Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH2:22])=[O:13])[N:3]=[CH:4][CH:5]=1.F[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH:22][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[O:13])[N:3]=[CH:4][CH:5]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using (2-(2H-1,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 445 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ 8.35-6.60 (m, 10H), 4.85-2.70 (m, 5H), 1.85-0.65 (m, 8H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:17]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:1]1=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C1OCCCCC1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 1 mmol of caprolactone in 0.5 mL THF was added to a solution of LDA in 0.5 mL THF at -78° C. and this stirred for 2 h. Then a solution of 1.1 mmol of a benzylbromide in 0.14 mL DMPU was added to the above mixture and after stirring for 1 h at -15° C., the 2-benzylcaprolactone was isolated by extraction and chromatography.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[F:14][C:15]([F:25])([F:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>C1COCC1>[F:14][C:15]([F:24])([F:25])/[C:16](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:3]\[C:1]#[N:2]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C/C=C(/c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (6.1 g, 34.5 mmol) in 15 mL of THF was added sodium hydride (60% content, 1.4 g, 34.5 mmol). The mixture was stirred at room temperature. for 2 hours. 2,2,2-Trifluoro-1-phenylethanone (3 g, 17.2 mmol) was added and the mixture was stirred for 4 hours. After evaporation of THF, the residue was taken up in ethyl acetate (100 mL) and quenched with water (50 mL). The organic phase was washed with water (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (petrol ether: ethyl acetate=10:1) to afford the title compound (1.5 g, yield 29%) as an oil. LC-MS: m/z 198 (M+H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:31])[CH3:30].N1C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([O:21][C:29](=[O:31])[CH3:30])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CC(OC(C)=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate is reacted with 1.1 equivalent of acetyl chloride and 1.0 equivalent of pyridine in benzene to yield ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-acetoxypentanoate. Similarly, using n-propanoyl chloride and isopropanoyl chloride yield the respective 3-n-propanoate and 3-isopropanoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C3C=CC(O)=CC=3)[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C1(O)C=CC=CC=1>[C].[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCC(c2ccc(O)cc2)(c2ccc(O)cc2)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 200 °C
Yield: 91 %

Procedure:
Into a 300-ml stainless steel autoclave were charged 18.7 g (0.060 mole) of 4,4-bis(4-hydroxyphenyl)cyclohexanecarboxylic acid, 2.9 g (0.072 mole) of sodium hydroxide, 100.0 g of phenol, and 0.4 g of 5% palladium-carbon catalyst. After the air within the autoclave was displaced with nitrogen gas, the reaction mixture was heated at 200° C. for 6 hours. After completion of the reaction, the reaction mixture was filtered to separate unreacted phenol therefrom. The filter cake was dissolved in 50 g of a 20% aqueous solution of sodium hydroxide, and the resulting solution was filtered again to recover the catalyst. In order to precipitate the desired product, the filtrate was brought to pH 1 by the addition of diluted hydrochloric acid. The crystals so formed were collected by filtration, washed with water, and then dried to obtain 11.7 g of 4'-hydroxybiphenyl-4-carboxylic acid in the form of white crystals. Liquid-chromatographic analysis revealed that this product had a purity of 93%, and the greater part of the impurities comprised 4-(4'-hydroxyphenyl)cyclohexanecarboxylic acid. The yield of 4'-hydroxy-biphenyl-4-carboxylic acid as corrected for its purity was 85%.
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]([C:14]([NH:16][C@H:17]([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[N:5][C:4]2=[N:30][CH:31]=[CH:32][C:3]=12>CO.C(Cl)Cl.[Pd]>[OH:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:29]=[CH:28][C:13]([C:14]([NH:16][C@H:17]([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[N:5][C:4]2=[N:30][CH:31]=[CH:32][C:3]=12
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nccc-3c2O)cc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC[C@H](NC(=O)c1ccc(CCn2cnc3nccc-3c2O)cc1)C(=O)OC
Reaction time: 24 h
Yield: 60.4 %

Procedure:
A mixture of 1.1 g of dimethyl N-[4-(4-hydroxypyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate in 100 mL of 50% methanol in methylene chloride and 0.8 g of 3% palladium-on-carbon is hydrogenated at 50 p.s.i. for 24 hours, filtered, and concentrated under reduced pressure. Ether is added to the residue and the solid is collected by filtration and dried to yield 0.67 g of dimethyl N-{4-[2-(4-hydroxypyrrolo[2,3-d]pyrimidin-3-yl)ethyl]benzoyl}-L-glutamate. mp 170-172° C. 1NMR (d6 -DMSO) δ1.94-2.14 (m, 2H), 2.44 (t, J=7.4 Hz, 2H), 2.93-3.02 (m, 2H), 3.57 (s, 3H), 3.63 (s, 3H), 4.40-4.70 (m, 1H), 6.71 (s, 1H), 7.29 (d, J=8.2 Hz, 2 H), 7.77 (m, 3 H), 8.66 (d, J=7.4 Hz, 1H), 11.52 (s, 1H), 11.71 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C:34]1([CH:41]=[O:42])[CH2:38][CH2:39][CH3:40])=[O:32])([CH3:29])([CH3:28])[CH3:27]>CCOCC>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C:34]1([CH:41]([OH:42])[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1)[CH2:38][CH2:39][CH3:40])=[O:32])([CH3:28])([CH3:29])[CH3:27]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Reactant: CCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCC1(C(O)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a stirred solution of 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (0.587 g, 1.66 mmol) in ether (20 mL) at −78° C. and under nitrogen was added tert-butyllithium (2.30 mL of 1.51 M solution in pentanes, 3.49 mmol) dropwise. After 90 minutes, a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.400 g, 1.66 mmol) in ether (1 mL) was added to the reaction mixture dropwise. After stirring for one hour, the reaction mixture was warmed to ambient temperature over 30 minutes. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL) then extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (0.90 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) gave 2-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-methyl]-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.576 g, 1.12 mmol, 53%) as a colourless gum.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[N:16]1([C:22]2[C:27]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[F:15][C:6]1[C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=[C:4]([CH:5]=1)[CH2:3][NH:2][C:30](=[O:31])[CH:29]=[CH:28][C:27]1[C:22]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: O=C(O)C=Cc1cccnc1N1CCOCC1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2cccnc2N2CCOCC2)cc1F
Yield: 70.1 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (57 mg, 0.22 mmol) was reacted with 3-(2-morpholin-4-yl-pyridin-3-yl)-acrylic acid (52 mg, 1.0 eq) to give N-(5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-morpholin-4-yl-pyridin-3-yl)-acrylamide (67 mg, 69.5%) after purification by column chromatography (Hex/EtOAc=1/7).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]([O:15]C)=[O:14])[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)(=O)C>[C:1]1([C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cn1nnnc1-c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cn1nnnc1-c1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of 100 mg of methyl 5phenyl-1-tetrazoleacetate, 0.6 ml of acetic acid and 1 ml of a 4N-hydrochloric acid was stirred at 80°to 90° C. for 2 hours. The reaction solution was evaporated under reduced pressure. The precipitated solid was filtered, washed with cold water and recrystallized from 50% ethanol-water, to give 64.1 mg (yield: 69.2%) of 5-phenyltetrazole-1-acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13](CC1C=CC(OC)=CC=1OC)[C:12](=[O:27])[C:11]1[CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[CH:30]=[CH:31][C:10]2=1)=[O:5])[CH3:2].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][NH:13][C:12](=[O:27])[C:11]1[CH:28]=[C:29]([CH:32]([CH3:33])[CH3:34])[CH:30]=[CH:31][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1cc(C(C)C)ccc1-2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncn2c1CNC(=O)c1cc(C(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,4-Dimethoxy-benzyl)-8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (410 mg, 0.9 mmol) was suspended in CH2Cl2 (3.0 mL), cooled in ice, and diluted slowly with trifluoroacetic acid (2.0 mL). The resulting solution was treated at 5° C. with trifluoromethanesulfonic acid (1.0 mL, 1.3 mmol). The red solution was stirred at room temperature for 2 h. The mixture was then evaporated and dissolved in CH2Cl2 (20 mL), washed with sodium hydrogen carbonate (10%, 2×5 mL) and the organic layer was dried (Na2SO4) and evaporated. Trituration with EtOAc. Yield: 250 mg (90%). m/z 313 (MH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30](B(O)O)=[CH:31][CH:32]=2)[CH:27]=[CH:26]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.CN(C=O)C>[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:2]3[CH:3]=[C:4]4[N:10]([O:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH:9]=[CH:8][C:5]4=[N:6][CH:7]=3)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1
Reactant: Brc1cnc2ccn(Oc3ccccc3)c2c1
Reactant: Cn1ccc2cc(B(O)O)ccc21
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: CN(C)C=O
Product: Cn1ccc2cc(-c3cnc4ccn(Oc5ccccc5)c4c3)ccc21

Procedure:
6-bromo-1-phenoxy-1H-pyrrolo[3,2-b]pyridine (56 mg, 0.205 mmol, 1.0 eq), Pd(PPh3)4 (13 mg), 2.0 M K2CO3 (1.0 ml), DMF (1.2 ml), and (1-methyl-1H-indol-5-yl)boronic acid (1.5 eq, 0.315 mmol) were refluxed under N2 overnight. The crude products were purified with preparation HPLC to give the product in 50%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Yield: 85.8 %

Procedure:
According to the method of Preparation 25(a), 2-bromo-5-nitrotoluene (15 gm, 69.4 mmol) was treated with phenyl boronic acid (12.7 gm, 104.1 mmol) under palladium catalysis, using 2M aqueous sodium carbonate as base at reflux in dimethoxyethane for 16 h. After being cooled, the mixture was separated the organic layer was diluted with diethyl ether and washed with water (twice). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane to hexane:ethyl acetate 95:5) to give 2-methyl-4-nitro-1-phenylbenzene as a yellow solid (12.7gm, 86%).
Reaction SMILES: C(O)(=O)C.Cl.[NH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[C:13]([F:16])[CH:14]=2)[CH2:9][CH2:8]1.[CH3:21][C:22]([CH3:24])=O.[BH4-].[Na+]>CO>[F:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][C@H:7]2[NH:6][CH:22]([CH3:24])[CH3:21])=[CH:11][C:12]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc2c(cc1F)[C@H](N)CC2
Reactant: CC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc2c(cc1F)[C@H](NC(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Glacial acetic acid (0.33 ml) was added to a mixture of (R)-methyl 1-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-05) [see above] (4.1 g, 19.6 mmol, 1 eq) and acetone (28.8 ml, 392.3 mmol, 20 eq) in methanol (100 ml), and the reaction mixture was stirred for 3 h at room temperature. It was then cooled to 0° C. and NaBH4 (2.23 g, 58.8 mmol, 3 eq) was added in portions. Stirring was carried out for a further 2 h at room temperature. After monitoring by TLC, concentration was carried out under reduced pressure and the residue was diluted with water (100 ml). Extraction with dichloromethane (150 ml) was carried out and the organic phase was washed with sat. sodium hydrogen carbonate solution (100 ml) and dried over sodium sulfate. The solvent was distilled off under reduced pressure and then the crude product was purified by column chromatography (Alox, 10% ethyl acetate/hexane) to yield the desired product in the form of a light-brown liquid. Yield: 76% (3.75 g, 19.61 mmol)
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:5])[CH3:4].[OH-].[Na+].I[CH2:9][CH:10]=[CH:11][C:12]1[CH2:13][S:14][C@@H:15]2[CH:35]([NH:36][C:37](=[O:67])/[C:38](=[N:64]\[O:65][CH3:66])/[C:39]3[N:40]=[C:41]([NH:44]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:42][CH:43]=3)[C:34](=[O:68])[N:16]2[C:17]=1[C:18]([O:20]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C(OCC)(=O)C.CCCCCC>[NH2:44][C:41]1[S:42][CH:43]=[C:39](/[C:38](=[N:64]/[O:65][CH3:66])/[C:37]([NH:36][CH:35]2[C:34](=[O:68])[N:16]3[C:17]([C:18]([O-:20])=[O:19])=[C:12](/[CH:11]=[CH:10]/[CH2:9][N+:3]([CH3:5])([CH3:4])[CH3:2])[CH2:13][S:14][C@H:15]23)=[O:67])[N:40]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[N+](C)(C)C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylamine hydrochloride (6.31 g, 66 mmole) was added to an aqueous NaOH solution (2N, 33 ml) covered with ethyl acetate (100 ml). The organic layer was separated, dried over NaOH pellets, and added to a suspension of diphenylmethyl 3-(3-iodo-1-propen-1-yl)-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (X-1, 32 g, 33 mmole) in a mixture of ethyl acetate and n-hexane (300 ml/150 ml). The mixture was stirred for one hour at room temperature and then filtered to give the blocked title compound, which was treated with trifluoroacetic acid (50 ml) and anisole (10 ml) for one hour at room temperature. The mixture was concentrated under reduced pressure and the residue was triturated with ether to give 10.3 g of dark brown solid, which was treated with water (100 ml) at room temperature. After removal of insolubles by filtration, the filtrate was chromatographed on a column of HP-20 (200 ml) by eluting with 30% aqueous methanol. The eluate was concentrated and lyophilized to give 2.3 g of the crude title compound, which was purified by preparative HPLC (Waters Associates, System 500, PrepPAK 500/C18, 15% CH3OH) to afford 880 mg (5%) of the title compound I-1D. Estimated purity 75% (by HPLC).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH:16]=[O:17])=[N:14][CH:15]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(OCC)(=O)C>[Br:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH:16]([OH:17])[C:2]([F:4])([F:3])[F:1])=[N:14][CH:15]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C=O)ncc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)C(F)(F)F)ncc1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
(Trifluoromethyl)trimethylsilane (2.0M solution in tetrahydrofuran, 0.75 mL) was added to a solution of 5-bromo-4-methylpicolinaldehyde (150 mg, 0.75 mmol). The mixture was cooled at 0° C. and tetra-N-butylammonium fluoride (1.0M solution in tetrahydrofuran, 2.2 mL) was added dropwise over 2 minutes. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (170 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.29 (s, 1H), 5.04 (d, J=7.2 Hz, 1H), 4.95 (p, J=6.7 Hz, 1H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:29][CH:28]=1)([OH:20])=[O:18]
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
7-Methyl-2-propylimidazo[4,5-b]pyridine (described in Example 9) was alkylated with 2-t-butoxycarbonyl-4'-bromomethylbiphenyl and the resulting protected derivatives was deprotected according to the procedure described in Step 2 of Example 3.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu][C:13]#[N:14]>CN1C(=O)CCC1.O>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([CH:9]([CH3:11])[CH3:10])=[CH:8][C:2]=1[C:13]#[N:14]
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1ccc(N)c(C#N)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Combine 2-bromo-4-isopropyl aniline (7.5 g, 35 mmol) and copper (I) cyanide (3.76 g, 42 mmol) in NMP (30.0 mL) and heat at 200° C. for 2 hours. Cool to ambient temperature and dilute with water (300 mL). Extract with ethyl acetate to give 4.58 g of the crude product. Silica gel chromatography, eluting with methylene chloride, gives 3.20 g of the title compound as a red oil: mass spectrum (ion spray): m/z=161 (M+1); 1H NMR (300 MHz, DMSO-d6): δ 7.21 (m, 2H), 6.73 (d, 1H), 5.79 (s, 2H), 2.73 (quintet, 1H), 1.12 (d, 6H).
Reaction SMILES: [C:1]([CH:4]1[CH:18]2[CH:7]([CH2:8][C:9]3[C:17]4[C:16]2=[CH:15][CH:14]=[CH:13][C:12]=4[N:11](S(C2C=CC=CC=2)(=O)=O)[CH:10]=3)[N:6]([CH3:28])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([CH:4]1[CH:18]2[CH:7]([CH2:8][C:9]3[C:17]4[C:16]2=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][CH:10]=3)[N:6]([CH3:28])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)C1CN(C)C2Cc3c[nH]c4cccc(c34)C12

Procedure:
Debenzenesulphonylation of the 9-acetyl compound (Example 4) (0.20 g) was achieved with potassium hydroxide in refluxing ethanol by the procedure previously described.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][CH:8]=1.Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.2758 mmol; 142.5 mg) in Methanol (10 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 186 as an off-white solid (105.6 mg, 91%). 1H NMR (400 MHz, DMSO) δ 9.66-9.62 (s, 1H), 9.48-9.44 (s, 1H), 9.33-9.28 (s, 1H), 8.65-8.61 (d, J=3.5 Hz, 2H), 7.54-7.45 (dd, J=21.6, 8.5 Hz, 2H), 4.02-3.96 (d, J=10.3 Hz, 1H), 3.90-3.84 (d, J=11.7 Hz, 4H), 3.03-2.96 (d, J=9.0 Hz, 1H), 2.89-2.82 (m, 1H), 2.65-2.61 (s, 3H), 1.98-1.86 (t, J=10.6 Hz, 2H), 1.78-1.67 (d, J=10.2 Hz, 1H), 1.45-1.35 (dd, J=19.2, 8.9 Hz, 1H); MS (ESI) m/z: 417.2 [M+H]+
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C([O:11][C:12](=O)[C:13](Br)([CH3:15])[CH3:14])C>C(O)C>[CH3:14][C:13]1([CH3:15])[NH:8][CH:1]2[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6]2)[NH:7][C:12]1=[O:11]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCO
Product: CC1(C)NC2CCCCC2NC1=O

Procedure:
5.4 parts of o-phenylene diamine are placed in a flask and ethyl-2-bromoisobutyrate added thereto with ethanol solvent. The reaction mixture is heated and 3,3-dimethyl-3,4-dihydroquinoxalin-2-one is recovered. Upon hydrogenation in the presence of catalyst, 3,3-dimethyl-decahydroquinoxalin-2-one is formed which, when used at 0.5 phr concentration in polypropylene in a manner analogous to that set forth in Example 1A above, provides stabilization for about 2000 hours (see Table I).