Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26]C)[CH2:6][N:7]1[CH:11]=[CH:10][N:9]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:8]1=[S:22].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[OH:26])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:8]1=[S:22]
Reactant: COc1ccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
A solution of 3-(3,4-dimethoxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (900 mg, 2.37 mol), prepared as in Example 15, in methylene chloride was cooled to 0° C. under nitrogen and then boron tribromide (1M, 7.1 mL, 7.1 mmol) in an additional 10 mL of methylene chloride was added dropwise. The mixture was allowed to cool to room temperature, stirred for 16 hours and then slowly added to water. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with methylene chloride/methanol (96:4) and then crystallized from methanol/ethanol/hexane to give 3-(3,4-dihydroxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (520 mg), m.p. 173°-174° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24]([O:26][CH3:27])=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.O.O.O.O.O.[Cl-].[Cs+]>C(O)(=O)C>[CH2:27]([O:26][C:24]1[CH2:25][N:21]([C@@H:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[N:12]=2)=[O:9])[C:22](=[O:28])[CH:23]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccccc1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2CC(OCc3ccccc3)=CC2=O)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 5.4 %

Procedure:
A solution of (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (prepared as in Example 1, 94 mg, 0.24 mmol) in a hydrochloric acid (gas) saturated acetic acid (5 mL) was heated in a sealed tube at 75° C. for 2 h. After that time the reaction mixture was cooled to room temperature, and concentrated. The residue was added to benzyl alcohol (1000 mg, 9.15 mmol), and toluene-4-sulfonic acid hydrate (10 mg), cesium chloride hexahydrate (0.3 g) on silica gel (Sabitha, G.; Reddy, M. N.; Sudhakar, K.; Yadav, J. S.; Letters Org. Chem, 2005, 2, 763-766). The mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate and purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-2-(4-benzyloxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (6 mg, 5%): LR-ES-MS m/z calculated for C26H34N4O4 [M]+ 466, observed [M+H]+ 467; 1H NMR (300 MHz, CDCl3) δ ppm 0.77 (br. s., 1H) 1.08 (br. s., 2H) 1.08 (br. s., 6H) 1.32-2.07 (m, 8H) 2.89 (br. s., 1H) 3.79-3.96 (m, 1H) 3.88 (br. s., 2H) 3.98-4.15 (m, 1H) 4.78 (br. s., 1H) 4.92 (br. s., 2H) 5.16 (br. s., 1H) 6.61 (br. s., 1H) 7.08-7.43 (m, 5H) 8.81 (br. s., 1H).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]([C@H:14]([OH:19])[C@H:15]([OH:18])[CH:16]=[O:17])[C@H:10]([OH:13])[CH2:11][OH:12])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22].C(O)[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@](O)(CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O.O>>[OH:17][CH:16]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:9]([O:8][C@@H:6]2[O:7][C@H:2]([CH2:1][OH:23])[C@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]2[OH:20])[C@H:14]([OH:19])[C@H:15]1[OH:18]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)[C@H](O)CO
Agent: OC[C@H]1O[C@@H](O[C@@H]2[C@@H](CO)O[C@](O)(CO)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: O
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
As is evident from FIGS. 7 and 8, 1H-NMR spectrum of Isomerized saccharide A was completely identical with that of epilactose standard. As is evident from FIGS. 9 and 10, 1H-NMR spectrum of Isomerized saccharide B was completely identical with that of lactulose standard. From the results, it was confirmed that Isomerized saccharides A and B, formed from lactose, are epilactose and lactulose, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[Br:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(Br)c1-c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Product: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccccc1
Yield: 39 %

Procedure:
The reaction mixture of 5-(2-benzyloxy-5-nitro-phenyl)-4-bromo-1-methyl-1H-pyrazole was reduced in the presence of SnCl2.2H2O, in a similar manner as described in Example 1.1, providing 4-benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.079 g, 0.22 mmol, 39% for three steps). LCMS m/z (%)=358 (M+H79Br, 98), 360 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.45 (s, 1H), 7.15-7.26 (m, 3H), 7.10 (d, J=6.6 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 6.66 (dd, J=2.8, 8.6 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 4.83 (AB quartet, J=12.0, 17.2 Hz, 2H), 3.62 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>ClC(Cl)C>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:22])[CH2:20][CH3:21]
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: CCC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 39.4 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.10 g, 0.42 mmol), propionyl chloride (0.036 mL, 0.42 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 49 mg of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-ylpropanamide (49 mg). MS (ES) m/z 297.2; HPLC purity 100% at 210-370 nm, 10.0 min.; 99.3% at 250 nm, 10.0 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C19H24N2O+H+, 297.19614; found (ESI, [M+H]+), 297.1973.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14](=O)[CH3:15])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].[CH3:17]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]([C:14]([CH3:15])=[CH2:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CC(=O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CS(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C(C)c1ccc(C(F)(F)F)c(F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride (1.96 g, 49.0 mmol) was added DMSO (40 ml) in one portion at 0° C. and the reaction mixture was heated at 80° C. for 40 minutes. After cooling to ambient temperature, to this was added a solution of methyltriphenylphosphonium bromide (17.5 g, 49.0 mmol) in anhydrous DMSO (50 ml) dropwise at 0° C. After being stirred for 1 hour at ambient temperature, to this was added a solution of 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone (5.04 g, 24.5 mmol) in anhydrous DMSO (40 ml) dropwise at 0° C. and the reaction was stirred at ambient temperature for 1.5 hours. The mixture was quenched with water (150 ml) and extracted with hexane. The combined solution was washed with water then brine, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (3.20 g containing hexane) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[CH3:17][NH:18][CH2:19][CH:20]=[CH2:21]>C1COCC1>[CH2:19]([N:18]([CH3:17])[C:7]([C:6]1[C:5]([I:12])=[C:4]([C:3]([I:16])=[C:2]([NH2:1])[C:10]=1[I:11])[C:13]([Cl:15])=[O:14])=[O:8])[CH:20]=[CH2:21]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: C=CCNC
Solvent: C1CCOC1
Product: C=CCN(C)C(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reaction time: 8 h

Procedure:
Typically 5-amino-2,4,6,triiodoisophthaloyl dichloride (1) (100 g, 168 mmol) was dissolved in anhydrous THF (500 ml), the N-methyl allylamine (25 ml) was dissolved in 50 ml THF, and added dropwise to the solution over 1 hour. The mixture was heated to 50 deg C. and stirred overnight. The crude mixture was analysed by LCMS and this confirmed that the reaction mixture contained the desired product, ‘bis-acid chloride’ and ‘bis-N-methyl-allylamide’. The reaction was also monitored by TLC (2% MeOH in DCM) on silica gel plates, bis-acid chloride had an Rf of ˜0.98, the mono-N-methylallylamide ˜0.73 and the bis-N-methylallylamide ˜0.25. Once the reaction was deemed complete, the solution was filtered, vacuumed to dryness, then dissolved in 500 ml of ethyl acetate this solution was then loaded onto silica and purified on a 750 g column using ethyl acetate (B) and petrol (A) (10%→100% B over ˜10 column volumes). The pure fractions were collected and identified by TLC, the desired fractions were then vacuumed to dryness. The structure was confirmed by 1H and 13C NMR and purity by LCMS.
Reaction SMILES: [H-].[Na+].Cl.[NH:4]1[CH2:7][CH:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[N:18]=[C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=[C:15]([NH2:27])[N:14]=3)[N:9]=2)[CH2:5]1.[F:28][C:29]([F:40])([F:39])[CH2:30]OS(C(F)(F)F)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:26][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]1[N:16]=[C:15]([NH2:27])[N:14]=[C:13]([C:10]2[N:9]=[C:8]([CH:6]3[CH2:5][N:4]([CH2:30][C:29]([F:40])([F:39])[F:28])[CH2:7]3)[O:12][N:11]=2)[N:18]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CNC3)n2)n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CN(CC(F)(F)F)C3)n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 16 mg, 0.41 mmol) in anhydrous DMF (20 mL) at 0 C was added 6-[5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine hydrochloride (Intermediate 129, 50 mg, 0.138 mmol) and trifluoromethanesulfonic acid 2,2,2-trifluoro-ethyl ester (160 mg, 0.69 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 h and then was quenched with saturated ammonium chloride aqueous solution (10 mL) and evaporated to dryness. The solid obtained was dissolved in EtOAc (20 mL), washed with water (2×25 mL), dried over magnesium sulfate and evaporated to dryness. The resulting crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method B) to afford the title compound as white solid (5 mg, 9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].C([Mg]Cl)(C)C.[B:17](OC)([O:20]C)[O:18]C>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([B:17]([OH:20])[OH:18])[CH:3]=1)#[N:6]
Reactant: COB(OC)OC
Reactant: COc1ccc(C#N)cc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1B(O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
3-Bromo-4-methoxybenzonitrile (3.0 g, 14.2 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mLs). The solution cooled at −10° C. and stirred while isopropylmagnesium chloride (17.7 mmol, 8.8 mLs, 2.0 M in THF, 1.25 eq.) was added. The mixture was stirred for 1 hour and then trimethyl borate (1.87 g, 17.7 mmol, 2.0 mL) was added dropwise. The mixture was allowed to warm slowly to room temperature for 1 hour. The solvent was evaporated and the residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to a minimum volume under reduced pressure. The residue was recrystallized from hexanes to give 5-cyano-2-methoxybenzeneboronic acid (2.48 g, 99%) as a fluffy white powder.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:37])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[F:36])[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:37][C:21]([CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][C:27]=2[F:36])[CH2:24][CH2:25]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(C(F)(F)F)cc2F)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 28.3 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.26 g), tetrahydrofuran (2 ml) and magnesium (22 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (Example 21) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C8; solvent: methanol; flow rate: 2 ml/min) to afford 1-(2-fluoro-3-(3-phenoxyphenyl) prop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (38 mg, 27%).
Reaction SMILES: COC(=O)[CH:4]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)C(OC)=O>Cl>[CH3:4][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)C(C(=O)OC)c1ncccc1[N+](=O)[O-]
Agent: Cl
Product: Cc1ncccc1[N+](=O)[O-]
Yield: 92.7 %

Procedure:
A modified procedure of Cash et al. (Org. Biomol. Chem. 2005, 3. 3701-3706) was used. Dimethyl-2-(3-nitropyridin-2-yl)malonate (1.4 g, 5.5 mmol) was dissolved in 70 ml 6 M HCl and refluxed for 8 h. After neutralization with saturated Na2CO3 solution the solution was extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by bulb tube distillation (0.35 mbar; 70-80° C.). 2-Methyl-3-nitropyridine (0.7 g, 5.1 mmol, 92%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3) 8.72 (pdd; 3J=1.2 Hz; 3J=4.7 Hz; 1H; H-6); 8.27 (pdd; 3J=1.2 Hz; 3J=8.2 Hz; 1H; H-4); 7.35 (pdd; 3J=4.7 Hz; 3J=8.2 Hz; 1H; H-5); 2.86 (s; 3H; CH3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[N:11]3[C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[NH2:36][C:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:25]3[N:11]4[C:12]5[CH:24]=[CH:23][CH:22]=[N:21][C:13]=5[NH:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[C:10]4=[N:9][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:31][CH:30]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccc(O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 34 h
Yield: 116.6 %

Procedure:
tert-Butyl (1-{4-[2-(4-hydroxyphenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (34 mg, 0.060 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 34 hours. The mixture was concentrated to afford the desired product (33 mg, 96%) as a brown solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.71-8.67 (m, 3H), 8.13 (dd, J=4.6, 1.4 Hz, 1H), 7.94 (dd, J=8.0, 1.4 Hz, 1H), 7.53 (d, J=9.7 Hz, 2H), 7.41 (t, J=7.7 Hz, 1H), 7.32-7.28 (m, 4H), 7.15 (t, J=7.4 Hz, 1H), 6.89 (dd, J=8.6, 1.7 Hz, 1H), 6.76 (dd, J=8.6, 4.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 3.73-3.65 (m, 1H), 3.51-3.45 (m, 1H), 2.60-2.53 (m, 2H), 2.23-2.14 (m, 1H), 1.86-1.78 (m, 1H). LCMS: 472 [M+H].
Reaction SMILES: [O:1]1[C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH2:12][CH2:13][C:4]=2[N:3]=[C:2]1[NH2:14].I[CH2:16][CH2:17][CH3:18]>C(#N)C>[CH2:16]([N:10]1[CH:11]2[C:6]([C:5]3[O:1][C:2]([NH2:14])=[N:3][C:4]=3[CH2:13][CH2:12]2)=[CH:7][CH2:8][CH2:9]1)[CH2:17][CH3:18]
Reactant: Nc1nc2c(o1)-c1cccnc1CC2
Reactant: CCCI
Solvent: CC#N
Product: CCCN1CCC=C2c3oc(N)nc3CCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4,5-dihydrooxazolo[5,4-f]quinolin-2-amine, 5.0 g (26.7 mmol), (Example 27), in 200 ml of acetonitrile is refluxed with 1-iodopropane, 10.2 g (60 mmol), for 24 hours. The volatiles are then removed in-vacuo and the resulting solid is washed with diethyl ether and dried. The resulting 2-amino-4,5-dihydrooxazolo[5,4-f]quinolinium iodide is dissolved in 150 ml of water and treated with sodium borohydride, 1.7 g (50 mmol), in small portions. The mixture is stirred at room temperature for 2 hours. Following acidification with 10% hydrochloric acid, the mixture is stirred for another hour. The volatile components are removed in-vacuo and the residue is partitioned between chloroform and 1% ammonium hydroxide. The organic extract is concentrated and purified by column chromatography to give (±) 4,5,5a,6,7,8-hexahydro-6-propyloxazolo [5,4-f]quinolin-2-amine.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[F:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc([N+](=O)[O-])cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (63 mg, 74%), MS (ISP) m/z=340.5 [(M+H)+], mp 309° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[OH-].[Na+].[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
1-[Benzyloxycarbonyl]-4-[3-nitro-2-pyridinyl]piperazine (PREPARATION 99), is dissolved in dioxane (923 ml) and cooled to 0°. Then aqueous titanium trichloride (20%, 555.3 ml) is added cautiously. After stirring 30 min the reaction is diluted with aqueous sodium hydroxide solution (2N, 1.5 l) and filtered through celite. The filter cake is washed with methanol/chloroform (10/90). The combined organic layers are washed with water, saline, dried and concentrated in vacuo to afford the desired product, NMR (300 MHz, CDCl3) 7.80, 7.38-7.32, 6.99, 6.88, 5.17, 3.67 and 3.12 δ.
Reaction SMILES: COC1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([C:19](=[O:44])[CH2:20][NH:21][C:22](=[O:43])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=2)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])C=C(OC)C=1.CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C>>[CH2:12]([N:13]([C:19](=[O:44])[CH2:20][NH:21][C:22](=[O:43])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:5][CH3:4]
Reactant: COc1cc(CCN(CCC(=O)O)C(=O)CNC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc(OC)c1
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Product: CCCCN(CCC(=O)O)C(=O)CNC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1

Procedure:
3-[[2-(3,5-dimethoxy-phenyl)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound X;
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[CH2:39]([O:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH3:40]>C(#N)C>[CH2:39]([O:41][C:42](=[O:45])[CH:43]=[CH:44][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1)[CH3:40]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1ccc2occ(Br)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1coc2ccc(C=O)cc12
Temperature: 120 °C
Yield: 42 %

Procedure:
In a sealed tube 3-Bromo-1-benzofuran-5-carbaldehyde (500 mg, 2.22 mmol) was dissolved in 7 ml of ACN. To this solution was added PPh3 (1.16 g, 4.44 mmol), Pd(II)acetate (500 mg, 2.2 mmol), Et3N (073 mL, 5.55 mmol) and finally acrylic acid ethyl ester (2.41 ml, 22 mmol). The tube was sealed and the reaction was heated at 120° C. for one hour. The crude was filtered on celite to eliminate inorganic contaminations. The solvents were evaporated and the crude was purified by silicagel chromatography using cyclohexane-AcOEt 95-5 to 50-50. A pale yellow solid was obtained (400 mg, yield:42%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[O:29])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(F)cc1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1ccnn1C
Yield: 66.4 %

Procedure:
4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 4-fluorophenyl isocyanate (11.8 μL, 0.105 mmol) in a similar manner as described in Example 1.2 to afford Compound 142 as a white solid in 66.4% yield. LCMS m/z (%)=398 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.33 (s, 1H), 8.25 (s, 1H), 7.61-7.56 (m, 3H), 8.49 (s, 1H), 7.42 (s, 1H), 7.11-7.04 (m, 3H), 6.24 (s, 1H), 4.11 (t, J=5.85 Hz, 2H), 3.77 (s, 3H), 2.62 (t, J=5.85 Hz, 2H), 2.20 (s, 6H).