Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O)([O-:3])=[O:2].C(P(CCCC)(CCCC)[CH2:22][CH:23]1[O:27][CH2:26][CH2:25][O:24]1)CCC.CC([O-])(C)C.[K+].O>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:22][CH:23]1[O:27][CH2:26][CH2:25][O:24]1)([O-:3])=[O:2]
Reactant: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Reactant: CCCC[PH](CCCC)(CCCC)CC1OCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1-n1cccc1C=CC1OCCO1
Yield: 66 %

Procedure:
2.98 g (13.8 mmol) 2a, 1.2 eqv. of tributyl-[1,3]dioxolan-2-ylmethyl-λ5-phosphane and 1.5 eqv. KOtBu in DMSO was stirred at 60° C. for 24 hours. The reaction was monitored by TLC (EtOAc:petroleum ether 1:2). After cooling, the reaction mixture was poured into water and extracted with ether and the solvent was evaporated. The semi-solid residue was diluted with ether and filtrated to remove residual Bu3PO and the product was purified by column chromatography (EtOAc: petroleum ether 1:2) to yield 2.6 g (66%) of 3a.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.Cl>C(O)C.[Pd]>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 40 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
2,3,4-Trifluoroaniline (0.83 g) and ethyl pyruvate (1.15 g) were dissolved in ethanol (8 ml). After adding 5% Pd—C (0.11 g) and conc. hydrochloric acid (0.03 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 3 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.32 g) was obtained as slightly yellow oily substance. Various spectral data of this product was identical with those obtained in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]([CH2:14]O)[C:11]([CH3:16])=[N:10]1.[OH-].[Na+].[BrH:19]>O>[Br:19][CH2:14][C:12]1[C:11]([CH3:16])=[N:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:13]=1
Reactant: Br
Reactant: Cc1nn(-c2ccc(F)cc2F)nc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2F)nc1CBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(2,4-Difluorophenyl)-5-methyl-2H-1,2,3-triazole-4-methanol (i.e. the product of Step B, 0.70 g, 3.1 mmol) was suspended in 48% hydrobromic acid in water (16 mL). The mixture was heated to reflux with stirring for 2 h. The reaction mixture was diluted with water, cooled to 0° C. and basified with 50% aqueous sodium hydroxide solution. The reaction mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated under reduced pressure to obtain the title compound (0.75 g) as a pale yellow oil. The title compound was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([NH:29][C@H:30]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[ClH:44]>C(OCC)(=O)C>[ClH:44].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([NH:29][C@H:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)=[O:28])[CH2:10]2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1

Procedure:
A mixture of 1.00 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-1-(t-butoxycarbonyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] and 10 ml of ethyl acetate was heated to form a solution. 2.5 ml of a 4N solution of hydrogen chloride in ethyl acetate were then added to this solution, and the resulting mixture was heated under reflux for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and then, in order to remove the acid, ethyl acetate was added to the residue and the solvent was again removed by distillation under reduced pressure. The residue was triturated with diethyl ether and washed by decantation to give 630 mg of the title compound, as a powder.
Reaction SMILES: [OH-].[K+].F[C:4]1[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]=1[F:12].[CH:13]([OH:16])([CH3:15])[CH3:14]>C(OCC)C>[CH:13]([O:16][C:4]1[C:7]([F:8])([F:9])[C:6]([F:10])([F:11])[C:5]=1[F:12])([CH3:15])[CH3:14]
Reactant: FC1=C(F)C(F)(F)C1(F)F
Reactant: CC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)OC1=C(F)C(F)(F)C1(F)F

Procedure:
70 g (1.23 mol) of powdered potassium hydroxide are metered into a solution of 200 g (1.23 mol) of 1,2,3,3,4,4-hexafluorocyclobutene and 90 g (1:5 mol) of isopropanol in 800 ml of diethyl ether at room temperature. The mixture is stirred for a further hour and worked up as described in Example 1. The product is then distilled.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.O[CH2:27][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:33]([O:32][C:31]([NH:30][C@@H:28]([CH3:29])[CH2:27][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1)=[O:37])([CH3:36])([CH3:35])[CH3:34]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(O)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8 %

Procedure:
Diisopropyl azodicarboxylate (1.9 M solution in toluene, 9.52 mL) was added to a mixture of methyl 5-hydroxypyridine-2-carboxylate (5.00 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (8.58 g), triphenylphosphine (12.9 g), and THF (50 mL) at 0° C. dropwise. The mixture was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (810 mg) as a mixture with impurities. A mixture of methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (810 mg, a mixture with impurities), THF (8 mL), methanol (8 mL), and 1 M sodium hydroxide (8 mL) was stirred at room temperature for 4 hr. The mixture was neutralized with 1 M hydrochloric acid at 0° C., and brine was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylic acid (765 mg) as a mixture with impurities. A mixture of 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylic acid (765 mg, a mixture with impurities), 4-aminobenzene-1,3-diol hydrochloride (417 mg), HATU (982 mg), N,N-diisopropylethylamine (0.902 ml), and DMF (7 mL) was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (442 mg) as a pale yellow oil.
Reaction SMILES: [CH:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH3:14])=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.[C:22](Br)(Br)([Br:24])[Br:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:23][C:22]([Br:24])=[CH:1][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH3:14])=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=C(Br)Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (902 mg, 3.12 mmol) in CH2Cl2 (30 mL), CBr4 (1.55 g, 4.68 mmol) was added at 0° C. followed by PPh3 (2.45 g, 9.35 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and directly purified via FCC eluting with Heptane/DCM 100:0 to 0:100 to provide the title compound. MS (ESI+) m/z 446.0, 448.0, 444.0, 446.9 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:18])=[O:7]
Reactant: Cc1c(C(=O)O)cccc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-trifluoromethyl-2-methylbenzoic acid 5.00 g, oxalyl dichloride 3.42 g, N,N-dimethylformamide about 50 mg and tetrahydrofuran 200 mL was stirred at 25° C. for one hour. The reaction mixtures were concentrated under reduced pressure to give 3-trifluoromethyl-2-methylbenzoic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)=[O:37]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccc5ccccc5c4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 2-naphthoyl chloride (57 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH3:41])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:41][O:40][C:22]1[CH:21]=[C:20]([CH:39]=[CH:38][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:19][O:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (406 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate-layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (595 mg, yield 55%), which was then recrystallized from ethyl acetate-hexane. melting point: 107–108° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO.COCCOC>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Reactant: COc1cccc(B(O)O)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 1b (1.0 g, 1.79 mmol) in bezene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosphine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 11c (348 mg, 32.3%). MS (CI) m/z 502.2 (MH+-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[C:24]([CH3:30])=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:25]3[C:24]([CH3:30])=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1nn(C)cc1C(=O)O
Product: Cc1nn(C)cc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1,3-dimethyl-1H-pyrazole-4-carboxylic acid as starting materials, MS (LC/MS): 425.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:10]=2[N+:24]([O-])=O)=[CH:4][CH:3]=1>CCO.CC(O)=O.[Fe]>[NH2:24][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccccc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(NC(=O)c2ccccc2)ccc1Sc1ccc(O)cc1
Temperature: 80 °C
Yield: 87.5 %

Procedure:
A suspension of the product from Example 220b (0.67 g, 1.8 mmol) and Fe powder (0.31 g, 5.5 mmol) in a mixture of EtOH (6.7 mL) and HOAc (6.7 mL) was gradually heated to 80° C. and heated at 80° C. for 3 hours. The reaction mixture was evaporated. The residue was portioned between EtOAc and 10% NaHCO3 and then filtered (through celite). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound, which was purified by washing with i-Pr2O to give the desired compound as pale brown crystals (0.53 g, 86%).
Reaction SMILES: [N:1]1([CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[C:11]([CH3:18])=[N:10]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[NH2:27]OS(O)(=O)=O>O>[NH2:27][N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)[N:10]=[C:11]([CH3:18])[C:12]1=[O:17]
Reactant: Cc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]c1=O
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2n(N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
A mixture of 5 parts of 6-[(1H-imidazol-1-yl)phenylmethyl]-3-methyl-2(1H)-quinoxalinone, 3.3 parts of sodium hydroxide and 30 parts of water was stirred for 1 hour at room temperature. 5 Parts of hydroxylamine-O-sulfonic acid were added and the reaction mixture was stirred for 4 hours at 20° C. The product was extracted with dichloromethane (3×65 parts). The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 2 parts (38.2%) of 1-amino-6-[(1H-imidazol-1-yl)phenylmethyl]-3-methyl-2(1H)-quinoxalinone; mp. 192.8° C. (comp. 85).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8]2([S:14][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:7][N:6]1[C:15](=[O:40])[CH:16]([NH:21][C:22](=[O:39])[CH:23]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[NH:24][C:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:4].[Li+].[OH-]>C1COCC1.O>[CH:33]1([CH:23]([NH:24][C:25]([C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)=[O:26])[C:22]([NH:21][CH:16]([C:17]([CH3:19])([CH3:20])[CH3:18])[C:15]([N:6]2[CH:5]([C:3]([OH:4])=[O:2])[CH2:9][C:8]3([S:10][CH2:11][CH2:12][CH2:13][S:14]3)[CH2:7]2)=[O:40])=[O:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COC(=O)C1CC2(CN1C(=O)C(NC(=O)C(NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)SCCCS2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(NC(=O)C(NC(=O)c1cnccn1)C1CCCCC1)C(=O)N1CC2(CC1C(=O)O)SCCCS2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ester 33 (50 mg) in THF-water (400 uL–100 uL) was treated with LiOH (7 mg) and the mixture stirred for 3 hours at room temperature. The mixture was evaporated, diluted with EtOAc, washed with 1.0N HCl and brine then dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2-[2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-6,10-dithia-2-aza-spiro[4.5]decane-3-carboxylic acid 34 as a white solid which was used in the next step without further purification. Mass Spec. MH+=578.0, MH−=576.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[C:11]([OH:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:14]1COCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Oc1cnn(-c2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: COc1cnn(-c2ccc(Br)cc2)n1
Temperature: 60 °C

Procedure:
2-(4-bromophenyl)-2H-1,2,3-triazol-4-ol (200 mg, 0.833 mmol) was weighed into a 20 ml vial equipped with a septa cap. THF (10.0 ml) was added. To this was added cesium carbonate (814 mg, 2.5 mmol), followed by the addition of methyl iodide (65.8 uL, 1.04 mmol) via syringe. The reaction was heated at 60° C. for 16 hours. Water (20 ml) was added and the product was extracted with ethyl acetate (2×75 ml). Organic phases were combined, dried over potassium carbonate, filtered and concentrated to furnish a light tan solid (190 mg, 89% TY). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.04 (s, 3H) 7.30 (s, 1H) 7.56 (d, J=8.98 Hz, 2H) 7.84 (d, J=8.98 Hz, 2H)
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:18]=3[CH:17]=2)=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:44]2)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:18]=3[CH:17]=2)=[S:44])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1F
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1F
Temperature: 25 °C

Procedure:
A solution of 54.4 mg (0.119 mmol) ethyl 2-fluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 40) and 57.7 mg (0.143 mmol) of [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's Reagent) in 12.0 ml of benzene was refluxed overnight. Upon cooling to room temperature, the mixture was filtered and the filtrate concentrated under reduced pressure. The title compound was isolated by column chromatography (10 to 25% EtOAc/hexanes) as a yellow solid. 1H NMR (CDCl3): δ 9.08 (1H, s), 7.92 (1H, br s), 7.90 (1H, t, J=8.2 Hz), 7.66 (1H, dd, J=2.0, 6.0 Hz), 7.38 (3H, m), 7.18 (4H, m), 6.01 (1H, t, J=4.7 Hz), 4.35 (2H, q, J=7.1 Hz), 2.36 (3H, s), 2.33 (2H, d, J=4.7 Hz), 1.38 (3H, t, J=7.1 Hz), 1.33 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:19]1([O:25][C:26]([N:5]2[C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=[C:4]2[C:8]([F:11])([F:10])[F:9])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1nc(Cl)c(Cl)[nH]1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Oc1ccccc1)n1c(C(F)(F)F)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
20.5 g (0.1 mol) of 4,5-dichloro-2-trifluoromethyl-imidazole were dissolved in 150 ml of dioxane, 10.1 g (0.1 mol) of triethylamine were added thereto and 16.05 g (0.1 mol) of chloroformic acid phenyl ester were then added dropwise whilst cooling at 10°-15° C. The mixture was stirred for a further 2 hours at room temperature, the triethylamine hydrochloride which had separated out was filtered off and the filtrate was evaporated in vacuo. The oily residue was distilled. The main fraction boiled at 106.5°-107° C./0.08 mm Hg. 28.6 (88% of theory) of 4,5-dichloro-2-trifluoromethyl-imidazole-1-carboxylic acid phenyl ester were obtained.