Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH:7]1[C:11]([C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=4[CH:37]=3)[CH:15]=[CH:16][CH:17]=2)=NN=[N:8]1>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[O:25][C:21]3[CH:20]=[CH:19][C:18]([C:14]4[CH:15]=[CH:16][CH:17]=[C:12]([C:11]5[O:5][C:1]([CH:2]([CH3:4])[CH3:3])=[N:8][N:7]=5)[CH:13]=4)=[CH:37][C:22]=3[C:23]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:31][CH:30]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnc(C(C)C)o4)c3)cc12
Reaction time: 8 h
Yield: 20.7 %

Procedure:
Isobutyryl chloride (90 mg, 0.847 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.085 mmol) in pyridine (1 mL) at 100° C. It was allowed to stir overnight. The reaction was concentrated and diluted with EtOH (3 mL) and treated with excess 1N NaOH (500 μL) and stirred at 60° C. for 2 hours to hydrolyze the acylated amide. The mixture was filtered and the filtrate was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (8 mg, 20%). 1H NMR (500 MHz, CD3OD) δ ppm 8.31-8.35 (1H, m), 8.03 (1H, d, J=7.94 Hz), 7.95-8.00 (3H, m), 7.93 (1H, d, J=7.93 Hz), 7.67-7.74 (3H, m), 7.25-7.30 (2H, m), 3.37-3.40 (1H, m), 2.99 (3H, s), 1.49 (6H, d, J=7.02 Hz). LC-MS retention time: 2.28 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=14.30 min, purity=94%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.50 min, purity=93%.
Reaction SMILES: COP([C:7](=[N+:11]=[N-])[C:8](=O)[CH3:9])(=O)OC.[C:13]([NH:17][C:18]1C(C=O)=N[C:21]2[C:26]([N:27]=1)=[C:25]([C:28]1[NH:36][C:35]3[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=3[CH:29]=1)[CH:24]=[CH:23][CH:22]=2)([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].CO.C(Cl)Cl>CO.CCOCC>[C:13]([NH:17][C:18]1[C:7]([C:8]#[CH:9])=[N:11][C:21]2[C:26]([N:27]=1)=[C:25]([C:28]1[NH:36][C:35]3[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=3[CH:29]=1)[CH:24]=[CH:23][CH:22]=2)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C=O
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: C#Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 23 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
Dimethyl(1-diazo-2-oxopropyl)phosphonate (Anichem, Inc., North Brunswick, N.J.; 8.63 μl, 0.06 mmol) was added to a suspension of 3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde (307b) (19.0 mg, 0.05 mmol) and K2CO3 (28.9 mg, 0.21 mmol) in MeOH (1.0 mL) and the resulting mixture was stirred at 23° C. for 16 h. Additional dimethyl(1-diazo-2-oxopropyl)phosphonate (20 μl, 0.13 mmol) was added, and the resulting mixture was stirred at 23° C. for 17 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(3-(tert-butylamino)-2-ethynylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (2.8 mg, 7.79 μmol, 15% yield) as a yellow solid (following trituration with Et2O (0.5 mL)): 1H NMR (400 MHz, CDCl3) δ ppm 12.39 (1H, br. s.), 8.14 (1H, d, J=7.4 Hz), 8.10 (1H, d, J=8.0 Hz), 8.04 (1H, d, J=3.9 Hz), 7.72 (1H, t, J=7.8 Hz), 6.82 (1H, d, J=3.7 Hz), 5.49 (1H, br. s.), 3.81-3.86 (1H, m), 3.68-3.75 (2H, m), 3.06 (2H, t, J=6.9 Hz), 1.96 (9H, s). m/z (ESI, +ve) 360.2 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:15]2[O:14][CH:13]([C:16]([Cl:19])([Cl:18])[Cl:17])[O:12][CH:11]([C:20]([Cl:23])([Cl:22])[Cl:21])[C:10]=2[CH:9]=[C:8]([CH3:24])[CH:7]=1.C(O)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:24][C:8]1[CH:7]=[CH:6][C:15]2[O:14][CH:13]([C:16]([Cl:17])([Cl:19])[Cl:18])[O:12][CH:11]([C:20]([Cl:22])([Cl:23])[Cl:21])[C:10]=2[CH:9]=1
Reactant: Cc1cc(N)c2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C

Procedure:
Solid sodium nitrite (1.34 g.) was added in portions to a boiling suspension of 8-amino-6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin (4.7 g.) in a mixture of absolute ethanol (20 ml.), toluene (5 ml.) and concentrated sulphuric acid (1.34 ml.). The mixture was heated under reflux for 3 hours, cooled to ambient temperature and evaporated to dryness under reduced pressure. The oily residue was triturated with petroleum ether (b.p. 60°-80° C.) and filtered, and the solid was crystallised from aqueous ethanol to give 6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin m.p. 134°-135° C.
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.C([Li])CCC.[CH:16]1([C:20]([O:22][CH3:23])=[O:21])[CH2:19][CH2:18][CH2:17]1.CI.Cl>O1CCCC1.CCCCCC.CCOCC>[CH3:1][C:16]1([C:20]([O:22][CH3:23])=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)NC1CCCCC1
Reactant: COC(=O)C1CCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CI
Product: COC(=O)C1(C)CCC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A solution of 27 gm of isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran (THF) was cooled to -20° C. under argon and treated with 115 ml of 1.6 M n-butyl lithium in hexane. The solution was stirred for about 30 min. at -20° C. and then cooled to -70° C. A solution of 14 grams of methyl cyclobutane carboxylate in 100 ml of THF was added dropwise over a one hour period. After the addition was complete, the solution was allowed to warm to near 0° C. and 33 grams of methyl iodide was added rapidly. The reaction mixture was allowed to warm to room temperature and then was poured into a mixture of ether and 1N HCl. The organic layer was separated and combined with a subsequent ethyl acetate extraction of the aqueous layer. The combined organic extracts were washed with dilute sodium sulfite solution, twice with water and dried over sodium sulfate. The solvent was removed by distillation at atmospheric pressure, and the residue was distilled under reduced pressure to give 11.4 grams of methyl 1-methylcyclobutane carboxylate.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(OC2C=CC(OC(C)C(O)=O)=CC=2)=CC=1.S(Cl)(Cl)=O.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C1C=CC=CC=1.O>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Agent: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Solvent: c1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
34.5 g of α-[4-(4-trifluoromethylphenoxy)phenoxy]-propionyl chloride synthesized by a conventional method (as described in, for example, Synthetic Organic Chemistry, supra) from α-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid and thionyl chloride was dissolved in 200 ml of benzene, and while maintaining the solution at 20° to 25° C., 19.5 g of aniline was added. The reaction was performed at 30° C. for 1 hour. The reaction product was poured into 300 ml of water to precipitate and washed with water, and then dried with anhydrous sodium sulfate. After drying, benzene was evaporated off, and the residue was recrystallized from a mixture of ethanol and petroleum ether (2:1 by volume) to afford 36 g of the final product having a melting point of 129° to 131° C. The yield was 90%.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:37][C:38]([F:53])([F:52])[C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[C:42](O)=[O:43]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:42](=[O:43])[C:41]2[CH:45]=[C:46]([C:48]([F:49])([F:50])[F:51])[CH:47]=[C:39]([C:38]([F:37])([F:52])[F:53])[CH:40]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and 3,5-bis(trifluoromethyl)benzoic acid (31.0 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:3]2[S:2][C:6]3[CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:5]=3[N:4]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Agent: I
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1ccc(F)cc1
Yield: 35.2 %

Procedure:
Acylation of 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, 100 mg; 0.32 mmol) with 4-fluorobenzoyl chloride (0.116 mL; 0.96 mmol) in a manner similar to that described in Example 1, Step 3 provided 35 mg of 4-Fluoro-N-(8H-indeno[1,2-d]thiazol-2-yl)-benzamide 3. EI-HRMS m/e calcd for C17H11FN2OS 310.0576, found 310.0577.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[CH:15]=[CH2:16]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (7.05 g, 21.33 mmol, prepared as described in Epp et al., WO 2013003740 A1) and vinyltri-n-butyltin (7.52 mL, 25.6 mmol) were suspended in 1,2-dichloroethane (71.1 mL) and the mixture was degassed with Argon for 10 min. Bis(triphenylphosphine)palladium(II) chloride (1.497 g, 2.133 mmol) was then added and the reaction mixture was stirred at 70° C. overnight (clear orange solution). The reaction was monitored by gas chromatography-mass spectrometry (GC-MS). After 20 h, the reaction mixture was concentrated, adsorbed onto Celite, and purified by column chromatography (SiO2; hexanes/ethyl acetate gradient) to afford the title compound as a light brown solid (3.23 g, 65.7%): mp 99-100° C.; 1H NMR (400 MHz, CDCl3) δ 6.87 (dd, J=18.1, 11.6 Hz, 1H), 5.72 (dd, J=11.5, 1.3 Hz, 1H), 5.52 (dd, J=18.2, 1.3 Hz, 1H), 4.79 (s, 2H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −138.79 (s); EIMS m/z 230.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[NH:12]1[C:16](B(O)O)=[CH:15][CH:14]=[N:13]1.COCCOC.ClCCl>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.C(N(CC)CC)C>[N+:7]([C:6]1[S:5][C:4]([CH:10]=[O:11])=[CH:3][C:2]=1[C:16]1[CH:15]=[CH:14][NH:13][N:12]=1)([O-:9])=[O:8]
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])s1
Reactant: OB(O)c1ccn[nH]1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(-c2cc[nH]n2)c([N+](=O)[O-])s1
Temperature: 80 °C
Yield: 100.4 %

Procedure:
A flask containing 4-bromo-5-nitrothiophene-2-carbaldehyde (1.00 g, 4.24 mmol), (1H-pyrazol-5-yl)boronic acid (510 mg, 4.56 mmol), ethyleneglycol dimethyl ether (20 mL), triethylamine (1.80 mL), water (2.00 mL) and bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (340 mg, 0.42 mmol) was evacuated and purged with nitrogen twice, then heated at 80° C. under nitrogen for 4 h. The reaction was cooled to room temperature, poured into a saturated solution of ammonium chloride (20 mL), extracted with ethyl acetate (3×10 mL), combined organics washed with a saturated solution of ammonium chloride (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with ethyl acetate in hexanes, to yield 5-nitro-4-(1H-pyrazol-3-yl)thiophene-2-carbaldehyde as a yellow oil (950 mg, 28%). 1H NMR (400 MHZ, DMSO-d6) δ 6.99 (s, 1H), 7.94 (s, 1H), 8.42 (s, 1H), 10.07 (s, 1H).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[C:6](=[O:12])[NH:5][C:4]1=[O:13].Br[CH2:15][CH2:16][CH:17]=[CH2:18]>CN(C)C=O>[CH2:18]([N:8]1[C:7]2[C:6](=[O:12])[NH:5][C:4](=[O:13])[N:3]([CH3:2])[C:11]=2[N:10]=[CH:9]1)[CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 65 °C

Procedure:
47 g (0.25 mol) of the monosodium salt of 3-methylxanthine (prepared as described in Example 1b) and 34.8 g (0.25 mol) of 97% strength 1-bromo-3-butene in 750 ml of dimethylformamide are stirred for 8 hours at 110° C. Thereafter, the precipitated sodium bromide is removed by filtration of the still hot reaction mixture, the filtrate is concentrated in vacuo, the solid residue is dissolved in 250 ml of 2N sodium hydroxide solution, the solution is heated to about 65° C. and 2N hydrochloric acid is added, while stirring, until the pH reaches 9. After cooling, the solid formed is filtered off under suction, washed salt-free with water, rinsed with methanol and then dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([CH:11]([CH2:14][CH3:15])[CH2:12]O)[CH3:10]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH:11]([CH2:14][CH3:15])[CH2:9][CH3:10])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCC(CC)CO
Product: CCC(CC)COc1cccc(Br)c1

Procedure:
Coupling of 3-bromophenol (17) (5.0 g, 28.9 mmol) with 2-ethylbutan-1-ol (3.25 g, 31.79 mmol) was conducted following the procedure given for Example 6. The reaction mixture was concentrated under reduced pressure then triturated with diethyl ether. The suspension was filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (100% hexanes) gave 1-bromo-3-(2-ethylbutoxy)benzene a clear liquid. Yield (5.04 g, 62%): 1H NMR (400 MHz, DMSO-d6) δ 7.20 (t, J=8.0 Hz, 1H), 7.11 (t, J=2.2 Hz, 1H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 6.92 (dd, J=8.4, 2.6 Hz, 1H), 3.84 (d, J=5.6 Hz, 2H), 1.61-1.53 (m, 1H), 1.46-1.30 (m, 4H), 0.86 (t, J=7.4 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4]([OH:11])[N:3]=1.NC1N=C(N)C(N)=[C:15]([OH:21])N=1>C(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH:9][CH:15]=[O:21])=[C:4]([OH:11])[N:3]=1
Reactant: Nc1nc(N)c(N)c(O)n1
Reactant: Nc1nc(N)c(N=O)c(O)n1
Solvent: O=CO
Product: Nc1nc(N)c(NC=O)c(O)n1

Procedure:
The invention relates to an improved process for the catalytic hydrogenation of 2,4-diamino-6-hydroxy-5-nitrosopyrimidine (DAHNP) and the reaction of the resulting 2,4,5-triamino-6-hydroxy-pyrimidine (TAHP) with formic acid to yield 2,4-diamino-5-formylamino-6-hydroxy-pyrimidine (DAFHP).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 4-methyl-3-nitrobenzoyl chloride (2.0 g) in dichloromethane (20 ml), a solution of triethylamine (0.7 ml) and 3-chloro-4-fluoroaniline (0.7 g) in dichloromethane (15 ml) was added dropwise in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room temperature overnight. The completion of reaction was indicated by TLC. Then potassium carbonate solution (10%) was added to precipitate a solid. The mixture was left to stand, and filtered. The filter cake was washed with water, and dried to give a pale yellow powdered solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:4])[CH3:3].[OH:28]O.[OH-].[Na+]>CO.ClCCl.O>[CH3:4][C:2]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]2([O:28][CH:18]2[C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A solution of N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide (4.77 g, 12.8 mmole) in methanol (55 mL) and dichloromethane (11 mL) was cooled to 12° C. and treated in one portion with 30% aqueous hydrogen peroxide (3.3 mL) followed by dropwise addition of an aqueous sodium hydroxide solution prepared by dissolving sodium hydroxide (0.38 g) in water (2.2 mL). After one hour, the cooling bath was removed and the reaction was stirred for an additional 3 hours. Most of the solvent was then removed in vacuo. The residue was dissolved in dichloromethane and purified by flash chromatography (hexane-20% ethyl acetate and hexane-40% ethyl acetate) to give N-(1,1-Dimethylethyl)-4,5-epoxy3-oxoandrostane-17β-carboxamide (3.3 g, 66.2%) as a solid foam. This material was a mixture of the 4α,5α- and 4β,5β-isomers and it was used as is in further reactions.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:33][CH2:34][O:35]C)[N:18]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl.C(#N)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:33][CH2:34][OH:35])[N:18]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Agent: BrB(Br)Br
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCCn2c(CCO)nc3c(N)nc4ccccc4c32)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Boron tribromide (5.50 mL of 1 M in dichloromethane) was added dropwise to a chilled (0° C.) suspension of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide (1.0 g, 2.2 mmol; U.S. Pat. No. 6,677,349, Example 253) in dichloromethane (20 mL). The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with methanol. Hydrochloric acid (about 10 mL of 6 N) was added and the mixture was stirred at 50° C. overnight. The mixture was diluted with water (50 mL) and ethyl acetate (100 mL) and then brought to neutral pH with solid sodium hydroxide. The layers were separated and the aqueous was extracted with ethyl acetate (×2). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide a white solid. This material was suspended in hot acetonitrile, allowed to cool, and then the solvent was decanted. The resulting material was dried under vacuum to provide about 200 mg of N-{3-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide as a white solid, m p. 231-232° C. Anal. calcd for C22H25N5O3S.0.20 CH4O: % C, 59.79; % H, 5.85; % N, 15.70. Found: % C, 59.44; % H, 5.89; % N, 15.52.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:20][N:19]([CH3:21])[C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: C1CNCCN1
Product: CN(C)c1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 51 %

Procedure:
2-chloro-1-(4-dimethylaminophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-dimethylaminophenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (51% yield). ESI/MS 349 (M+H); RT=2.44 min; NMR (CDCl3) 10.24 (1H, s); 8.25 (1H, d, J=9 Hz); 7.20 (3H, m); 7.10 (1H, m); 6.97 (1H, d, J=9 Hz); 6.83 (2H, d); 3.29 (4H, m); 3.05 (6H, s); 2.82 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:15]#[C:16][C:17]([CH3:24])([CH3:23])[O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1>C(#N)C.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]=[C:16]3[O:21][C:20](=[O:22])[CH2:19][O:18][C:17]3([CH3:24])[CH3:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1C#CC(C)(C)OCC(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C=C1OC(=O)COC1(C)C
Temperature: 120 °C
Yield: 83.3 %

Procedure:
Silver carbonate (0.17 g, 0.61 mmol) is added to a solution of [3-(4′-chloro-4-methyl-biphenyl-3-yl)-1,1-dimethylprop-2-ynyloxy]acetic acid (2.1 g, 6.13 mmol) in anhydrous acetonitrile (15 ml) in a microwave vial. The reaction mixture is stirred and heated to 120° C. for 40 minutes under microwave irradiation to give a brown suspension. The mixture is evaporated in vacuo, then diluted with water and extracted with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo to give 6-[1-(4′-chloro-4-methylbiphenyl-3-yl)methylidene]-5,5-dimethyl-[1,4]dioxan-2-one (1.75 g) as a solid.