Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>CN(C)C=O>[CH3:3][C:4]1[N:5]=[CH:6][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:8]=1
Reactant: Cc1c[nH]cn1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C=O)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
4.20 g of sodium hydride (a 60% suspension thereof in a mineral oil) was suspended in 150 ml of dimethylformamide to obtain a suspension. 8.62 g of 4-methylimidazol was added to the suspension at a room temperature under stirring in portions. After one hour, 12.4 g of 4-fluorobenzaldehyde was added to the obtained mixture. The obtained mixture was stirred for 4 hours and poured into ice-water. The obtained mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and distilled under a reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol (50:1)) to obtain a solid product. This solid product was washed with ether to obtain 2.67 g of the title compound as a pale yellow powder (yield: 14%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:59][C:60]1[CH:61]=[CH:62][CH:63]=[C:64]2[C:69]=1[NH:68][C:67](=[O:70])[C:66]([CH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1)=[CH:65]2>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:74]4[CH2:75][CH2:76][CH:71]([C:66]5[C:67](=[O:70])[NH:68][C:69]6[C:64]([CH:65]=5)=[CH:63][CH:62]=[CH:61][C:60]=6[F:59])[CH2:72][CH2:73]4)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(c2cc3cccc(F)c3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (49 mg, 0.098 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (70 μl, 0.402 mmol) was added to the mixture followed by TBTU (34.5 mg, 0.107 mmol). 8-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (33.0 mg, 0.117 mmol) was added to the mixture. Reaction stirred at room temperature for 3.5 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 59% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.91 (s, 1H) 11.81 (s, 1H) 7.77 (s, 1H) 7.48 (s, 2H) 7.26-7.41 (m, 1H) 7.06-7.18 (m, 1H) 5.58 (d, J=16.79 Hz, 1H) 5.40 (d, J=17.09 Hz, 1H) 4.55 (d, J=12.51 Hz, 1H) 4.28-4.44 (m, 1H) 4.06-4.22 (m, 2H) 3.86-4.07 (m, 1H) 3.13-3.24 (m, 2H) 3.06 (t, J=10.83 Hz, 1H) 2.98 (dd, J=16.48, 8.24 Hz, 1H) 2.84-2.95 (m, 1H) 2.65 (t, J=12.05 Hz, 1H) 2.33-2.48 (m, 1H) 1.93 (d, J=10.07 Hz, 1H) 1.78-1.89 (m, 1H) 1.47-1.62 (m, 1H) 1.32-1.46 (m, 1H). High resolution MS m/e (M+H)+=726.0337.
Reaction SMILES: C([O:8][C:9]([C:11]1([NH:17][CH:18]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:19][CH2:20][N:21]2[C:29](=[O:30])[C:28]3[CH:27]=[C:26]4[CH:31]=[CH:32][CH:33]=[CH:34][C:25]4=[CH:24][C:23]=3[C:22]2=[O:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:39]([O:38][C:36]([CH:18]([NH:17][C:11]1([C:9]([OH:10])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[CH:27]=[C:26]3[CH:31]=[CH:32][CH:33]=[CH:34][C:25]3=[CH:24][C:23]=2[C:22]1=[O:35])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)C(CCN1C(=O)c2cc3ccccc3cc2C1=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(CCN1C(=O)c2cc3ccccc3cc2C1=O)NC1(C(=O)O)CCCCC1
Reaction time: 2 h

Procedure:
1-[1-tert-Butoxycarbonyl-3-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)propylamino]cyclohexanecarboxylic acid benzyl ester (416 mg, 0.729 mmol) was dissolved in acetic acid (85 mL) and 10% palladium on activated carbon (440 mg) was added. The mixture was hydrogenated under 3 atmospheres pressure at room temperature for 2 hours. The catalyst was removed by passage through a 0.45 m nylon filter and the filtrate was concentrated under vacuum to afford 1-[1 -tert-butoxycarbonyl-3-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)propylamino]cyclohexanecarboxylic acid as a white solid, 308 mg (88%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[O:15][CH2:16][CH2:17]Cl)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K].O>CN(C)C=O>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[O:15][CH2:16][CH2:17][N:23]2[C:22](=[O:24])[C:21]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]4[C:19]2=[O:29])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCOc1c2ccccc2cc2ccccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1c2ccccc2cc2ccccc12

Procedure:
2-(9-Anthryloxy)ethyl chloride (7.0 g) and potassium phthalimide (2.8 g) were heated to 130° C. in dimethylformamide (70 ml) for 7 hours. The cooled solution was added to water and extracted with ethyl acetate. The extract was dried and evaporated to yield N-[2-(9-anthryloxy)ethyl]phthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a mixture of (5-chloro-pyridine-2-yl)-methanol (706 mg, 4.92 mmol) described in Manufacturing Example 63-1-1 and dichloromethane (70 mL) was added thionyl chloride (539 μL, 7.38 mmol), which was stirred for 1 hour at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (620.0 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1C.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[C:12]([OH:13])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(Br)cccc1[N+](=O)[O-]
Yield: 30.5 %

Procedure:
To a mixture of 2-bromo-6-nitrotoluene (8 g), sodium carbonate (18.1 g) and water (500 mL) was added potassium permanganate (23.4 g), and the mixture was heated for reflux overnight. The insoluble material was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (three times). The extract was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 2-bromo-6-nitrobenzoic acid (2.78 g). Tin (II) chloride dihydrate (9.18 g) was dissolved in concentrated hydrochloric acid (30 mL). To the solution was added 2-bromo-6-nitrobenzoic acid (2.78 g), and the mixture was stirred at 80° C. for 1.5 hours. The insoluble material was collected by filtration, washed with 2 mol/L hydrochloric acid and dried under reduced pressure. The obtained crystal (2.05 g) was suspended in concentrated hydrochloric acid (35 mL). To the suspension was added a solution of sodium nitrite (0.79 g) in water (6 mL) under ice-cooling, and the mixture was stirred for 20 minutes. To the reaction mixture was added a solution of tin (II) chloride dihydrate (5.78 g) in concentrated hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (1.27 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[NH:7][N:6]=[CH:5]2>C(O)C.O.N>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2cn[nH]c2cc1[N+](=O)[O-]
Agent: N
Solvent: O
Solvent: CCO
Product: Cc1cc2cn[nH]c2cc1N
Yield: 72.2 %

Procedure:
8 g (45.2 mmol) of 5-methyl-6-nitro-indazole (formula 51), obtained according to E. Noelting, Ber. Dtsch. Chem. Ges. 37 (1904) 2556, are dissolved in 640 ml of 50% aqueous ethanol. A mixture of 80 g of ferrous sulphate in 400 ml of water and 80 ml of aqueous ammonia were added. The reaction mixture was refluxed for 20 hours and filtered while still hot. Removal of the ethanol and purification of the precipitated product with charcoal yielded 4.80 g (72%) of the target compound, m.p. 241°-242° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10]C)=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[C:4]([O:12][CH3:13])[C:5]=1[OH:10]
Reactant: COc1cc(I)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(I)cc(OC)c1O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 5-iodo-1,2,3-trimethoxybenzene (3.2 g) in 1,2-dichloroethane (40 mL) was added aluminum chloride (1.6 g). The mixture was stirred at 60° C. for 4 hours and evaporated. The residue was dissolved in 1 M aqueous sodium hydroxide solution and washed with ether. The aqueous layer was then acidified and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound as white crystalline powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:22]=2[CH3:23])=[O:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:8]2[CH:7]=[CH:6][C:5]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:22]=3[CH3:23])=[O:17])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:10][CH2:11]1
Reactant: Cc1c(C(=O)Nc2ccc(N3CCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCN(C)C)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
N-[3-Cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (2 g), 2-dimethylaminoethyl chloride hydrochloride (0.85 g) and potassium carbonate (0.8 g) were added to dimethylformamide (20 ml) and the mixture was stirred at 60° C. for 3 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. Ethanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.3 g), melting point: 185° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(F)cc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound which contains less than 10% of the Z isomer as a white foam, MS (ESI+): m/z=427.08 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][C:4](=[O:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18].[N+:20]([O-])([OH:22])=[O:21]>C(OC(=O)C)(=O)C.C(O)(=O)C>[OH:1][C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:20]([O-:22])=[O:21])[CH:9]=2)[CH2:6][CH2:5][C:4](=[O:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)C1=C(O)C(c2ccc(C)cc2)CCC1=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)C1=C(O)C(c2ccc(C)c([N+](=O)[O-])c2)CCC1=O
Temperature: 5 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
3-hydroxy-2-propionyl-4-(4-methylphenyl)cyclohex-2-ene-1-one (1.2 g) in acetic anhydride (3 g) was cooled to 5° C. A solution of fuming nitric acid (0.42 g) in glacial acetic acid (0.3 g) and acetic anhydride (0.3 g) was added dropwise over a period of 5 minutes. After stirring for a further 1 hour at 5° C. and 2 hours at room temperature, the mixture was poured onto ice-water (100 ml). The aqueous solution was extracted with diethyl ether. The extracts were washed with aqueous sodium bicarbonate, dried over magnesium sulphate, filtered and the ether evaporated in vacouo. The residue was purified on a silica gel column using chloroform as eluant to give the title compound (0.5 g) as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1>C(#N)C>[Br:25][C:13]1[C:14]([NH2:17])=[N:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(C2CCC3(CC2)OCCO3)cn1
Solvent: CC#N
Product: Nc1ncc(C2CCC3(CC2)OCCO3)nc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-amine (620 mg, 2.64 mmol) was added Acetonitrile (20 mL) and then was added NBS (469 mg, 2.64 mmol) in portions over 2 min. The reaction was stirred at room temperature for 20 min and quenched with saturated sodium bicarbonate solution, and 250 mL of ethyl acetate was added. The aqueous was extracted and the organic layer was washed with saturated sodium bicarbonate, water (2×), saturated salt solution, then dried with sodium sulfate, filtered and concentrated to residue to give 650 mg of the desired product, used as is, (79% yield). LCMS (m/z): 314.1/316.1 (MH+), 0.61 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13]([O:15][CH3:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=Cc2ccc(OC)c(OC)c2)C(=O)O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1ccc(OC)c(OC)c1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)prop-2-enoic acid (2 g, 6.37 mmol) was dissolved in dimethyl formamide (DMF) (4 mL) and added potassium carbonate (K2CO3) (2.28 g, 16.6 mmol) followed by methyl iodide (CH3I) (0.48 mL, 7.64 mmol) drop wise. The reaction mixture was stirred for 2 hours at room temperature (RT) and the reaction was monitored by TLC. Upon the completion of reaction, K2CO3 was filtered and cold water (100 mL) was added to the filtrate. The resulting precipitate was filtered to get pale yellow solid (2 g, 100%).
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH3:30])[NH:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:24]([O:23][C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:32])=[O:8])=[O:31])[CH3:30])=[O:29])[CH3:28])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of 0.015 moles of t-butyloxycarbonylalanylalanylproline benzyl ester in 50 ml of methanol is reduced with hydrogen at 40 lbs pressure in the presence of 1 gm of 10% Pd/C. The reaction mixture is filtered and concentrated in vacuo to give t-butyloxycarbonylalanylalanylproline.
Reaction SMILES: CC1[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH3:11][C:12]1([CH:16]=O)[CH2:15][O:14][CH2:13]1>>[CH3:11][C:12]1([C:16]2[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[CH2:15][O:14][CH2:13]1
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Reactant: CC1(C=O)COC1
Product: CC1(c2nc(C(F)(F)F)c[nH]2)COC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 16.2, except 3-methyloxetane-3-carbaldehyde was used in place of acetaldehyde. m/z (ES+) 207(M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26]>C(Cl)(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][S:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCNS(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(N-Boc-4-piperidinyl)ethyl-amine (1-6) (0.45 g, 2.0 mmoles) in CHCl3 (20 ml) was treated with added triethylamine (0.405 g, 4.0 mmoles) followed by 3-chlorosulfonylbenzoyl chloride (3-1) (0.44 g, 2.0 mmoles) and the resulting solution was stirred at room temperature for 16 hours. The solvent was then removed and the residue was taken up in EtOAc and washed with H2O, 10% KHSO4 solution, brine and dried (Na2SO4). Solvent removal provided a residue that was purified by flash chromatography on silica gel eluting with CHCl3 (95)/MeOH(5) to give pure 4-1.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:19]([OH:22])(=[O:21])=[O:20]>ClCCl>[C:1]([O:9][C:10]1[CH:15]=[C:14]([S:19]([OH:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1OC(=O)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)O)cc1OC(=O)c1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
A stirred solution of 2-methoxyphenyl benzoate (10 g) in dichloromethane (100 mL) from 0-5° C. is treated dropwise with chlorosulfonic acid (2.9 mL) and the solution is then stirred for 3 hours from 0-5° C. The precipitate which forms is filtered off, washed with cold dichloromethane, and dried in vacuo, to give 3-benzoyloxy-4-methoxybenzenesulfonic acid (11.45 g), in the form of a white solid, m.p. 139-140° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2.[C-]#N.[K+].[Cu][C:24]#[N:25]>CO>[C:24]([C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2)#[N:25]
Reactant: N#C[Cu]
Reactant: Clc1c2ccccc2nc2cc3ccccc3cc12
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: N#Cc1c2ccccc2nc2cc3ccccc3cc12
Temperature: 160 °C
Reaction time: 4.5 h
Yield: 136.7 %

Procedure:
A mixture of 12-chloro-benz[b]acridine (2.3 g, 8.68 mmol), potassium cyanide (620 mg, 9.55 mmol) and copper(I) cyanide (391 mg, 4.43 mmol) in anhydrous methanol (16 ml) was bubbled with nitrogen for 1 minute and then kept in a sealed tube. The mixture was heated at 160° C. with stirring for 4.5 hours and cooled. The red-brown mixture was evaporated and the residue was flash-chromatographed (W. C. still et al: J. Org. Chem., 43, 2923, (1978)) on a silica column (Baker silica gel, Cat #7024-1) packed with hexane and eluted with 10% ethyl acetate-hexane, yielding red 12-cyano-benz[b]acridine (1.54 g, 70%). Rf 0.7 (silica gel, hexane/ethyl acetate 2:1). MS (FAB, Thioglycerol Matrix): m/z 255 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:17](=[O:19])[CH3:18])[C:6]=2[CH2:5]1)[CH2:2][CH3:3].[N+:20]([O-])([O-:22])=[O:21].[K+]>OS(O)(=O)=O>[N+:20]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]3[CH2:15][CH2:16][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]=3[N:7]2[C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)([O-:22])=[O:21]
Reactant: CCCN1CCc2c(n(C(C)=O)c3ccccc23)C1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCN1CCc2c(n(C(C)=O)c3cc([N+](=O)[O-])ccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To 1-(2-propyl-1,2,3,4-tetrahydro-beta-carbolin-9-yl)-ethanone (1.05 g, 4.1 mmol) in conc. H2SO4 was added KNO3 (435 mg, 4.3 mmol) in small portions at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for an additional 30 minutes. The reaction mixture was poured onto 250 ml of ice and extracted once with ethyl acetate. The aqueous phase was made alkaline and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield 1.2 g of crude product (70% purity).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18].CO.C(N(CC)CC)C>>[OH:18][CH2:17][CH:16]([N:15]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[CH2:19][OH:20]
Reactant: NC(CO)CO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1C(CO)CO

Procedure:
5-nitro-isochromen-1-one (4.2 g, 0.022 mol) and Serinol (2.0 g, 0.022 mol) were refluxed in methanol (40 mL, 1 mol) for 1 hour. TLC showed that all of the starting material was consumed. Triethylamine (5 mL, 0.04 mol) was added to the mixture and the reaction mixture was refluxed overnight. The volatiles were removed via rotovapor, and the residue was purified by flash column chromatography (40 g of silica gel, 0-50% EtOAc/Hexane), and gave a green yellow solid. MS m/z=264.7 (M+1).