Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CC1C=CC([N+]([O-])=O)=CC=1NC(N)=N.[N+]([O-])(O)=O.CC1C=CC([N+]([O-])=O)=CC=1NC(N)=N.[C:34]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)(=[O:36])[CH3:35].CO[CH:45](OC)[N:46]([CH3:48])[CH3:47]>>[CH3:45][N:46]([CH3:48])[CH:47]=[CH:35][C:34]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:36]
Reactant: CC(=O)c1cccnc1
Reactant: COC(OC)N(C)C
Agent: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Agent: Cl
Solvent: O=[N+]([O-])O
Product: CN(C)C=CC(=O)c1cccnc1

Procedure:
In other aspects the invention provides a process for the preparation of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine comprising: (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; and (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C.C(Cl)Cl>C(OCC)(=O)C>[C:14]1([P:7](=[C:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.3 %

Procedure:
The t-butyl (triphenylphosphoranylidene)propionate was prepared as follows: Triphenylphosphine (33 g), t-butyl 2-bromopropionate (22 g) and triethylamine (12.7 g) were dissolved in ethyl acetate (150 ml), and stirred and heated under reflux for 48 hr, under an atmosphere of nitrogen. Methylene chloride (300 ml) was added to the cooled solution; the mixture was thoroughly washed with sodium hydroxide solution (10% w/w, 300 ml), water (200 ml) and brine; and dried (MgSO4). The solvent was evaporated and the residual oil triturated with hexane (2×200 ml) to give t-butyl (triphenylphosphoranylidene)propionate (33 g, 67%) as a yellow powder; mp 144°-151°; partial NMR (250 MHz, CDCl3): 1.0(br signal, 9H, t-butyl), 1.55(d, J=14.4 Hz, 3H, CH3), 7.3-7.9(complex m, 15H, ArH).
Reaction SMILES: Br[C:2]1[C:3]([C:22]#[N:23])=[CH:4][C:5]2[N:6]([C:8]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.[CH3:24]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:16]1([O:15][CH2:14][C:8]2[N:6]3[CH:7]=[C:2]([CH3:24])[C:3]([C:22]#[N:23])=[CH:4][C:5]3=[N:10][C:9]=2[CH:11]([CH3:13])[CH3:12])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CB(O)O
Reactant: CC(C)c1nc2cc(C#N)c(Br)cn2c1COC1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cn2c(COC3CCCCC3)c(C(C)C)nc2cc1C#N
Temperature: 25 °C
Yield: 62 %

Procedure:
6-Bromo-3-cyclohexyloxymethyl-2-isopropylimidazo[1,2-a]pyridine-7-carbonitrile (100 mg, 0.266 mmol) obtained in step 2 was dissolved in 1,4-dioxane-water (2/1) (1.5 mL), and the solution was stirred under heat and reflux for 3 hours after adding methylboronic acid (64.0 mg, 1.07 mmol), sodium carbonate (85.0 mg, 0.802 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (44.0 mg, 0.0539 mmol). The reaction mixture was allowed to cool to room temperature, and, after adding water, the mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL). The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=98/2) to give 3-cyclohexyloxymethyl-2-isopropyl-6-methylimidazo[1,2-a]pyridine-7-carbonitrile (51.4 mg, yield 62%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:33][C:34](=[O:38])[N:35]([CH3:37])[N:36]=2)[CH:27]=1)[C:15]([C:17]1[C:18]([Cl:25])=[N:19][C:20]([CH3:24])=[N:21][C:22]=1[Cl:23])=[S:16])=O)(C)(C)C.Cl.C(OCC)(=O)C>>[ClH:23].[Cl:23][C:22]1[C:17]([C:15]([N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]3[O:33][C:34](=[O:38])[N:35]([CH3:37])[N:36]=3)[CH:27]=2)=[S:16])=[C:18]([Cl:25])[N:19]=[C:20]([CH3:24])[N:21]=1
Reactant: Cc1nc(Cl)c(C(=S)N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)c2cccc(-c3nn(C)c(=O)o3)c2)c(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c(C(=S)N(C[C@@H]2CCCN2)c2cccc(-c3nn(C)c(=O)o3)c2)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 159.7 %

Procedure:
To (S)—N-(1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl)-4,6-dichloro-N-[3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylthiopyrimidine-5-carboxamide (1.30 g, 2.18 mmol) obtained in Step 6 was added 4 mol/L hydrochloric acid-ethyl acetate (11 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was crystallized from hexane and ethyl acetate. The resulting solid was filtered and dried. This procedure was repeated to give (S)-4,6-dichloro-N-(pyrrolidin-2-ylmethyl)-N-[3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylthiopyrimidine-5-carboxamidehydrochloride (898 mg, 77%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[CH:16]([O:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:18])[CH3:17].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>>[F:15][C:4]1[CH:3]=[C:2]([C:25]2[C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Nc1ncc(-c2ccc(Cl)cc2F)cn1
Reactant: CC(C)Oc1ncccc1B(O)O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC(C)Oc1ncccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a microwave vial the following were added 5-(4-chloro-2-fluorophenyl)-pyrimidin-2-amine (50 mg, 0.22 mmol), (2-isopropoxypyridin-3-yl)boronic acid (51 mg, 0.28 mmol) and X-Phos precatalyst (4 mg, 0.005 mmol). The vial was flushed with nitrogen and then THF (0.5 mL) and 0.5 M K3PO4 (0.9 mL) were added. Both THF and the K3PO4 solution were sparged separately for 30 min prior to use. The resulting biphasic mixture was stirred at rt overnight. The reaction mixture was then poured into sat. NaHCO3 (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4) and concentrated to dryness. The crude product was purified by HPLC to give the title compound (35 mg, 48%). MS (ESI): mass calcd. for C18H17FN4O, 324.14; m/z found, 325.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=1.4, 2H), 8.21-8.13 (m, 1H), 7.68-7.60 (m, 1H), 7.50-7.36 (m, 3H), 6.99-6.91 (m, 1H), 5.51-5.37 (m, 1H), 5.15 (s, 2H), 1.38 (d, J=6.2, 6H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)CCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc(NCCS(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
To a solution of 2-methanesulfonylethylamine (1.3 g, 10.56 mmol) and DIPEA (3.5 mL, 31.69 mmol) in DMF (15 mL) was added 4-fluoro-3-nitro-benzoic acid methyl ester (1.2 g, 15.84 mmol) in portions. The reaction mixture was allowed to stir for 15 h at room temperature. It was then diluted with water and extracted with EtOAc. The organic layers were washed with water, brine and concentrated to give 4-(2-methanesulfonyl-ethylamino)-3-nitro-benzoic acid methyl ester (83%). 1H NMR (300 MHz, CDCl3) δ 8.9 (d, 1H), 8.6 (t, 1H), 8.2 (d, 1H), 6.9 (d, 1H), 4.0 (q, 2H), 3.9 (s, 3H), 3.4 (t, 2H), 3.0 (s, 3H).
Reaction SMILES: [N:1]1([CH2:10][C:11](OC)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)Cn1ccc2cccnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCn1ccc2cccnc21
Yield: 87.1 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 7.50 g of methyl 7-azaindol-1-acetate (prepared as described in Preparation 17), 1.80 g of lithium aluminum hydride and 260 ml of anhydrous tetrahydrofuran were used, to give 5.57 g of the title compound, melting at 52.7-53.3° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=O.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C(O)C>C(Cl)(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH:8]=[N:31][C:28]2=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Cl)cc32)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
TFA (2.2 ml, 28 mmol) was added to a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.00 g, 9.38 mmol), 1-(4-chlorophenyl)hydrazine hydrochloride (1.68 g, 9.38 mmol) and ethanol (0.2 mL) in CHCl3 (200 mL) at about 0° C. The reaction mixture was then stirred at about 50° C. overnight. After cooling, the reaction was quenched by the addition of 10% NH4OH (20 mL) and ice (60 mL). The organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to yield tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate which was used in the next step without further purification (2.57 g, 85%). LCMS (APCI+) m/z 221, 223 [M+H−Boc]+; Rt=3.67 min.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[C:16]([CH2:17][CH:18]=[CH2:19])=[CH:15][C:14]([Cl:20])=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(BCCC(C)C)CC(C)C.[OH-:32].[Na+].OO>C1COCC1>[CH2:1]([C:8]1[O:9][C:10]2[C:16]([CH2:17][CH2:18][CH2:19][OH:32])=[CH:15][C:14]([Cl:20])=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=CCc1cc(Cl)cc2nc(Cc3ccccc3)oc12
Agent: CC(C)CCBCCC(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCc1cc(Cl)cc2nc(Cc3ccccc3)oc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 2-benzyl-5-chloro-7-allylbenzoxazole (2.2 g, 8 mmol) in THF (12 ml) was added to a solution of di-iso-amylborane (1.13 g, 8 mmol) in THF. The reaction was allowed to stir at room temperature for 21 hours and then 3 N sodium hydroxide solution (4 ml) was added followed by 30% hydrogen peroxide (4 ml). After 3 hours, the reaction mixture was partitioned between dichloromethane and water. The dichloromethane solution was washed with water (3×100 ml) and the solvent was evaporated under reduced pressure. The residue was purified over flash chromatographic silica gel to give the title compound (600 mg) eluted with 1:1 dichloromethane/hexane. The material was recrystallized three times from toluene to give the title compound (200 mg), trip 78-80° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[C:30]([O:37][CH3:38])(=[O:36])[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][CH:31]([C:30]([O:37][CH3:38])=[O:36])[C:32]([O:34][CH3:35])=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1)C(=O)OC

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine (100 g) in dry dimethylformamide (500 ml), dimethyl malonate (43.16 ml) and 28% (w/w) methanolic solution of sodium methoxide (60.77 g) were added, and the resultant mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with ethyl acetate, washed with water and dried over magnesium sulfate. Removal of the solvent gave (2R,4R)-1-benzyloxycarbonyl-2-(2,2-dimethoxycarbonylethyl)-4-t-butyldimethylsiloxypyrrolidine.
Reaction SMILES: [CH2:1]([N:5]([CH3:12])[CH2:6][CH2:7][C:8]([CH3:11])([NH2:10])[CH3:9])[CH2:2][CH2:3][CH3:4].[C:13](ON1C(=O)CCC1=O)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1>[CH2:1]([N:5]([CH3:12])[CH2:6][CH2:7][C:8]([NH:10][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:11])[CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCCCN(C)CCC(C)(C)N
Solvent: C1CCOC1
Product: CCCCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
Crude N1-butyl-N1,3-dimethylbutane-1,3-diamine (5.00 g, 29.0 mmol) was dissolved into THF (100 mL). To this solution was added CbzOSu (7.23 g, 1 equiv, 29.0 mmol) in one portion. The reaction was left to stir at room temperature for 3 d. The solvent was removed and the residue was taken up in a mixture of diethyl ether (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1M HCl (50 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 10-80% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a white solid (3.55 g, yield: 40.0%). 1H NMR (CDCl3, 400 MHz): δ 0.83-0.87 (t, J=7.2, 3H), 1.25-1.35 (m, 2H), 1.40 (s, 6H), 1.41-1.45 (m, 2H), 1.59-1.62 (t, J=6.4, 2H), 2.18 (s, 3H), 2.28-2.32 (t, J=6.4, 2H), 2.43-2.47 (t, J=6.4, 2H), 5.04 (s, 2H), 7.27-7.37 (m, 5H). LRMS (ESI+) for C18H30N2O2 (306.2); Found: 307 (MH+).
Reaction SMILES: NCCC[N:5]1[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][N:7]([C@@H:8]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10]([N:15]=[N+:16]=[N-:17])[CH2:9]2)[C:6]1=[O:23].CCN(CC)CC>CO>[CH3:22][C:19]1[C:20](=[O:21])[NH:5][C:6](=[O:23])[N:7]([C@@H:8]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10]([N:15]=[N+:16]=[N-:17])[CH2:9]2)[CH:18]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCCN)c1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
A solution of 10 mg MTAF (Example 31), 10 mg of 3-AP-AZT (Example 28) and 2.5 ul Et3N in 250 ul MeOH was incubated 90 minutes at 56° C., then 24 hours at room temperature and chromatographed twice over RPF 250 um using the solvent system MeOH/H2O/HOAc (50+50+3). The product (Rf =0.25) was homogeneous on TLC and was found to provide a satisfactory tracer for quantitation of AZT by FPIA.
Reaction SMILES: O.O.O.[Br:4]([O-])=O.[Na+].[Cl:8][C:9]1[C:21]([Cl:22])=[C:20]([C:23]([C:25]2[N:29]([CH2:30][CH3:31])[N:28]=[CH:27][CH:26]=2)=[O:24])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>O>[Cl:8][C:9]1[C:21]([Cl:22])=[C:20]([C:23]([C:25]2[N:29]([CH2:30][CH3:31])[N:28]=[CH:27][C:26]=2[Br:4])=[O:24])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)COc1ccc(C(=O)c2ccnn2CC)c(Cl)c1Cl
Reactant: [O-][Br+][O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)c2c(Br)cnn2CC)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.3 %

Procedure:
A solution of 1.88 g of sodium bromite trihydrate in 5 ml of water is added dropwise at room temperature to a solution of 1.85 g of ethyl [2,3-dichloro-4-(1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetate and the mixture is stirred at room temperature for 15 hours. The reaction mixture is evaporated to remove solvent and the residue is dissolved in 20 ml of water. The aqueous solution is made alkaline with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is crystallized with a mixture of isopropyl ether and hexane to give 1.98 g of ethyl [2,3-dichloro-4-(4-bromo-1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetate.
Reaction SMILES: CC(OC([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=O)(C)C.[CH3:21][NH:22][CH3:23].N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69]>CN(C)C=O.ClCCl.C(OCC)(=O)C>[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69].[NH2:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:18]([N:22]([CH3:23])[CH3:21])=[O:20]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@@H](N)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of Boc-L-4-chlorophenylalanine (Bachem California Inc., Torrance, Calif., USA; 5.0 g, 16.7 mmol), dimethylamine (2 M in tetrahydrofuran; 12.5 mL, 25 mmol), 1-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 2.69 g, 19.9 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluororophosphate (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 7.5 g, 19.8 mmol) and diisopropylethylamine (8.8 mL, 50.5 mmol) in N,N-dimethylformamide was stirred at 0° C. for 30 min and then at room temperature for 10 min. Ethyl acetate was added and the mixture was washed with water and brine. The organic phase was dried over sodium sulfate, filtered and evaporated to give a white solid. The solid was dissolved in dichloromethane (30 mL). Trifluoroacetic acid (30 mL) was added and the solution was stirred for 2 h at room temperature. The solvents were evaporated to give (S)-2-amino-3-(4-chloro-phenyl)-N,N-dimethyl-propionamide trifluoroacetate salt as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[CH:44][C:45]([C:48]#[N:49])=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(C#N)cc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C#N)cc4)c3)c2cc1OC
Yield: 4.6 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (108 mg, 0.3 mmol) described in Example 328A, to afford 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (8 mg, 4%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.28 (s, 9H), 3.99 (m, 6H), 6.41 (s, 1H), 7.24-7.41 (m, 6H), 7.79 (d, J=8.7 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H), 8.62 (s, 1H), 8.69 (s, 1H), 9.25 (s, 1H); LC-MS (ESI) m/z 580 (M+H)+.
Reaction SMILES: [F:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:10][S:11]([O:5][CH2:4][CH2:3][C@@H:2]([F:1])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC[C@H](F)CCO
Solvent: c1ccncc1
Product: CCCC[C@H](F)CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
To a 100 ml flask were added 8.7 g of (S)-3-fluoroheptanol and 21.5 g of pyridine in a nitrogen stream, and the solution was kept at 5° to 10° C. To the solution was added dropwise 7.5 g of methanesulfonyl chloride over 30 minutes, followed by stirring at 15° C. or less for 5 hours. The reaction mixture was poured into 200 ml of ice-water and extracted with ethyl acetate. The organic layer was washed successively with a diluted hydrochloric aqueous solution and water, dried over magnesium sulfate, and freed of the solvent by distillation at 30° C. or lower to obtain 12.7 g (93.18%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH2:18][CH:19]=2)=[CH:10][C:9]=1[N+:24]([O-])=O)=[O:6]>CO.C(O)(=O)C.[Zn]>[NH2:24][C:9]1[CH:10]=[C:11]([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH2:16][CH:15]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=1[O:2][CH3:1]
Reactant: CNCCN1CC=C(c2ccc(NC(=O)c3ccccc3OC)c([N+](=O)[O-])c2)CC1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CNCCN1CC=C(c2ccc(NC(=O)c3ccccc3OC)c(N)c2)CC1
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of 203 (143.9 mg, 0.225 mmol) in MeOH (4.5 mL) and Acetic Acid (1.1 mL) at room temperature was added Zinc dust (85 mg, 1.307 mmol). The solution was stirred 1 h and then filtered and concentrated and the crude residue was purified by flash chromatography (10 to 30% MeOH in DCM) and the material was further triturated with hexane to afford 205 (30 mg, 0.060 mmol, 27%) as a yellow solid. LRMS (ESI): calc. 380.2, found 381.2 (MH)+. 1H-NMR (CDCl3+CD3OD) δ(ppm): 8.15 (dd, J=8.0, 2.2 Hz, 1H), 7.46 (ddd, J=8.8, 8.8, 2.3 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.07 (dd, 7.4, 7.4 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.82-6.79 (m, 2H), 3.98 (s, 3H), 3.19-3.16 (m, 2H), 3.08-3.04 (m, 2H), 2.79-2.71 (m, 4H), 2.64 (s, 3H), 2.52-2.47 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)=[O:4].[OH-].[Na+]>CO>[C:17]([O:16][C:14]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc21
Yield: 68.7 %

Procedure:
A solution of 2,3-dihydro-indole-1,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester (2.3 g, 8.29 mmol) in methanol (30 mL) was treated with 3 N aqueous sodium hydroxide (2.77 mL, 8.29 mmol) and heated at reflux for 4 hours. An additional portion of 3N aqueous sodium hydroxide (1.38 mL, 4.14 mmol) was added and the solution was heated at reflux for an additional 28 hours. The solution was concentrated in vacuo and then diluted with water. The resultant solution was neutralized with 2N hydrochloric acid (6.3 mL). The product precipitated and was collected by filtration and washed with water, to give the product 1.5 g (69%). 1H NMR (DMSO-d6): δ 1.51 (s, 9 H), 3.10 (t, 2 H), 3.95 (t, 2 H), 7.53-7.82 (m, 3 H) and 12.59 (s, 1 H).