propanoic acid (43 mg, 0.16 mmol) in methylene chloride (1.2 mL, 19 mmol). The mixture was stirred for 1 hour at room temperature, after which the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted with DCM (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by reverse phase HPLC to give (S)-2-(4-chlorophenyl)-3-(2-hydroxy -2-methylpropylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (33 mg, 51%). 1HNMR (CDCl3, 500 MHz) δ 8.59 (s, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 5.06 (m, 1H), 4.48 (m, 1H), 3.92 (m, 2H), 3.15 (m, 2H), 2.94 (m, 2H), 2.02 (m, 2H), 1.19 (m, 6H), 1.06 (d, 3H). LCMS M+1 488.3
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH:41]3[CH2:43][CH2:42]3)=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH:41]3[CH2:42][CH2:43]3)=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K29) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow oil (223 mg, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)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: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 95.8 %

Procedure:
A mixture of 4-bromobenzoic acid ethyl ester (2.7 mL, 16.5 mmol), 4-methoxy phenylboronic acid (2.5 g, 16.5 mmol) and sodium carbonate (7.7 g, 72.6 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL) was flushed with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine)palladium(0) catalyst (0.95 g, 0.82 mmol), the reaction was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% of dichloromethane in hexane provided the title compound (4.05 g, 95.8%) as a pale yellow solid, m.p. 101–103° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:74]1[CH:79]=[CH:78][C:77](B2OC(C)(C)C(C)(C)O2)=[C:76]([CH3:89])[CH:75]=1)([C:55]1[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]2([O:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:67][CH2:66][CH2:65][CH2:64]2)=[C:57]([CH3:73])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:77]2[CH:78]=[CH:79][C:74]([C:52]([CH2:53][CH3:54])([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]4([O:68][Si:69]([CH3:71])([CH3:72])[CH3:70])[CH2:67][CH2:66][CH2:65][CH2:64]4)=[C:57]([CH3:73])[CH:56]=3)[CH2:50][CH3:51])=[CH:75][C:76]=2[CH3:89])=[CH:7][CH:6]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 64.1 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 34 mg, 0.147 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (62 mg, 0.294 mmol) and water (0.2 mL) were added to a solution of 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 32-(4); 54.6 mg, 0.098 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (36.5 mg, 64%).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[C@H:8]2[S:7]1.Cl.C(OCC)(=O)C>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Nc3ccccc3)[C@H]2S1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Nc3ccccc3)[C@H]2S1
Yield: 34 %

Procedure:
Acetic acid (8 ml) and zinc powder (6 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate (4.1 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1 hour under ice-cooling and then 3.5 hours at room temperature. After the reaction, 10% hydrochloric acid and ethyl acetate were added to the reaction mixture. The insoluble material was filtered off and the ethyl acetate layer was separated, and then extracted with a sodium bicarbonate aqueous solution. The extract was acidified with 10% hydrochloric acid and extracted with ethyl acetate, after which the extract was dried over magnesium sulfate. After the solvent was distilled off, the residue was crystallized by adding ether to give 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid (1.0 g), mp 148° to 151° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].[I:8][C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1.C(O)C>ClCCl>[I:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([NH:3][NH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)NN
Reactant: O=C=Nc1cccc(I)c1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)NNC(=O)Nc1cccc(I)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A solution of ethyl carbazate (1.25 g) in dichloromethane (20 ml) was treated with 3-iodophenylisocyanate (1.7 g) at 0° C. The reaction mixture was allowed to warm to 20° C. and stirred for 2 h. Ethanol (2 ml) was added and the mixture was stirred for 0.5 h. The solvents were removed under reduced pressure and the residue was triturated in diethyl ether. The white solid was collected by filtration to give the title compound (2.4 g). LCMS RT=2.81 min
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].CN1CC[O:19][CH2:18][CH2:17]1.C(Cl)(=O)C>C(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[C:6]([NH:7][C:18](=[O:19])[CH3:17])[CH:8]=1
Reactant: CN1CCOCC1
Reactant: CCCS(=O)(=O)c1ccc(C)cc1N
Solvent: O
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)c1ccc(C)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
A solution of 5-methyl-2-(propylsulfonyl) aniline (Intermediate 228; 6.0 g, 28 mmol) in DCM (100 ml) was added N-methyl morpholine (4.3 g, 42.1 mmol) and Acetyl chloride (2.4 g, 31 mmol). The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with water (200 ml), the organic layer was washed with brine solution and dried over sodium sulphate and evaporated. The crude product was purified by column chromatography (silica) using petroleum ether/ethyl acetate as eluent to afford the title compound (5.0 g, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:23][CH2:22][C:21](=[N:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:42](Br)[CH:43]=[CH2:44].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O.[Zn]>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])([CH2:44][CH:43]=[CH2:42])[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C=CCBr
Reactant: Cc1cc(F)ccc1[C@H]1CC(=NS(=O)C(C)(C)C)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Reaction time: 16 h

Procedure:
To a suspension of (2R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-4-{[(1,1-dimethylethyl)sulfinyl]imino}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide (Intermediate 1, 50 mg, 0.082 mmol) and Zinc powder (16.14 mg, 0.247 mmol, Aldrich) in THF (1.5 mL) was added at 25° C. allyl bromide (0.021 mL, 0.247 mmol, Aldrich) and the reaction mixture was stirred at this temperature for 16 hrs. Brine and EtOAc were added and the resulting mixture was filtrated over Celite® and the two phases were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic phases were dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc; 25M Si cartridge) to give two different products:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:28]>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:33]([C:32]4[CH:36]=[CH:37][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=4)=[O:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 92 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxycarbonylbenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 92%. Melting point: 220-223° C. (Methanol).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH3:4].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[C:16]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:3](=[O:5])[CH3:4])=[CH:7]1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a stirred slurry of sodium hydride (3.77 g, 50% in oil, 7.86 mmol, extracted with hexanes) in THF (30 ml) at 0° C. under nitrogen was added dropwise 3-acetyl indole (10.0 g, 62.9 mmol) in THF (15 ml). After warming to room temperature and stirring one hour, the mixture was cooled to 0° C. and benzyl chloroformate (8.97 ml, 62.9 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. The excess sodium hydride was destroyed at 0° C. with 40 ml H2O. The mixture was then extracted three times with CHCl3 (total volume 120 ml), dried with MgSO4, filtered and evaporated to an off-white solid. Recrystallization from hexanes afforded 15.85 g (86%) of product: mp 112°-113°;