Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3](=[O:19])[O:4][C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[CH:6]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][N:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3](=[O:19])[O:4][C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[C:6]=1[Br:26]
Reactant: CN(C(=O)Oc1ccn(Cc2ccccc2)c(=O)c1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN(C(=O)Oc1ccn(Cc2ccccc2)c(=O)c1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH2Cl2 (7 mL) was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was purified by flash chromatography (silica gel) using EtOAc/hexanes (1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 413) and concentrated. The dried product showed about 14% of di-brominated product by analytical HPLC. The compounds were separated by reverse phase HPLC using a 10-90% acetonitrile in water, 30 min gradient at a 100 mL/min flow rate, to afford (after lyophilization) the salt of the desired compound. The salt was diluted in EtOAc and washed with NaHCO3. The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford the desired compound (0.271 g, 58%) as a beige solid.
Reaction SMILES: C(OC[C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH:23][CH:24]2[N:29]([C@@H:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][C@@H:31]3[O:39][CH3:40])[C:28]([NH2:41])=[N:27][C:26](Cl)=[N:25]2)[CH2:11]1)C1C=CC=CC=1.[C:43]([O-:46])(O)=O.[Na+]>CO.C(Cl)Cl.[Pd]>[Si:16]([O:15][C@H:14]1[CH2:13][C@H:12]([NH:23][C:24]2[N:41]=[C:28]([NH:29][C@@H:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][C@@H:31]3[O:39][CH3:40])[N:27]=[CH:26][N:25]=2)[CH2:11][C@H:10]1[CH2:43][OH:46])([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17]
Reactant: O=C([O-])O
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N1C(N)=NC(Cl)=NC1N[C@@H]1C[C@@H](COCc2ccccc2)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(N[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)n1
Reaction time: 48 h
Yield: 57 %

Procedure:
A suspension of N-((1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentyl)-6-chloro-M-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazine-2,4-diamine (250 mg, 0.00041 mol) and 10% Pd/C (44 mg, 0.000041 mol) in methanol (1.61 mL) was stirred under an atmosphere of hydrogen for 2 days. The reaction was purged with nitrogen and filtered through celite with EtOAc. The filtrate was concentrated to obtain a yellow oil. The oil was taken up in CH2Cl2 and saturated NaHCO3. The layers were separated and the aqueous was extracted with CH2Cl2 (1×). The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to obtain 114 mg (57%) of the title compound. LC/MS: Rt=1.68 min, ES+ 486 (FA standard).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1.S(Cl)([Cl:37])=O>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CO)cc3)CCCCN12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CCl)cc3)CCCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-[4-[2-(hydroxymethyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.318 g) in CH2Cl2 (5 mL) was added thionyl chloride (0.2 mL) and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and the residue was redissolved in CH2Cl2 (5 mL) and evaporated again. The residue was dried under vacuum to give 6-[4-[2-(chloromethyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:7][N:6]([CH:8]2[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH2:5]1)#[N:2].[ClH:45]>C1COCC1.O1CCOCC1>[ClH:45].[ClH:45].[ClH:45].[CH:13]12[NH:15][CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]([N:6]1[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:23]3[CH:27]=[C:26]([C:28]4[C:29]5[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:30]=5[N:31]=[CH:32][N:33]=4)[CH:25]=[N:24]3)[CH2:7]1)[CH2:14]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(N1CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CC6CCC(C5)N6)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate (123 mg, 0.2 mmol) in THF (3 mL) was added a 4 N solution of HCl in dioxane (3 mL). After being stirred at room temperature for 2 hours, the solution was concentrated. The residue obtained was used for the next reaction. LC-MS: 519.3 (M+H)+.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)[C:44]#[N:45]>CC(N(C)C)=O>[F:21][C:15]1[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[C:6]1[O:22][C:1]([NH:45][CH3:44])=[N:4][N:5]=1
Reactant: CC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: N#CC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid N′-acetyl-hydrazide (400 mg; 0.93 mmol; 1 eq) in DMA (5 mL), PS-Triphenyl-phosphine (1.22 g; 4.66 mmol; 5 eq), Trichloro-acetonitrile (269 mg; 1.86 mmol; 2 eq) and DIEPA (0.49 mL; 2.8 mmol; 3 eq) were added. The reaction mixture was stirred at 100° C. for 4 hrs. The mixture was filtered and the solution was subjected to preparative HPLC to afford the product (98 mg). LC/MS (Method A) [5.03 min; 412(M+1)]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:23])[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:23][C:10]2[S:11][C:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(Cc3ccc([N+](=O)[O-])cc3)s2)cc1
Yield: 62.9 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 9 and p-cyanobenzoyl chloride prepared in the step 1 of Example 13 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was recrystallized with a solvent mixture of ethyl acetate and petroleum ether to obtain a product as a off-white solid in a yield of 62.9%, mp: 244-245└. 1H-NMR (CDCl3, 400 MHz) δ: 4.33 (2H, s, CH2), 7.07 (2H, t, 3JFH=3JHH=8.44 Hz, ArH), 7.38 (2H, d, J=8.40 Hz, ArH), 7.43 (2H, dd, 3JHH=8.72, 4JFH=5.32 Hz, ArH), 7.75 (2H, d, J=7.84 Hz, ArH), 7.98 (2H, d, J=8.12 Hz, ArH), 8.20 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 458.3 (M+, 79), 129.9 (100); HREI-MS Calcd. for C24H15FN4O3S: 458.0849. found: 458.0850. Anal. Calcd. for C24H15FN4O3S: C, 62.88; H, 3.30; N, 12.22. found: C, 62.52; H, 2.96; N, 12.04.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C=O)=[N:4][C:3]=1/[C:10](=[N:65]/[O:66][CH:67]1[CH2:71][CH2:70][CH:69]=[CH:68]1)/[C:11]([NH:13][C@@H:14]1[C:63](=[O:64])[N:16]2[C:17]([C:47]([O:49][CH:50]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])=[C:18]([S:21][CH2:22][C:23]3[CH:24]=[N:25][N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:27]=3)[CH2:19][S:20][C@H:15]12)=[O:12].CO.Cl>O1CCCC1>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3](/[C:10](=[N:65]/[O:66][CH:67]2[CH2:71][CH2:70][CH:69]=[CH:68]2)/[C:11]([NH:13][C@@H:14]2[C:63](=[O:64])[N:16]3[C:17]([C:47]([O:49][CH:50]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:48])=[C:18]([S:21][CH2:22][C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:4]=1
Reactant: O=CNc1nc(/C(=N/OC2C=CCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)CS[C@H]23)c(Cl)s1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(/C(=N/OC2C=CCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cn[nH]c4)CS[C@H]23)c(Cl)s1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
To a stirred mixture of solution of diphenylmethyl 7β-[2-(5-chloro-2-formylaminothiazol-4-yl)-2-(Z)-(2-cyclopenten-1-yloxyimino)acetamido]-3-[(1-tritylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (3.82 g) in the mixture of methanol (40 ml) and tetrahydrofurane (12 ml) was added dropwise conc. hydrochloric acid (i.56 ml) at room temperature. After the mixture was stirred for 3 hours, the solvent was evaporated in vacuo. The residue was diluted with the mixture of water and ethyl acetate while the pH was adjusted between 8.0 and 8.5 with saturated sodium hydrogen carbonate. The organic layer was collected, washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on silica gel (eluent: dichloromethane-acetone) to afford diphenylmethyl 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(2-cyclopenten-1-yloxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (1.77 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20].C(N)CCC>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[C:22](/[N+:19]([O-:21])=[O:20])\[CH3:23])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Reactant: CC[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCCCN
Product: C/C(=C\c1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1)[N+](=O)[O-]
Temperature: 80 °C

Procedure:
5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde (4.00 g, 14.5 mmol), nitroethane (3.00 ml, 40.7 mmol), n-butylamine (1.7 ml, 17.5 mmol) and acetic acid (7.5 ml) were mixed and heated up to 80° C. for 2 h. After cooling to RT the mixture was filtered. The precipitate was crystallized from ethanol affording 2.58 g of the title product. 1H-NMR (400 MHz; d6-DMSO): δ 2.62 (s, 3H), 7.39 (d, 1H), 7.57 (d, 1H), 7.87 (m, 1H), 8.00 (s, 1H), 8.11 (m, 1H), 8.22 (m, 1H).
Reaction SMILES: [K].[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[NH:8][C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1>CN(C)C=O>[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[N:8]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:8]4[C:7](=[O:12])[C:6]5([CH2:13][C:14]([CH3:16])([CH2:17][CH3:18])[NH:15][C:4]([CH3:20])([CH2:2][CH3:3])[CH:5]5[CH3:19])[NH:10][C:9]4=[O:11])=[CH:25][CH:24]=3)[C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3]
Reactant: CCC1(C)CC2(NC(=O)NC2=O)C(C)C(C)(CC)N1
Reactant: BrCc1ccc(CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CCC1(C)CC2(NC(=O)N(Cc3ccc(CN4C(=O)NC5(CC(C)(CC)NC(C)(CC)C5C)C4=O)cc3)C2=O)C(C)C(C)(CC)N1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 80 ml of dimethylformamide were added 8.0 g of the potassium salt of 7,9-diethyl-6,7,9-trimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 3.1 g of α,α'-dibromo-p-xylene; the mixture was heated, with stirring, at 60° C for 3 hours. The mixture was then concentrated by evaporation under reduced pressure and the residue was dissolved in chloroform. The chloroform solution was washed with water and dried over magnesium sulphate; the chloroform was then removed. The residue was purified first by column chromatography on silica gel (eluent: a 6 : 3 : 0.5 by volume mixture of ethyl acetate, benzene and triethylamine) and then by recrystallization from ethanol, giving 5.0 g of Compound 43 as crystals melting at 272° - 274° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[CH2:12](Cl)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:13][CH2:12][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COCn2cnc3ccccc32)cc1
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To a solution of benzimidazole (500 mg, 4.23 mmol) in 10 mL DMF at 0° C., was added NaH (60%, 169 mg, 4.23 mmol). The mixture was stirred for 20 min, then BOM-Cl (802 μL, 4.65 mmol) was added. The mixture was stirred at rt for 4 h, then was diluted with EtOAc. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), filtered through 1″ SiO2 (eluting with EtOAc). The crude product was purified by flash chromatography (30 to 100% EtOAc/hexanes gradient) to afford 453 mg of Intermediate 10.1 as a white crystalline solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Referring to Scheme 1, a solution of methyl 4-bromomethylbenzoate (0.5 mmol) in DMF (2.5 mL) was treated with benzimidazole (0.5 mmol) and solid K2CO3 (0.6 mmol). After stirring at 23° C. for 4 h, the reaction was poured into water (10 mL) and the resulting solid was isolated by filtration. The filter cake was rinsed with water and allowed to dry in vacuo to yield methyl 4-((1H-benzo[d]imidazol-1-yl)methyl)benzoate.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:3][CH2:2]1.[I:15]I.S(=O)(=O)(O)O.O>CC(O)=O>[CH:1]1([C:4]2[C:13]([I:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C2CC2)cc1C
Reactant: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(C2CC2)cc1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 86.1, 2.68 g, 13.4 mmol, 95%) in AcOH (50 mL) were added NaIO4 (1.51 g, 7.08 mmol), iodine (3.58 g, 14.1 mmol), and sulfuric acid (106 μL, 2.0 mmol, 0.15 equiv). The reaction mixture was stirred overnight at 110° C. After cooling to ambient temperature, water (100 mL) was slowly added and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with Na2S2O3 (aq., sat., 3×30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50) as the eluent to yield 2.0 g (45%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2](O)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[Si]([Br:24])(C)C>ClCCl.C(OCC)C>[C:13]1([C:2]([Br:24])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)Br
Reactant: CCCCCCCCCCC(C)(O)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCC(C)(Br)c1ccccc1
Reaction time: 1 h

Procedure:
0.942 g (3.6 mmol) of 1-methyl-1-phenylundecyl alcohol was dissolved in 5 ml of dichloromethane, 1 ml of trimethylsilyl bromide (7.2 mmol) was added and the mixture stirred for 1 h under protection from moisture. The solution was diluted with 15 ml of diethyl ether, washed with water (3×10 ml), 15 ml brine, dried and evaporated to give 1.18 of crude 2-phenyl-2-bromododecane. 795 mg of silver trifluoroacetate (3.6 mmol) was dissolved in 5 ml THF. To the crude bromide was added 500 mg of 1-methyl-1-phenylundecyl hydroperoxide (1.8 mmol) dissolved in 10 ml THF. This mixture was cooled in ice-salt bath to −15° C. and the silver trifluoroacetate solution added with a pipette. 2 ml of brine was then added, followed by 10 ml conc. NaHCO3. The reaction mixture was stirred and filtered. The reaction flask and the filter cake were rinsed with 15 ml diethyl ether. The aqueous phase was separated and the organic phase washed with conc. NaHCO3, 15 ml water, 15 ml brine, dried and evaporated to give 1.40 g of a yellowish oil. Purification was done using a 1:9 ether:pentane mixture as eluent. The yield was 409 mg (43%). 13C-NMR (CDCl3) δ 14.33, 22.91, 23.96, 24.06, 24.19, 29.55, 29.72, 29.82, 30.24, 32.13, 40.68, 40.97, 84.18, 126.16, 126.69, 127.86, 145.59, 145.71
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(OCC)C>N1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([F:1])[CH:18]=[C:17]([F:19])[CH:16]=3)=[CH:15][CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Oc3cc(F)cc(F)c3)cc2)cc1
Temperature: -20 °C
Yield: 92.8 %

Procedure:
To a solution of 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (2.66 g, 10.0 mmol) in pyridine (2.8 g), p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was gradually added with stirring while cooling at -20° C., and the resultant mixture was allowed to stand in a refrigerator overnight. Diethyl ether was added to the reaction mixture, which was washed with dilute hydrochloric acid until the aqueous layer became acidic, followed by washing with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The obtained ether layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give 2-[4-(3,5-difluorophenoxy)phenoxy]ethyl p-toluenesulfonate (3.90 g).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCOCC1.ClC1C=C(Cl)C(Cl)=CC=1[O:40][C:41](=O)[CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>CN(C)C=O>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:41](=[O:40])[CH2:42][NH:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
14.2 g (42 mmoles) of glycine benzyl ester p-toluenesulfonate are dissolved in 100 ml of dimethyl formamide, 4.6 ml (42 mmoles) of N-methylmorpholine and 14.2 g (40 mmoles) of tert.-butoxycarbonyl-glycine 2,4,5-trichlorophenyl ester are added, and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated, and the residue is dissolved in a mixture of 150 ml of ethyl acetate and 50 ml of water. The ethyl acetate phase is washed twice with 30 ml of ice-cooled 1 n aqueous hydrochloric acid, each, and then with water, dried over sodium sulfate and evaporated. The residue is triturated with a 1:1 mixture of diisopropyl ether and petroleum ether, filtered, the solid is washed with the same solvent mixture and dried in a desiccator. 11.0 g (82.8%) of tert.-butoxycarbonyl-glycyl-glycine benzyl ester are obtained; m.p.: 83° C., Rf14 =0.1-0.2.
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[F:12])=O.[OH-].[Na+]>C(O)C.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[C:6]([F:12])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 59.5 %

Procedure:
Under a nitrogen atmosphere, a suspension of 718 g (3.8 moles) of 4-chloro-2-fluoroacetanilide in 2653 mL of ethanol was stirred as a solution of 304 g (7.6 moles) of sodium hydroxide in 1075 mL of water was added. Upon completion of addition the reaction mixture was warmed to 80° C. during a 2.3 hour period. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to a volume of approximately 2000 mL. The concentrate was dissolved in 2000 mL of ethyl acetate and washed with 500 mL of water. The organic layer was concentrated under reduced pressure to a residual oil. The oil was filtered to remove a solid, then distilled under reduced pressure to yield 329 g of 4-chloro-2-fluoroaniline; b.p. 93°-100° C./16-20 mm.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:65])[CH2:40][CH2:41][C@@H:42]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([NH2:61])(=[O:60])=[O:59])=[CH:54][C:53]=1[N+:62]([O-:64])=[O:63])[CH2:43][S:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:61][S:58]([C:55]3[CH:56]=[CH:57][C:52]([NH:51][C@H:42]([CH2:41][CH2:40][N:39]([CH3:38])[CH3:65])[CH2:43][S:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[C:53]([N+:62]([O-:64])=[O:63])[CH:54]=3)(=[O:59])=[O:60])=[O:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1[N+](=O)[O-]
Yield: 36.7 %

Procedure:
The title product (162.8 mg, yield: 32%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 32 utilizing (R)-4-(4-((tert-butyldimethylsilyloxy)(4 ′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 249.6 mg, 0.47 mmol) and (R)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide (INTERMEDIATE 19, 208.8 mg, 0.49 mmol). The title product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→10% MeOH/DCM).