Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH3:32])[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)=[NH:40])C=CC=CC=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[Na+]>CCOC(C)=O.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1.C1(C)C=CC=CC=1>[NH2:40][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH3:32])[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(Br)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CN(S(=O)(=O)c2ccc(N)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
A 250-mL round-bottomed flask was charged with (2-(2-((2S)-4-((5-bromo-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.00 g, 1.76 mmol), 1,1-diphenylmethanimine (0.382 g, 2.11 mmol), 30 mL of toluene, sodium tert-butoxide (0.405 g, 4.22 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.273 mL, 0.439 mmol, Sigma-Aldrich, St. Louis, Mo.), and tris(dibenzylideneacetone)dipalladium (0) (0.101 g, 0.176 mmol, Strem Chemicals, Newburyport, Mass.). The round-bottomed flask was sealed and heated at 90° C. for 15 h. After that time, the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was concentrated to give a brown oil. To this was added 25 mL of THF and 15 mL of 5M HCl in dioxane. After 15 min, 17 mL of 5M NaOH was added and the mixture was extracted with EtOAc. The layers were separated, the organics were dried (MgSO4), filtered, and concentrated to give an orange oil. Purification via column chromatography on silica gel (120 g of silica, 0 to 65% EtOAc in hexanes) gave 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.510 g) as a tan solid. 1H NMR (400 MHz, CD3OD) δ=8.57 (s, 2H), 7.19 (d, J=4.1 Hz, 1H), 6.04 (d, J=4.1 Hz, 1H), 5.10 (br. s., 1H), 4.71 (d, J=13.7 Hz, 1H), 3.71 (d, J=11.7 Hz, 1H), 3.56 (d, J=11.5 Hz, 1H), 3.31-3.23 (m, 1H), 2.61 (dd, J=3.7, 11.5 Hz, 1H), 2.46 (dt, J=3.5, 11.8 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 506.0 (M+H)+. GK-GKRP IC50 (Binding)=0.252 μM; GK-GKRP EC50 (LC MS/MS-2)=0.161 μM.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:15]1([C:18](OCC)=[O:19])[CH2:17][CH2:16]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>CCOCC>[OH:14][CH:7]([C:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(C(=O)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC1(C(O)c2ccccc2)CC1
Yield: 81.4 %

Procedure:
Under a nitrogen stream, lithium aluminum hydride (4.55 g, 0.12 mol) was suspended in dehydrated ether (120 ml) and a solution (50 ml) of ethyl 1-benzoylcyclopropanecarboxylate (21.83 g, 0.1 mol) in dehydrated ether was added dropwise over 50 min while stirring under ice-cooling. The mixture was stirred at room temperature for 1.5 h, and 10% aqueous sodium hydrogen carbonate (15 ml) was slowly added dropwise under ice-cooling. Then 20% aqueous sodium hydroxide (30 ml) was added dropwise, and the mixture was stirred for 30 min. The ether layer was separated by decantation and the residue was washed twice with 30 ml of ether. The ether layer was combined, washed with saturated brine, dehydrated over anhydrous magnesium sulfate and concentrated. The residual solution (16.9 g) was purified by silica gel column chromatography (chloroform/methanol=20/1) to give the title compound (14.51 g) as a colorless oil (yield 81%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([SH:23])[CH:20]=[CH:21][CH:22]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[S:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([OH:16])[CH:18]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Oc1cccc(S)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Sc3cccc(O)c3)c2cc1OC
Temperature: 40 °C
Yield: 92.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol), (prepared as described for the starting material in Example 1), was added to a solution of 3-hydroxybenzenethiol (168 mg, 1.3 mmol) and N,N-diisopropylethylamine (233 μl, 1.3 mmol) in DMF (5 ml). After heating at 40° C. for 10 minutes, the reaction mixture was allowed to cool, diluted with water, acidified to pH3 and the mixture extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was recrystallised from a mixture of ethanol and ether to give 6,7-dimethoxy-4-(3-hydroxyphenylthio)quinazoline (259 mg, 93%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[N:10]2[N:9]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:37]>C1(C)C=CC=CC=1>[Cl:37][C:15]1[N:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[C:11]2[N:12]=[C:13]([CH3:17])[N:14]=1
Reactant: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (I-2A-1a; 30.0 g, 80.8 mmol) in toluene (400 ml) at room temperature was added diisopropylethylamine (30.3 ml, 173 mmol) and then POCl3 (15.9 ml, 168 mmol) over 10 minutes. The mixture was heated at 80° C. for 5 hours, cooled to room temperature, and then slowly quenched by slow addition to half saturated brine (300 ml). The biphasic mixture was flitered through Celite® to remove the brown solids that formed on quench. The organic layer was separated and washed with saturated aqueous NaHCO3 (200 ml) and then brine (200 ml). The organic solution was concentrated, in vacuo, to ½ volume and then filtered through a cotton plug. The solution was further concentrated to ¼ volume, at which point, a yellow solid began to precipitate. Hexane (300 ml) was then added and stirred for 1 hour. The solids were collected on a sintered glass funnel and dried, in vacuo, to afford the desired product I-2A-1b (22.3 g, 71%) as a dark-yellow solid: +APcI MS (M+1) 389.1; 1H NMR (400 MHz, CD2Cl2) δ 7.50-7.39 (m, 6H), 7.28 (d, J=8.7 Hz, 2H), 2.73 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccccc1CBr
Yield: 104.2 %

Procedure:
To 1-tert-butyl-2-methyl-benzene (940 mg, 6.34 mmol), NBS (1.24 g, 1.1 eq) and AIBN (20 mg, catalytic amount) was added CCl4 (12 mL), which was then refluxed for 1 h. The suspended particles were removed by filtration, and washed with CCl4. The organic layers were combined and concentrated under reduced pressure to give 1.5 g of a yellow liquid in a stoichiometric yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([F:18])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:18])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(-c2ccc(C=O)c(Cl)c2)cc1F
Agent: BrB(Br)Br
Product: O=Cc1ccc(-c2ccc(O)c(F)c2)cc1Cl

Procedure:
The title compound was prepared by reacting 3-chloro-3′-fluoro-4′-methoxy-1,1′-biphenyl-4-carbaldehyde (990 mg, 3.75 mmol) with boron tribromide (11.25 mL of 1 N solution in methylene chloride, 11.25 mmol) according to Method F to yield 940 mg (100%) of yellowish solid. The compound was used in the next step without purification. The analytical sample was obtained by HPLC purification: mp 206-208° C.; 1H NMR (DMSO-d6): δ 7.06 (1H, t, J=8.79 Hz), 7.51-7.53 (1H, m), 7.71 (1H, dd, J=2.47 Hz, J=12.63 Hz), 7.81-7.83 (1H, m), 7.89 (1H, d, J=7.96 Hz), 7.91 (1H, d, J=1.66 Hz), 10.329(1H, s), 10.330 (1H, s); IR 1667 cm−1; MS (ESI) m/z 249/251 (M−H)−.
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C:34](C)([CH3:36])[CH3:35])[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](=O)(O[C@H]1CCOC1)[O:40]N1C(=O)CCC1=O.C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C@H:34]1[CH2:36][CH2:39][O:40][CH2:35]1)[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was dissolved in a 1:1 solution of CH2Cl2/TFA (1 mL) and allowed to stir at room temperature for 1 hour. The solution was then extracted into ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated to a clear oil. The resulting oil was then dissolved in THF (1 mL) and combined with 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl] carbonate (0.05 mmol, 13 mg) DIEA (0.08 mmol, 14 μL) and allowed to stir for 15 hours. The reaction was neutralized by the addition of acetic acid and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate), providing 19 mg (37%) of a white solid. H1-NMR (CDCl3): δ 7.70 (2H,d), 7.29-7.17 (6H,m), 6.97 (2H,d), 5.1 (1H,s), 4.76 (1H,d), 4.17 (1H,m), 3.86 (3H,s), 3.87-3.70 (6H,m), 3.68-3.60 (1H,m), 3.06 (1H,bs), 2.89 (2H,m), 2.02 (3H,m), 1.89 (1H,m), 1.71 (2H,m), 1.28-1.08 (6H,m); MS (ESI): M+Na=585.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]([CH:22]2[CH2:27][CH2:26][CH2:25][CH:24]=[CH:23]2)[CH2:13][C@H:12]1[NH:28]C(OCCCC)=O>C1(C)C(C)=CC=CC=1.[C].[Pd]>[O:10]=[C:11]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:13][C@H:12]1[NH2:28]
Reactant: CCCCOC(=O)N[C@@H]1CN(C2C=CCCC2)c2ccccc2NC1=O
Agent: [Pd]
Solvent: Cc1ccccc1C
Solvent: O=[N+]([O-])c1ccccc1
Product: N[C@@H]1CN(c2ccccc2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Nitrobenzene (22.16 g) and 10% palladium carbon (6 g) were added to a solution of (3R)-2-oxo-3-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (12.87 g) in xylene (200 ml), the mixture was refluxed for one hour and 30 minutes. The reaction mixture was allowed to cool, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (30 ml), 4N HCl-dioxane (20 ml) was added, the resultant mixture was stirred at 50° C. for one hour. After allowed to cool, crystals so precipitated were collected by filtration, the crystals were washed with 2-propanol, to thereby obtain hydrochloride of the title compound. The compound was dissolved under heating in the mixed solvent of methanol and water, allowed to cool, saturated sodium bicarbonate was added for neutralization, crystals so precipitated were collected be filtration, the crystals were washed with water and dried, to thereby obtain 5.55 g of the title compound (Yield: 86%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22](B(O)O)=[CH:23][C:18]=2[CH:17]=[CH:16]1>>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:2]3[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:23][C:18]=2[CH:17]=[CH:16]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccc2occc2c1
Product: Nc1nnc(-c2ccc3occc3c2)c(-c2ccccc2)n1
Yield: 39.2 %

Procedure:
6-(1-benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine (225 mg, 47%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and benzofuran-5 boronic acid (0.32 g, 1.99 mmol) according to the general procedure of Example 1.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([Cl:28])=[C:26]4[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]4[C@@H:29]4[CH2:31][C@@H:30]4[F:32])=[CH:20][C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.Cl>>[ClH:28].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]4[C@@H:29]4[CH2:31][C@@H:30]4[F:32])=[CH:20][C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3c(F)cc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3Cl)CC1CCO2
Agent: Cl
Product: NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4[C@@H]3C[C@@H]3F)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]-oct-7-yl)-6-fluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 180°-185° C. (with decomposition).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[CH:11]=[C:12]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])[CH:13]=[CH:14][CH:15]=3)=[C:4]2[CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[CH:11]=[C:12]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])[CH:13]=[CH:14][CH:15]=3)=[C:4]2[CH:3]=[N:2]1
Reactant: CC(C)(C#N)c1cccc(-c2ccnc3[nH]ncc23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CN)c1cccc(-c2ccnc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
To 2-(3-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-methylpropanenitrile (22 mg, 0.084 mmol) was added slowly a 2 M solution of lithium aluminium hydride (167.70 ml, 0.336 mmol) in tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was allowed to cool down to room temperature and was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were freeze-dried to give the title compound as a white solid (12 mg, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[CH:14]=[C:15]([NH:22][C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)=[O:24])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:28][C:25]([OH:26])([CH3:27])[C:23]([NH:22][C:15]2[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:13]([CH3:12])[CH:14]=2)=[O:24])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(Cl)c([N+](=O)[O-])c2)ccc1[N+](=O)[O-]

Procedure:
3-(4-Chloro-3-nitrophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-chloro-3-nitrophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-0.2% methanol). 1H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 2.53 (3H, s), 4.10 (1H, d, J=9.9 Hz), 4.36 (1H, d, J=9.9 Hz), 6.28 (1H, s), 7.28 (1H, dd, J=9.0 Hz, J=3.0 Hz), 7.62 (1H, d, J=9.0 Hz), 7.68 (1H, d, J=3.0 Hz), 7.88 (1H, dd, J=9.0 Hz, J=2.3 Hz), 7.92 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=9.0 Hz), 10.15 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1(Cl)[Cl:8].[CH3:10][O:11][S:12]([O-:15])(=[O:14])=[O:13].[Na+]>C(#N)C>[CH3:10][O:11][S:12]([O-:15])(=[O:14])=[O:13].[CH3:1][NH+:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH:3]1[Cl:8]
Reactant: CN1CCN(C)C1(Cl)Cl
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CC[NH+](C)C1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
3.00 g (17.75 mmol) of 1,3-dimethyl-2,2-dichloroimidazolidine and 2.38 g (17.75 mmol) of sodium methylsulfate are mixed with 20 ml of dry acetonitrile. The reaction mixture is stirred for 5 hours at room temperature, and the precipitate NaCl is filtered off. The solvent is distilled off, and the residue is dried for 1 hour under a reduced pressure of 7 Pa and at 50° C., giving 4.09 g of 1,3-dimethyl-2-chloroimidazolidinium methylsulfate as a viscous material, corresponding to a yield of 94.2%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1B(O)O>CN(C=O)C>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][C:25]=5[CH3:24])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: Cc1ccncc1B(O)O
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 35 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-methylpyridin-3-ylboronic acid were reacted. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 139 (89 mg, 35%). 1H NMR (400 MHz, DMSO) δ 8.57-8.29 (m, 3H), 8.12 (d, J=15.0, 1H), 7.38 (dd, J=8.3, 2.4, 2H), 7.20 (d, J=8.3, 1H), 5.73 (dt, J=13.1, 6.6, 1H), 4.45 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 2.37 (s, 3H), 1.48 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[OH-].[K+].Br[CH2:20][CH2:21][O:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH2:30]([O:29][C:27]([C:26]1[CH:32]=[CH:33][C:23]([O:22][CH2:21][CH2:20][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[C:3]2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:24][CH:25]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)c1ccc(OCCBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCCn2c(-c3cccnc3)c(C)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4.17 g of 3-methyl-2-(3-pyridyl)indole, 0.64 g of tetra-n-butyl ammonium bromide and 1.2 g of powdered KOH in 500 ml of acetonitrile, while stirring at room temperature under nitrogen, is added 5.06 g of ethyl p-(2-bromoethoxy)benzoate [for preparation see U.S. Pat. No. 2,790,825 (1957)]. The suspension is stirred for five days. After filtration to remove KBr, the filtrate is concentrated to an oil which is dissolved in ethyl acetate and extracted with 3 N HCl. The acid layer is separated and treated with 3 N NaOH. This suspension is extracted with ethyl acetate (3×100 ml) and the organic extract is separated, dried over MgSO4, and concentrated to give as an oil 1-[2-(4-ethoxycarbonylphenoxy)ethyl]-2-(3-pyridyl)-3-methylindole.
Reaction SMILES: Cl.CN(C)CCCCl.[Cl:9][C:10]1[CH:43]=[CH:42][C:13]2[S:14][C:15]3[CH:41]=[CH:40][CH:39]=[CH:38][C:16]=3[C:17]3[N:18](COCC[Si](C)(C)C)[C:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[N:20][C:21]=3[C:12]=2[CH:11]=1>>[Cl:9][C:10]1[CH:43]=[CH:42][C:13]2[S:14][C:15]3[CH:41]=[CH:40][CH:39]=[CH:38][C:16]=3[C:17]3[NH:18][C:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[N:20][C:21]=3[C:12]=2[CH:11]=1
Reactant: CN(C)CCCOCc1nc2c(n1COCC[Si](C)(C)C)-c1ccccc1Sc1ccc(Cl)cc1-2
Agent: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOCc1nc2c([nH]1)-c1ccccc1Sc1ccc(Cl)cc1-2

Procedure:
By a reaction of alcohol 34 (0.34 mmole) and 3-dimethylaminopropylchloride-hydrochloride (4.8 mmole), {3-[5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-dimethyl-amine in the form of an oily product was obtained;
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[O:9][C:10]([CH3:11])=[C:6]([CH2:5][CH2:4][NH2:1])[N:7]=2)=[CH:13][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCN
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a solution of 4-(2-azido-ethyl)-2-(4-benzyloxy-phenyl)-5-methyl-oxazole (660 mg) in THF (10 ml) were added water (0.3 ml) and triphenylphosphine (570 mg). The reaction mixture was stirred over night at RT. Then the solvent was removed and the residue was purified by chromatography (CH2Cl2/MeOH 4:1) yielding 2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethylamine (380 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([N+:11]([O-])=O)=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][C:3]1=2>CCO.[OH-].[Pd+2].[OH-]>[NH2:11][C:9]1[C:10]2[N:2]([CH3:1])[C:3]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:4]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CCc2c(c3cccc([N+](=O)[O-])c3n2C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCc2c(c3cccc(N)c3n2C)C1
Reaction time: 18 h
Yield: 66 %

Procedure:
Ethyl 5-methyl-6-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (340 mg, 1.12 mmol) and palladium hydroxide (60 mg) were dissolved in EtOH (50 mL) and stirred for 18 h under H2 (55 psi). The mixture was filtered through Celite and the filtrate was evaporated to give ethyl 6-amino-5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a light tan solid (202 mg, 66%). 1H NMR (CDCl3, 300 MH) δ 6.85-7.02 (m, 2H), 6.43-6.51 (d, 1H, J=7.0 Hz), 4.80 (br. s, 2H), 4.21 (q, 2H, J=6.6 Hz), 3.90 (s, 3H), 3.80-3.88 (m, 2H), 2.75-2.80 (m, 2H), 1.27 (t, 3H, J=7.3 Hz) ppm.