Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10]([F:19])=[C:11]2[C:17]([NH2:18])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1.C[C:21]1([C:24]([OH:26])=O)[CH2:23][CH2:22]1.[O:27]=[C:28]1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[Br:8][C:9]1[C:10]([F:19])=[C:11]2[C:17]([NH:18][C:24]([C:21]3([O:27][CH3:28])[CH2:23][CH2:22]3)=[O:26])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC1(C(=O)O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
Triethylamine (550 mg, 0.757 mL, 5.43 mmol) was slowly added to a mixture of 5-bromo-4-fluoro-1H-indol-3-amine (250 mg, 1.087 mmol, Example 1, step H), 1-methylcyclopropanecarboxylic acid (151 mg, 1.30 mmol) and bis(2-oxooxazolidin-3-yl)phosphinic chloride (415 mg, 1.63 mmol) in anhydrous dichloromethane (10 mL). The resulting solution was stirred at room temperature for 3 hours. The mixture was concentrated, and the residue purified by reverse phase chromatography (Biotage SP4 C-18 25M column, 10-75% CH3CN/water, 25CV) to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methoxycyclopropanecarboxamide (216.5 mg, 60%) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (br s, 1H), 9.57 (s, 1H), 8.36 (d, 1H), 7.54 (d, 1H), 3.39 (s, 3H), 1.16-1.11 (m, 4H). LCMS (APCI+) m/z 327.9 (M+H)+, Retention time=2.96 minutes.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (300.0 mg, 0.95 mmol) in DMSO (2 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (227.0 mg, 1.14 mmol), DIEA (367.0 mg, 2.82 mmol). The resulting solution was stirred overnight at 100° C. and then diluted with water (10 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 20%-50% ethyl acetate in petroleum ether to afford methyl 3-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (200 mg, 44%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O=[C:17]1[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH2:18][N:19]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:20][CH2:21][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:5])=[O:4]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
Trifluoromethanesulfonic anhydride (12.4 mL, 73.7 mmol) was added over approximately 0.1 h, via syringe, to a stirred solution of the product of step B (27.1 g, 67.0 mmol) and N,N-diisopropylethylamine (14.0 mL, 80.4 mmol) in methylene chloride (250 mL) at −78° C. After allowing to warm to ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate, poured into water and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution; 0–20% ethyl acetate/hexanes as eluent) afforded the title compound as an amber colored oil (17.6 g).
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+].C(=O)([O-])[NH2:19].[NH4+].O>S1(CCCC1)(=O)=O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:19])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: NC(=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: [NH4+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Ammonium picrate (0.18 g, 0.75 mmol) and ammonium carbamate (0.59 g, 7.5 mmol) are suspended in sulfolane (3 ml) and stirred for 2 hr with the application of heat which raises the temperature of the reaction from 25° C. to 177° C. The reaction is continued an additional 6 hr at 177° C. and cooled to ambient temperature. Water (30 ml) is added to the slurry and the product is collected, washed with water and dried to yield 0.12 g (68%) of picramide (Table 1, entry 3).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To 1,1-dimethylethyl (2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D21) (15 g, 44.8 mol) in MeOH (150 mL) and water (150 mL) at 80° C. was added ammonium chloride (11.9 g, 0.224 mol) and iron powder (7.5 g, 0.134 mol) with vigorous stirring. The reaction was stirred at 80° C. for 2 h then filtered through Celite® while still hot and the filter cake was washed with further DCM. The filtrate layers were separated and the aqueous layer was washed with DCM (×3). The DCM layers were combined, dried (Na2SO4) and concentrated to give the crude product which was purified by column chromatography. Elution with 20-70% EtOAc/petroleum ether gave the title compound as a white solid (9.46 g).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:6][C:5]([O:9][CH3:10])([O:7][CH3:8])[CH2:4]1>C(O)(O)C>[O:11]1[C:3]2([CH2:6][C:5]3([O:7][CH2:8][CH2:10][O:9]3)[CH2:4]2)[O:2][CH2:1][CH2:12]1
Reactant: COC1(OC)CC(OC)(OC)C1
Agent: CC(O)O
Product: C1COC2(CC3(C2)OCCO3)O1
Temperature: 25 °C

Procedure:
4.56 g of 1,1,3,3-tetramethoxycyclobutane (content 96.7 percent, 25 mmol) in 19.7 g of ethanediol was heated to 135° C. Thus, first the main separation of the resulting methanol at normal pressure and then (after 2 hours) the rest of the readily volatile components were distilled off at 200 mbar. The product crystallized out from the residue during cooling to room temperature and was filtered off and dried at 20° C./0,005 mbar. The yield of product was 2.11 g, with a content (GC) of 82.8 percent, which corresponds to 40.6 percent of theory. Other data concerning the product is:
Reaction SMILES: [CH2:1]([NH:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:20]1(O)[C:24](=[O:25])[C:22](=O)[C:21]=1[OH:26].[CH2:28]([CH:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:29]>C1CCCCC1>[CH2:1]([N:9]([C+:20]1[C:21]([O-:26])=[C:22]([N:9]([CH:10]2[CH2:11][C:12]([CH3:19])([CH3:18])[NH:13][C:14]([CH3:17])([CH3:16])[CH2:15]2)[CH2:29][CH2:28][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C+:24]1[O-:25])[CH:10]1[CH2:11][C:12]([CH3:18])([CH3:19])[NH:13][C:14]([CH3:17])([CH3:16])[CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(O)CC
Reactant: CCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: O=c1c(O)c(O)c1=O
Solvent: C1CCCCC1
Product: CCCCCCCCN(c1c([O-])[c+](N(CCCCCCCC)C2CC(C)(C)NC(C)(C)C2)[c+]1[O-])C1CC(C)(C)NC(C)(C)C1
Yield: 84.4 %

Procedure:
Under agitation, 339.6 g (1.26 moles) of 99.4% strength 4-n-octylamino-2,2,6,6-tetramethylpiperidine, 7.2 g (0.063 mole) of quadratic acid, and 150 cc of ethylhexanol was heated to boiling with reflux for 2.5 hours in a 1-liter stirred flask with water trap attached thereto; the solid matter was dissolved even before reaching reflux above 150° C. The sump temperature was 220° C. The amount of water removed from the cycle was 2.2 cc. Crystals precipitated from the reaction solution. After washing with petroleum ether and drying, 25.8 g was obtained. Yield: 84.4% of theory, mp 171°-175° C. (from cyclohexane). Extinction (g/l.cm) at 278 nm: 21; at 335 nm: 77.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([S:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]1([S:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[S:1][CH2:2][C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)CS
Reactant: O[C@@H]1CCCC[C@H]1Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CS[C@@H]1CCCC[C@H]1Sc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Mercaptoacetic acid (0.44 g, 0.0048 mole) was added to a cold solution of the compound of Example 6 (1.0 g, 0.0048 mole) in methylene chloride (5 ml) containing trifluoracetic acid (3.5 ml). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated to an oil with a rotary evaporator. The residue was dissolved in diethyl ether (50 ml), washed three times with 20 ml of 5% sodium bicarbonate, followed by in hydrochloric acid (10 ml) and water (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to a colorless oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR, infrared spectroscopy and elemental analysis.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[C:3]#[N:4].[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[CH3:5][C:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:1])[CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:4]
Reactant: CC(C)(C#N)N1CCCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(C)(C(N)c1ccccc1)N1CCCCC1
Yield: 56 %

Procedure:
The title compound (1.16 g, 56%) was prepared from 2-methyl-2-(1-piperidinyl)propanenitrile D7 (1.30 g, 8.6 mmol), and phenyllithium in dibutylether (5.2 ml of a 1.8M solution; 9.4 mmol) in THF (15 ml), followed by reaction with sodium borohydride (0.975 g, 25.7 mmol) in methanol (20 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.76 (3H, s), 0.91 (3H, s), 1.44 (2H, m), 1.54-1.65 (4H, m), 1.95 (2H, m), 2.57 (4H, m), 4.19 (1H, s), 7.20-7.31 (3H, m), 7.40 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:5]2[CH2:4][NH:3]1.Cl.CO>C(OCC)C>[CH2:13]1[C@H:6]2[C@H:5]([CH2:4][NH:3][C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=32)[CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2c3ccccc3C(=O)NC[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C1NC[C@@H]2CNCC[C@@H]2c2ccccc21
Reaction time: 8 h

Procedure:
To a suspension of Example 180G in 400 mL of diethyl ether was added 80 mL of HCl/methanol (5/V) at 25° C. The mixture was stirred overnight. The solid formed was collected and dried to obtain the title compound as the hydrochloride salt.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[I:26][CH3:27]>C(O)C>[I-:26].[CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N+:22]([CH3:27])([CH3:25])[CH2:21][CH:20]=2)[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Reactant: CI
Solvent: CCO
Product: C=CCC1(C2=CC[N+](C)(C)CC2)c2ccccc2CCc2ccccc21
Product: [I-]
Temperature: 25 °C
Yield: 66 %

Procedure:
Dissolved 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine (0.50 g, 1.5 mmol) in 30 mL of absolute ethanol, and added 1 mL of iodomethane. Refluxed for 1 hour. Cooled to room temperature, and evaporated to a solid. Triturated with ether, and then recrystallized from dichloromethane-ether to give 0.47 g (66% yield) of 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1,1-dimethyl-1,2,5,6-tetrahydropyridinium iodide as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH:15]1([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:2]([NH:24][NH2:25])=[N:3][CH:4]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Nc1ccc(C2CCCCC2)cc1)c1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc(C(=O)Nc2ccc(C3CCCCC3)cc2)cn1
Yield: 99 %

Procedure:
6-Chloro-N-(4-cyclohexylphenyl)nicotinamide (0.40 g) and hydrazine monohydrate (3 mL) were suspended in ethanol (6 mL), and the suspension was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was then collected by filtration and washed with an ethyl acetate-ethanol mixed solvent. The solid was dried under reduced pressure to obtain the title compound (0.39 g) as a white solid (yield: 99%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=C(CBr)[CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[NH2:22][NH2:23].[CH2:24]([OH:26])[CH3:25]>O.CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[OH:26][CH2:24][C:25]1[CH:13]=[CH:12][C:11]2[O:10][C:9]3[C:18]4=[C:5]([C:3](=[O:2])[NH:22][N:23]=[C:17]4[C:16]=2[CH:15]=1)[CH:6]=[CH:7][CH:8]=3
Reactant: NN
Reactant: CCO
Reactant: COC(=O)c1cccc2oc3ccc(CBr)cc3c(=O)c12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of compound 41 (4.2 mmol) in 20 mL of water and 20 mL of acetone was added silver nitrate (8.4 mmol). The reaction mixture was stirred at 50° C. for 2 hours. Black precipitate was filtered out. The filtrate was concentrated in vacuo. To the residue was added 100 mL of ethyl acetate. The organic layer was washed with water and brine, then dried with MgSO4. Solvents was removed in vacuo to afford a white solid in 86% yield. The white solid was added to a mixture of hydrazine and ethyl alcohol. The mixture was stirred for 2 hours under reflux. The solution was concentrated in vacuo. To the concentrated solution was added water. A white precipitate was formed, filtered out, and washed with extra water. The white solid was collected and dried to give a white solid product 57 in 95% yield. MS (ES+): 267, 1H-NMR (DMSO-d6, 400 MHz): 12.56 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.91-7.81 (m, 2H), 7.63 (dd, J=7.5 and 2.0 Hz, 1H), 7.43 (dd, J=8.5 and 2.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H); Anal. Calcd. for C15H10N2O3.(0.08 hydrazine): C, 67.02; H, 3.87; N, 11.25. Found: C, 67.29; H, 3.82; N, 11.51.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[CH:17]([CH3:19])[CH3:18].F[C:21]1[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[CH:23][C:22]=1[CH3:31].O>CS(C)=O>[CH3:27][C:26]1[CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=[C:22]([CH3:31])[C:21]=1[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)c1n[nH]c2ccc(O)cc12
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]nc(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
86 mg (0.624 mmol) of potassium carbonate are added to a solution of 110 mg (0.624 mmol) of 5-hydroxy-3-isopropyl-1H-indazole in 5 ml of DMSO and the mixture is stirred for 1 h. After addition of 106 mg (0.624 mmol) of 4-fluoro-3,5-dimethylnitrobenzene in portions, the mixture is then firstly stirred at room temperature for 2 h, then at 100° C. for 3 h. After cooling to room temperature, the mixture is added to 10 ml of water and the aqueous phase is extracted 3× with ethyl acetate. The combined organic extracts are washed with water and satd NaCl soln, dried over sodium sulphate and concentrated in vacuo. By purification of the resulting residue on silica gel (cyclohexane/ethyl acetate 3:1), 84 mg (41%) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indazole are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C>[Br:20][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([NH2:9])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1nc(N)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 6-methoxy-3-nitropyridin-2-amine (1.56 g, 9.2 mmol) in 15 mL of DMF at rt was added N-bromosuccimide (1.81 g, 10.1 mmol) in portions. The resulting mixture was stirred at rt for 1 h. TLC showed the reaction was complete. The reaction mixture was quenched with water and the reddish brown solid was collected by filtration, washed with water, and dried in a vacuum oven to give 5-bromo-6-methoxy-3-nitropyridin-2-amine (2.1 g, 92%). LCMS (ESI) m/z 248, 250 (M+H)+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:11]=[C:12]([CH:15]([C:21]2[NH:22][C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[C:24]3[C:29](=[O:30])[N:28]([CH3:31])[C:27](=[O:32])[N:26]([CH3:33])[C:25]=23)[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[S:13][CH:14]=1.N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Si:1]([O:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]([C:21]1[NH:22][C:23]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[C:24]2[C:29](=[O:30])[N:28]([CH3:31])[C:27](=[O:32])[N:26]([CH3:33])[C:25]=12)[C:12]1[S:13][CH:14]=[C:10]([Cl:9])[N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO)c3nc(Cl)cs3)c2n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO[Si](C)(C)C(C)(C)C)c3nc(Cl)cs3)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
tert-Butyldimethylsilyl chloride (309 mg, 2.047 mmol) was added to a solution of 7-(1-(4-chlorothiazol-2-yl)-3,4-dihydroxybutyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (817 mg, 1.706 mmol), imidazole (232 mg, 3.41 mmol) and DMAP (20.84 mg, 0.171 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 50 mins. A further portion of tert-butyldimethylsilyl chloride (100 mg, 0.662 mmol) was added and the mixture stirred for a further 1 hour. The reaction mixture was diluted with EtOAc and washed with 0.1M HCl(aq) (1×) and brine (3×). The organic phase was dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-60% EtOAc/hexane, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [S:1]1(=[O:15])(=[O:14])[C:6]2[S:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:5]=2[CH:4]=[N:3][NH:2]1.[H-].[Na+].[CH3:18][CH:19]([CH3:22])[CH2:20]Br>CN(C=O)C.O>[CH3:18][CH:19]([CH3:22])[CH2:20][N:2]1[N:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([NH2:13])(=[O:11])=[O:12])[S:7][C:6]=2[S:1]1(=[O:14])=[O:15]
Reactant: CC(C)CBr
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NN=C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CN1N=Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
The product from step C (0.05 g, 0.18 mmol) was dissolved in DMF (1 mL). Sodium hydride (0.016 g, 40 mmol of a 60% suspension in mineral oil) was added slowly at room temperature. The mixture was stirred for 15 min and then 2-methylbromopropane (0.024 mL, 0.40 mmol) was added. The mixture was warmed to 60° C. and stirred for 12h. DMF was evaporated under high vacuum. The residue obtained was diluted with water (1 mL) and the mixture was extracted with ethyl acetate (3×1 mL). The combined extracts were dried over MgSO4 and evaporated to provide an oil which was purified by flash column chromatography (silica, hexane-ethyl acetate gradient) to give the desired compound as a white solid, crystallization in ethyl acetate-hexane gave 0.032 g (52%). mp:130°-132° C. 1HNMR (CDCl3):δ:0.96 (6H, d, 2CH3); 2.18 (1H, m, CH); 3.78 (2H, d, CH2); 5.27 (2H, s, NH2 exchangeable); 7.67 (1H, 1s, CH); 7.91 (1H, s, CH=N). Analysis calculated for C9H13N3O4S3 : C, 33.42; H, 4.05; N, 12.99. Found: C, 33.51; H, 4.04; N, 12.91.
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH2:13][CH3:14])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O)=O.C([O-])(=O)C.[NH4+:19].N>C(O)(=O)C>[CH2:13]([C:4]1[NH:3][CH:1]=[N:19][C:5]=1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:14]
Reactant: [NH4+]
Reactant: CCC(NC=O)C(=O)c1cccnc1
Agent: CC(=O)[O-]
Agent: N
Solvent: CC(=O)O
Product: CCc1[nH]cnc1-c1cccnc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
A mixture of 2-formylamino-1-(3-pyridyl)-1-butanone (640 mg) and ammonium acetate (5.13 g) in acetic acid (5 ml) was stirred at 100° C. for 1.5 hours. After cooling, 28% aqueous ammonia was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-diethyl ether to obtain 5-ethyl-4-(3-pyridyl)imidazole (520 mg) as colorless powder.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][O:7][CH2:8][C@@H:9]1[C@H:11]([CH:12]=O)[C@:10]1([CH3:26])[C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:25])[CH3:24])[CH:15]=1.[CH3:27][CH2:28][O:29][C:30]([CH3:32])=[O:31]>C1COCC1.CN1CCCN(C)C1=O.CCCCCC>[CH3:6][O:7][CH2:8][C@@H:9]1[C@H:11](/[CH:12]=[CH:1]/[C:2](/[CH3:3])=[CH:32]/[C:30]([O:29][CH2:28][CH3:27])=[O:31])[C@@:10]1([CH3:26])[C:14]1[CH:15]=[C:16]([CH:23]([CH3:25])[CH3:24])[CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: CCOC(C)=O
Reactant: COC[C@@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Product: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
n-Butyl lithium in hexane (1.6 M, 0.56 mL, 0.89 mmol) was added to a solution of triethylphosphono-3-methyl-2E-butenoate (264 mg, 1.0 mmol) in 5 mL of THF and 3 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) at −78° C. After stirring for 5 min, a solution of Intermediate 45 (15 mg, 0.20 mmol) in 1 mL of TF was added by cannulation. The resulting solution was stirred at −7° C. for 2 h and then quenched with saturated NH4Cl. The mixture was then extracted with diethyl ether (3×5 mL), washed with brine (1×10 mL), dried (Na2SO4) and concentrated to give a crude colorless oil. Purification by column chromatography using 5%. EtOAc in hexane afforded the title compound (20 mg, 85% yield) as a white solid: