Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: c1cn[nH]c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
A mixture of (R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 13.2, 100 mg, 0.215 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (104 mg, 0.321 mmol), Pd(PPh3)2Cl2 (15.2 mg, 0.022 mmol), Na2CO3 (91 mg, 0.862 mmol), DME (914 μL), water (261 μL) and EtOH (131 μL) in a MW vial was sealed, evacuated/purged 3 times with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (3 mL), then stirred overnight with Si-Thiol (Silicycle 1.44 mmol/g, 90 mg, 0.129 mmol). The mixture was centrifuged and the supernatant was filtered through a 0.45 μm PTFE filter and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, from 15% to 20% in 6 min) to yield the title compound as a yellow transparent oil. UPLC-MS (Condition 3) tR=1.28 min, m/z=581.2 [M+H]+, m/z=580.4 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:25]=[C:15]3[NH:16][C:17](=O)[C:18]4[C:23]([N:14]3[N:13]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:25]=[C:15]2[N:16]=1
Reactant: COc1ccc(Nc2nc3[nH]c(=O)c4ccccc4n3n2)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2nc3nc(Cl)c4ccccc4n3n2)cc1OC
Temperature: 90 °C

Procedure:
A suspension of 2-(3,4-Dimethoxy-phenylamino)-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one (57 mg) in phosphorus oxychloride (5 mL) was heated at 90° C. for 2 h. Evaporation. The residue was suspended in dichloromethane, washed with cold sodium bicarbonate, brine and dried (Na2SO4). Filtration and concentration gave crude (5-Chloro-[1,2,4]triazolo[1,5-a]quinazolin-2-yl)-(3,4-dimethoxy-phenyl)-amine (68 mg). LC-MS: m/e=356.1 (M+H),
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1>C(OCC)(=O)C.[Pt]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(F)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2cccc(F)c2)c(F)c1
Reaction time: 6 h
Yield: 98.1 %

Procedure:
12.68 g (47.8 mmol) 2-fluoro-1-(3-fluoro-benzyloxy)-4-nitro-benzene is dissolved in 150 ml ethyl acetate. 1.27 g platinum 5% on charcoal is added and the mixture is hydrogenated at RT and normal pressure for 6 hours. The catalyst is filtered off and the solution evaporated to yield 11.03 g (98%) of a dark brown liquid. MS: m/e=235.1 (M+).
Reaction SMILES: C1C2C(=CC=CC=2)[C@H](N)[C@@H]1O.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2.[OH-].[K+]>C(O)(C)C.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2
Reactant: Nc1cccc2c1CC(=O)CC2
Agent: Cl[Ru]Cl
Agent: N[C@H]1c2ccccc2C[C@H]1O
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)O
Product: Nc1cccc2c1CC(O)CC2
Reaction time: 1 h
Yield: 65 %

Procedure:
To a stirred solution of benzeneruthenium(II) chloride dimer (3.10 mg, 0.006 mmol) and (1S, 2R)-(−)-cis-1-amino-2-indanol (3.7 mg, 0.025 mmol) in degaussed iso-propanol was heated at 80° C. for 20 minutes under argon. The mixture was added to the solution of 8-amino-3,4-dihydronaphthalen-2(1H)-one (50 mg, 0.310 mmol) in isopropanol (3 mL) at room temperature. A solution of potassium hydroxide (3.48 mg, 0.062 mmol) in isopropanol (1 mL) was added, and the mixture was stiired at 45° C. for 1 hour. The mixture was passed through silica gel and washed with ethylacetate. The filtrate was concentrated under reduced pressure to afford the 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol chiral enantiomer (33.0 mg, 65% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C>Cl.C(O)(=O)C>[F:21][C:19]1[C:18]([F:22])=[C:17]([F:23])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:24])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A suspension of 0.88 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine in a mixture of 10 cm3 of 17.5% aqueous hydrochloric acid solution and 10 cm3 of acetic acid is heated with stirring to a temperature in the region of 100° C. for 3 hours. After cooling to approximately 20° C., the product is drained and washed with 3 times 10 cm3 of water. 0.75 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3carboxylic acid is obtained in the form of a pale yellow solid, which decomposes at 352° C. and which is used without further purification for the subsequent steps.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][CH2:6]N1C2C=CC=CC=2N=N1.[BH4-].[Na+].Cl.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][CH3:6]
Reactant: Fc1cccc(NCn2nnc3ccccc32)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
1-((3-Fluoroanilino)methyl)-1H-benzotriazole (173.9 g) was slurried in dry tetrahydrofuran. Sodium borohydride (32.5 g) was added portionwise to the mixture at room temperature. After addition was complete, the mixture was heated at reflux for 4 hours. The solution was cooled and poured slowly into 400 mL of 5 M hydrochloric acid with ice and stirred for 1 hour at room temperature. The solution pH was adjusted to 9-10 using 10 M sodium hydroxide solution. The product was extracted using diethyl ether. The ether extracts were washed successively with 1 M sodium hydroxide solution, saturated sodium chloride solution, and water. The organic phase was dried over sodium sulfate and evaporated under reduced pressure to yield 87.5 g (97%) of 3-fluoro-N-methylaniline as a colorless oil. [NMR (200 MHz, DMSO-d6): δ 2.76 (s, 3H); 3.41 (br s, 1H); 6.59-6.92 (m, 3H); 7.27 (q, J=8.0 Hz, 1H)].
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:16]([N:4]1[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1CNCC(C)O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CC(C)O1
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a tetrahydrofuran solution (500 mL) of 2,6-dimethylmorpholine (Aldrich Co.) (mixture of cis/trans isomers) (25.02 g, 217.24 mmol), triethylamine (51.48 mL, 369.31 mmol) was added at room temperature, and the mixture was stirred for 15 minutes. Then, benzyl bromide (43.93 mL, 369.31 mmol) was added dropwise over 30 minutes, and the mixture was stirred for 4 days. A saturated aqueous solution of sodium hydrogen carbonate (200 mL) was added to the reaction liquor, and the mixture was stirred for 30 minutes, and then extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 65i, n-hexane to ethyl acetate/n-hexane 1:1), to obtain the title compound (10.7 g, 24%) as an oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=4)[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]O>>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=4)[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Product: CN(C)CCOc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 74 %

Procedure:
Obtained in 74% yield by an analogous method to Example 860, starting from 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol and 2-(dimethylamino)ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])=[CH:5][CH:4]=1.[CH:27]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:13]2[CH2:18][CH2:17][N:16]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[O:11])=[CH:7][CH:8]=1
Reactant: BrC1CCCC1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(Cl)cc2)C2CCNCC2)cc1
Product: COc1ccc(CC(=O)N(Cc2ccc(Cl)cc2)C2CCN(C3CCCC3)CC2)cc1

Procedure:
Starting materials: 42ELH89 (0.25 g, 0.67 mmol, 1.0 eq.), cyclopentylbromide (0.3, 3.0 eq.)
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=4)[CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(Cn2ccc3ccc(Br)cc32)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Cn2ccc3ccc(-c4ccc(C(F)(F)F)cc4)cc32)cc1
Yield: 67.3 %

Procedure:
Following the procedure described in Step 2 of Example 5, 6-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (0.490 g, 1.43 mmol) was coupled to 4-trifluoromethylbenzeneboronic acid (0.300 g, 1.58 mmol), using tetrakis(triphenylphosphine) palladium (0.0560 g, 0.0484 mmol) and sodium carbonate (0.615 g, 5.80 mmol) in water (2.8 mL), ethanol (1.4 mL) and toluene (10 mL). Purification by flash chromatography using hexane as an eluant afforded 1-[4-(tert-butyl)benzyl]-6-[4-(trifluoromethyl)phenyl]-1H-indole as a white solid (0.392 g, 67%), mp 134-135° C. 1HNMR (200 MHz, DMSO-d6): δ 7.85 (d, 3H, J=7.7 Hz), 7.75 (d, 2H, J=7.7 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.55 (d, 1H, J=4.1 Hz), 7.25-7.4 (m, 3H), 7.15 (d, 2H, J=7.7 Hz), 6.5 (d, 1H, J=2.6 Hz), 5.45 (s, 2H), and 1.2 ppm (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])O[C:5](=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH3:16][N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:15])[N:18]([N:17]([CH3:16])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5](=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: CN(N)c1ccccc1
Reactant: O=C1OC(=O)C(c2ccc(Cl)cc2)=C1Cl
Solvent: ClC(Cl)Cl
Product: CN(c1ccccc1)N1C(=O)C(Cl)=C(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.65 g (15 mmol) of 3-chloro-4-(4-chlorophenyl)furan-2,5-dione were initially charged in 75 ml of chloroform and, at room temperature, admixed dropwise with stirring with 1.83 g (15 mmol) of N-methyl-N-phenylhydrazine dissolved in 15 ml of chloroform, and the mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure and the residue was taken up in 200 ml of methylene chloride, washed three times with in each case 150 ml of water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 4.6 g of a crystalline solid, m.p. 155-157° C.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:13]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O>[CH2:13]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:35])=[CH:37][CH:38]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 31.4 g. of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide over 30 minutes at room temperature. Stirring is continued for a further 30 minutes. In the meantime, a mixture of 36.2 g. of p-hexadecylaminobenzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated to an oil which is co-evaporated twice with added dioxane to remove excess thionyl chloride. To the resulting oily residue of p-hexadecylaminobenzoyl chloride hydrochloride is added, in one portion, the previously prepared mixture of sodium benzene-sulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and is then filtered through a bed of diatomaceous earth. The filtrate is poured into 2 l. of water, and 250 ml. of saturated sodium chloride solution is added to coagulate the precipitate. The mixture is filtered and the product is washed with water and partially air dried. The product is dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion. The layers are separated, the organic phase is dried over anhydrous sodium sulfate and filtered through a bed of 300 g. of hydrous magnesium silicate. The product is eluted with an additional 3 l. of methylene chloride. The first approx. 1 l. of filtrate is set aside and the remainder is evaporated to dryness. The residue is crystallized three times from toluene and the product is dried in the Abderhalden at 65° C. to provide 10.8 g. of the title compound as colorless crystals melting point 136°-137.5° C.
Reaction SMILES: [C:1]1([S:7]([CH3:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10]O>O>[C:1]1([S:7]([CH3:9])(=[O:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccccc1
Reactant: OO
Solvent: O
Product: CS(=O)(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
A complex (4) (1.9 mg, 1 mol %) was weighed out in a Schlenk flask, to which racemic phenylmethylsulfoxide (28 mg, 0.2 mmol) was added. Water (0.5 mL) was added, followed by stirring for 10 minutes at 20° C. A 30% hydrogen peroxide solution (9 μL, 0.4 eq) was added, followed by stirring the resultant mixture for 3 hours at room temperature. To the reaction mixture, water (5 mL) was added, followed by extraction using ethyl acetate. An organic phase was dried over anhydrous sodium sulfate, followed by filtration and then it was concentrated under reduced pressure. By purifying the concentrate using silica gel column chromatography (ethyl acetate), 6.5 mg (21% yield) of phenylmethylsulfone was obtained, and 22.1 mg of phenylmethylsulfoxide (79%) was recovered. Optical purity was determined to be 12% ee for a S form after measured by HPLC analysis.
Reaction SMILES: [N:1]([C@H:4]1[C:34](=[O:35])[N:6]2[CH:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:8](OS(C)(=O)=O)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]>C1C=CC=CC=1.CCOC(C)=O>[N:1]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]
Reactant: CC(=O)OCC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)OCC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](N=[N+]=[N-])[C@H]2SC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-acetoxymethyl-cepham-4-carboxylate (0.72 g.), EM silica gel 60 (7.20 g.), and 3:1 PhH-EtOAc (20 ml.) is stirred in a stoppered flask for 4 days at room temperature. The mixture is filtered through a sintered glass funnel to remove the silica gel, which is washed with several portions of EtOAc. Evaporation of the filtrate and washings leaves an oil. This material is chromatographed on Baker silica gel using 9:1 φH-EtOAc as an eluting solvent, to provide p-nitrobenzyl 7α-azido-3-acetoxymethyl-ceph-3-em-4-carboxylate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:26]=[C:25]([N:27]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:24]=[CH:23][CH:22]=1.[CH3:46][N:47](C=O)C>CC([O-])=O.CC([O-])=O.[Pd+2].[C-]#N.[C-]#N.[Zn+2]>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:25]2[N:26]=[C:21]([C:46]#[N:47])[CH:22]=[CH:23][CH:24]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(Br)n2)cc1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(C#N)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Polystyrene supported triphenylphosphine (250 mg, 0.544 mmol) and Pd(OAc)2 (57 mg, 0.25 mmol) were combined in a glass vial along with DMF (5.5 mL). The vial was flushed with argon and a septum was affixed. The suspension was stirred for 1 h at room temperature. Solid Zn(CN)2 (426 mg, 3.63 mmol) and a solution of (6-bromo-pyridin-2-yl)-bis-(4-methoxy-benzyl)-amine (1.50 g, 3.63 mmol) in DMF (5.5 mL) were then added. The vial was flushed with argon, sealed, and heated at 140° C. in a microwave for 30 min. The reaction mixture was filtered and the volatiles were removed in vacuo. The residue was purified by flash chromatography on silica gel (10→50% EtOAc/hexanes) to give the title compound as a colorless oil, m/z 361.0 [M+2]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[ClH:19].Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@@H:37]3[CH:42]4[CH2:43][CH2:44][N:39]([CH2:40][CH2:41]4)[CH2:38]3)=[O:36])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.O>CN(C=O)C>[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:35]([C@@H:37]4[CH:42]5[CH2:41][CH2:40][N:39]([CH2:44][CH2:43]5)[CH2:38]4)=[O:36])=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: COc1cccc(N=C=O)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)Nc2ccc(-c3ccc(NC(=O)[C@H]4CN5CCC4CC5)cc3)cc2)c1
Reaction time: 18 h

Procedure:
45.4 mg (0.30 mmol) of 3-methoxyphenyl isocyanate and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)-N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. A preparative HPLC is carried out for further purification. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 22 mg (27.6% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11](C#N)=[C:10]([Cl:17])[N:9]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH:18]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([Cl:17])[N:9]=1)([CH3:19])[CH3:20]
Reactant: Cc1cc(NCCN(C(C)C)C(C)C)nc(Cl)c1C#N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc(Cl)nc(NCCN(C(C)C)C(C)C)c1

Procedure:
A solution of crude 2-(2-diisopropylaminoethylamino)-4-methyl-5-cyano-6-chloropyridine (4.0 g) in 20 ml of 50% (by volume) sulfuric acid is stirred at reflux for 16 hours over night. The solution is cooled and is cautiously poured into excess saturated sodium carbonate. The basic mixture is extracted with methylene chloride. After washing the extract with water, drying and filtering through activated carbon, the solvent is removed in vacuo. This gives 3.1 g of pale yellow oil which slowly solidifies. Extraction of the crude solid with hexane, cooling in dry ice-acetone and filtering gives 1.9 g. of white solid. The purified product melts at 64°-66° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
To a mixture of 6-fluoro-2-methyl-3-nitrobenzoic acid (21.2 g, 0.107 mol), powdered potassium carbonate (36.8, 0.266 mol) in DMF (200 mL) was added methyl iodide (37.8 g, 0.266 mol). The mixture was stirred at ambient temperature for 16 hours, then diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane) afforded 12.6 g (56%) of the title compound.