Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C(F)(F)F)=O>[CH:10]1[CH:11]=[CH:12][C:7]([CH:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[C:5]2[NH:1][CH:2]=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: O=Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1

Procedure:
Gas Chromatography. We previously reported that the GC trace of the crude reaction mixture, obtained with TFA catalysis, shows three major peaks.16 The GC trace of the crude reaction mixture obtained with 0.1 equiv of InCl3 and a pyrrole:benzaldehyde ratio of 100:1 for 1 h also shows three major peaks (FIG. 2A) that are assigned as 1 (tR=16.4 min), 2 (tR=17.0 min) and 3 (tR=21.8 min) based on comparison with authentic samples. Closer scrutiny of the same GC trace upon amplification of the scale reveals a number of additional minor peaks (FIG. 2B). The appearance and intensity of these minor peaks depend on the reaction conditions (catalyst, reaction time, and pyrrole:benzaldehyde ratio). For example, some of the minor peaks seen in InCl3 catalyzed reactions are not observed in TFA catalyzed reactions.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](Cl)=[O:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[CH2:21](N(CCC)C1CC2C(=CC=CC=2C(OC)=O)OC1)CC.[Li]C.O>O1CCCC1.[Cu]I>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](=[O:16])[CH3:21])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(=O)Cl)c2C1
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Agent: [Cu]I
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Dipropylamino-5-chloroformylchroman*HCl (4.42 g, 13.4 mmol), prepared from 3-dipropylamino-5-methyloxycarbonylchroman (Example 2) analogous to the procedure used in Example 3, in dry tetrahydrofuran (20 ml), was added to a pre-formed solution of lithium dimethylcuprate; prepared from MeLi and CuI, in 200 mL tetrahydrofuran at -78° C. The solution was stirred for 15 minutes at -78° C. and was then allowed to reach room temperature during 10 minutes. Then, 30 mL H2O was slowly added. The organic phase was decanted, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. The title compound was crystallized as salt from ethyl acetate. Mp 106°-108° C. (oxalate).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])[CH3:12]>C(#N)C.O.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][N:14]([C:11](=[O:13])[CH3:12])[CH2:15][CH2:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 87.2 %

Procedure:
A solution of 5.0 g (35.44 mmol) of 1-fluoro-4-nitrobenzene and 4.99 g (38.98 mmol) of N-acetylpiperazine in 50 mL of acetonitrile is heated at 60°C. for 15 hours. The resulting mixture is diluted with water and with ethyl acetate. After separation of the phases by settling and extraction of the aqueous phase with ethyl acetate, the organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. 7.7 g of the expected product are obtained in the form of a yellow solid, which is used as obtained in the following step. Yield=88.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[CH2:20]([O:22]/[CH:23]=[CH:24]/[C:25](Cl)=[O:26])[CH3:21]>ClCl.N1C=CC=CC=1>[CH2:20]([O:22]/[CH:23]=[CH:24]/[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2)=[O:26])[CH3:21]
Reactant: CCO/C=C/C(=O)Cl
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClCl
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (±)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (3.06 g, 12.2 mmol, described in Intermediate 4) in CH2 Cl2 (100 mL) and pyridine (40 mL) was added a solution of (E)-3-ethoxyacryloyl chloride [Tietze et al., Synthesis, 1993, 1079-1080](1.64 g, 12.2 mmol) in CH2 Cl2 (100 mL). The resulting mixture was stirred at ambient temperature for 1 h, then concentrated to dryness in vacuo. The residue was suspended in H2O (350 mL) with sonication and the solid was isolated by filtration and dried to give the title compound. MS: m/z=350 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH3:11][CH2:12][O:13][C:14]1[C:18](=O)[C:16](=[O:17])[C:15]=1[O:20]CC.CCCCCC.C(OCC)(=O)C>C(O)C>[CH2:12]([O:13][C:14]1[C:15](=[O:20])[C:16](=[O:17])[C:18]=1[NH:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[CH3:11]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: N#Cc1ccc(N)c(O)c1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O

Procedure:
A solution of 3-hydroxy-4-aminobenzonitrile (1.08 g, 0.008 mol) and diethyl squarate (1.19 ml, 0.008 mol) in dry ethanol (22 ml) was heated at 85° C. for two days. During the course of the reaction, a tan precipitate forms. TLC (1:1 hexane:ethyl acetate) indicates that no starting material is present. The solid is filtered through a Buchner funnel, washed with cold ethanol, and collected to give 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 1.19 g (0.0046 mol, 57%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>>[OH:9][CH2:10][CH2:11][N:12]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][OH:15]
Reactant: OCCNCCO
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCN(CCO)Cc1ccccc1
Temperature: 90 °C
Yield: 55.3 %

Procedure:
S. Gump and E.J. Nikaivitz in Example 3 of U.S. Pat. No. 2,504,977 issued April 25, 1950, show the reaction of 190 g of benzyl chloride with 315 g of N,N-bis(2-hydroxyethyl)amine at 100-125° C. for nine hours followed by addition of sufficient saturated potassium carbonate to neutralize "the formed hydrochlorides" and continued stirring of the mixture for thirty minutes at 90° C. The separated oil in isopropyl ether and ethanol was dried and distilled twice to produce 162 g (54.3% yield) of pure N,N-bis(2-hydroxyethyl)benzylamine. A 97 g portion of N,N-bis(2-hydroxyethyl)benzylamine was converted into 115 g (85.7% yield) of N,N-bis(2-chloroethyl)benzylamine hydrochloride (46.5% yield based on benzyl chloride) by adding dropwise with stirring 120 g of thionyl chloride in chloroform to a cooled (ice bath) chloroform solution of N,N-bis(2-hydroxyethyl)benzylamine, and then isolating the product and converting it to its hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[S-:10][C:11]#[N:12].[NH4+].C1C=CC=CC=1.C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][P:4]([N:12]=[C:11]=[S:10])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cl)OCC
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOP(=O)(N=C=S)OCC
Reaction time: 24 h

Procedure:
One molar equivalent of diethoxyphosphoryl chloride is reacted with a 1.1 to 1.2 molar equivalent of ammonium thiocyanate in the presence of an inert solvent, such as benzene, toluene, xylene or the like, at about 20° C to 30° C for a period of time of about 24 hours. The so obtained solution of diethoxyphosphinyl isothiocyanate of formula (III) is washed several times with water and dilute sodium bicarbonate solution, and then the isothiocyanate is isolated by removing the solvent in vacuo. This reaction step may be graphically illustrated as follows: ##STR2##
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Na].[K].[S-:12][C:13]#[N:14].[NH4+]>>[CH2:1]([O:3][P:4]([N:14]=[C:13]=[S:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOP(=O)(Cl)OCC
Agent: [K]
Agent: [NH4+]
Agent: [Na]
Product: CCOP(=O)(N=C=S)OCC
Reaction time: 3 h

Procedure:
One molar equivalent of diethoxyphosphoryl chloride of formula (II) is reacted with 1.0 to 1.2 molar equivalent of sodium-, potassium- or ammonium thiocyanate at a temperature range of 5° C to 30° C and, preferably, 15° C to 25° C for a period of time ranging from 2 to 4 hours to yield diethoxyphosphinyl isothiocyanate of formula (III). The reaction is slightly exothermic, but is easily controlled by a cooling bath.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH2:7]>>[Si:2]([O-:7])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
300 ml of sodium water glass was mixed with 2700 ml of de-ionized water to form an aqueous solution of sodium silicate, which was passed through a cationic exchange resin column, thereby forming silicic acid. 5 wt % aqueous KOH was added gradually at a temperature below 80° C. (preferably, 70-80° C.) until the pH value of the aqueous solution was greater than 10 so that the silicic acid was alkalized and under went polycondensation. The reaction product was cooled to 40° C., and was added with 300 ml of 10 wt % sodium aluminate aqueous solution. After 40 minutes, the reaction product was passed through a cationic exchange resin column to obtain a clear silica sol A.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O.Cl>>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C)cc1F
Reaction time: 48 h

Procedure:
2-Fluoro-4-methylbenzoic acid (30.0 g, 195 mmol) was dissolved in MeOH (600 mL, 10 mol), and 12 M HCl (3.2 mL, 39 mmol) was added. The mixture was heated to reflux and stirred for 48 hours, then cooled and concentrated. The recovered material was dried in vacuo for 24 hours to obtain Intermediate (6a) as a white solid that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1

Procedure:
A solution of 5-hydroxyindole 1-3 (5.50 g, 41.3 mmol, 1 equiv), tert-butyldimethylsilyl chloride (7.47 g, 49.6 mmol, 1.20 equiv), and imidazole (7.03 g, 103 mmol, 2.50 equiv) in N,N-dimethylformamide (20 mL) was stirred at 23° C. for 20 h. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water (3x), then dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (40% dichloromethane in hexanes, then 60% dichloromethane in hexanes) to give 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole as a colorless oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ8.00 (br s, 1H), 7.22 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=2.8 Hz), 7.06 (d, 1H, J=2.3 Hz), 6.76 (dd, 1H, J=8.6, 2.3 Hz), 6.44 (m, 1H), 1.00 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:19]([F:22])([F:21])[F:20])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[C:3]([C:19]([F:22])([F:20])[F:21])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Br)c(C(F)(F)F)nn1C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1-c1c(Br)c(C(F)(F)F)nn1C
Yield: 85 %

Procedure:
To a stirred solution of 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.08 g, 0.20 mmol) in EtOH (0.7 mL) was added SnCl2.2H2O (0.18 g, 0.80 mmol, 4.0 eq.) and the mixture was stirred at reflux for 2 hours followed by the removal of EtOH under vacuum. The resulting solid was dissolved in EtOAc and 1N NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated to give 3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.06 g, 0.17 mmol, 99% yield after two steps) as a white solid: LCMS m/z (%)=350 (M+H79Br, 95), 352 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 6.78 (dd, J=14.0, 6.0 Hz, 1H), 6.76 (dd, J=8.0, 4.0 Hz, 1H), 6.54 (d, J=4.0 Hz, 1H), 3.67 (s, 3H), 3.66 (s, 3H) 3.36 (broad s, 2H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>C(Cl)Cl.O>[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
1,1-Dimethylethyl (3S)-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (·9.3 mmol) was dissolved in DCM (25 mL) and treated with a 4M HCl solution in 1,4-dioxane (24 mL, 96 mmol). The reaction was stirred at room temperature for 3 h, at which time LC/MS indicated that all starting material was consumed. The reaction was concentrated in vacuo to give a thick gum. This material was dissolved in water and extracted with ethyl acetate. The aqueous phase was separated and treated with solid Na2CO3 to bring the pH to ˜10. The product was then extracted into CHCl3 (3×) and the combined organic phases were dried (Na2SO4) and concentrated to yield the desired product as an orange oil (2.3 g, 100% for two steps).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
According to General Method 3A, 28 g (132 mmol) of methyl 5-bromonicotinate and 30 g (158 mmol, 1.2 eq.) of 4-trifluoromethylphenylboronic acid were reacted. Yield: 32 g (85% of theory)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1)c1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of cyanuric chloride (2 g, 10.84 mmol) in DCM (40 ml) at 0-5° C. was added dropwise a solution of N-methyl aniline (1.16 ml, 10.84 mmol) and DIPEA (2.08 ml, 12.26 mmol) in DCM (30 ml). The resulting mixture was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was diluted with DCM (40 ml) the solution was then extracted with 2M aq. HCl (2×40 mL) and saturated brine (30 mL) and dried further over anhydrous sodium sulfate. The organic phase was evaporated to dryness to furnish the title compound as an off white solid (2.726 g, 99%). Method C HPLC-MS: MH+ requires m/z=255. Found: m/z=255, Rt=1.48 min (100%). 1H NMR (500 MHz, CDCl3) δ ppm 7.35-7.42 (2H, m), 7.29 (1H, d), 7.15-7.21 (3H, m), 3.48 (3H, s).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:10]([O-])=O.[Na+]>O>[Cl-:1].[C:3]1([N+:2]#[N:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: Cl
Reactant: Nc1ccccc1
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccccc1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of benzenediazonium chloride was prepared as follows: To an ice cold (about 5° C.) solution of aniline hydrochloride (3.24 g., 25 mmoles) in water (10 ml.) and concentrated hydrochloric acid (2.1 ml., 25 mmoles) was added dropwise with stirring a solution of sodium nitrite (1.9 g., 27.5 mmoles) in water (10 ml.). After addition the solution was stirred in the cold for an additional 15 minutes.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][C:14]([CH2:16][CH2:17][C:18]([CH3:20])=O)=O>C(O)(=O)C.C(Cl)Cl>[CH3:20][C:18]1[N:1]([N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[C:14]([CH3:13])=[CH:16][CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(C)n1N1C(=O)c2ccccc2C1=O
Yield: 98 %

Procedure:
A mixture of N-amino-phthalimide (50 g) and 2,5-hexadione (35.2 g) in 400 ml acetic acid was refluxed for 48 hours, stripped of solvent, slurried in methylene chloride and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried and stripped to yield N-(2,5-dimethylpyrrol-1-yl)-phthalimide (98%).
Reaction SMILES: O=O.[C:3]([N:6]1[CH2:15][CH2:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2/[C:7]/1=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:5])[CH3:4].CO.C(Cl)Cl>C(OCC)C>[C:3]([N:6]1[CH2:15][CH2:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C@@H:7]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)(=[O:5])[CH3:4]
Reactant: COc1ccc(/C=C2\C3=C(CCCC3)CCN2C(C)=O)cc1
Agent: O=O
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(C[C@H]2C3=C(CCCC3)CCN2C(C)=O)cc1
Reaction time: 20 h
Yield: 98.1 %

Procedure:
In a glove box (<1 ppm oxygen), a 500 ml steel autoclave was charged with 2-acetyl-1-(p-methoxybenzyl)-2,3,4,6,7,8-hexahydroisoquinoline (2.43 g, 8.17 mmol) (prepared according to example 2) 40 ml of methanol, 28 ml of methylene chloride and 100 ml of a methanol solution containing 0.082 mmol of Ru(TFA)2 (BIPHEMP) as catalyst. The hydrogenation was carried out at 100° and 60 bar for 20 h. The solution was concentrated to give an oil, which was dissolved in 300 ml of diethyl ether. To removed the catalyst the ether solution was passed through a short pad of silica gel. Concentration of the filters afforded 2.4 g of (S)-2-acetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline as a colorless oil; e.e. 94.3%.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:11]1[N:15]=[CH:14][N:13]([C:16]([N:18]2C=NC=C2)=[O:17])[CH:12]=1>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7].[NH2:13][C:16]([NH2:18])=[O:17].[NH:13]1[CH:12]=[CH:11][N:15]=[CH:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: NC(N)=O
Product: c1c[nH]cn1

Procedure:
Compounds 217-220, 230 and 231a, b, and c were all prepared in overall yields ranging from 20-40% following the route depicted in Scheme 7. The first step, performed at 0° C. under inert conditions used the di-t-butyl ester of Glutamic acid with CDI in the presence of base to form the intermediate Glu-urea-imidazole derivative 2. This intermediate was activated with MeOTf under basic conditions to afford the methylated imidazole 3, which under inert conditions reacted readily with amines. The tert-butyl ester protecting groups were removed using 20% TFA in DCM for 1 to 4 hour at room temperature. Upon completion of the deprotection, the reactions were concentrated on a rotary evaporator or blown dry with nitrogen and purified on a silica column or recrystallized. The final products were tested in vitro and in vivo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].O.[N+:14]([O-])([OH:16])=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-4-fluoro-5-nitrophenol (4.0 g, 17 mmol) in methylene chloride (29.5 mL), 2.0 M nitric acid in DCM (25 mL) was added and the mixture was stirred for 15 min at room temperature. The mixture was poured over cold water and extracted with methylene chloride to give the product.
Reaction SMILES: O.[CH2:2]([N:9]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:11]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>CO>[CH2:2]([N:9]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C@H:11]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Reactant: [H][H]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A 12-l stainless steel autoclave was charged on air with 1-benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid monohydrate (180.0 g, 0.54 mol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP)] (413.2 mg, 0.54 mmol, S/C 1,000) and methanol (7.1 l). The asymmetric hydrogenation was run for 20 h at 30° C. under 40 bar of hydrogen (99.3% conversion). After the pressure was released, a sample of the white suspension was evaporated to dryness affording crude (S,S)-Ia with 99.0% purity and >99.9% ee. The reaction suspension was concentrated to a volume of 1.8 l and stirred for 1 h at 0-5° C. After filtration, the filter cake was washed with cold methanol and dried on vacuum to yield 176.0 g (>99%) of (S,S)-Ia as a white solid with 99.0% purity and >99.9% ee.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g; that is prepared as described in Reference Example 36) in dry dimethylformanide (270 mL) under nitrogen is treated portionwise with potassium carbonate (79.5 g). After stirring at room temperature for 45 minutes, it is treated with cyclopentyl bromide (34.3 mL), and the resulting suspension is heated at 60° C. for 8 hours. After cooling, the solution is evaporated to low bulk under reduced pressure, to give an oil. This oil is treated with water (250 mL) and diethyl ether (300 mL), and the aqueous layer is washed with further quantities of diethyl ether (2×50 mL). The combined ethereal extracts are washed with brine (1×50 mL) and with water (3×50 mL), dried over magnesium sulfate and evaporated. The resulting residue is crystallized from methanol, to give 4-benzyloxy-3-cyclopentyloxybenzaldehyde (79 g), m.p. 55-56° C. [Elemental analysis: C,77.1; H,6.9%; calculated: C,77.0; H,6.8%].