Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[CH:35]([O:38][C:39]1[CH:40]=[C:41]([NH2:49])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)([CH3:37])[CH3:36]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:19])[CH3:20])([C:15]([NH:49][C:41]2[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=[C:39]([O:38][CH:35]([CH3:37])[CH3:36])[CH:40]=2)=[O:16])[CH2:10]1
Reactant: CC(C)Oc1cc(N)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(OC(C)C)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (25 mg, 0.091 mmol) and methanesulfonyl chloride (9 μL, 0.12 mmol) in THF (0.9 mL) at 0° C. was added diisopropylethylamine (0.047 mL, 0.27 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-isopropoxy-5-(trifluoromethyl)benzenamine (39 mg, 0.18 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 9.91 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.04-7.16 (m, 3H), 6.90-6.94 (m, 1H), 4.65 (septet, J=6.0 Hz, 1H), 3.97 (d, J=10.4 Hz, 1H), 3.66 (d, J=10.8 Hz, 1H), 3.04 (d, J=17.2 Hz, 1H), 2.66 (d, J=17.2 Hz, 1H), 2.36 (septet, J=6.8 Hz, 1H), 2.16 (s, 3H), 2.00 (s, 3H), 1.29 (d, J=6.0 Hz, 6H), 0.96 (t, J=6.4 Hz, 6H). LC-MS Rt (retention time): 3.08 min; MS: (ES) m/z 477 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[CH2:32][O:31]C5(CCCCC5)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2].O.Cl>CCO>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (1.24 g, 2.31 mmol) in EtOH (25 ml) and H2O (1.09 ml, 2.31 mmol) was added concentrate HCl (0.480 ml, 5.77 mmol) and the reaction was heated at reflux for 8 hours. The reaction was allowed to cool to ambient temperature and stirred overnight. The mixture was concentrated to a residue that was dissolved in EtOAc and saturated aqueous NaHCO3. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (3% MeOH/CH2Cl2) to afford (S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol as cream solids. The solids were dissolved in CH2Cl2 (25 ml) and 1N HCl in Et2O (20 ml) was added. The mixture was concentrated to dryness and dried in the vacuum oven to afford (S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.569 g, 49.9% yield) as an off-white solid. Mass spectrum (apci) m/z=458.1 (M+H—HCl).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[S:19](Cl)(=[O:21])=[O:20])[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:19]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]=[CH:10][CH:11]=[CH:12]2)(=[O:20])=[O:21]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: Cc1noc(NS(=O)(=O)c2cccc3cccnc23)c1Br
Yield: 62 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-8-quinolinesulfonamide was prepared, in the same manner as described in Example 96, from 5-amino-4-bromo-3-methylisoxazole and 8-quinolinesulfonyl chloride in 62% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 169°-171° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)[CH3:10])[CH:7]=1.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:18][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6]2[CH:7]=[C:2]([N:25]3[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]3)[CH:3]=[CH:4][C:5]=2[N+:19]([O-:21])=[O:20])[CH3:10])[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(C)cc(C(C)Nc2cc(F)ccc2[N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])c1
Yield: 43 %

Procedure:
5-fluoro-N-(1-(3,5-dimethylphenyl)ethyl)-2-nitrobenzenamine (762 mg, 2.4 mmol), t-butyl piperazine-1-carboxylate (443 mg, 2.4 mmol), N,N-diisopropylethylamine (614 mg, 4.8 mmol) were stirred at 80° C. in dry acetonitrile (50 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (469 mg, 41% yield). 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.05 (d, 1H), 6.49 (s, 2H), 6.33 (s, 1H), 6.14 (d, 1H), 5.70 (s, 1H), 4.47 (m, 1H), 3.76 (s, 6H), 3.43 (m, 4H), 3.23 (m, 2H), 3.15 (m, 2H), 1.62 (d, 3H), 1.46 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[C:14](=[O:28])[N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[C:14](=[O:28])[N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1c2c(-c3ccc(O)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 95.6 %

Procedure:
In an argon atmosphere, 2.3 g (6.2 millimoles) of Compound 11 obtained in Example 11 was dissolved in 100 ml of methylene chloride. The solution was cooled to 0° C. Slowly 1.8 ml (18.7 millimoles) of boron tribromide was added to the solution, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was cooled to 0° C., and then 30 ml of methanol was added. The mixture was stirred at room temperature for 30 minutes. 3/4 volume of the solvent was evaporated under reduced pressure. 18 ml of 3N hydrochloric acid was added. The precipitate was collected by filtration, and recrystallized from DMF-water to obtain 2.1 g (yield: 96.3%) of Compound 14.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:23][N:24](C)C=O>O.Cl>[OH:16][C:15]1[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]#[N:24])=[CH:3][CH:4]=2)=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: O=C(c1ccc(Br)cc1)c1ncccc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(C(=O)c2ncccc2O)cc1
Temperature: 90 °C
Yield: 45 %

Procedure:
10 g (35.96 mM) of (4-bromophenyl)(3-hydroxy-2-pyridinyl)methanone are mixed with 6.44 g (71.92 mM) of cuprous cyanide in 90 ml of dimethylformamide. The mixture is refluxed for 21 h. A solution of 19.25 g of ferric chloride in 42.5 ml of water and 6.7 ml of concentrated hydrochloric acid is prepared and added to the cooled reaction medium and the resulting mixture is then heated at 90° C. for 30 minutes. After cooling, ethyl acetate and water are added and the mixture is filtered on Celite. The product is then extracted with ethyl acetate and the organic phase is washed with saturated sodium chloride solution. The solvent is evaporated off under reduced pressure to give the desired product in the form of a yellow solid with a yield of 45%.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([SH:27])=[N:3][N:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: Sc1nnc(-c2ccccc2)c2ccccc12
Reaction time: 1.5 h

Procedure:
1-Hydroxy-4-phenylphthalazine (0.31 g, 1.5 mmol) in toluene (30 ml) is allowed to react with Lawesson's reagent (0.6 g, 1.5 mmol) and the mixture is stirred in an oil bath. (80-90° C.) for 1.5 hour until all starting material is used up. Evaporation of the solvent gives a yellow solid which is stirred with isopropyl ether. Filtration gives the title compound as a yellow solid which is recrystallized from hexane/THF/toluene:7.5/2.5/2.0 (0.3 g)
Reaction SMILES: C([O:3][CH2:4][CH3:5])C.Cl[C:7](Cl)(Cl)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=N.FC(F)(F)S(O)(=O)=O>C(OCC)(=O)C>[C:12]1([CH2:11][O:10][C:8]23[CH2:14][CH:13]([CH2:12][CH2:17][CH2:16]2)[CH2:5][C:4](=[O:3])[CH2:7]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOCC
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1CC2CCCC(OCc3ccccc3)(C1)C2
Temperature: 25 °C
Reaction time: 17 h
Yield: 70 %

Procedure:
A diethyl ether solution of 260 mg of 2,2,2-trichloro-1-(phenylmethoxy)ethanimine synthesized in the production example 30 was added to 4 ml of a diethyl ether solution of the compound obtained in the production example 29 to prepare the homogeneous solution, and the flask was immersed in an ice water bath. The solution in the flask was mixed with 10 μl of trifluoromethanesulfonic acid, gradually heated up to room temperature, and simultaneously stirred for 17 hours. After the reaction was finished, the reaction solution was diluted with ethyl acetate and extracted. The obtained organic layers were integrated, sequentially washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, and then dried over Na2SO4. The solvent was distilled away under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (120 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[NH:17][C:18]([C:21](OCC)=[O:22])=[N:19][N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[NH:17][C:18]([C:21]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:22])=[N:19][N:20]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCOC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)[nH]1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)[nH]2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-4H-1,2,4-triazole-3-carboxylate (30 mg, 0.08 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (31 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). A portion of the crude product was purified using prep method B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:31])(=[O:30])[NH:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:24]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CCCCNS(=O)(=O)c1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCNS(=O)(=O)c1cccc(NC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c1
Yield: 27 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-amino-N-butyl-benzenesulfonamide (53 mg, 0.21 mmol) as the coupling partner. Chromatography (1:1 ethyl acetate:dichloromethane) through SiO2 yielded 23 mg (27%) of the titled compound. ESI-MS m/z 502 (MH+), 500 (M−H−).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[OH:25][CH2:26][C:27](=O)[CH3:28].[BH3-]C#N.[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:27]([CH3:28])[CH2:26][OH:25])[CH:17]=2)=[CH:3]1
Reactant: CC(=O)CO
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(CO)Nc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c1
Reaction time: 8 h

Procedure:
To a mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg, 0.32 mmol) and hydroxyacetone (0.03 mL, 1.5 eq) in CH2Cl2 (12 mL) and THF (5 mL) was added NaCNBH3 (28 mg, 1.5 eq) and the reaction mixture was stirred overnight. The volatiles were removed under vacuo and the residue was purified by preparatory TLC to give 3-(1-methylindol-3-yl)-4-[3-(2-hydroxy-1-methylethylamino)phenyl]-1H-pyrrole-2,5-dione (8 mg). LC/MS: M+ 375(85.6%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1.N1CCCCC1>C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[C:17]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=1)[C:7](=[O:13])[NH:8]2
Reactant: COc1ccc(C=O)cc1-c1cccs1
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(=O)Nc3cccc(CCO)c32)cc1-c1cccs1
Yield: 46.9 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (1.6 g, 9.2 mmol), 4-methoxy-3-thiophen-2-yl-benzaldehyde (2 g, 9.2 mmol) and piperidine (4.5 mL, 85 mmol) in ethanol (46 mL) was heated to reflux for overnight. The reaction mixture was concentrated and the residue was chromatographed on a column of silica gel to give 1.63 g (47%) of 4-(2-hydroxy-ethyl)-3-(4-methoxy-3-thiophen-2-yl-benzylidene)-1,3-dihydro-indol-2-one as a yellow orange solid. 1HNMR (300 MHz, DMSO-d6) δ 10.53 (s, br, 1H, NH), 8.73 (d, J=2.1 Hz, 1H), 8.10 (dd, J=2.2 & 9.1 Hz, 1H), 7.74 (s, 1H, H-vinyl), 7.56-7.65 (m, 2H), 7.07-7.22 (m, 3H), 6.81 (d, J=7.5 Hz, 1H), 6.68 (dd, J=0.6, 7.5 Hz, 1H), 4.87 (t, J=4.5 Hz, 1H, OH), 3.97 (s, 3H, OCH3), 3.68-3.75 (m, 2H, CH2CH2OH), 3.09 (t, J=4.5 Hz, 2H, CH2CH2OH).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:23]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(Nc1ccccc1Cl)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 4-benzylpiperidine and 2-chlorophenyl isocyanate. 1H NMR (400 MHz, CDCl3): 8.19 (dd, J=8.3, 1.5 Hz, 1H), 7.33-7.12 (m, 7H), 7.03 (brs, 1H), 6.96-6.90 (m, 1H), 4.12-4.05 (m, 2H), 2.85 (td, J=13, 2.3 Hz, 2H), 2.57 (d, J=6.8 Hz, 2H), 1.82-1.69 (m, 3H), 1.34-1.20 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].[C:8](O)(=[O:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[Sn]>>[C:8]([O:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4])(=[O:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(CO)CO
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC(C)(C)CO
Temperature: 100 °C

Procedure:
64.2 g neopentyl glycol (0.617 mole), 246.9 g montanic acid (0.617 mole) and 0.4 g tin powder were heated to 210° C. as in Example 1 with application of a gentle vacuum. The vacuum was increased to 150 mbar over a period of 5 h. The product had an acid number of approximately 2. A brown-yellow hard wax having a dropping point of 72° C. was obtained after cooling to 100° C., bleaching and filtering.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[CH:14]=[N:15][N:16]=[C:9]1[C:8](=[O:17])[NH:7]2)([O-:3])=[O:2].[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19])[N:10]1[CH:14]=[N:15][N:16]=[C:9]1[C:8](=[O:17])[NH:7]2)([O-:3])=[O:2]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2n2cnnc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c([N+](=O)[O-])cc2n2cnnc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
This product (17) was dissolved in H2SO4 and cooled in an ice/H2O bath. KNO3 was added and the ice bath removed. The solution was stirred an additional 2 hours and then heated at 50° C. for 40 hours, yielding 7,8-dinitro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (18).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]3[C:11](=[CH:12][N:13](COCC[Si](C)(C)C)[N:14]=3)[CH:10]=2)[NH:5][CH:6]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(C(C)C)CC)(C)C.[NH:57]1[CH2:62][CH2:61][CH:60]([N:63]2[CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[NH:65][C:64]2=[O:73])[CH2:59][CH2:58]1>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28]([N:57]2[CH2:58][CH2:59][CH:60]([N:63]3[CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=4)[NH:65][C:64]3=[O:73])[CH2:61][CH2:62]2)=[O:34])[CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH3:18])[CH:17]=2)[NH:14][N:13]=[CH:12]3)[NH:5][CH:6]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1c[nH]c(C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c[nH]c(C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)n1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(4-methyl-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (25.2 mg, 0.052 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.5 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (10.0 mg, 0.055 mmol, 1.1 equiv) and diisopropylethylamine (36.2 μL, 4.0 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (13.0 mg, 0.055, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 10.1 mg (38%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.39-1.66 (m, 4H), 2.20 (s, 3H), 2.55 (s, 3H), 2.73-2.95 (m, 2H), 3.14-3.22 (m, 1H), 4.01-4.20 (m, 4H), 4.32-4.43 (m, 1H), 5.13-5.19 (m, 1H), 6.65 (s, 1H), 6.79 (d, J=7.6, 1H), 6.97 (dd, J=7.6, 7.3, 1H), 7.02 (s, 1H), 7.12 (d, J=7.3, 1H), 7.17 (dd, J=7.9, 7.3, 1H), 7.40 (s, 1H), 7.99 (s, 1H). Mass spec.: 513.3 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].[CH2:14]([O:16]C(=O)OCC)C.Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([OH:10])=[CH:9][C:14](=[O:16])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1cc(O)c2ccc(F)cc2o1
Temperature: 115 °C
Reaction time: 6 h

Procedure:
A solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (50 g, 0.33 mol) in toluene was added over 30 min to a suspension of NaH (60% oil, 65 g, 1.63 mol) in toluene. Then diethylcarbonate (59 mL, 0.49 mol) was added over 15 min and the reaction mixture was stirred at 115° C. for 6 h. The mixture was cooled to rt followed by the addition of HCl 2N and diluted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by trituration in hexane and Et2O to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][OH:13])([O-:3])=[O:2].CN(C=O)C.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(OCC)(=O)C>[Si:24]([O:13][CH2:12][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1c(CO)cccc1CO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a clean, dry round-bottom flask was added 2-nitro-1,3-benzenedimethanol (818 mg, 4.47 mmol), anhydrous DMF (40 mL), and imidazole (304.2 mg, 4.47 mmol). The solution was maintained at 0° C. while tert-butyldimethylsilylchloride (337 mg, 2.24 mmol) was slowly added. The resulting pale yellow solution was allowed to warm to room temperature and stirred overnight under argon before being diluted with ethyl acetate (100 mL), washed with water (5×50 mL), dried over MgSO4, filtered, concentrated on a rotary evaporator, and purified by silica gel chromatography (30% EtOAc:hexanes) to yield 3-(tert-butyldimethylsilyloxymethyl)-2-nitro-hydroxymethylbenzene as a yellow oil which crystallized upon further solvent removal in vacuo. The excess 2-nitro-1,3-benzenedimethanol was recovered and re-subjected to the reaction conditions to yield Compound 9 in 80% yield after three iterations.