Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH3:17])=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH3:17])=[CH:10][C:11]([CH:14]=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(CO)ncc1OCc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: COc1cc(C=O)ncc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
[5-(4-Chloro-benzyloxy)-4-methoxy-pyridin-2-yl]-methanol (640, 480 mg, 1.7 mmol) was dissolved in dimethyl sulfoxide (26 mL) and Dess-Martin periodinane (909 mg, 2.1 mmol) was added. The reaction was allowed to stir at room temperature for 2 hours. The reaction was concentrated under high vacuum and then poured into a solution of NaHCO3 and Na2S2O3. The mixture was extracted with ethyl acetate. The organic portions were dried with anhydrous sodium sulfate and filtered. The filtrate was adsorbed onto silica and purified by silica gel chromatography, ethyl acetate:hexanes, to provide the desired compound as a white powder (641, 343 mg, 72%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:7][C:4]1[S:3][C:2]([O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ncc(Br)s2)c1
Temperature: 140 °C
Yield: 80.4 %

Procedure:
A mixture of 2,5-dibromothiazole (500 mg, 2.06 mmol), methyl 3-hydroxybenzoate (313 mg, 2.06 mmol) and potassium carbonate (341 mg, 2.47 mmol) in DMF (4 mL) was heated at 140° C. in a microwave reactor for 20 min. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (520 mg, 80% yield). LCMS, [M+H]+=315.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccccc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (202 mg, 0.53 mmole), phenylboronic acid (130 mg, 1.07 mmole), cesium carbonate (522 mg, 1.60 mmole) and tetrakis(triphenylphosphine)palladium (62 mg, 0.05 mmole) in dioxane (2.8 ml) was refluxed for 16 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a yellow oil (93 mg). MS: (+) m/z 377.27 (M+H+)
Reaction SMILES: [CH:1]1([CH:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[CH:1]1([CH:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1
Reactant: CCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1N)C1CC1
Yield: 37.8 %

Procedure:
(1-Cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine (0.46 g, 1.26 mmol) and Na2S2O4 (1.76 g, 10.1 mmol) were treated substantially as described in Part E of Example 9 to yield 0.16 g (66%) of crude N2-(1-cyclopropyl-propyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine: MS (AP) m/z 336.3 [(M+H)+, 100].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:17]=[CH:16][CH:15]=3)=[O:12])=[C:4]2[N:3]=1.[NH3:29]>C(O)C>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([N:18]2[C:14]([NH:13][C:11]([C:10]3[CH:9]=[N:8][N:5]4[CH:6]=[CH:7][C:2]([NH2:29])=[N:3][C:4]=34)=[O:12])=[CH:15][CH:16]=[N:17]2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccnn1-c1cccc(C(F)(F)F)c1)c1cnn2ccc(Cl)nc12
Reactant: N
Solvent: CCO
Product: Nc1ccn2ncc(C(=O)Nc3ccnn3-c3cccc(C(F)(F)F)c3)c2n1
Temperature: 25 °C
Yield: 4 %

Procedure:
A solution of 5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (210 mg, 0.52 mmol) in ethanol (20 mL) saturated with ammonia was heated to 100° C. overnight in a sealed tube. After cooling to room temperature, solvent was removed under reduced pressure, and the resultant residue was purified by preparative HPLC to afford 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-(3-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-amide (8 mg, yield: 4%). 1H NMR (DMSO, 400 MHz): δ 9.94 (s, 1H), 8.62 (d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.49-7.69 (m, 8H), 6.53 (s, 1H), 6.37 (d, J=7.6 Hz, 1H). MS (ESI) m/z: 388.1
Reaction SMILES: CC([N:5]([C:9]1[C:10]([NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[CH:26][CH:25]=2)=[O:23])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)C(=O)[O-])(C)C.Cl.O1CCOCC1>C(OCC)(=O)C>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][O:34][C:32](=[O:33])[NH:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:22]([NH:21][C:10]3[C:9]([NH2:5])=[CH:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:11]=3)=[O:23])=[CH:29][CH:28]=2)[CH:37]=1
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,1-dimethylethyl{6-phenyl-2-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]pyridin-3-yl}carbamate (25 mg, 0.045 mmol) in ethyl acetate (5 mL) was treated with 4M HCl in dioxane (1.13 mL, 4.52 mmol) and stirred at ambient temperature for 16 hours. The reaction was evaporated in vacuo and purified by flash column chromatography (0-5% methanol(w/1% ammonia)/DCM) to give pyridin-3-ylmethyl[(4-{[(3-amino-6-phenylpyridin-2-yl)amino]carbonyl}phenyl)methyl]carbamate. 1H NMR (CD3OD, 600 MHz) δ 8.58 (br s, 1H), 8.49 (br s, 1H), 8.00 (d, J=8.21 Hz, 2H), 7.89 (d, J=7.63 Hz, 3H), 7.75 (t, J=5.87 Hz, 1H), 7.61 (d, J=8.21 Hz, 1H), 7.58 (d, J=6.75 Hz, 1H), 7.38 (m, 8H), 5.18 (s, 2H), 4.38 (d, J=5.87 Hz, 2H). MS: cal'd 454 (MH+), exp 454 (MH+). The in vitro HDAC1 IC50 of this compound is 84 nM. The IC50 of this compound in HCT-116 cells is 580 nM. Percent Cyp inhibitions at 10 μM are 46, 54 and 55%, for Cyp3A4, 2C9, and 2D6, respectively. The inflection point for MK-499 binding is >30 μM.
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]([CH3:36])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]([CH3:35])[C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:36][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]([CH3:35])[C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:28][CH:29]=3)=[CH:20][N:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:37])=[O:5]
Reactant: CN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(-c2ccc(OC(F)(F)F)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(-c2ccc(OC(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
2-Methyl-2-({4-[2-(methyl{5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (210 mg) obtained in Example 163-1 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (150 mg) as a white solid.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.O>C1(C)C=CC=CC=1>[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27]([CH2:26][N:23]2[CH:24]=[C:20]([CH2:19][OH:18])[N:21]=[CH:22]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Cn2cnc(CO)c2)cc1

Procedure:
A mixture of 4-(tert-butyldiphenylsilyloxymethyl)-1H-imidazole (9.25 g, 27.4 mmol), methyl 4-bromomethylbenzoate (6.297 g, 27.4 mmol) and TEA (2.782 ml, 27.4 mmol) in toluene (250 ml) was refluxed for 1.5 h. Water (500 ml) was added, the mixture was extracted with AcOEt, the organic phase washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the resulting oil was purified by flash chromatography on silica gel (CH2Cl2/MeOH: 100/0 to 98/2) to give:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[OH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>C(OCC)(=O)C>[OH:10][C:11]1[CH:18]=[CH:17][C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A solution of 70 ml. 40% nitric acid and 10 ml. concentrated sulphuric acid is added dropwise at 10° C. in the course of 1 hour to 24 g. (0.2 mole) 2-hydroxybenzonitrile in 20 ml. water. The reaction mixture is subsequently stirred for 24 hours at 20° C. and then shaken out with 100 ml. ethyl acetate. After evaporation of the organic solvent, the solid residue obtained is extracted twice with 500 ml. amounts of boiling n-hexane. Purification takes place by means of column chromatography on silica gel (silica gel 60; elution agent ethyl acetate). After evaporation of the solvent and crystallisation from ethyl acetate/toluene, there are obtained 2 g. of the desired product in the form of white crystals.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[S:7](N)(N)(=[O:9])=[O:8]>>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][NH:6][S:7]1(=[O:9])=[O:8]
Reactant: CNCCCN
Reactant: NS(N)(=O)=O
Product: CN1CCCNS1(=O)=O

Procedure:
To a solution of N-methyl-1,3-diaminopropane (37.6 mL, 312 mmol) and sulfamide (10.0 g, 104 mmol) were heated at reflux for 16 hr. The solvent was evaporated in vacuo and the residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1) to afford the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)CCCC.[OH-].[Na+].[CH3:20][C:21]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>[Cu]>[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:30])[F:31])[C:21]=2[CH3:20])=[CH:10][CH:9]=1
Reactant: Cc1c(N)cccc1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCO
Product: Cc1c(Nc2ccc(Cl)cc2C(=O)O)cccc1C(F)(F)F

Procedure:
To a solution of 25 g. of 2,5-dichlorobenzoic acid in 125 ml. of n-pentyl alcohol add 4.8 g. of sodium hydroxide pellets, 25 g. of 2-methyl-3-trifluoromethylaniline and 2 g. of copper powder. With constant stirring, reflux the reaction mixture for 18 hours. Concentrate the mixture to one half volume and dilute with water and ether. Acidify the aqueous layer to yield the product which is recrystallized from methanol, m.p. 220°-222° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:19]([NH:18][CH3:17])=[O:20])[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CNC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-methylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.01 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz), 7.68–7.61 (m, 2H), 7.45 (t, 1H, J=8.4 Hz), 7.16–7.03 (m, 3H), 6.68 (td, 1H, J=1.2 and 8.7 Hz), 2.90 (s, 3H); LCMS: purity: 95%; MS (m/e): 354(MH+).
Reaction SMILES: Cl.[C:2](O)(=[O:4])[CH3:3].[NH2:6][C@@H:7]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)=[O:9]>>[C:2]([NH:6][C@@H:7]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:9])(=[O:4])[CH3:3]
Reactant: CC(=O)O
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 60 %

Procedure:
Proceeding as in Example 1, but substituting acetic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 164, (S)-2-acetamido-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (35 mg, 60%). 1H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.40-7.25 (m, 5H), 7.10-6.90 (m, 7H), 6.45-6.40 (m, 1H), 4.80-4.45 (m, 3H), 4.00-3.90 (m, 1H), 3.60 (m, 1H), 1.60 (s, 3H). MS (EI) for C24H22F2N2O4 found 441 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[CH2:6][C@@H:5]([NH:7][C@@H](C2C=CC=CC=2)C)[C@H:4]([C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19]2)=[O:17])[CH2:3]1>[OH-].[Pd+2].[OH-].CO>[NH2:7][C@@H:5]1[CH2:6][S:2](=[O:1])(=[O:32])[CH2:3][C@H:4]1[C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19]1)=[O:17]
Reactant: C[C@@H](N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 20.5 h
Yield: 108.3 %

Procedure:
[1,1-Dioxo-(3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydrothiophen-3-yl]-[(S)-3-(4-fluoro-benzyl)-piperidin-1-yl]-methanone (790 mg, 1.72 mmol), palladium hydroxide (20 weight % on carbon, dry basis; 1.1 g) and methanol (50 mL) were combined in a pressure bottle and shaken under a hydrogen atmosphere (55-60 psig) for 20.5 h. The mixture was filtered through Celite, and the solids were washed thoroughly with methanol. The filtrate was concentrated to give the product as a solid (660 mg, quantitative), used without further purification. 1H NMR (300 mHz, CD3OD) δ7.20 (m, 2H), 7.00 (m, 2H), 4.45 and 4.32 (2m, 1H), 4.09 (m, 1H), 3.90 and 3.79 (2m, 1H), 3.7-3.4 (m, 2H), 3.13 (m, 2H), 2.87 and 2.69 (2m, 1H), 2.56 (m, 2H), 1.79 (m, 3H), 1.28 (m, 3H), 0.88 (m, 1H), ESI MS: (M+H)+=355.2.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[C:4]1([CH:3]=[CH:2][CH:1]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=CC=Cc1ccccc1
Temperature: 5 °C
Reaction time: 144 h

Procedure:
To a suspension of cinnamaldehyde (769.8 mg, 5.82 mmol), 1,1-dimethylnitroethane (1.20 g, 11.6 mmol) and zinc (1.14 g, 17.4 mmol) in ethanol (30 ml) was added acetic acid (2.10 g, 35.0 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 3 hours and let stand for 6 days. After cooling the mixture to 5° C., zinc acetate was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=1/1-0/1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin4-one (2.82 g, 0.01 mol), thionyl chloride (40 ml) and DMF (0.28 ml) was stirred and heated to reflux for 1 hour. The mixture was evaporated, the residue was taken up in toluene and evaporated to dryness to give 7-benzyloxy-4-chloro-6-methoxyquinazoline (3.45 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[N:6][OH:7])[NH2:5].[H-].[Na+].[N+:10]([C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1)[CH2:16][N:17]1[C:29]2[CH:28]=[N:27][C:26]([C:30](OC)=O)=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)([O-:12])=[O:11]>O1CCCC1>[N+:10]([C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1)[CH2:16][N:17]1[C:29]2[CH:28]=[N:27][C:26]([C:30]3[O:7][N:6]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=3)=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)([O-:12])=[O:11]
Reactant: COCC(N)=NO
Reactant: COC(=O)c1cc2c3ccccc3n(Cc3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1noc(-c2cc3c4ccccc4n(Cc4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)c3cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
A suspension of 2-methoxyacetamidoxime (260 mg, 2.5 mmol) and 4 Å molecular sieves (1 g) in anhydrous tetrahydrofuran (15 mL) was stirred at room temperature for 0.5 hours, then treated with sodium hydride (2.75 mmol, 110 mg of 60% mineral oil suspension). The mixture was heated at reflux for 1 hour. After cooling to room temperature, a suspension of methyl 9-(3,5-dinitrobenzyl)-9H-β-carboline-3-carboxylate (205 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added. The resulting mixture was heated at reflux for 15 hours, cooled, filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative thin layer chromatography with 4% 2M NH3—CH3OH in CH2Cl2 as eluent to afford the desired product (86 mg, 38% yield) as a white solid. 1H NMR (DMSO-d6) δ9.41 (s, 1H), 9.24 (s, 1H), 8.72 (t, J=1.9 Hz, 1H), 8.59 (d, J=7.8, 1H), 8.49 (d, J=1.9 Hz, 2H), 7.94 (d, J=8.3 Hz, 1H), 7.73 (t, J=7.8Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 6.20 (s, 2H), 4.67 (s, 2H), 3.42 (s, 3H); MS (APCI; (M+H)+) m/z 461.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:28]1>O1CCOCC1>[CH3:25][N:23]([CH3:24])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[CH2:28]2)=[O:7])[CH2:12][CH2:13]1
Reactant: c1ccc2c(C3CCCNC3)c[nH]c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCCC(c3c[nH]c4ccccc34)C2)CC1
Yield: 20.6 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (529 mg, 1.5 mmole) was added to a solution of 3-piperidine-3-yl-1H-indole (300 mg, 1.5 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 20 hours. The reaction mixture was worked up by distilling off the solvent. The residue contained, in addition to phenol, also the two diastereoisomers of 3-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (50 g). Methanol/EE (1:1; 900 ml) was used as eluent. The non-polar diastereoisomer of 3-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (220.6 mg, m.p. 165°-170° C., 32%) and the polar diastereoisomer of 3-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (142 mg, m.p. 95°-99° C., 31%) were thereby obtained in pure form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[F:19])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg+].[Br-]>C(Cl)Cl.C(OCC)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])([CH3:21])[CH3:17])=[CH:12][C:11]=1[F:19])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg+]
Reactant: CC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)c(F)c1
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(C)(C)O)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
To a solution of (S)-tert-butyl(1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (296 mg, 1.05 mmol) in DCM (5.2 mL), cooled to 0° C. (water/ice bath) under N2, was added 3M MeMgBr (1.4 mL, 4.21 mmol) in diethyl ether. Reaction mixture allowed to stir for 5 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with DCM. Phases partitioned, aqueous phase extracted with DCM and the organic layers combined washed with water, brine, dried (Na2SO4), filtered and concentrated to (S)-tert-butyl(1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (288 mg, 0.97 mmol, 92% yield) afford as a colorless oil which slowly crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.39-1.48 (m, 12H) 1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).