Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)([O:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]N(C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:23][O:16][C:15](=[O:17])[CH2:14][O:13][C:10]1([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)(c2nccs2)C1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)COC1(c2nccs2)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of 2-(1-(tert-butoxycarbonyl)-3-(thiazol-2-yl)pyrrolidin-3-yloxy)acetic acid (7.5 g, 22.84 mmol) in dichloromethane (150 mL) was added N,N-dimethylformamide (1 mL) followed by dropwise addition of oxalyl chloride (1.999 mL, 22.84 mmol). The cold bath was then removed, and the reaction was stirred for 4 hours. Methanol (30 mL) was added to the ambient reaction, and the reaction was stirred for an additional 0.5 hours. The reaction was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 50% ethyl acetate in hexane, to give the product. MS ESI(+) m/z 342.8 [M+H]+.
Reaction SMILES: OC1C=C([NH:8][C:9]2[N:14]=[C:13]([NH:15]C3C=CC=C(O)C=3)[C:12](F)=[CH:11][N:10]=2)C=CC=1.Cl[C:25]1N=C(Cl)C(C#N)=C[N:26]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)N>>[OH:34][C:35]1[CH:36]=[C:37]([C:11]2[N:10]=[C:9]([NH2:8])[N:14]=[C:13]([NH2:15])[C:12]=2[C:25]#[N:26])[CH:39]=[CH:40][CH:41]=1
Reactant: Nc1cccc(O)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: N#Cc1cnc(Cl)nc1Cl
Product: N#Cc1c(N)nc(N)nc1-c1cccc(O)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and 3-hydroxyaniline were reacted to yield N2,N4-bis(3-hydroxyphenyl-5-cyano-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.73 (bs, 1H), 9.40 (s, 1H), 9.33 (bs, 1H), 9.24 (s, 1H), 8.47 (s, 1H), 7.20 (d, 1H, J=7.5 Hz), 7.11 (t, 1H, J=7.5 Hz), 7.09-7.02 (m, 2H), 6.99-6.89 (m, 3H), 6.54 (d, 1H, J=7.2 Hz), 6.37 (dd, 1H, J=1.8 and 8.4 Hz); LCMS: ret. time: 19.71 min.; purity: 97%; MS (m/e): 320 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[C:15]([C:18]1[CH:19]=[C:20]([CH:48]=[CH:49][CH:50]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([N+:31]([O-])=O)=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=1)=[O:35])(=[NH:17])[NH2:16].C(O)(=O)C>C(O)C.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[C:15]([C:18]1[CH:19]=[C:20]([CH:48]=[CH:49][CH:50]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([CH3:45])([CH3:46])[CH3:47])=[CH:40][CH:39]=1)=[O:35])(=[NH:16])[NH2:17]
Reactant: C[N+](C)(C)c1ccc(CNC(=O)c2cc3cc([N+](=O)[O-])ccc3n2Cc2cccc(C(=N)N)c2)cc1
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CC(=O)O
Product: C[N+](C)(C)c1ccc(CNC(=O)c2cc3cc(N)ccc3n2Cc2cccc(C(=N)N)c2)cc1
Yield: 70 %

Procedure:
This compound was prepared from [4-({[1-(3-amidino-benzyl)-5-nitro-1H-indole-2-carbonyl]-amino}-methyl)-phenyl]-trimethyl-ammonium trifluoroacetate trifluoroacetic acid salt (example 36) by hydrogenation in ethanol with 3 equivalents of acetic acid, catalyzed by Pd/C (10%). Yield: 70%. M.p. 114° C. (dec.). MS: 455.3 (M+).
Reaction SMILES: CN(C)C(Cl)=[O:4].[CH2:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])C.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>O1CCOCC1>[OH:18][CH2:17][CH2:16][CH2:15][NH:14][C:7](=[O:4])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCN(CC)CC
Reactant: NCCCO
Reactant: CN(C)C(=O)Cl
Solvent: C1COCCO1
Product: CCN(CC)C(=O)NCCCO
Temperature: 90 °C
Reaction time: 3 h

Procedure:
15.0 g (139.5 mmol) of N,N-dimethylcarbamoyl chloride and 80 mL dioxane were added to a 250 mL two-necked flask with a reflux condenser. Then 13.66 g (135 mmol) triethylamine and 10.44 g (139 mmol) of 3-amino-1-propanol were added. After exothermic evolution of heat subsided, the mixture was stirred for 1 h at 60° C. and for 3 h at 90° C., where a light brown suspension slowly formed. After the suspension had been cooled down to 50° C., the solid was filtered out.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[C:3]=1[C:4](O)=[O:5].CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=3)[NH:14][C:7]=2[C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Nc1ccc(OCc2ccccc2)cc1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=c1c2cc(OCc3ccccc3)ccc2[nH]c2c([N+](=O)[O-])ccc(Cl)c12

Procedure:
Four grams of 2-chloro-5-nitro-6-[[4-(phenylmethoxy)phenyl]amino]benzoic acid was suspended in 80 ml of boiling 1,2-dichloroethane to which 0.2 ml of N,N-dimethylaniline was added followed by 8.0 ml of phosphorus oxychloride. The mixture was stirred under reflux for 30 minutes and cooled overnight. The resulting suspension was filtered providing the title compound as a red solid, mp 216°-217° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([CH2:23][C:24]([O:26]CC)=[O:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:3]1.C1COCC1.[OH-].[Li+].Cl>CO>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:3]1
Reactant: CCOC(=O)Cn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a suspension of the product of Example 52B in 1:1 THF:methanol (6 mL) was added 0.5 N aqueous lithium hydroxide (6 mL). The mixture was stirred at room temperature for 2 hours, adjusted to pH 3 with 1.0 N HCl, and filtered. The filter cake was washed with water and dried to give the title compound (0.133 g, 86%). MS (ESI−) m/z 399 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 5.16 (s, 2H), 7.54 (m, 2H), 7.67 (d, J=7.72 Hz, 1H), 7.77 (t, J=7.72 Hz, 1H), 7.92 (d, J=7.72 Hz, 1H), 8.60 (dd, J=8.09, 1.84 Hz, 1H), 8.84 (dd, J=4.60, 1.65 Hz, 1H), 13.11 (br s, 1H), 13.79 (br s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:15])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:14][CH:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCC(O)Cc1ccccc1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccccc1C)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (4.9 g, 127.8 mmol) in THF (150 ml) was added 1-o-tolylpent-4-en-2-ol (15 g in THF, 85.22 mmol) at 0° C. stirred for 30 min. Then added benzylbromide (17.85 g, 102.2 mmol) at 0° C. then reaction mixture was stirred for room temperature for 16 h. Then quenched with ice cold H2O and concentrated under reduced pressure to afford crude compound. The title compound was separated by separation method-A and E. (Yield 13.0 g).
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].[Br:8][C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18]Br)[C:12]=2[S:11][CH:10]=1>C(O)C>[Br:8][C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH:18]=[O:2])[C:12]=2[S:11][CH:10]=1
Reactant: BrCc1cccc2c(Br)csc12
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=Cc1cccc2c(Br)csc12

Procedure:
With stirring, 68.2 g (0.74 mole) of 2-nitropropane are added dropwise at room temperature, over a period of 45 minutes, to a Na-ethoxide solution prepared under an argon atmosphere from 14.2 g (0.61 mole) of sodium and 800 ml of abs. ethanol. 137 g (0.61 mole) of 3-bromo-7-bromomethylbenzothiophene are then added dropwise at room temperature, over a period of 1.5 hours, to the resulting white suspension. After the reaction mixture has been stirred for one day, the solvent is evaporated off from the reaction mixture in vacuo, the resulting residue of 101.2 g is dissolved in a mixture of hexane:diethyl ether 1:1 and the solution is purified by chromatography on silica gel. After evaporation of the solvent, 81 g (80% of the theoretical amount) of 3-bromo-7-benzothiophene-carbaldehyde are obtained as residue.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.CN(C(N1CC1)=O)C.[CH2:25]([CH:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41]I)[CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]>C1COCC1.CCCCCC.C1COCC1>[CH2:25]([CH:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:35][CH2:36][CH:37]([CH2:40][CH2:41][C:15]3[C:10]([F:9])=[N:11][C:12]([F:16])=[CH:13][CH:14]=3)[CH2:38][CH2:39]2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]
Reactant: CCCC1CCC(C2CCC(CCI)CC2)CC1
Reactant: Fc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)C(=O)N1CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1CCC(C2CCC(CCc3ccc(F)nc3F)CC2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.02 mol of lithium diisopropylamide in THF/hexane (prepared analogously to Example 1) is added dropwise at 25° C. to a mixture of 0.2 mol of 2,6-difluoropyridine, 0.02 mol of N,N-dimethylethyleneurea, 0.02 mol of 2-(4'-propylbicyclohexyl-4-yl)-1-iodoethane and 25 ml of THF. Stirring for 1.5 hours and workup as described in Example 1 give the pure product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:27])[CH:20]=[C:21]([C:22]4[CH:26]=[CH:25][S:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O.C(OCC)C>[N:28]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([Cl:27])[CH:20]=[C:21]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccsc4)c3O2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3ccsc3)c2O1
Temperature: 70 °C
Reaction time: 6 h
Yield: 83.4 %

Procedure:
To a solution of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.5 g, 10.69 mmol) in dimethylsulfoxide (150 mL) was added sodium azide (3.6 g, 55.38 mmol) and the reaction mixture was heated to 70° C. and allowed to stir for 6 h. The reaction mixture was cooled to room temperature and diluted with water (300 mL) and diethyl ether (200 mL). The aqueous layer was separated and extracted with diethyl ether (200 mL). The combined organic layers were washed with water (3×200 mL), saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent removed in vacuo to afford 2.6 g (83%) of (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran as a white solid. mp 50-52° C.; Anal. calcd. for C13H10ClN3OS: C, 53.52; H, 3.45; N, 14.40. Found: C, 53.50; H, 3.33; N, 14.26.
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].CCCCCCC>C1COCC1.C(OCC)(=O)C>[C:1]([O:4][N:5]([S:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Br:15])(=[O:24])=[O:23])[C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)ONC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1Br

Procedure:
tert-Butyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate (41) is prepared according to Scheme 2. A solution of [(tert-butoxy)carbonyl]amino acetate (0.68 g, 3.9 mmol) in THF (5 ml) is added dropwise to a stirred solution of sodium hydride (0.16 g of a 60% dispersion, 3.9 mmol) in THF (10 ml). Stirring is continued for 30 minutes, whereupon 2-bromobenzene sulfonyl chloride (1.0 g, 3.9 mmol) is added. The reaction mixture is stirred at room temperature for 3 hours after which time tlc (1:1 heptane:ethyl acetate) shows no starting material remains. The reaction mixture is quenched by the addition of water (30 ml) and extracted into ether (2×50 ml). The combined organics are dried over sodium sulfate, filtered and concentrated in vacuo to yield the desired material as a yellow oil, which is purified by silica column chromatography eluting with heptane: ethyl acetate (4:1; v:v). (0.96 g, 60%), 1H NMR (360 MHz, DMSO-d6) δ ppm 8.12-8.26 (1H, m), 7.87-8.06 (1H, m), 7.61-7.79 (2H, m), 2.32 (3H, s), 1.26 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([CH2:34][OH:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([CH:34]=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12)OCc1ccccc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of N-benzyloxycarbonyl-(L)-phenylalanyl-(L)-tryptophanol (0.60 g) and triethylamine (0.53 ml) in dimethyl sulfoxide (DMSO) (7 ml), a solution of pyridine-sulfur trioxide complex (pyridine.SO3) in DMSO (7 ml) was added drop by drop. After stirring at room temperature for 1 hour, the reaction mixture was poured over ice water and extracted with ethyl ether (60 ml×3). The ethyl ether layer was washed by sequential additions of a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline and then dried (MgSO4). After the solvent was distilled off, the residue was solidified from THFhexane-ethyl ether to yield N-benzyloxycarbonyl-(L)-phenylalanyl-(L)-tryptophanal (0.44 g, 74%) as a colorless powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1C(=O)c1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
To a solution of 5-acetamidoindane (1.0 g, 5.7 mmol) and benzoyl chloride (732 mL, 6.3 mmol) in 15 mL of CH2Cl2 at 0° C. was added AlCl3 (1.52 g, 11.4 mmol) as a solid. The mixture was stirred to rt overnight. A spatula full of AlCl3 was added and the mixture heated to reflux for 3 days. The solution was then poured into a mixture of concentrated HCl and ice, and stirred. The mixture was then diluted with water and extracted with 2×50 mL of CH2Cl2. The extract was washed with brine, then dried over MgSO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography eluting with EtOAc/hexane to give the title compound (200 mg, 13%). 1H NMR (CDCl3): 10.95 (s, 1H), 8.50 (s, 1H), 7.68 (d, 2H), 7.59 (t, 1H), 7.49 (t, 2H), 7.37 (s, 1H), 2.99 (t, 2H), 2.83 (t, 2H), 2.22 (s, 3H), 2.10 (p, 2H).
Reaction SMILES: [OH-:1].[Na+].[CH:3](=O)[C:4]1[C:5]([O:10][CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.Cl.[NH2:14]O>O.C(O)C>[CH3:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]=[N:14][OH:1]
Reactant: NO
Reactant: [OH-]
Reactant: COc1ccccc1C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C=NO
Reaction time: 3 h
Yield: 117.6 %

Procedure:
Add sodium hydroxide (8.50 g, 220 mmol) in water (150 mL) to a solution of o-anisaldehyde (25.0 g, 180 mmol) and hydroxylamine hydrochloride (15.4 g, 220 mmol) in ethanol (150 mL) and water (150 mL) at room temperature and stir the mixture for 3 hours. Acidify the mixture to pH 6 with 1 N HCl solution and collect the solids by vacuum filtration to provide 2-methoxybenzaldehyde oxime (32.0 g, 99%).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[CH2:17][S:18](Cl)(=[O:20])=[O:19])=[CH:12][CH:11]=1>O1CCCC1>[CH3:1][NH:2][S:18]([CH2:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[CH:11][CH:12]=1)[CH3:22])(=[O:20])=[O:19]
Reactant: CC(CS(=O)(=O)Cl)c1ccc(-c2ccccc2F)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)CC(C)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To 10 mL of 40% aqueous methylamine was added 0.3 g (1.0 mmol) of 2-(4-(2-fluorophenyl)phenyl)propanesulfonyl chloride above in 3 mL of tetrahydrofuran and the mixture stirred at room temperature for 16 hours. The reaction mixture was extracted three times with 5 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (25 g of silica gel, 35% ethyl acetate/hexanes) of the residue afforded 0.1 g (42%) of the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](N3C(=O)CCC3=O)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>CC(C)=O.O>[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([N:1]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(CC(=O)O)c1ccc2c(c1)CCCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(CC(=O)O)c1ccc2c(c1)CCCN2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A suspension of (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)-butyric acid (2.6 g) and sodium bicarbonate (2.2 g) in acetone (40 ml) and water (40 ml) was treated with 2,5-dioxo-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (4.0 g) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate evaporated to low bulk. The residue was treated with dilute hydrochloric acid and the resulting gummy precipitate was extracted into a mixture of tetrahydrofuran, ethyl acetate and dichloromethane. This solution was washed with brine, then dried and then evaporated to give the title compound (5.8 g) as a light brown oil, which solidified on standing. MS (ES+) 464 (MNa+), MS (ES−) 440 (M−).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:5]2[CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4]2)=[C:21]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: CC1(C)CCNCC1
Reactant: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reaction time: 22 h
Yield: 71.6 %

Procedure:
To a solution of 4,4-dimethylpiperidine (1.245 g, 11.00 mmol) and DIEA (3.49 ml, 20.00 mmol) in anhydrous CH3CN (40 mL) was added ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.21 g, 10 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.). After 22 h, the reaction mixture was concentrated and the residue was purified by flash chromatography using 1-lit each 2.5, 5, 7.5 and 10% EtOAc/Hex to afford ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.846 g, 7.16 mmol, 71.6% yield) as yellow solid. 1H NMR (500 MHz, CDCl3) δ 4.37 (q, J=7.1 Hz, 2H), 3.67-2.75 (br.s., 4H), 2.71 (s, 3H), 2.44 (s, 3H), 1.42 (t, J=7.1 Hz, 3H), 1.38 (t, J=5.6 Hz, 4H), 1.00 (s, 6H). LCMS (M+H)=399.4.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[N:5][N:4]=[N:3]1.C(N(CC)CC)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].CCOC(C)=O>C1COCC1>[C:25]1([O:24][C:22](=[O:23])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)=[CH:8][CH:9]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1nnnc1-c1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nnnc1-c1ccc(NC(=O)Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 29.2 %

Procedure:
4-(1-Methyl-1H-tetrazol-5-yl)-phenylamine (190 mg, 1.08 mmol, 1 eq.), triethylamine (0.14 ml, 1.08 mmol, 1 eq.), in 10 ml of THF under nitrogen were cooled to 0° C. A 5 ml solution of phenyl chloroformate (0.14 ml, 1.08 mmol, 1 eq.), was added dropwise via an addition funnel. Worked up after 16 hours by adding EtOAc then rinsing 3× with H2O. The organic layer was dried over MgSO4, then stripped to obtain yellow solids which were purified over silica gel in 3:1 hexanes/EtOAc to 100% EtOAc. Obtained 93 mg of white solids as product. Mass Spec, 296 (M+H). NMR (300 MHz, DMSO-d6) δ 10.65 (s, 2H), 7.86 (d, 2H, J=7 Hz), 7.76 (d, 2H, J=7 Hz), 7.44 (t, 2H, J=7 Hz), 7.28 (t, 2H, J=7 Hz), 4.18 s, 3H).
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]2[S:19][CH2:18][C@@H:17]3[NH:20][C:21]([NH:23][C@H:16]23)=[O:22])=[O:10])C(=O)C1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:16]2[C@@H:17]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:19]1)=[O:8]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 3 h

Procedure:
3A-LK resin (0.1 g, 0.065 mmol) was washed with DMF. The ivDde protecting group was removed with 4% NH2NH2 in DMF (5 min, 10 min). After washing with DMF (3×5 mL), MeOH (3×15 mL), and DMF (3×5 mL), a solution of biotin-OSu (67 mg, 0.195 mmol) and DIEA (68 μL, 0.39 mmol) in DMF (2 mL) was added to the beads. The coupling proceeded at room temperature for 3 h. Kaiser test was negative. The beads were washed with DMF (5×5 mL), MeOH (3×5 mL), and DCM (3×5 mL). The beads were then dried under vacuum for 1 h before adding a cleavage mixture of 95% TFA: 2.5% water: 2.5% triisopropylsilane. The cleavage reaction was conducted at room temperature for 2 h. The liquid was collected and precipitated with diethyl ether. The crude product was purified using preparative RP-HPLC and lyophilized to give the designed product. ESI-MS, m/z 1699 (MH+).