Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1([C:7]2[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=2)OCCCO1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1cncc(B2OCCCO2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2cccnc2)cc1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
A mixture of pyridine-3-boronic acid 1,3-propanediol cyclic ester, 4-bromoiodobenzene (1.1 eq), [1,1 ′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) and 2M aqueous sodium carbonate (5 eq) in N,N-dimethylformamide (2 ml/mmol) was stirred at 85° C. for 4 hours. After quenching with saturated aqueous ammonium chloride solution the mixture was partitioned between ethyl acetate and water and the crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ethyl acetate and hexane to afford the 3-(4-bromophenyl)pyridine compound as a solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41]I)[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCCOCCCCI
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 25 h
Yield: 96.1 %

Procedure:
A mixture of 0.871 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.536 g of 4-[4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]butanoic acid ethyl ester and 0.94 g of anhydrous potassium carbonate in 40 ml of anhydrous acetone was stirred at reflux for 17 hours. An additional 1.0 g of potassium carbonate was added and reflux was continued for 25 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was chromatographed on 200 g of silica gel. Elution with 20% ethyl acetate-toluene gave 2.71 g (96% yield) of 4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[CH3:28][NH:29][CH3:30]>C1COCC1>[CH3:28][N:29]([CH2:21][C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:12]([C:8]3[C:7]([NH:6][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=4[F:27])=[CH:11][NH:10][N:9]=3)=[N:13][C:14]=2[CH:20]=1)[CH3:30]
Reactant: CNC
Reactant: O=Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Yield: 17.3 %

Procedure:
The compound was prepared in a manner analogous to Example 22B, however using 2,6-difluoro-N-[3-(5-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (57.4 mg, 0.16 mmol), dry THF (5 ml), 3 Å molecular sieves, dimethylamine (35% in EtOH) (55 μL, 0.31 mmol) and triacetoxy sodium borohydride (100 mg, 0.47 mmol) to give N-[3-(5-dimethylaminomethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (11 mg, 18%) as a yellow solid. (LC/MS: Rt 2.85, [M+H]+ 397.17).
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.B1(C=C)OB([CH:39]=[CH2:40])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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>[C:28]([O:27][C:26](=[O:32])[NH:25][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:17]1[C:2]([CH:39]=[CH2:40])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Reactant: C=CB1OB(C=C)OB(C=C)O1
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
Solvent: c1ccncc1
Solvent: CCO
Product: C=Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 33.5 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.250 g, 0.496 mmol) (prepared as described in Example 3, Part B) 2,4,6-trivinylcyclotriboroxane pyridine complex (0.239 g, 0.991 mmol), Na2CO3 (0.158 g, 1.487 mmol) and Pd(PPh3)4 (0.029 g, 0.025 mmol) in toluene (1 mL) water (0.1 mL), and ethanol (0.3 mL) was purged with nitrogen gas and heated at 90° C. for 16 h. After cooling, the reaction mixture was transferred to separatory funnel containing water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (60% ethyl acetate: petroleum ether) to afford a (S)-tert-butyl(4-methyl-1-((6-methyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.150 g, 0.166 mmol, 34% yield) as a yellow solid. LC/MS (ESI) m/e 452.4, [(M+H)+, calcd for C26H34N3O4, 452.2]; LC/MS retention time (method D): tR=0.95 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:34]=2)O1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1

Procedure:
Following the procedure described for Intermediate 99 with 4-bromo-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine and 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate gave the title compound. ESMS [M+H]+: 518.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21].Cl.[F:23][C:24]([F:34])([F:33])[C:25]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:30]1[CH2:31][CH2:32][CH:28]([NH:27][C:25](=[O:26])[C:24]([F:34])([F:33])[F:23])[CH2:29]1)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21]
Reactant: O=C(NC1CCNC1)C(F)(F)F
Reactant: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)C(C)S2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c2n(c3cc(N4CCC(NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.2 %

Procedure:
A mixture of 1.00 g of ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, 2.1 g of 3-trifluoroacetylaminopyrrolidine hydrochloride, 1.46 g of 1,8-diazabicyclo[5,4,0]-7-undecene and 20 ml of N,N-dimethylformamide was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo, and, to a suspension of the residue in 20 ml of methanol, 30 ml of water was added. The precipitate was collected by filtration to give 1.22 g of the desired compound, which was recrystallized from a mixture of chloroform and ethanol to give colorless crystals, m.p. 255°-257° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.ClS([N:18]=[C:19]=O)(=O)=O.CN(C)C=O.O>C(COC)OC>[Br:1][C:2]1[NH:3][C:4]([C:19]#[N:18])=[CH:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: Clc1ccc(-c2cc[nH]c2Br)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(Br)[nH]1
Reaction time: 8 h
Yield: 33151.5 %

Procedure:
A freshly prepared sample of 2-bromo-3-(p-chlorophenyl)pyrrole (4.0 g., 0.015 mmol) is dissolved in dry dimethoxyethane (25 mL). Then while holding the temperature below 25° C., chlorosulfonyl isocyanate (3.08 g., 0.022 mmol) is added. After stirring overnight, the solution is treated with dimethylformamide (6 mL) and stirred for 3 hours. Finally, the solution is poured into water precipitating a brown solid (3.8 g, 90%). Dry column chromatography (80/20 hexane/ethyl acetate) yields 1.4 g (33%) of white solid with m.p. 202°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)=O)[N:18]=3)=[C:4]2[CH:3]=1.C(OCC)(=O)C.[CH:40]1([NH2:43])[CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:43][CH:40]4[CH2:42][CH2:41]4)[N:18]=3)=[C:4]2[CH:3]=1
Reactant: NC1CC1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(S(C)=O)n2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(NC3CC3)n2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (118 mg, 0.24 mmol) in cyclopropylamine (5 mL) was heated at 45° C. in a sealed tube for 5 hours. The reaction mixture was cooled to room temperature and ethyl acetate was added to the reaction mixture. The organic phase was washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by chromatography (7:3 hexanes/ethyl acetate) gave N-{4-[5-chloro-7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopropylamine (96 mg, 83%) as a yellow solid. 1H NMR (CDCl3) δ 8.10 (broad s, 1H), 8.00 (d, 1H), 7.55 (d, 2H), 6.98 (d, 2H), 6.33 (d, 1H), 6.09 (d, 1H), 5.98 (d, 1H), 5.68 (s, 1H), 3.93 (m, 1H), 3.86 (s, 3H), 2.84 (m, 1H), 2.10 (m, 2H), 1.78–1.65 (m, 6H), 0.90 (m, 2H), 0.63 (m, 2H). MS m/z 475 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[O:13].Cl[CH2:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O>[NH:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[O:13]
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CC(C)(NC(=O)c1ccc2ccccc2c1O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCc1nc2ccccc2[nH]1)C(=O)O
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
0.45 g of the Wang-resin-bound 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid (loading 0.35 mmol/g) was placed in a reaction vessel with 3 ml of dimethylformamide. To this was added 0.058 g of 2-chloromethyl-1H-benzoimidazole, 0.228 g of cesium carbonate and 0.023 g of potassium iodide. The reaction was then placed in a vortex shaker overnight. The resin was filtered, washed four times each with dimethylformamide, methanol and dichloromethane. To this was added a solution of 30% trifluoroacetic acid, 65% dichloromethane and 5% triethylsilane and left in vortex shaker for 1.5 hours. The resin was filtered and the filtrate concentrated in vacuo. Purification by flash chromatography on silica with dichloromethane/methanol afforded 25 mg of 2-{[1-(1H-Benzoimidazol-2-ylmethoxy) naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)=[O:4].[CH3:17][NH2:18]>S(Cl)(Cl)=O.CN(C)C=O.O>[CH3:17][NH:18][C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])=[O:10]
Reactant: CN
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A mixture of 4-methoxycarbonyl-2-nitrobenzoic acid (3.6 g, 0.016 mol) in thionyl chloride (32 mL) was heated to reflux in the presence of two drops of dimethylformamide for 3 h. Thionyl chloride was distilled and the concentrate was left under vacuum for 0.5 h. The residue was dissolved in dichloromethane (10 mL) and added to a solution of aqueous methylamine (40%, 2.0 g, 0.026 mol) in water (5 mL) over a period of 5 min. The mixture was further stirred for 10 min and the white precipitate was collected by filtration. The cake was washed with water, dried, and recrystallized from ethyl acetate-hexane to give 2.1 g (55%) of methyl 4-(methylamino)carbonyl-3-nitrobenzoate as white needles, mp 155° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[C:6]1(=[O:12])[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:5])([CH3:4])[N:10]1[C:6](=[O:12])[CH2:7][CH2:8][C:9]1=[O:11]
Reactant: O=C1CCC(=O)N1
Reactant: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
780 ml (6.1 moles) of trimethylchlorosilane were added with vigorous stirring over 2 hours to a mixture of 400 g (4 moles) of succinimide, 900 ml (6.5 moles) of triethylamine and 2700 ml of toluene and the mixture was refluxed with stirring for one hour and was then cooled to room temperature. The mixture was filtered and the filter was washed with one liter of toluene and one liter of petroleum ether (b.p = 40°-60° C). The combined filtrate and washings were concentrated to 700 ml and then distilled at reduced pressure to 573 g (3.4 moles -- 84% yield) of N-trimethylsilyl succinimide with a boiling point of 62° C at 0.33 mm Hg.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:36][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[S:36][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[N:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(O)c1ncc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@@H](Oc1cc(-c2cnc(C(C)(C)O)s2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 33.5 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one (100 mg, 0.243 mmol), 2-(5-bromothiazol-2-yl)propan-2-ol (80 mg, 0.36 mmol), 1,2-dimethoxyethane (3 mL), 1 N Na2CO3 aqueous solution (1.08 mL, 1.08 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (20.8 mg, 0.018 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 51.5 mg (yield 33.5%). 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.41 (d, J=1.2 Hz, 1H), 7.05 (m, 1H), 5.99 (s, 1H), 4.85 (m, 1H), 3.69 (m, 1H), 3.40-3.35 (m, 1H), 3.22-3.16 (m, 1H), 2.87-2.75 (m, 1H), 2.40-2.20 (m, 2H), 1.53 (s, 6H), 1.31 (d, J=6.0 Hz, 3H), 1.14-1.07 (m, 2H), 1.06-0.97 (m, 2H) ppm; MS (ESI+) m/z 427.18 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH:11]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:36])[C:6]([CH3:8])=[CH2:7])=[O:4].C1OC1C.[Br:41]N1C(=O)CCC1=O>ClCCCl.[Hg]>[CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])[CH:11]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:36])[C:6]([CH2:8][Br:41])=[CH2:7])=[O:4]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC1CO1
Agent: [Hg]
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 34.3 %

Procedure:
To a solution of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one 3.6 g (7 mmoles) in 230 ml of 1,2-dichloroethane were added 5 ml of propylene oxide and 1.9 g (10.5 mmoles) of N-bromosuccinimide. The mixture was irradiated under nitrogen for 2 hours at 14° C with a Nanovia TQ 150 mercury high pressure lamp using a Pyrex filter. After washing twice with 150 ml of a 0.067 molar aqueous potassium phosphate solution buffered to pH 5.8, washing twice with 100 ml of water, drying and treating with decolorizing charcoal, the reaction mixture was concentrated. After adding a mixture of ethyl acetate, diethyl ether and n - hexane, the precipitate was chromatographed on silica gel (methylene chloride ethyl acetate 9:1 (v/v) to obtain 1.3 g (2.4 mmoles; 34% yield) of 1-(1-methoxycarbonyl-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li][CH2:23][CH2:24][CH2:25]C.C(Br)C=C>C1COCC1>[CH2:25]([C@@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[NH:12][C:11]1=[O:21])[CH:24]=[CH2:23]
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Temperature: 0 °C

Procedure:
A 100 mL flame-dried round-bottomed flask equipped with a magnetic stir bar was charged with (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (1.32 g, 4.12 mmol) (Example 1, Step E) and anhydrous THF (41.2 mL). This solution was cooled to 0° C. under argon and BuLi (3.30 mL, 8.24 mmol) was added. After 10 minutes allyl bromide (0.357 mL, 4.12 mmol) was added. After an additional 45 minutes the reaction was quenched by the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification using a Combiflash Companion (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) with a 120 g SiO2 column and eluting with 10 to 100% EtOAc/hexanes provided the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[S:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:4]=[S:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CON(C)C(=S)c1[nH]c2ccccc2c1-c1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: S=Cc1[nH]c2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-Methoxy-N-methyl-3-phenylthioindole-2-carboxamide (1.57 g, 5.26 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to 0° C. under nitrogen. A solution of lithium aluminum hydride in tetrahydrofuran (5.76 mL, 1M) was added slowly via syringe and the reaction stirred a total of 1.5 h. Ethyl acetate (30 mL) was added, followed by saturated sodium potassium tartrate solution. The layers were separated and the organic phase washed with saturated brine and dried over magnesium sulfate. Filtration and evaporation of solvent gave the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[N:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=1[OH:24])([O-])=O.[OH-].[Na+].C1C2C(=[O:40])C3C(=CC=CC=3)C=2C=CC=1.N(C1C=CC=CC=1)=NC1C=CC=CC=1.S(=O)(=O)(O)O>O.C(O)CCC>[OH:24][C:14]1[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[N:12]1[N+:11]([O-:40])=[C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]2=[N:1]1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: Cc1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 745.9 %

Procedure:
2-nitro-4-chloro-2'-hydroxy-3'-t-butyl-5'-methylazobenzene 23.2 g was added to a mixture of n-butanol 60 g, water 10.6 g and 97% sodium hydroxide 6.9 g, and the resultant mixture was stirred while raising temperature to 65° C. Thereafter, the mixture was cooled to 50° C., and 9-fluorenone 1.5 g was added to the mixture. The reaction mixture was then heated to 90° C. in one hour, and the mixture was stirred at 90°~96° C. for five hours to effect reaction, thus almost all of the azobenzene having disappeared. Thereafter, water 50 ml was added to the reaction liquor, and the reaction liquor was neutralized to pH 8~9 with 62% sulfuric acid 10 g to precipitate a crystal. The crystal thus obtained was filtered to separate the crystal, and the separated crystal was then fully washed with water and further with a small amount of methanol. The washed crystal was then dried, thus producing 20.6 g of 2-(2-hydroxy-3-t-butyl-5-methylphenyl)-5-chlorobenzotriazole-N-oxide having a melting point of 160° to 163° C. at the yield of 93.0%.