Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[CH2:39][NH2:40])=O)(C)(C)C.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:40][CH2:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]3)=[O:22])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CCCCN1)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (1 mmol) was coupled with 2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3 mmol) using EDC (2 mmol) in DMF (10 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 432. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.5-8.65 (m, 2H) 8.38 (m, 1H) 8.22 (m, 1H) 7.95 (m, 1H) 7.55 (m, 1H) 7.28 (m, 1H) 7.20 (d, 1H) 7.05 (d, 2H) 6.68 (d, 2H) 3.5 (m, 2H) 3.3 (m, 2H) 2.95 (m, 1H) 2.6-2.85 (m, 3H) 2.48 (m, 1H) 1.0-1.7 (m, 6H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: COc1cc(Br)ccn1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(N2CCN(c3cnccc3C3CC3)C2=O)ccn1
Yield: 52.4 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 4-bromo-2-methoxypyridine (111.1 mg, 0.591 mmol), 1,4-dioxane (5 mL), copper iodide (9.39 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (6.98 mg, 0.049 mmol) and potassium phosphate (312.9 mg, 1.476 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 80 mg of the product (52% yield).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(=CC)C.[OH:19]P([O-])(O)=O.[K+].[O-]Cl=O.[Na+]>O.CC(O)(C)C.[OH-].[Na+].C1COCC1>[C:1]1([C:7]2[O:11][C:10]([C:12]([OH:19])=[O:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(-c2ccccc2)o1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(-c2ccccc2)o1
Reaction time: 4 h
Yield: 70.2 %

Procedure:
To a solution of the product from Step 103a (0.650 g, 3.78 mmol, 1 eq) in water (5.5 mL), t-BuOH (18.0 mL), and THF (18.0 mL) is added 2-methyl-2-butene (3.2 mL, 30.2 mmol, 8 eq), potassium phosphate monobasic (1.54 g, 11.3 mmol, 3 eq), then NaClO2 (1.03 g, 11.3 mmol, 3 eq) in that order. After four hours, the reaction is complete and diluted with 1 N NaOH (100 mL). The aqueous solution is extracted with ether (2×100 mL), and the aqueous layer is acidified with conc. HCl. The resulting solution is extracted with CH2Cl2 (3×100 mL). The organic layers are dried over MgSO4, and the solvent removed. The product is purified by silica gel chromatography using a Biotage Flash 40M column (10% EtOAc/1% formic acid/heptane). The solid remaining after removal of the solvent is filtered and recrystallized from EtOH and water to give the acid as a white crystalline solid (0.499 g, 70.2%). HRMS (FAB) calculated for C11H8O3+H 189.0473, found 189.0403.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:14][C@@H:13]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[C:27]([O:26][C:24]([NH:23][C@@H:13]1[CH2:14][C@@H:15]([C:18](=[O:22])[N:19]([CH3:20])[CH3:21])[CH2:16][CH2:17][C@@H:12]1[NH2:11])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CN(C)C(=O)[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1
Yield: 97.1 %

Procedure:
(1S,2S,4R)-N1-Benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine (560 mg) was dissolved in tetrahydrofuran (100 ml), and 10% palladium on carbon (220 mg) was added to stir the mixture for 17 hours in a hydrogen atmosphere. After the catalyst was removed by filtration, the filtrate was concentrated to obtain the title compound (370 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[NH2:12])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:12][C:11]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:9]([N:4]3[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]3)[CH:10]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(cis-3,5-dimethyl-1-piperazinyl)-4-(methyloxy)aniline (D2) (800 mg, 3.40 mmol) in dichloromethane (50 ml) was treated with morpholinomethyl-polystyrene HL resin (1.70 g, 4.0 mmol/g loading, 6.80 mmol) followed by 4-bromobenzenesulfonyl chloride (1.30 g, 5.09 mmol). The resulting solution was stirred at room temperature overnight and was then filtered, washing with methanol, and the filtrate concentrated in vacuo. The residue was then purified using an SCX ion exchange cartridge (Varian bond-elute) eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and reduced in vacuo to afford a crude product which was purified further by chromatography on silica gel eluting with (0 to 20% methanol in dichloromethane) to afford the title compound (E101). MS (ES+) m/e 454/456 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:7]=2[NH:6][S:5]1(=[O:19])=[O:18])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:39][C:40]1[CH:48]=[C:47]2[C:43]([C:44]([C:49]3[CH2:50][CH2:51][N:52]([CH2:55][CH2:56]O)[CH2:53][CH:54]=3)=[CH:45][NH:46]2)=[CH:42][CH:41]=1.C(OCC)(=O)C>CN(C=O)C.O>[F:39][C:40]1[CH:48]=[C:47]2[C:43]([C:44]([C:49]3[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][N:6]4[C:7]5[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][C:8]=5[CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[S:5]4(=[O:19])=[O:18])[CH2:53][CH:54]=3)=[CH:45][NH:46]2)=[CH:42][CH:41]=1
Reactant: OCCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Reactant: CC(C)N1Cc2cc(S(C)(=O)=O)ccc2NS1(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1Cc2cc(S(C)(=O)=O)ccc2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
To a stirred solution of 3,4-dihydro-3-(1-methylethyl)-6-methylsulfonyl-1H-2,1,3-benzothiadiazine-2,2-dioxide (0.38 g, 0.00125 mol), triphenylphosphine (0.39 g, 0.0015 mol) and 2-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethanol (0.26 g, 0.0015 mol) in DMF (10 ml) at −5° C. was added dropwise under nitrogen diethyl azodicarboxylate (0.24 ml, 0.0015 mol). The reaction was stirred at −5° C. for 10 mins then allowed to warm to room temperature stirring for a further 20 mins. After the addition of ethyl acetate (30 ml) and water (20 ml), the organic layer was washed with water (4×20 ml) the organics dried (MgSO4) and concentrated in vacuo to afford 0.52 g of 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3,4-dihydro-3-(1-methylethyl)-6-methylsulfonyl-1H-2,1,3-benzothiadiazine-2,2-dioxide as a yellow solid. Mp 118-120° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12](I)[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.C(#N)C.C(N(CC)CC)C.[CH2:28]([NH:31][C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[C:29]#[CH:30]>CN(C=O)C.[Cu](I)I>[C@@H:1]1([N:9]2[CH:13]=[C:12]([C:30]#[C:29][CH2:28][NH:31][C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:42])([F:43])[F:41])[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: C#CCNC(=O)CCCCCNC(=O)C(F)(F)F
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(CCCCCNC(=O)C(F)(F)F)NCC#Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
1-(2-Deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (354 mg, 1 mmol, containing α-anomer) was azeotroped twice with anhydrous acetonitrile in a 50 mL flask, followed by addition of copper iodide (31 mg, 160 μmol) and tetrakistriphenylphosphine palladium (0) (58 mg, 50 μmol). After these materials were dissolved in anhydrous DMF (5 mL), triethylamine (210 μL, 1.5 mmol) was added while stirring at room temperature and further stirred at room temperature under light-shielding conditions. To this mixture, a solution of N-(2-propynyl)-6-trifluoroacetamidohexanamide (396 mg, 1.5 mmol) in DMF (4 mL) was added dropwise and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (5-10% CH3OH in CH2Cl2) and C18-HPLC (39-41% CH3CN in H2O, 15 minutes) to give the desired product as an amorphous substance (408 mg, yield 83%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:12]3[C:13]([OH:18])=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:5]3[NH:1][N:2]=[N:3][N:4]=3)[CH:7]=2)[C:13]=1[OH:18])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Reaction time: 8 h
Yield: 26.7 %

Procedure:
3′-(1H-Tetrazol-5-yl)-biphenyl-2-ol 8d (3.5 g, 14.7 mmol) was dissolved in 145 mL of ethanol under argon atmosphere. Fuming nitric acid (0.565 mL, 13.2 mmol) was added dropwise at 35° C. After the reaction mixture was reacted at room temperature for 1 hour, 150 mL of water was added. After standing overnight, the mixture was filtered. The filter cake was washed with 100 mL of water and dissolved in 500 mL of ethyl acetate and 250 mL of water. The separated organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was purified by silica gel column chromatography to obtain the title compound 3-nitro-3′-(1H-tetrazol-5-yl)-biphenyl-2-ol 8e (1 g, yield 27.0%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.[N+:13]([O-])([O-:15])=[O:14].[K+].CCOC(C)=O>OS(O)(=O)=O.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([Br:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C)c(Br)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Bromo-3-methylbenzoic acid methyl ester (10.13 g, 44 mmol) was dissolved in a mixture of H2SO4 120 mL and TFA (15 mL) at room temperature. The solution was cooled on an ice bath and KNO3 (4.65 g, 46 mmol) was added portionwise over 30 min. The mixture was stirred at ambient temperature for 4 hours during which it warmed to rt. TLC analysis (after mini aqueous workup) showed total disappearance of starting material (30% EtOAc/Hex). The solution was poured onto ice and the aqueous slurry was extracted with EtOAc (3×150 mL). The organic layer was washed with 5% Na2CO3 (3×75 mL), NaHCO3 (3×50 mL), water (2×100 mL), brine (100 mL), then was dried over sodium sulfate. Concentration of the solution yielded a yellowish solid/gel substance (11.6 g) which was one spot by TLC. 1H NMR analysis shows two (major) products in ˜2:1 ratio, corresponding to the o- and m-nitrobenzoate derivatives. The material was carried onto the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CC(C)O
Product: Clc1nc(Nc2ccccc2)c2ccccc2n1

Procedure:
A solution of 2,4-dichloro-quinazoline (15 g) N,N-diisopropyl-ethylamine (24.9 ml) and aniline (7.5 ml) in isopropanol (75 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is crystallized from diethylether-toluene (1:1) to give 2-chloro-4-phenylamino-quinazoline, m.p. 194-196° C.
Reaction SMILES: C(OO)(=[O:3])C.[Cl:6][C:7]1[C:8]([O:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[N:9][CH:10]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[Cl:6][C:7]1[CH:12]=[C:11]([OH:3])[CH:10]=[N:9][C:8]=1[O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)OO
Reactant: CC1(C)OB(c2cnc(OC3CCC3)c(Cl)c2)OC1(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1cnc(OC2CCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Acetic acid solution of peracetic acid (35%, 4.2 mL, 21.3 mmol) was added to a solution of 3-chloro-2-cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 20, 4.4 g, 14.2 mmol) in glacial acetic acid (26 mL) and water (13 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Aqueous solution of sodium thiosulfate (0.5 M, 80 mL) was added and the mixture was stirred for 30 minutes at room temperature. The aqueous layer was extracted with EtOAc (3×40 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 10% EtOAc in heptane to afford the title compound as a clear oil (2.05 g, 72%):
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:16])[C@H:13]([CH3:15])[NH2:14])[CH3:10].Cl[CH2:18][C:19]1[C:20]([N+:26]([O-:28])=[O:27])=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1>C(O)C>[CH2:9]([O:11][C:12](=[O:16])[C@H:13]([CH3:15])[NH:14][CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[C:20]=1[N+:26]([O-:28])=[O:27])[CH3:10]
Reactant: Cc1cccc(CCl)c1[N+](=O)[O-]
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@H](C)NCc1cccc(C)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 120 ml of triethylamine in 200 ml of absolute ethanol was added dropwise over a period of 30 minutes to a solution of 91.8 g of L-alanine ethyl ester hydrochloride in 300 ml of absolute ethanol. The mixture was warmed to 60° C., a clear solution resulting. To this solution was added dropwise within 1 hour a solution of 55.5 g of 3-(chloromethyl)-2-nitrotoluene in 300 ml of absolute ethanol. Thereafter, the temperature was increased to 80° C. and the mixture was stirred at this temperature overnight. Thereafter, the mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 600 ml of water. The solution was extracted three times with methylene chloride and the extracts were washed successively with water and with saturated sodium chloride solution, dried and evaporated. The thus-obtained crude product was purified by chromatography on silica gel using methylene chloride/5% methanol for the elution. There was obtained N-(3-methyl-2-nitrobenzyl)-L-alanine ethyl ester in the form of a yellow oil; [α]D =-36° (c=1% in methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[CH:27][CH:26]=3)[N:19]=2)([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36].Cl.CN(C)CCCN=C=NCC.O>C(Cl)(Cl)Cl>[CH2:39]([O:38][C:34]([NH:35][NH:36][C:14]([C:11]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[N:29]([C:30]([CH3:33])([CH3:31])[CH3:32])[N:28]=[CH:27][CH:26]=3)[N:19]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:16])=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)NNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 535 mg of 1-(tert-butoxycarbonyl)-4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid in 10 ml of chloroform were added 214 mg of benzyl carbazate and 291 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with chloroform. The chloroform solution was dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=10/1) to give the title compound as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[O:28]C)=[O:9])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[OH:28])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.12 g (13.0 mmol) of (4-fluorophenyl)[2-methoxy-5-(2,6-dimethyl-4nitrophenoxy) phenyl]methanone in 100 ml methylene chloride is chilled in an ice bath and 40 ml (40 mmol) of 1.0 M boron trichloride in methylene chloride is gradually added. The solution is stirred at room temperature overnight, then poured into 300 ml of ice water and stirred 2 hours. The organic layer is separated, washed with 5% aqueous sodium carbonate, water, dried (CaSO4) and evaporated. The residue is recrystallized from ethanol to give (4-fluorophenyl)[2-hydroxy-5-(2,6-dimethyl-4 nitrophenoxy)phenyl]methanone, m.p. 148°-150°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.C([Cl:25])(=O)C.ClN1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.ClCCCl.O>[Cl:25][C:14]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(c2cccc(N)c2)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(c2cc(N)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(1-methylpiperidin-4-yl)aniline (D6, 1.0 g, 5.3 mmol) in dichloromethane (50 ml) containing triethylarnine (1.1 ml, 7.9 mmol) was added dropwise acetyl chloride (0.40 ml, 5.6 mmol) and the mixture stirred at room temperature overnight. The mixture was washed with aqueous 10% sodium carbonate and the organics dried (Na2SO4), and evaporated in vacuo to a red semi-solid (1.49 g). To a solution of the solid in 1,2-dichloroethane (100 ml) was added N-chlorosuccinimide (1.2 g, 9.0 mmol) and the mixture heated at 80° C. for 28 h. On cooling, water (50 ml) was added and the aqueous basified with aqueous 10% sodium carbonate. The aqueous was extracted with dichloromethane (3×), the combined organics dried (Na2SO4). and evaporated in vacuo to a brown solid (650 mg). A stirred solution of the solid in ethanol (10 ml) and 2M NaOH (16 ml) was heated at reflux under argon for 18 h. The mixture was concentrated in vacuo, partitioned between ethyl acetate and water and the aqueous further extracted with ethyl acetate (3×). The combined organics were dried (Na2SO4) and evaporated in vacuo to the title compound as a pale brown solid (403 mg, 35%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:9]=[C:8](/[CH:10]=[CH:16]/[N:17]([CH3:19])[CH3:18])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOc1ccc([N+](=O)[O-])c(C)n1
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(/C=C/N(C)C)n1
Temperature: 25 °C

Procedure:
To a stirred solution of the compound prepared in Example 421 (1.88 g) in N,N-dimethylformamide (25 mL) was added N,N-dimethylformamide dimethylacetal (1.61 mL) at room temperature. The resulting purple solution was placed in an oil bath and heating was started to 140° C. The mixture was heated for 30 minutes, cooled to room temperature, the solvent evaporated in vacuo, coevaporated from methanol and dried further under high vacuum for 2 hours. This material was triturated in 1:1 hexane-ether and collected by filtration to afford the title compound as red solids (2.2 g) with the following physical data.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=[O:5].[N-:15]=[N+:16]=[N-:17].[Na+].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:15]([CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=[O:5])=[N+:16]=[N-:17]
Reactant: N=C(N)Nc1nc(C(=O)CBr)cs1
Reactant: [N-]=[N+]=[N-]
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 50 g (0.14 mol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 23.6 g (0.36 mol) of sodium azide, and 250 ml of dimethylformamide was stirred at room temperature for 1.5 hours. The mixture was poured into 1.5 liters of water, and the aqueous solution was made basic with solid sodium carbonate. The resulting precipitate was filtered, washed well with water, and dried, thereby affording 30.6 g (93%) of 2-azido-1-(2-guanidino-4-thiazolyl)-ethanone as a light brown crystalline solid, mp 177° (dec). Analytically pure material can be prepared by recrystallization from absolute ethanol: Calcd. for C6H7N7OS: C, 32.00; H, 3.13; N, 43.53; S. 14.24; found: C, 32.22; H, 3.43; N, 41.93; S, 13.97.