Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH:8]=1.C1(C(=[N:33][C:34]2[CH:35]=[C:36]([CH:43]=[CH:44][N:45]=2)[C:37](N(OC)C)=[O:38])C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:33][C:34]1[CH:35]=[C:36]([C:37]([C:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH:8]=2)=[O:38])[CH:43]=[CH:44][N:45]=1
Reactant: CON(C)C(=O)c1ccnc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: Ic1cn(C2COC2)c2ccncc12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Nc1cc(C(=O)c2cn(C3COC3)c3ccncc23)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropyl magnesium chloride (8.16 mL, 1.28 mmol, 2M in diethyl ether) was added to 3-iodo-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 53, 4.45 g, 14.8 mmol) in THF (90 mL) at 0° C., under nitrogen. The mixture was stirred at 0° C. for 1 hour then a solution of 2-[(diphenylmethylene)amino]-N-methoxy-N-methylisonicotinamide (Preparation 51, 5.12 g, 14.8 mmol) in THF (30 mL) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred at this temperature for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with DCM/MeOH 95:5 (7×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-5% MeOH in DCM followed by a second purification by silica gel column chromatography eluting with 30-50% EtOAc in DCM. The residue was dissolved in THF (90 mL) and 0.5M HCl (90 mL) was added followed by stirring at room temperature for 30 minutes. The reaction was quenched by the addition of 1N NaOH to pH 6-7 and the mixture eluted through an SCX cartridge washing through with MeOH followed by ammonia in MeOH (300 mL, 2M solution). The filtrate was concentrated in vacuo, azeotroping with toluene. The residue was dissolved in DCM:MeOH 90:10 (20 mL) and poured into diethyl ether (1000 mL) to precipitate a white solid. After filtering the white solid was dried to afford the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17]Cl>>[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: Cc1cc(C)c(Cn2ccc3ccc(C(=O)O)cc32)c(C)c1
Yield: 47.2 %

Procedure:
The titled compound (790 mg) as a pale yellow solid was prepared from methyl indole-6-carboxylate (1.0 g) and 2,4,6-trimethylbenzyl chloride (1.2 g) according to the method of Example 1.
Reaction SMILES: [N+:1]([CH:4]1[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]3[CH2:10][NH:9][C:8](=[O:17])[C:7]=3[C:6]=2[CH2:5]1)([O-])=O.C1COCC1.O.NN>CCO.[Ni]>[NH2:1][CH:4]1[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]3[CH2:10][NH:9][C:8](=[O:17])[C:7]=3[C:6]=2[CH2:5]1
Reactant: O=C1NCc2ccc3c(c21)CC([N+](=O)[O-])CO3
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NC1COc2ccc3c(c2C1)C(=O)NC3
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of 8-nitro-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one ((69), 700 mg, 2.99 mmol) in EtOH (35 ml)/THF (5 ml) was added hydrazine monohydrate (1.65 ml, 34 mmol), followed by addition of Raney-Nickel (50 mg). The reaction mixture was stirred for 4 hr. The catalyst residue was filtered under vacuum and organic solution was concentrated in vacuo to give the title compound as a solid (420 mg, 69%). MS (ES) m/z 205.1
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: O=Cc1csc2c(F)cccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)NCc1csc2c(F)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluorothiophenol (4.14 g, 32.6 mmol) was dissolved in anhydrous THF (100 mL). Potassium tert-butoxide (1.0 M in THF, 35.8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde dimethyl acetal was added and the mixture was stirred for 3 days. Water (100 mL) was added and the solution was extracted with diethyl ether (3×100 mL). The extracts were concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to yield 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene (6.42 g) as a colorless oil. Chlorobenzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. The 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene was then added slowly turning the solution dark. After 3 hours of heating, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophenyl (0.77 g). The 7-fluorobenzothiophenyl (0.77 g, 5.1 mmol) and dichloromethyl methyl ether (0.872 g, 7.6 mmol) were dissolved in anhydrous DCM (25 mL). Titanium tetrachloride (1.0 M in DCM, 7.6 mL, 7.6 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g). The 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g, 3.77 mmol) and sulfamide (1.7 g, 18 mmol) were combined in anhydrous ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.148 g, 3.92 mmol) was added. After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Mg+].[Br-].[OH-].[Na+]>CCOCC>[CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
To 1-benzhydryl-azetidin-3-one (1.0 g, 4.2 mmol) in ether (100 mL) at 0° C. was added CH3MgBr (1.5 mL, 3M in ether). The mixture was warmed to rt over 1 h and 1N NaOH (3 mL) was added. The organic layer was concentrated providing the title compound (1.1 g). MS (ESI): mass calcd. for C17H19NO, 253.2; m/z found, 254.2 [M+H]+. 1H NMR (CDCl3): 7.42-7.11 (m, 10H), 4.32 (s, 1H), 3.14 (d, J=8.5 Hz, 2H), 2.96 (d, J=8.5 Hz, 2H), 1.43 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[OH-:33].[Na+]>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4]([OH:33])[N:3]=1
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(O)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
(S)-4-Amino-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (66 mg, 0.145 mmol) in THF (2 mL) was combined with sodium hydroxide (0.289 mL, 0.289 mmol) to give a yellow solution, which was heated to 50° C. and stirred for 3 hours. The product was purified by LC/MS using a 5-30% CH3CN gradient in H2O with 0.035% formic acid. The pure fractions were combined and lyophilized to give a formic acid salt of the title compound as a white solid (7 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.46 (m, 3 H), 2.70-2.85 (m, 2H), 3.00-3.13 (m, 2 H), 3.81 (s, 8 H), 5.67-5.86 (m, 1 H), 6.43-6.53 (m, 1 H), 7.05-7.23 (m, 1 H), 7.27-7.45 (m, 2 H), 7.52-7.64 (m, 1 H), 7.85-7.94 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H22N8O2, 395.4; found 395.5.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH2:8]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>N1C=CC=CC=1>[CH2:8]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[S:3][C:4]([CH3:7])=[N:5][N:6]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
2-Amino-5-methyl-1,3,4-thiadiazole (150 mg, 1.3 mmol) was suspended in pyridine (0.5 mL). p-Dodecylbenzenesulfonyl chloride (300 mg, 0.87 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (5 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (310 mg, 0.73 mmol, 84%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 149-150° C.; 1H NMR (500 MHz, CDCl3) δ 0.88 (3, t, J=7.0 Hz), 1.20-1.36 (18, m), 1.54-1.63 (2, m), 2.51 (3, s), 2.63 (2, t, J=7.5 Hz), 7.25 (2, d, J=7.5 Hz), 7.83 (2, d, J=7.5 Hz), 12.36 (1, br s); 13C NMR (125 MHz, CDCl3) δ 14.1, 16.5, 22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.4, 128.8, 138.3, 148.3, 154.1, 168.6; MS (ESI+, m/z) Calcd for C21H34N3O2S2 424.2092. found 424.20 (M+H)+; HRMS (ESI+, m/z) Calcd for C21H34N3O2S2 424.2092. found 424.2085 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[C:9]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:11]
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc(Br)c1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1ncccc1Br
Yield: 25.6 %

Procedure:
Under nitrogen, a solution of 156 g (0.90 mol) of 3-bromopyridine N-oxide from step 1 was dissolved in 1000 mL of acetonitrile and treated with 256 mL (1.84 mol) of triethylamine and 275 g (2.8 mol) of trimethylsilyl cyanide. The reaction was stirred at reflux overnight and concentrated in vacuo; the residue was dissolved in 2.5M aqueous sodium hydroxide and extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated in vacuo; this residue was decolorized with carbon and recrystallized from methanol to give 42.2 g (26%) of 2-cyano-3-bromopyridine as a cream colored solid: mp 97°-98° C.; NMR (CDCl3) δ7.42 (dd, J=8 and 5 Hz, 1H), 8.05 (dd, J=8 and 2 Hz, 1H), 8.67 (dd, J=5 and 2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21](O)=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:47][C:48](=[NH:60])[C:49]1[CH:54]=[CH:53][C:52]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:51][CH:50]=1>CN(C=O)C.O.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:21]2[O:22][N:60]=[C:48]([C:49]3[CH:50]=[CH:51][C:52]([O:55][C:56]([F:57])([F:58])[F:59])=[CH:53][CH:54]=3)[N:47]=2)[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:9]=1
Reactant: N=C(NO)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(C(=O)O)sc1Cc1cccc(N2CCN(C)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)sc1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
A mixture of 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid (70 mg, 0.21 mmol), EDC.HCl (49 mg, 0.25 mmol) and HOBT (34 mmol, 0.25 mmol) in DMF (2 mL) was stirred at RT for 30 min. N-hydroxy-4-(trifluoromethoxy)benzimidamide (55 mg, 0.25 mmol) was added and the reaction mixture was stirred for 1 h at RT and then at 140° C. for another 2 h. The reaction mixture was cooled to RT, diluted with H2O (5 mL) and taken into EtOAc (10 mL). The organic layer was separated, washed with H2O (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated to afford the crude product, which was purified by pre-HPLC (Mobile phase: A=10 mM NH4HCO3/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge (C18, 5 um, 30 mm*150 mm) to give 5-(4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a yellow solid (2.0 mg, 2%). MS (ES+) C25H24F3N5O2S requires: 515, found: 516[M+H]+; 1H-NMR (500 MHz, CD3OD) δ ppm 8.24 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 8.24 (t, J=8.0 Hz, 1H), 6.94-6.92 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 4.23 (s, 2H), 3.23 (t, J=4.5 Hz, 4H), 2.63 (t, J=4.5 Hz, 4H), 2.54 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:15].Br[CH2:18][CH2:19][C:20]([OH:22])=[O:21]>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:3]1[CH3:15]
Reactant: O=C(O)CCBr
Reactant: CC1=Nc2ccc3ccccc3c2C1(C)C
Solvent: Clc1ccccc1Cl
Product: CC1N(CCC(=O)O)c2ccc3ccccc3c2C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 112.2 %

Procedure:
A mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (10.0 g, 47.8 mmol) and 3-bromopropanoic acid (7.3 g, 47.8 mmol) in 1,2-dichlorobenzene (50 mL) was heated with stirring at 110° c. for 18 h. After the resulting mixture was cooled to room temperature, the precipitated was collected by filtration, triturated with DCM thoroughly, and dried under vacuum to afford 15.2 g of light brown powder (88%). ESI-MS: observed for [MH]+ 281.31.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.BrC[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]=1.O>O1CCCC1>[C:26]1([C:18]2[N:17]=[C:16]([CH2:5][CH2:4][C:3]([OH:11])=[O:10])[C:25]3[C:20]([CH:19]=2)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1nc(-c2ccccc2)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1nc(-c2ccccc2)cc2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
Sodium hydride (6.5 g, 80% strength in oil) is placed with tetrahydrofuran (160 cc) under nitrogen, and a solution of diethyl malonate (34.9 g) in anhydrous tetrahydrofuran (200 cc) is added dropwise. After 1 hour's stirring at room temperature (approximately 20° C.), a solution of 1-bromomethyl-3-phenylisoquinoline (16.2 g) in anhydrous tetrahydrofuran (200 cc) is added. After 20 hours' stirring at 20° C., water (200 cc) is added and the aqueous phase extracted with ethyl acetate. The organic phase is dried and evaporated to dryness under reduced pressure. The residual product is chromatographed on silica gel with a cyclohexane/ethyl acetate (8:2 by volume) mixture as eluant. The product (11.5 g) is recovered, taken up in concentrated hydrochloric acid (115 cc) and brought to boiling for 20 hours. Water (200 cc) is added, and the precipitate is filtered off and washed with water and acetone. 3-Phenyl-1-isoquinolinepropanoic acid (6.7 g) m.p. 160° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[NH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[N:24]=[CH:23][N:22]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[N:24]=[CH:23][N:22]=[C:21]([CH2:20][N:6]2[C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)[C:26]=1[CH3:27]
Reactant: COc1ncnc(CCl)c1C
Reactant: O=[N+]([O-])c1c[nH]c2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncnc(Cn2cc([N+](=O)[O-])c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a stirred suspension of 3-Nitro-1H-pyrrolo[3,2-b]pyridine (25b) (0.5 g, 3.04 mmol) and K2CO3 (0.5 g, 9.12 mmol) in DMF (10 mL) was added 4-(chloromethyl)-6-methoxy-5-methylpyrimidine (0.7 g, 6.09 mmol) and the resulting mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured in to water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with brine and the solvent was evaporated under reduced pressure to yield 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-3-nitro-1H-pyrrolo[3,2-b]pyridine (25c) [300 mg (33%)] as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](OCC)(=[O:13])[C:10]([CH3:12])=O>C(Cl)(Cl)Cl>[CH3:12][C:10]1[C:9](=[O:13])[NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccncc1N
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccncc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of 3,4-diamino pyridine (10 g) and ethyl pyruvate (53 g) in chloroform (100 mL) was stirred at ambient temperature overnight. The precipitated solid was filtered off, washed with DCM, and dried to afford 2-methyl-4H-pyrido[3,4-b]pyrazin-3-one (14 g) as a yellowish solid. 2 g of this material was suspended in DMF (10 mL) and treated with PyBroP (6 g) and DIPEA (3.3 mL,) at ambient temperature overnight. The precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-1-yloxy)-2-methyl-pyrido[3,4-b]pyrazine (1.7 g) as a white solid. This material was suspended in ethanol (50 mL), hydrazine hydrate was added, and resulting mixture was heated at 85° C. for 15 min. The solid was filtered off, washed with ethanol, and dried to afford IIc (0.95 g) as a yellow solid sufficiently pure for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10](O)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I.[Cl-].[NH4+]>C1COCC1>[I:37][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CC(O)c1cccc([N+](=O)[O-])c1
Reactant: II
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CCI)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
5 g of 3-nitrophenylethanol, 9.4 g of triphenylphosphine and 3.1 g of imidazole are dissolved in 250 ml of THF, mixed in portions with 9.1 g of iodine and stirred for 15 hours at room temperature. The reaction mixture is mixed with ammonium chloride solution and extracted with dichloromethane. The organic phase is washed in succession with sodium thiosulfate solution and water and dried on sodium sulfate. After purification by chromatography on silica gel, 7.51 g of the title compound is obtained.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH:8]=C)[CH2:2][CH2:3][CH3:4].[O:15]=[O+][O-]>CO>[CH2:1]([O:5][CH:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH:8]=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCC(OCCCC)OCCCC
Reactant: O=[O+][O-]
Solvent: CO
Product: CCCCOC(CC=O)OCCCC
Temperature: 35 °C

Procedure:
300 g of 4,4-di-n-butoxybutene are dissolved in 1 liter of methanol and are reacted with ozone, and subsequently hydrogenated, analogously to the procedure indicated in Example 8. The hydrogenation is carried out in such a way that the content of peroxides in the hydrogenation solution does not exceed 0.02 mole/liter, and a pH value between 4 and 5 and a temperature of 35° C. are maintained. The consumption of hydrogen is 32.4 standard liters, corresponding to 96% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([I:8])[CH:7]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([I:8])[CH:7]=1)[CH:9]=[O:10]
Reactant: OCc1cc(F)cc(I)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(F)cc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-fluoro-5-iodophenyl)methanol (9.79 g, 35.0 mmol) was dissolved in DCM (94 mL) and then silica gel (18.0 g) was added. To the mixture at room temperature was added PCC (18.3 g, 45.0 mmol) portion-wise and the mixture agitated at room temperature for 1 h and followed by TLC. After 1 h, TLC indicated complete conversion of the SM to a non-polar (presumably aldehyde). The reaction mixture was filtered over 1-inch plug of silica pad and eluted with 30% Ether in DCM (200 mL). The filtrate was concentrated in vacuo to afford the crude product, which was taken to the next step without further purification.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19])=[CH:12][CH:11]=1.[C:22](=[S:24])=[S:23].O>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:23][C:22]([SH:24])=[CH:19][C:18](=[O:20])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)CC(=O)c1ccc(Br)cc1
Reactant: S=C=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(S)sc(-c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of LDA (20 mL, 40 mmol) in 40 mL anhydrous THF under an atmosphere of nitrogen was added slowly a solution of 1-(4-Bromophenyl)-butane-1,3-dione (4.84 g, 20 mmol) dissolved in THF (30 mL). After addition was complete the mixture was allowed to warm slowly to ambient temperature and stir for 10 minutes. The solution was re-cooled to −78° C. for the addition of a solution of carbon disulfide (1.2 mL, 20 mmol) in THF (20 mL). This temperature was maintained for 2 hours, before warming slowly to ambient temperature and stirred for 18 hours. Cold water (150 mL) was added and mixture was heated to 60° C. with good stirring for 3 hours. The volatiles were removed in vacuo and the aqueous solution was washed with diethyl ether (2×100 mL). The aqueous solution was acidified to pH 1 with 2N HCl, and the orange precipitate was filtered from the acid, washed with water, and dried by vacuum desiccation. Orange solid (5.07 g, 85%); LCMS m/z 299, 301 ([M+1]+) 298, 300 ([M−1]−), 1H-NMR (D6-DMSO): 7.10 (s, 1H, H-3), 7.36 (s, 1H, H-5), 7.69 (d, 2H, J=8.6 Hz, Arom), 7.76 (d, 2H, J=8.6 Hz, Arom); infrared spectrum (cm−1): 815, 950, 1008, 1072, 1202, 1451, 1364, 1451, 1487, 1508, 1584.