Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl.CN(C1C=CN=CC=1)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
Boc-Pro-OH (50.0 g, 0.23 mol) was dissolved in dichloromethane (500 mL), and EDCI (89.1 g, 0.46 mol), DMAP (5.7 g, 0.05 mol), DIPEA (162 mL, 0.93 mol) and benzyl alcohol (48 mL, 0.46 mol) were added dropwise. The mixture was stirred at room temperature for 12 hours. The mixture was washed several times with an aqueous solution of 5% citric acid. The organic layer was dried over sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound as yellow oil (70.0 g, 99%).
Reaction SMILES: Br[CH2:2][C:3](=[O:34])/[C:4](=[N:31]/[O:32]C)/[C:5](N[C@@H]1C(=O)N2[C@@H]1SCC(CSC1N(C)N=C(O)C(=O)N=1)=C2C(O)=O)=[O:6].[C:35]([O:39]C(=O)CC(C)=O)([CH3:38])([CH3:37])[CH3:36].N([O-])=O.[Na+]>C(O)(=O)C.O>[C:35]([O:39][C:5](=[O:6])/[C:4](=[N:31]\[OH:32])/[C:3](=[O:34])[CH3:2])([CH3:38])([CH3:37])[CH3:36]
Reactant: CO/N=C(/C(=O)CBr)C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
The (6R,7R)-7-[4-bromo-2-[(Z)-methoxyimino]-3-oxobutyramido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows: 592.1 g of acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. To this solution is added dropwise at 5°-10° C. during 21/2 hours a solution of 290.6 g of sodium nitrite in 655 ml of water. The resulting yellow suspension is stirred for 30 minutes at 20° C., treated with 940 ml of water and stirred for a further 2 hours. The mixture is treated with 900 ml of water and 900 g of ice and extracted in the stirring vessel three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 of water each time, then treated with 5 l of water and the pH-value is adjusted to 6.8 with sodium hydrogen carbonate. After separating the aqueous phase, the organic phase is washed once with water. Thereafter, the ethyl acetate solution is dried over sodium sulphate and evaporated in vacuo at 40° C. There is obtained (Z)-2-hydroxyimino-3-oxo-butyric acid tert-butyl ester as a yellow oil which is dried for a further 9 hours in a high vacuum at 40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.ClCCl>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:11]=[CH:10][C:9]1=2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of 6-amino-3,4-dihydronaphthalen-1(2H)-one (0.5 g, 3.1 mmol) in pyridine (5 mL) was added acetic anhydride (0.38 g, 3.7 mmol). The solution was stirred at room temperature for 3 hours. The reaction was then diluted with dichloromethane (50 mL). The organic layer was separated, washed with 2M HCl (2×25 mL), brine (50 mL), dried using sodium sulfate and concentrated under reduced pressure. The crude was product was obtained as an off colored solid (0.5 g, 79%) and used in the next reaction without any further purification. 1H NMR (CDCl3, 400 MHz): δ 8.94 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.20 (d, J=8.0 Hz, 1H0, 2.96 (t, J=6.2 Hz, 2H), 2.62 (quintet, J=6.0 Hz, 2H), 2.12 (s, 3H), 2.11 (t, J=6.0 Hz, 2H); LCMS [M+H]: 204.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:22][C:23]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[F:31])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]([F:21])([F:20])[F:19])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:33]1[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:31][C:24]1[CH:25]=[C:26]([F:30])[CH:27]=[C:28]([F:29])[C:23]=1[CH2:22][N:10]1[C:9]([C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:8]=[CH:7][CH:6]=2)=[C:17]2[C:12]([C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=[CH:16]2)=[N:11]1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: C#Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(C#Cc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)c1
Yield: 46.8 %

Procedure:
A solution of 3-(3-ethynylphenyl)-2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazole (0.103 g, 0.24 mmol), ethyl 3-iodobenzoate (0.042 mL, 0.25 mmol), tetrabutylammonium acetate (0.108 g, 0.36 mmol) and 8.8 mg of tris-(dibenzylidineacetone)-dipalladium in 2 mL of dry DMF was stirred at ambient temperature for 3 hours. The reaction mixture was partitioned with ethyl acetate and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography (silica 60, CH2Cl2-hexane, 1:1) to give the title compound (0.065 g).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:2]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]([S:23]([CH3:26])(=[O:24])=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1)(=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1ccc(CN(CCCCCCC(=O)O)S(C)(=O)=O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(CN(CCCCCCC(=O)O)S(C)(=O)=O)cc1
Yield: 108.3 %

Procedure:
A solution of 7-{[4-(1-hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid (88 mg, 0.21 mmol) and Dess-Martin reagent (145 mg, 0.34 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 72 h. Sodium thiosulfate solution was added and the reaction mixture was stirred until all solids were dissolved. The aqueous layer was extracted with CH2Cl2 (2×), and the organic solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (CH2 Cl2to 5% MeOH/CH2Cl2) provided the title compound (93.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, 2H), 7.43 (d, 2H), 4.40 (s, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 2.85 (s, 3H), 2.28 (t, 2H), 1.71 (m, 2H), 1.50 (m, 4H), 1.15–1.40 (m, 8H), 0.85–0.95 (m, 3H).
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10][NH2:11].[OH-].[Na+].[CH2:15]=O>CC(O)C.O>[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10][NH:11][CH2:5][C:4]([CH3:15])([N+:1]([O-:3])=[O:2])[CH3:6]
Reactant: C=O
Reactant: CN(C)CCN
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CN(C)CCNCC(C)(C)[N+](=O)[O-]
Reaction time: 22 h

Procedure:
To a solution of 2-nitropropane (2.07 g, 23.2 mmol) and N1,N1-dimethyl-ethane-1,2-diamine (2.22 g, 25.2 mmol) in 2-propanol (5 ml) was added 5 M NaOH in H2O (30 ul, 0.15 mmol), H2O (1 ml). 37% Formaldehyde in H2O (1.8 ml, 24 mmol) was added dropwise, and the reaction stirred for 22 h. The solution was concentrated in vacuo to half volume, acidified with sat. NaHSO4 to pH 2, and washed with 3× 100 ml CH2Cl2. 15% NaOH in H2O was added to pH 12, and the slurry extracted with 3× 100 ml CH2Cl2. The organic phases were combined, dried on MgSO4, concentrated in vacuo, and used without further purification. ESI/APCI (pos) expected for C8H19N3O2: 189.15. Found: 190 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(C(=O)O)ccc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(N)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-4-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-4-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]([C:17]([N:19]2[CH2:24][C:23]3([CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[O:22][CH2:21][CH2:20]2)=[O:18])=[CH:14][CH:13]=1)=[O:11].C1(C)C=CC=CC=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:22]1[C:23]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:24][N:19]([C:17]([C:15]2[S:16][C:12]([C:10]([O:9][CH3:8])=[O:11])=[CH:13][CH:14]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 4-(5-(methoxycarbonyl)thiophene-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 30, step a) (0.45 g) in dichloromethane (40 mL) and the resultant mixture was allowed to stand at 20° C. for 1 hour. Toluene (50 mL) was added and the solvents removed under reduced pressure to afford the subtitled compound. Yield 0.46 g.
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=3[C:12]3=[N:20][O:21][C:22]([CH3:23])=[C:11]3[C:10]2=[O:24])[CH2:4]1.[C:25]1([S:31]([N:34]([CH2:41][C:42](O)=[O:43])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:25]1([S:31]([N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:41][C:42]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH:5]([N:9]3[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=4[C:12]4=[N:20][O:21][C:22]([CH3:23])=[C:11]4[C:10]3=[O:24])[CH2:4]2)=[O:43])(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Reactant: O=C(O)CN(c1ccccn1)S(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: I
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CN(c3ccccn3)S(=O)(=O)c3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 144 h
Yield: 47 %

Procedure:
To a solution of 5-(3-amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide, 130 mg (0.28 mmol) in 10 mL of DMF was added 82 mg (0.28 mmol) of (benzenesulfonyl-pyridin-2-yl-amino)-acetic acid (Bionet), 46 mg (0.34 mmol) of 1-hydroxy-7-azabenzo-triazole, 66 mg (0.34 mmol) of EDC, 5 mg of DMAP and 120 μL (0.84 mmol) of TEA. The reaction mixture was stirred six days at rt. and was concentrated to dryness. The residue was dissolved in 20% isopropanol/chloroform, washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using a MeOH/chloroform gradient and concentrated to dryness. The residue was slurried in ether/hexanes and concentrated to dryness to yield 79 mg (47%) of the title compound as a tan foam. MS (ion spray) 606.1 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]3[C:9](=[CH:10][N:11]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)[N:12]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][C:30]1(Br)[C:35](=[O:36])[NH:34][C:33](=[O:37])[NH:32][C:31]1=[O:38].C1CN2C(=NCCC2)NC1.C(#N)C>CO.C(O)(=O)C>[CH:5]([O:6][CH:7]([CH3:15])[CH3:8])([CH3:24])[CH3:4].[CH3:26][O:27][CH2:28][CH2:29][C:30]1([O:1][C:2]2[CH:25]=[CH:24][C:5]([O:6][C:7]3[CH:15]=[CH:14][C:13]4[C:9](=[CH:10][N:11]([C:16]5[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=5)[N:12]=4)[CH:8]=3)=[CH:4][CH:3]=2)[C:31](=[O:38])[NH:32][C:33](=[O:37])[NH:34][C:35]1=[O:36]
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: N#Cc1ccc(-n2cc3cc(Oc4ccc(O)cc4)ccc3n2)cc1
Agent: C1CN=C2NCCCN2C1
Solvent: CC#N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)OC(C)C
Product: COCCC1(Oc2ccc(Oc3ccc4nn(-c5ccc(C#N)cc5)cc4c3)cc2)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
A mixture of 4-[5-(4-Hydroxy-phenoxy)-indazol-2-yl]-benzonitrile (0.070 grams, 0.22 mmol), 2-methoxyethylbromobarbiturate (0.10 grams, 0.4 mmol), 1,5,7-triazabicyclo[4.4.0]dec-5-ene bound to polystyrene (0.44 grams) and acetonitrile (2.3 mL) was shaken for 24 hours at room temperature. The mixture was treated with a solution of acetic acid in methanol (1:4 v/v), shaken for 20 minutes, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by radial chromatography eluting with 3:2 ethyl acetate-hexanes. Trituration of the purified product with iso-propyl ether afforded 4-(5-{4-[5-(2-Methoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-indazol-2-yl)-benzonitrile (0.027 grams) as a colorless solid. MS: 512.7 [M+H]+; 510.6 [M−H]−
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[C:14]=2[F:22])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]=2[F:22])[O:11][CH3:12])=[CH:24][CH:25]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1Oc1ccccc1
Reaction time: 24 h
Yield: 58.4 %

Procedure:
A mixture of (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-3-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide (150 mg), phenyl boronic acid (58 mg), copper (II) acetate (79 mg), pyridine (0.18 ml) and activated molecular sieves (4 A) at rt in CH2Cl2 under an argon atmosphere was stirred for 24 h. More copper (II) acetate (40 mg), phenyl boronic acid (29 mg) and pyridine (0.9 ml) were added to the mixture and stirring was continued for 16 h. The mixture was filtered and the cake washed with 15 ml CH2Cl2. The filtrate was washed with 1.0 N HCl (25 ml), 1.0 N NaOH (25 ml) and brine (25 ml), dried (MgSO4), filtered and concentrated (rotavapor) to leave the crude product as a brown gum. The crude product was purified by flash chromatography (cyclohexane=5 cyclohexane/EtOAc 2:3) to give (RS)-N-(4-Cyano-benzyl)-2-(2-fluoro-4-methoxy-3-phenoxy-phenyl)-2-methoxy-acetamide (107 mg) as an off-white foam. MS 421.2 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH:17]([F:19])[F:18])=[CH:14][NH:13][C:12](=[O:20])[CH:11]=2)[CH:3]=1.CC(C)([O-])C.CC(C)([O-])C.[Mg+2].CC(C)([O-])C.[K+].Br[CH:39]([CH3:43])[C:40]([OH:42])=[O:41]>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH:17]([F:18])[F:19])=[CH:14][N:13]([CH:39]([CH3:43])[C:40]([OH:42])=[O:41])[C:12](=[O:20])[CH:11]=2)[CH:3]=1
Reactant: CC(Br)C(=O)O
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1OC(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC(C(=O)O)n1cc(OC(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
163 mg (0.55 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile, 2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassium tert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted at 45° C. and worked up according to General Method 4A. Owing to incomplete conversion, the crude product was then once more reacted as described above with 1.2 eq. of magnesium di-tert-butoxide, 0.65 eq. of potassium tert-butoxide and 0.8 eq. of 2-bromopropionic acid (racemate) in 3.5 ml of tetrahydrofuran and worked up analogously. Yield: 270 mg (purity 63%, 84% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]([OH:20])=O.Br[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:25][CH2:26][NH2:27].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[F:40]>>[Cl:33][C:34]1[CH:35]=[C:36]([C:22]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:24]([CH2:25][CH2:26][NH:27][C:18]([C:3]3[CH:4]=[C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:6]=[CH:7][C:2]=3[OH:1])=[O:20])[CH:23]=2)[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: COc1ccc(CCN)cc1Br
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Product: COc1ccc(CCNC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2O)cc1-c1ccc(F)c(Cl)c1
Yield: 24.5 %

Procedure:
The resin-bound 4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (20 mg, 0.06 mmol) obtained as in Example 1 was reacted with 3-bromo-4-methoxy-phenethyl amine (57 mg, 0.25 mmol) following general procedure A to give resin bound 4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-3-bromo-4-methoxy-phenyl)-ethyl]-amide(18 mg, 0.05 mmol). The above resin bound amide was treated with 3-chloro-4-fluoro-phenyl boronic acid (43 mg, 0.25 mmol) as described in the general procedure D to provide the title compound (8.0 mg,).
Reaction SMILES: Cl.CO[C:4](=O)[C@@H:5]([CH2:8][SH:9])[NH:6][CH3:7].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:23](=[O:26])(O)[O-:24].[Na+]>CN(C=O)C>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][N:6]([CH2:7][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[C@@:5]([CH3:4])([C:23]([OH:24])=[O:26])[CH2:8][SH:9]
Reactant: O=C([O-])O
Reactant: BrCc1ccc2ccccc2n1
Reactant: CN[C@H](CS)C(=O)OC
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@](CS)(C(=O)O)N(Cc1ccc2ccccc2n1)Cc1ccc2ccccc2n1

Procedure:
The ligand N,N-bis[(2-quinolyl)methyl]-(S)-methly-L-cysteine was prepared from the dropwise addition of (S)-methyl-L-cysteine methylester hydrochloride (2.0 g, 10.8 mmol) in 10 mL DMF to a stirring solution of 2-bromomethylquinoline (4.8 g, 21.6 mmol) and sodium bicarbonate (4.1 g, 49 mmol) in 40 mL. The mixture was allowed to react for 4 h at 80° C. Evaporation of the solvent followed by column chromatography with 3:1 hexancs:ethyl acetate (Rf 0.3) afforded the ester of the ligand (1.7 g, 82%). Saponification was achieved by stirring the ester (1.9 g, 4.4 mmol) in 8 mL THF with LiOH(4.6 mL, 1M) for 2.5 h. The solution was then extracted with methylene chloride, and the aqueous layer acidified with 0.5M HClO4 to pH 6. Several extractions with methylene chloride followed by drying and evaporation of the solvent afforded the crude acid. Purification by column chromatography with ethyl acetate afforded the pure ligand (0.57 g, 31%).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])C.[OH-].[K+]>CCO.O>[CH3:30][C:5]([CH3:31])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 74.1 %

Procedure:
To a solution of 209j (11.63 g, 25.6 mmol) in EtOH and H2O (3:1, 200 mL) was added powdered KOH (85%, 4.31 g, 65.3 mmol). The resulting mixture was refluxed for 19 h and concentrated in vacuo until all of the EtOH was removed. Water (200 mL) was added and the resulting mixture was extracted with Et2O (2×200 mL). The aqueous phase was acidified with aqueous HCl (4 M) to pH ˜1 and extracted with Et2O (3×200 mL). The combined Et2O layers of the latter extraction were dried over anhydrous Na2SO4 and evaporated in vacuo. The remaining white solid was recrystallized from heptane/iPr2O to give 210j (7.56 g, 74%) as white crystals. Mp 74.3-77.3° C. 1H NMR (CD3OD): δ (ppm): 2.43 (t, J=7.3, 4H), 1.57-1.50 (m, 8H), 1.33-1.21 (m, 16H), 1.14 (s, 12H). 13C NMR (CD3OD): δ (ppm): 214.5, 182.1, 43.6, 43.2, 42.0, 31.2, 30.4, 30.38, 26.2, 25.9, 25.0. HRMS: Calcd for C23H42O5 (M+): 398.3028. found: 398.3032.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.[CH2:35]([O:37][C:38](=[O:45])[C@H:39]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH2:40])[CH3:36]>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:40][C@H:39]([C:38]([O:37][CH2:35][CH3:36])=[O:45])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1
Product: CCOC(=O)[C@H](CC(C)C)NCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1

Procedure:
From Intermediate 4E and L-leucine ethyl ester LCMS purity 98%, m/z 560 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.10-1.20 (6H, m), 1.45-1.55 (3H, t), 1.65-1.85 (2H, m), 1.90-2.00 (1H, m), 2.15-2.30 (2H, m), 2.85-3.05 (2H, m), 3.55 (1H, m), 4.35-4.50 (4H, m), 6.00 (1H, d), 7.10 (1H, d), 7.45-7.55 (1H, m), 7.80-7.85 (1H, m), 7.95 (1H, d).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1.[CH3:43][C:44]1([CH3:56])[N:49]([O:50])[C:48]([CH3:52])([CH3:51])[CH2:47][CH:46](N=C=S)[CH2:45]1.O.O=C[C@@H]([C@@H]([C@@H](CO)O)O)O>CN(C=O)C>[CH3:51][C:48]1([CH3:52])[N:49]([O:50])[C:44]([CH3:56])([CH3:43])[CH2:45][CH2:46][CH2:47]1.[CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1
Reactant: CC1(C)CC(N=C=S)CC(C)(C)N1[O]
Agent: NCCNC(=O)Cc1cccc(NC(=O)Cc2ccc(Nc3ncnc4c3ncn4[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Agent: O=C[C@H](O)[C@H](O)[C@H](O)CO
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCCC(C)(C)N1[O]

Procedure:
ADAC, 2 (11.8 mg, 20 umol), was suspended in 0.5 ml DMF and treated with 4-isothiocyanato-TEMPO (2,2,6,6,-tetramethyl-1-piperidinyloxy, free radical (7 mg, Aldrich). After 1 hour 1.5 ml water was added to the solution, and the precipitate was collected, washed with a minimum of MeOH and ether, and recrystallized from DMF/ether/petroleum ether, to give a product which was homogeneous by thin layer chromatography and gave proton NMR and ESR spectra consistent with the structure. Yield 8.3 mg (51%). Cf-MS peak at 758 (m+1-MeO) and 626 (m+1 -ribose). IR shows a peak at 1580 cm-1, characteristic of a thiourea carbonyl stretch.