Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:9][C:10]1[C:11]([S:16](Cl)(=[O:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([NH:8][S:16]([C:11]2[C:10]([CH3:9])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1cccnc1S(=O)(=O)Cl
Product: Cc1ccc(NS(=O)(=O)c2ncccc2C)cc1

Procedure:
prepared by reaction of p-tolylamine with 3-methyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=2)=[O:4].[C:24]([CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15](=[O:17])[NH:34][CH:31]1[CH2:32][CH2:33][CH:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:29][CH2:30]1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(C(=O)O)cc2c(CC2CCCC2)n1
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1
Yield: 104.5 %

Procedure:
A solution of 1-cyclopentylmethyl-isoquinoline-3,7-dicarboxylic acid 3-methyl ester (38 mg, 0.121 mmol) in DMF(1.5 mL) was treated with 4-tert-butylcyclohexylamine (0.028 g, 0.181 mmol), HBTU (69 mg, 0.181 mmol), and DIEA (0.075 mL, 0.424 mmol) by the General Procedure A to give 57 mg of the desired 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester as a colorless oil. This was used directly for the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:34][C@@H:35]1[C:53](=[O:54])[N:37]2[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][S:43][C:44]3[S:45][C:46]([CH3:49])=[N:47][N:48]=3)[CH2:40][S:41][C@H:36]12>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([NH:34][C@@H:35]2[C:53](=[O:54])[N:37]3[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][S:43][C:44]4[S:45][C:46]([CH3:49])=[N:47][N:48]=4)[CH2:40][S:41][C@H:36]23)=[O:18])=[CH:12][CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cc4ccc(CNC(=O)OC(C)(C)C)s4)[C@H]3SC2)s1
Reaction time: 4 h

Procedure:
The starting material is prepared as follows: A solution of 4.08 g of 2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid in 200ml of methylene chloride containing 1.65 ml of 4-methyl-morpholine is cooled to -20° under exclusion of moisture and treated dropwise with 1.95 ml of chloroformic acid isobutyl ester. After 30 minutes a solution of 5.16 g of 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid and 7.20 ml N,O-bis-(trimethylsilyl)-acetic acid amide in 150 ml of methylene chloride is added, whereupon the reaction mixture is stirred during one hour at -20° and during four hours while the temperature is allowed to slowly rise to room temperature and is then evaporated under reduced pressure. The residue is dissolved in water with the addition of sodium hydrogen carbonate until the pH reaches 8. The solution is washed with ethyl acetate, the separated aqueous layer is acidified to pH 2 with aqueous phosphoric acid of 20% strength and is extracted with ethyl acetate. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. One thus obtains the 7β-[2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid; thin layer chromatogram (silicagel): Rf = 0,40 (system: n-butanol/acetic acid/water45:45:10), ultraviolet absorption spectrum (ethanol): λmax 244 mμ (ε = 16900); infrared absorption spectrum (in mineral oil): characteristic bonds at 2,93 μ, 5,60 μ, 5,90 μ, and 6.55 μ.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([CH2:27][C:28]([OH:30])=[O:29])=[C:19]2[CH3:31])(=[O:17])=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#N.[F:32]C1C=C(S(N2C3=NC=CC=C3C(CC(O)=O)=C2C)(=O)=O)C=CC=1F>>[F:32][C:3]1[CH:4]=[C:5]([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([CH2:27][C:28]([OH:30])=[O:29])=[C:19]2[CH3:31])(=[O:16])=[O:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(N2CCOCC2)c(C#N)c1
Reactant: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(F)c(F)c1
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(N2CCOCC2)c(F)c1

Procedure:
The titled compound is prepared analogously to [1-(3-cyano-4-morpholin-4-yl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Intermediate 151b) by replacing [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester with [1-(3,4-difluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (Example 59) and by heating using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 60-80° C. for 4 hours. (MH+ 434)
Reaction SMILES: [CH2:1]1COCC1.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH:10]=[O:11].C[Mg]Br>CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH3:1])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: C1CCOC1
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into the THF (8 ml) solution of 3-bromo-5-fluorobenzaldehyde (374 mg, 1.84 mmol) which was cooled in ice/water bath was added methylmagnesium bromide in Et2O (3.0 M, 0.92 ml) dropwise under an atmosphere of nitrogen. The combined mixture was stirred at 0° C. for 1 h and then at rt for 1 h. After that time, the mixture was quenched with saturated NH4Cl (10 ml) followed by water (10 ml), extracted with EtOAc (2×25 ml). The extracts were washed with water (2×15 ml), brine (15 ml), dried over MgSO4, filtered and concentrated in vacuo to give a beige oil. It was purified by chromatography on silica gel (15 g) eluting with 10% (100 ml), 15% (100 ml), 20% (100 ml) and 25% (100 ml) EtOAc/hexane to give the title compound. 1H NMR (400 MHz, CDCl3): δ=1.47 (d, J=6.4 Hz, 3H), 1.87 (d, J=3.6 Hz, 1H), 4.83-4.90 (m, 1H), 7.02-7.06 (m, 1H), 7.14 (td, J=2.0 & 8.0 Hz, 1H), 7.31 (t, J=1.6 Hz, 1H). MS (ES+): m/z 201.22/203.18 [MH+−H2O]. HPLC: tR=3.07 min (polar—5 min, ZQ3).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=2)[N:15]=[CH:14][C:13]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)OCC)C.[C:32]([O:36][C:37](=[O:48])[NH:38][C@H:39]1[CH2:44][CH2:43][C@H:42]([CH2:45][CH:46]=O)[CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33].C(OCC)(=O)C>O1CCCC1>[C:32]([O:36][C:37](=[O:48])[NH:38][C@H:39]1[CH2:40][CH2:41][C@H:42]([CH2:45][CH:46]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][C:13]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:43][CH2:44]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOP(=O)(Cc1c(OCc2ccccc2)cnc2ccc(OC)nc12)OCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(OCc3ccccc3)c(C=CC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sodium hydride (86 mg, 1.91 mmol, 2.3 eq) is added at 0° C. to a stirred solution of (3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-ylmethyl)-phosphonic acid diethyl ester (350 mg, 0.83 mmol, 1.0 eq) in tetrahydrofuran (30 mL) and the resulting mixture is stirred at 0° C. for 1 hour before the addition of a solution of [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (200 mg, 0.83 mmol, 1.0 eq) in tetrahydrofuran (5 mL). After 15 hours stirring at room temperature, the reaction mixture is quenched with ammonium chloride aqueous solution (20 mL), tetrahydrofuran is removed and the resulting residue is extracted with ethyl acetate (3×50 mL) and brine (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 6:1, v/v) to afford {trans-4-[3-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-allyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (548 mg, 55% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 10 mL of acetonitrile. To the stirred solvent were added 4-(benzyloxy)-2-hydroxybenzaldehyde (1.0 g, 4.38 mmol), potassium carbonate (1.21 g, 8.76 mmol). The reaction mixture was brought to 0° C., was added methyl iodide (1.135 g, 8.76 mmol) in acetonitrile (5 mL) drop wise and stirred at room temperature for 16 h. The reaction mixture was concentrated to distill off the solvent. The residue was extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL) and saturated brine solution (40 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product obtained as a white solid (1.06 g, yield: 100.0%).
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][C:4](=[N:8][OH:9])[C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:21][CH3:22])(=O)=O>CC(C)=O>[CH2:21]([O:9][N:8]=[C:4]([CH2:3][C:2]([CH3:1])=[CH2:10])[C:5](=[O:7])[CH3:6])[CH3:22]
Reactant: CCOS(=O)(=O)OCC
Reactant: C=C(C)CC(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)CC(=NOCC)C(C)=O
Temperature: 23 °C
Reaction time: 2 h

Procedure:
285.7 g of 5-methylhex-5-ene-2,3-dione 3-oxime from Example 1 were dissolved in 750 ml of acetone and admixed with 335.8 g of potassium carbonate. 362 g of diethyl sulfate in 300 ml of acetone were then added dropwise, and the mixture was stirred at 23° C. for 2 hours. The solvent was then removed under reduced pressure, the residue was taken up in methyl tert-butyl ether/water and the aqueous phase was extracted repeatedly with methyl tert-butyl ether. The combined organic phases were washed with 15% strength ammonia solution and water and dried over sodium sulfate, and the solvent was removed under reduced pressure. This gave 355.4 g of the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(OC1C=CC=CC=1O)C1C=CC=CC=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1OCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Yield: 96 %

Procedure:
To a stirred solution of 2-nitrophenol. (1) (1.4 g, 10 mM) and ethyl 4-bromobutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is added 2 g (14.5 mM) of anhydrous, ground potassium carbonate. The resultant colored mixture is then heated under a nitrogen atmosphere at gentle reflux until the color due to the phenol anion has dissipated and a yellow mixture remains. Concentration of the cooled and filtered mixture yields an oil which on flash chromatography (silica gel, ethyl acetate/hexane- or methylene chloride as eluant) yields 2.4 g (96% yield) of the title compound (3) as an oily liquid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[C:5]([C:8]#[N:9])[S:6][CH:7]=1.CO[Na].[NH4+:15].[Cl-]>CO.C(Cl)Cl>[F:11][C:2]([F:1])([F:10])[C:3]1[N:4]=[C:5]([C:8]([NH2:15])=[NH:9])[S:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1nc(C(F)(F)F)cs1
Agent: CO[Na]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: N=C(N)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 32 %

Procedure:
To a solution of compound 285b (28.12 g, 1.0 eq.) in MeOH (13 mL) in an ice/water bath was added MeONa (853 mg, 0.1 eq.) portionwise. The reaction mixture was stirred in the ice/water bath for 15 min and at room temperature for 1 hr. NH4Cl (16.88 g, 2.0 eq.) was then added and the mixture was stirred at room temperature for 4 days. Solvent was removed in vacuo. The solid obtained was suspended in DCM (60 mL) and recovered by filtration. The solid was suspended in MeOH (50 mL) and filtered. The filtrate was concentrated under reduced pressure to yield compound 285 as a white solid in 32% yield. MS (ESI, EI+) m/z=196 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]([OH:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:30]2[CH2:31][CH2:32][O:33][C@H:28]([CH3:27])[C@H:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.96 g, 1.9 mmol), (2R,3S)-2-methylmorpholine-3-carboxylic acid (0.28 g, 1.9 mmol) and potassium carbonate (0.53 g, 3.8 mmol) in anhydrous ethanol (35 mL) was stirred at 25° C. for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=15/1) to give the title compound as a yellow solid (0.48 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].O.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:16][C:15](=[O:24])[NH:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1(CO)CCCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1(CO)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-amino-1-cyclopentanemethanol (1.15 g, 10 mmol) and NaHCO3 (0.84 g, 10 mmol) in acetone (14 mL)/water (14 ml) at room temperature was added benzyl succinimidyl carbonate (2.5 g, 10 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (DCI) m/z 250 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].N[C:37]1[CH:38]=[N:39][CH:40]=CC=1>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][C:1]1[CH:40]=[N:39][CH:38]=[CH:37][CH:2]=1)=[O:5]
Reactant: Nc1cccnc1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)Nc4cccnc4)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 3-aminopyridine.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH:26]([N:33]=[C:34]=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH:26]([NH:33][C:34]([N:17]1[CH2:16][CH2:15][N:14]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1)=[O:35])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)c1ccccc1)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of diphenylmethyl piperazine (0.3 g, 1.18 mmol) in dry CH2Cl2 (10 ml) was added diphenylmethyl isocyanate (0.22 ml, 1.18 mmol) drop wise under nitrogen. The resulting mixture was stirred at room temperature over night. Removal of solvent under reduced pressure followed by column chromatography using hexane:ethyl acetate (3:1) gives the desired product in 80% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: O=[N+]([O-])c1ccccc1Nc1ccc(CCO)cc1
Temperature: 150 °C
Yield: 54.2 %

Procedure:
A mixture of 2-chloronitrobenzene (3.9 g, 25 mmol) and 4-aminophenylethyl alcohol (4.1 g, 30 mmol) was placed in a sealed tube and heated at 150° C. for 3 h. The reaction mixture was cooled and purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 3.5 g (55%) of the title compound as orange solids: 1H-NMR (CDCl3)δ2.90 (2H, t, J=6.5 Hz), 3.91 (2H, t, J=6.5 Hz), 6.81-6.70 (1H, m), 7.40-7.16 (6H, m), 8.21 (1H, dd, J=1.5, 8.8 Hz), 9.47 (1H, s).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of hydroquinone (33.00 g, 0.30 mol) and potassium carbonate (45.6 g, 0.33 mol) in dry DMF (250 mL) was stirred at 40° C. for 30 minutes. Allyl bromide (5.20 mL, 0.06 mol) was added and the reaction was stirred overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with hexane/ethyl acetate (4:1) to afford 4-allyloxyphenol.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.O.[Pd]>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)OC1CCNCC1
Yield: 92 %

Procedure:
10% Pd/C (500 mg) was added to a solution of 1-benzylpiperidin-4-yl acetate [(11 g, 47 mmol), J. Org. Chem. 68(2), 613-616; 2003] in a mixture of ethanol and water (90:10, 110 mL), and the mixture was stirred at 60° C., under 60 psi of hydrogen gas for 18 hours. The reaction mixture was then filtered through Arbocel®, washing through with ethanol, and the filtrate was concentrated in vacuo to afford the title product in 92% yield, 7.2 g.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of ethyl 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (145 mg, 0.29 mmol) in dioxane (1.5 mL) was added 1 M LiOH aqueous solution (1.16 mL, 1.161 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid. The solid precipitate was collected to give the title compound (125 mg). LCMS m/z=471.8 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.55-1.65 (m, 1H), 2.00-2.10 (m, 1H), 2.17-2.26 (m, 2H), 2.65 (dd, J=16.1, 8.5 Hz, 1H), 3.00 (dd, J=16.1, 5.4 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.94 (m, 1H), 4.14-4.22 (m, 1H), 5.19 (s, 2H), 6.23 (s, 1H), 6.91 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.83 (s, 1H), 7.94 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1)[CH3:2].C1C2C=CC3C(=CC([CH:39]=[O:40])=C4C=3C=CC=C4)C=2C=CC=1>C(Cl)Cl>[CH2:1]([C:3]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH:39]=[O:40])[CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Solvent: ClCCl
Product: CCc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Yield: 76 %

Procedure:
6-Ethylchrysene (Cambridge Chemical, Inc., 60 g, 0.234 mol) was formylated according to the procedure outlined in 1A, except that CH2Cl2 (1 L) was used as the reaction solvent. The crude material was chromatographed on a plug of SiO2 (1 kg) using PhCH3 as the eluting solvent, afforded 50.38 g (76%) of 12-ethyl-6-chrysenecarbaldehyde mp 138°-139°, (C,H).