Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][NH:5]1.Cl[CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[F:34].O>CN(C=O)C>[F:34][C:25]1[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=[CH:29][C:24]=1/[CH:23]=[CH:22]/[CH2:21][N:5]1[C:4](=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6]1
Reactant: Fc1c(C=CCCl)cccc1C(F)(F)F
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1nn(C/C=C/c2cccc(C(F)(F)F)c2F)c(=O)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
64.8 g (1.62 mol) of a 60% suspension of sodium hydride in oil are added portionwise under a nitrogen atmosphere to a solution of 341.9 g (1.472 mol) of ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate (prepared according to the process described in Patent EP 2895) in 5 l of anhydrous DMF, the temperature being maintained between 25° and 30° C. The addition lasts approximately one hour. The mixture is then heated for 30 minutes at 60° C. The mixture is cooled to room temperature and a mixture of 421.6 g (1.76 mol) of 1-(3-chloro-1-propenyl) -2-fluoro-3-(trifluoromethyl) benzene (prepared according to Example D1) and 98 ml of anhydrous DMF is added over 30 min. The temperature rises to 38° to 40° C. The mixture is then heated for 3 hours at 60° C. and is then allowed to return to room temperature overnight. The mixture is poured into 7 l of water and extracted with 2 times 4 l of ethyl acetate. Washing is carried out with water, the organic phase is dried over Na2SO4, filtered and evaporated under vacuum and the solid obtained is recrystallized from a hexane/ethyl acetate (4/1 ) mixture. Weight obtained: 474.7 g (Yd.=74%) M.p.=104°-106° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25]([C:27]5[O:31][C:30](C=O)=[CH:29][CH:28]=5)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35][CH2:36][CH2:37][NH2:38].[Cl:39][CH2:40]Cl>>[ClH:39].[ClH:39].[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[CH:26]=[C:25]([C:27]5([CH2:40][NH:38][CH2:37][CH2:36][S:35][CH3:34])[CH2:28][CH:29]=[CH:30][O:31]5)[N:24]=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSCCN
Reactant: ClCCl
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cn2)o1
Product: CSCCNCC1(c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cn2)CC=CO1
Product: Cl

Procedure:
5-(4-((4-Benzenesulphonyl-phenyl)amino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (250 mg) and (methylthio)ethylamine (185 mg)) in dichloromethane (5 ml) were reacted together as in Procedure D. Purification using a Bond Elut™ cartridge, gave a yellow solid (245 mg), 70 mg of which was converted to the hydrochloride salt, (yellow solid, 68 mg); m/z 532 (M+1)+.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:22][C:23]1[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:24]=1[CH2:25][CH2:26][C@H:27]1[O:32][CH2:31][C@@H:30]([CH2:33][O:34][C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])[N:29](C(OC(C)(C)C)=O)[CH2:28]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C@@H:4]([C:5]([NH:22][C:23]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:24]=2[CH2:25][CH2:26][C@H:27]2[O:32][CH2:31][C@@H:30]([CH2:33][O:34][C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])[NH:29][CH2:28]2)=[O:7])[NH2:1])=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(F)cc1)C1CCOCC1

Procedure:
The title compound was prepared from (2S,3R)-2-azido-3-(4-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (Example 1033, step 1) and the product of step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=629 (M+H)+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:9][C:10]1([F:31])[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:20][C:19]1=[O:30]>N1C=CC=CC=1.O>[Si:1]([O:17][CH2:16][C@H:13]1[O:12][C@@H:11]([N:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:20][C:19]2=[O:30])[C:10]([F:31])([F:9])[C@@H:14]1[OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
tert-Butyldimethylsilyl chloride (737 mg, 4.89 mmol) was added to a solution of 8 (1.367 g, 4.08 mmol) in 8 mL of pyridine at 0° C. under N2. The reaction mixture was stirred overnight at RT, diluted with H2O, then extracted with EtOAc. The organic extract was washed with saturated aqueous CuSO4 solution, and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:1→3:1 EtOAc/Hexane) to give 1.4 g of 57 (white solid, 76% yield): 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.14-8.16 (d, 1H), 7.14-7.16 (d, 1H), 6.42-6.43 (d, 1H), 6.20-6.23 (t, 1H), 4.17-4.23 (m, 3H), 3.98-4.08 (m, 2H), 3.87-3.90 (m, 1H), 1.25-1.28 (t, 3H), 0.94 (s, 9H), 0.14 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:32]([N:31]([CH3:30])[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6])[CH3:33]
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: CCNC
Product: CCN(C)c1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)ccn1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and N-methylethylamine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.25 (m, 2H), 7.84 (m, 1H), 7.56 (m, 2H), 7.45 (d, 1H), 7.17 (s, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 4.31 (t, 2H), 3.62 (m, 4H), 3.06 (s, 3H), 2.88 (t, 2H), 2.57 (t, 4H), 1.10 (t, 3H). MS: 435.2 (M+1)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.COCCOC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
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: COCCOC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
A mixture of Pd(PPh3)4 (354 mg, 1.58 mmol), 2-chloro-5-nitropyridine (5.00 g, 31.5 mmol), and phenylboronic acid (4.61 g, 37.8 mmol) was degassed and filled with nitrogen gas three times. The mixture was treated with 40 mL of DME and aqueous 2 M potassium carbonate (80.0 mmol) solution and heated to reflux. After 4 hours, the reaction mixture was cooled to room temperature and diluted with 100 mL of ethyl acetate and 50 mL of water. The phases were separated and the aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (0% to 50% ethyl acetate in hexanes, gradient) give 4.60 g of 5-nitro-2-phenylpyridine (73% yield).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][CH2:22]C3CC3)=[C:15]([CH3:26])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+].O.[CH3:31][C:32]#N.[CH2:34](O)C>O1CCCC1>[CH:32]1([N:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:27])=[CH:6][CH:7]=3)=[CH:14][C:15]=2[CH3:26])[CH2:21][CH3:22])[CH2:31][CH2:34]1
Reactant: CC#N
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(CNCCC3CC3)c(C)c2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1ccc(C#Cc2ccc(CC(=O)O)cc2)cc1C)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of methyl(4-{4-[(cyclopropylethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-acetate (Compound 129, 140.0 mg, 0.39 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up followed by HPLC (Partisil-10 pac 10% H2O—CH3CN) afforded the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:12][C@@H:13]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15].[BH4-].[Na+].O>CO>[CH2:22]([N:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[C@@H:13]([NH:12][CH2:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C([C@H](Cc1ccccc1)NCc1ccc2[nH]ccc2c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
In an inert atmosphere, indole-5-carboxaldehyde (108 mg, 0.75 mmol) and 2-amino-1-(4-benzyl-piperazin-1-yl)-(S)-3-phenyl-propan-1-one (162 mg, 0.50 mmol) were dissolved in dry MeOH (4.0 mL) and refluxed for 4 h. The reaction mixture was cooled to rt followed by slow addition of sodium borohydride (28 mg, 0.75 mmol). Stirring was continued for 1 h. Water (1 mL) was added to the reaction mixture followed by evaporation of the solvent under reduced pressure. The residue was dissolved in EtOAc (10 mL) and washed with sat. sodium hydrogencarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 200 mg (80%) of 1-(4-benzyl-piperazin-1-yl)-2-[(1H-indol-5-ylmethyl)-amino]-(S)-3-phenyl-propan-1-one. LC-MS: tR=0.65 min; [M+H]+=453.39.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH2:57])=[N:53]2)=[C:47]([C:58]([F:61])([F:60])[F:59])[CH:46]=1>CN(C=O)C.CO>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:57][C:54]1[CH:55]=[CH:56][N:52]([CH2:51][C:48]2[CH:49]=[CH:50][C:45]([I:44])=[CH:46][C:47]=2[C:58]([F:61])([F:59])[F:60])[N:53]=1)=[O:10]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1ccncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-fluoro-4-pyridinecarboxylic acid (38 mg, 0.269 mmol, Aldrich) was added a solution of HATU (100 mg, 0.263 mmol, Advanced asymmetrics) in DMF (0.5 ml), DIPEA (0.11 ml, 0.630 mmol) and then a solution of 1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 39)(75 mg, 0.204 mmol) in DMF (0.5 ml). The resulting orange solution was stirred at ambient temperature overnight. The reaction mixture was diluted with methanol (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (86 mg); LCMS: (System 4) MH+=491, tRET=3.0 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]Br>CC(C)=O>[Cl:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C#N)ccc1OCCCCl
Temperature: 27.5 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
To 74.5 gms (0.5 mole) of 4-Hydroxy-3-methoxybenzonitrile in 450 ml. of acetone was added 138 gms (1 mole) of potassium carbonate and the resultant reaction mixture was stirred at about 25-30° C. for about 5 min. To the reaction suspension 110 gms (0.7 mole) of 3-Chloro-1-bromo propane was added drop-wise at about 25-35° C. for about 30 mins. The resultant reaction mixture was refluxed for about 12 hrs. The undissolved inorganic salts was filtered off and washed with acetone. The solvent was distilled completely under vacuum and the residue was re-crystallized from 300 ml of isopropyl alcohol to afford the title compound as white crystalline solid. Yield: 92.5 gms (% Yield: 82%).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:5][C:6]([NH:8][CH:9]1[C:29](=[O:30])[N:11]2[C:12]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7])=[O:4].C(O)(=O)C.[N:35]([O-])=[O:36].[Na+]>O1CCCC1.O>[Br:1][CH2:2][C:3]([C:5](=[N:35][OH:36])[C:6]([NH:8][CH:9]1[C:29](=[O:30])[N:11]2[C:12]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:17])=[CH:13][CH2:14][S:15][C@H:10]12)=[O:7])=[O:4]
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 34.9 %

Procedure:
4-Nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (8.40 g.) was suspended in a mixture of tetrahydrofuran (150 ml.) and water (30 ml.) To the suspension were added acetic acid (50 ml.) and a solution of sodium nitrite (1.20 g.) in water (15 ml.) under ice-cooling, and stirred at 20° to 22° C. for 1.5 hours. The resultant solution was poured into ice-water (300 ml.) and stirred for 20 minutes. The precipitating substance was collected by filtration, washed with water, dried and then recrystallized from ethyl acetate to give 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 3.1 g.), mp 153° to 162° C.
Reaction SMILES: [CH3:1]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[C:26]1[C:32]([N:33]2[C:40]3[N:36]([N:37]=[C:38]([C:41]4[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=4)[CH:39]=3)[CH:35]=[CH:34]2)=[C:31]([CH3:47])[CH:30]=[CH:29][C:27]=1[NH2:28].[CH3:48][O:49][CH2:50][C:51]1[CH:52]=[C:53]([CH:57]=[C:58]([S:60]([F:65])([F:64])([F:63])([F:62])[F:61])[CH:59]=1)[C:54](O)=[O:55]>CN(C=O)C.CO>[CH3:1][C:29]1[CH:30]=[C:31]([CH3:47])[C:32]([N:33]2[C:40]3[N:36]([N:37]=[C:38]([C:41]4[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=4)[CH:39]=3)[CH:35]=[CH:34]2)=[CH:26][C:27]=1[NH:28][C:54](=[O:55])[C:53]1[CH:57]=[C:58]([S:60]([F:65])([F:64])([F:63])([F:62])[F:61])[CH:59]=[C:51]([CH2:50][O:49][CH3:48])[CH:52]=1
Reactant: COCc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)c(C)c1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: COCc1cc(C(=O)Nc2cc(-n3ccn4nc(-c5cccnc5)cc34)c(C)cc2C)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
75 mg (0.198 mmol) of HATU, 24 mg (0.198 mmol) of 4-N,N-dimethylaminopyridine (DMAP) and 50 mg (0.165 mmol) of the compound of Example 11A were added to a solution of 51 mg (0.173 mmol) of the compound of Example 74A in 1 ml of anhydrous DMF. The reaction mixture was stirred at RT for 1 h, then diluted with about 2 ml of methanol and subsequently directly separated into its components by preparative HPLC (Method 32). Evaporation of the product fractions and drying of the residue under high vacuum gave 60 mg (63% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1Br.CCCCCC.C([Li])CCC.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C.Cl>C1COCC1>[C:14]1([C:5]2[CH:4]=[C:3]([B:32]([OH:37])[OH:33])[C:2]([Br:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cc(-c2ccccc2)c(-c2ccccc2)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc(-c2ccccc2)c(-c2ccccc2)cc1Br
Temperature: -100 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml Schlenk reaction vessel were added under a nitrogen atmosphere 755 mg (1.95=mol) of 1,2-dibromo-4,5-diphenylbenzene synthesized in 2) and 12 ml of THF. The solution was cooled to −100° C. and 1.3 ml (2.1 mmol) of a hexane solution of n-butyllithium (manufactured by Kanto Chemical Co., Ltd., 1.59M) was added dropwise. After 30 minutes of aging, 472 my (2.51 mmol) of triisopropyl borate (manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise. After the temperature was gradually raised to room temperature, 3N hydrochloric acid was added and phase separation was conducted. The organic phase was concentrated under reduced pressure to obtain 770 my of a white solid (2-phenyl-5-bromo-4-biphenylboronic acid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[S:5][C:6]=1[CH2:7][CH3:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C@@H:58]3[C@@H:63]([NH3+:64])[C:62]([F:66])([F:65])[CH2:61][CH2:60][CH2:59]3)=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55](=[O:56])[NH:57][C@H:58]3[CH2:59][CH2:60][CH2:61][C:62]([F:66])([F:65])[C@@H:63]3[NH:64][C:9]([C:4]3[S:5][C:6]([CH2:7][CH3:8])=[C:2]([Br:1])[CH:3]=3)=[O:11])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1
Reactant: CCc1sc(C(=O)O)cc1Br
Reactant: [NH3+][C@@H]1[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCc1sc(C(=O)N[C@@H]2[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CCCC2(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-5-ethylthiophene-2-carboxylic acid (300 mg, 1.15 mmol) and BOP (762 mg, 1.72 mmol) were dissolved in DMF (11.5 mL) and stirred at room temperature for 5 minutes. (1R,6S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-difluorocyclohexanaminium chloride (432 mg, 1.16 mmol) was added followed by diisopropylethyl amine (0.50 mL, 2.87 mmol) and the solution was stirred at room temperature for 18 h. The solution was diluted with water, and extracted with dichloromethane (×3). The organic layers were collected, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography affording the title compound as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.72 (d, 2H); 7.46 (dd, 2H); 7.36 (s, 1H); 7.35 (d, 2H); 7.23 (dd, 2H); 6.36 (d, 1H); 5.14 (d, 1H); 4.36 (dd, 1H); 4.29 (dd, 1H); 4.13 (dd, 1H); 4.01 (dd, 1H); 3.86 (dd, 1H); 2.70 (q, 2H); 2.82 (m, 1H); 2.17 (m, 1H); 1.86 (m, 2H); 1.65 (m, 1H); 1.43 (m, 1H); 1.18 (t, 3H). LRMS (APCI) calc'd for (C28H27BrF2N2O3S) [M+H]+, 589.1. found 589.1.
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][C:10](=[O:20])[NH:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([CH3:8])[CH3:7].CN(C)CCN(C)C.[S:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1>C1COCC1>[F:18][C:16]1[CH:17]=[C:12]([NH:11][C:10](=[O:20])[O:9][CH:6]([CH3:8])[CH3:7])[CH:13]=[C:14]([F:19])[C:15]=1[C:32]1([OH:35])[CH2:33][CH2:34][S:29][CH2:30][CH2:31]1
Reactant: CC(C)OC(=O)Nc1cc(F)cc(F)c1
Reactant: O=C1CCSCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (2.5M in hexanes, 57.2 mL, 0.143 mol) was added dropwise with stirring at −78° C. to (3,5-difluoro-phenyl)-carbamic acid isopropyl ester (15.0 g, 0.07 mol) and N,N,N′,N′-tetramethylethylenediamine (21.04 mL, 0.139 mol) in THF (150 mL), and stirred for 20 min at this temperature. Tetrahydrothiopyran-4-one (8.50 g, 0.073 mol) dissolved in THF (10 mL) was then added dropwise at −78° C., stirred for 1 h, and then allowed to warm to room temperature. The reaction was stirred for another hour and then quenched with saturated aqueous ammonium chloride (100 mL). The reaction mixture was extracted with ethyl acetate, the extracts washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash column chromatography (30% ethyl acetate/hexane) to give the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[F:20][C:21]([Si](C)(C)C)([F:23])[F:22].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)([OH:8])[C:21]([F:23])([F:22])[F:20])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(c2ncc(Br)s2)C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
To a solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl) carbonyl]cyclohexane-carboxylate (608 mg, 1.756 mmol) in THF (15 ml) was added trifluoromethyl trimethylsilane (0.520 ml, 3.51 mmol). Then, tetrabutylammonium fluoride (7.0 ml, 7.00 mmol) was added to the mixture slowly. After 1 h, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (0-20% EtOAc in hexane) to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI calc'd. for C14H17BrF3NO3S [M+H]+ 416, 418. found 416, 418. 1H NMR (500 MHz, CDCl3) δ 7.68 (s, 1H), 4.11 (q, J=7.1, 2H), 2.47-2.32 (m, 1H), 2.28-1.92 (m, 4H), 1.55-1.16 (m, 5H), 0.90 (t, J=7.3, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15]O.[BrH:17].[Br:18]Br>C(Cl)Cl>[Br:17][C:5]1[C:4]([CH2:15][Br:18])=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:13][CH3:14]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Reactant: BrBr
Reactant: Br
Solvent: ClCCl
Product: COc1c(Br)c(CBr)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Alcohol 26 (9.80 g, 45.0 mmol) was dissolved in CH2Cl2 (150.0 mL) in a flame-dried 500 mL round bottom flask. Concentrated HBr (22.0 mL) was added to displace the alcohol, the solution was stirred for 2 h at room temperature. The reaction was then diluted with CH2Cl2 (300.0 mL) and Br2 (2.40 mL, 47.7 mmol) was added dropwise dissolved in CH2Cl2 (50.0 mL) at room temperature. The reaction was stirred for 6 hours further before being washed with brine, dried over MgSO4, and filtered. The resulting solid was purified using flash column chromatography (1:19 EtOAc:hexanes) to provide 36 (9.02 g, 25.1 mmol, 56%) as a yellow powder.