Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=[C:3]([C:9]([OH:11])=[O:10])[CH:2]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[ClH:19]>[Pd].C(O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[CH:2][CH:1]=2)[CH2:15][CH2:14]1.[ClH:8].[ClH:19]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1

Procedure:
The synthesis of WBZ4, as shown in scheme 3 below, begins with treatment of 2-methyl-5-nitroaniline (1) with 65% nitric acid in ethanol followed by the addition of cyanoamide to give the corresponding 2-methyl-5-nitroaniline-guanidine nitrate (2). Once completed, nicotinate (3) was first treated with sodium hydrate and refluxed with ethyl acetate to form methyl 6-methylnicotinylacetate. The intermediate acetate was then hydrolyzed to form 3-Acetyl-6-methylpyridine (4). The product (4) was treated with methyl dimethoxyforamide to give 3-dimethylamino-1-(3-(6-methyl-pyridyl)-2-propene-1-one (5). The nitrate salt (2) is treated with (5) and sodium hydroxide in refluxing isopropanol to give N-(2-Methyl-5-nitrophenyl)-4-(3-(6-methyl-pyridyl))-2-pyrimidine-amine (6) which is subsequently hydrogenated with 10% palladium on carbon to give N-(2-Methyl-5-aminophenyl)-4-(3-6-methyl-pyridyl)-2-pyrimidine-amine (7). The WBZ4 synthesis will consist of the reaction of α-chloro-p-toluylic acid (8) with 4-methyl-piperazine in ethanol followed by treatment with concentrated HCl to give the corresponding dihydrochloride 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (9) which is subsequently treated with thionyl chloride to give the corresponding acid chloride dihydrochloride (10). Subsequent condensation with N-(2-Methyl-5-aminophenyl)-4-(3-(6-methyl)-pyridyl)-2-pyrimidine-amine (7) in pyridine affords Formula 5 (WBZ4).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([N:9]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:35][CH:36]=1)=[O:39])[CH3:42]
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)NCc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2OC)cc1
Yield: 72.4 %

Procedure:
Using 4-aminomethyl-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (60 mg, 0.123 mmol) and ethyl chloroformate (13 μl, 0.136 mmol), the procedure of Inventive Example 94 was repeated to obtain 50 mg (72.7%) of the title compound in a colorless amorphous form.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-aspartic acid dimethyl ester hydrochloride (2.0 g, 10 mmol) was dissolved in dichloromethane (30 ml), phenyl chloroformate (1.3 mL, 11 mmol) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) were added at 0° C., and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:15]([CH3:25])[CH:14]=3)=[O:12])=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([NH:32]C(=O)C)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:36]=1.Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)=[C:15]([CH3:25])[CH:14]=3)=[O:12])=[C:9]([C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)[S:8][C:7]=2[CH:36]=1
Reactant: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)c(C)c3)c(-c3ccc(NC(C)=O)cc3)sc2c1
Agent: Cl
Product: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)c(C)c3)c(-c3ccc(N)cc3)sc2c1

Procedure:
A solution of 200 mg (0.40 mmol) of 3-methyl-4-[(1-pyrrolidinyl)methyl]phenyl 6-methoxy-2-(4-acetamidophenyl)benzo[b]thiophen-3-yl ketone (Part H) in 5 mL of MEOH was treated with 5 mL of conc. aq HCl. The reaction was heated to mild reflux for 1 hr and was concentrated in vacuo. The residue was taken up in 25 mL. of H2O, the solution basified to pH 12 with 5 N aq NaOH, and the mixture was extracted with EtOAc (2×25 mL). Trhe comrbined organic extracts were dried (K2CO3), filtered, and concentrated in vacuo to give 175 mg (0.38 mmol; 96%) of the title compound as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:21])[C:6]2[CH2:7][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:9][CH2:10][C:11]=2[CH:12]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:21][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[C:11]3[C:6]=2[CH2:7][CH:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:9][CH2:10]3)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(C2CCc3cc(OC)cc(O)c3C2)cc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(OCc5ccccc5)cc4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.7 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1998, 39 (19), 2937-2940. To a solution of 3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-ol (853 mg) and 4-benzyloxyphenylboronic acid (1.4 g) in dichloromethane (30 ml) were sequentially added copper(II) acetate (545 mg), molecular sieves 4A and triethylamine (1.5 g), and the solution was stirred for 8 hours and 40 minutes at room temperature. The insoluble material was filtered through celite pad, the filtrate was adsorbed onto silica gel and purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.2 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1.[H-].[Na+]>CN(C)C=O>[CH2:21]([N:11]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=1)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:32][CH2:31][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:22]([CH3:24])[CH3:23]
Reactant: OCC1CCOCC1
Reactant: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
4-fluoro-N-isobutyl-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (30 mg, 0.086 mmol) was dissolved in N,N-dimethylformamide (DMF) (3 mL) and to this solution was added (tetrahydro-2H-pyran-4-yl)methanol (12 mg, 0.10 mmol) and sodium hydride (2 mg, 0.10 mmol, 60% wt in mineral oil). The reaction was stirred under nitrogen for 2 hours at room temperature. The reaction was quenched then concentrated in vacuo and the crude product extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit, concentrated in vacuo and purified by mass directed autoprep (formic acid modifier) to give the title compound (17 mg). LCMS (2 min, formic) Rt 1.41 min, m/z (ES+) 447 (M+H).
Reaction SMILES: [I-].[C:2]([CH2:4][C:5]1[S:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[N+:9]=1[CH2:10][CH3:11])#[N:3].CO/[CH:18]=[CH:19]/[CH:20]=[C:21]1\[S:22](=[O:32])(=[O:31])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]\1=[O:26].C(Cl)(Cl)Cl.CO.C([O-])(=O)C.[Na+]>CO>[O:31]=[S:22]1(=[O:32])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25](=[O:26])/[C:21]/1=[CH:20]/[CH:19]=[CH:18]/[C:4](=[C:5]1\[S:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[N:9]\1[CH2:10][CH3:11])/[C:2]#[N:3]
Reactant: CC[n+]1c(CC#N)sc2ccccc21
Reactant: CO/C=C/C=C1/C(=O)c2ccccc2S1(=O)=O
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN1/C(=C(C#N)/C=C/C=C2/C(=O)c3ccccc3S2(=O)=O)Sc2ccccc21
Temperature: 25 °C

Procedure:
In a one-necked round bottom 100-mL flask equipped with magnetic stir bar and reflux condenser were added 2-(cyanomethyl)-3-ethyl-1,3-benzothiazol-3-ium iodide (1.00 g, 3.03 mmol), (2Z)-2-[(2E)-3-methoxyprop-2-en-1-ylidene]-1-benzothiophen-3-(2H)-one 1,1-dioxide (1.00 g, 4.00 mmol) and CHCl3-MeOH mixture (1:1, 20 mL). The flask was heated on an oil bath with stirring until boiling began, and a solution of sodium acetate (320 mg, 4.00 mmol) in 10 mL of methanol was added to the flask. The stirring was continued under reflux for an additional 30 min. The flask was cooled to room temperature and the precipitated solid was filtered, washed with methanol and dried. Green crystals. The yield was 730 mg (57% of theory).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:24][S:23][C:22](=[O:25])[NH:21][N:20]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].ClCCl>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH2:24][S:23][C:22](=[O:25])[NH:21][N:20]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)SC3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)SC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(3H,6H-1,3,4-thiadiazin-2-one-5-yl)pyridinium bromide (760 mg, 1.8 mmol) was dissolved in methanol (8 ml) and gradually added with sodium borohydride (680 mg, 18 mmol) under ice-cooling and then stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue obtained was added with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The residue obtained by evaporation was purified by column chromatography (dichloromethane-methanol=20:1) to obtain the titled compound (423 mg) as white crystals.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)[NH2:3].[C:16](OC(=O)C)(=O)[CH3:17].C(=O)(O)[O-].[Na+]>>[CH3:16][C:17]1[N:5]2[CH2:6][C:7]3[C:8]4[C:9]([NH:14][CH:15]=3)=[CH:10][CH:11]=[CH:12][C:13]=4[C:4]2=[N:2][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NNC1=NCc2c[nH]c3cccc1c23
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nnc2n1Cc1c[nH]c3cccc-2c13

Procedure:
5-Hydrazino-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrochloride (50 mg), described in Example 8, is heated at reflux with 3 ml of acetic anhydride for 2 hours. The mixture is cooled and then poured into a saturated solution of sodium bicarbonate. The resulting precipitate is collected and then dissolved in methanol. This solution is rendered acidic by the addition of HCl in ether. The mixture is treated with charcoal and concentrated to give the title compound.
Reaction SMILES: [Cl-].[Li+].[CH3:3][O:4][C:5](=[O:29])[C:6]1[CH:11]=[C:10]([Sn](CCC)(CCC)CCC)[CH:9]=[C:8]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)[CH:7]=1.[CH:30]([C:33]1[C:34](OS(C(F)(F)F)(=O)=O)=[N:35][S:36][N:37]=1)([CH3:32])[CH3:31]>C1COCC1.[Pd]>[CH3:3][O:4][C:5](=[O:29])[C:6]1[CH:7]=[C:8]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)[CH:9]=[C:10]([C:34]2[C:33]([CH:30]([CH3:32])[CH3:31])=[N:37][S:36][N:35]=2)[CH:11]=1
Reactant: CC(C)c1nsnc1OS(=O)(=O)C(F)(F)F
Reactant: CCC[Sn](CCC)(CCC)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2nsnc2C(C)C)c1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
Lithium chloride (0.094 g) and palladium II tetrakis(triphenylphosphine) (0.048 g) were suspended in dry THF under nitrogen atmosphere. To this suspension was added a solution of 3-(5-Methyl-pyridin-2-yl)-5-tripropylstannanyl-benzoic acid methyl ester (0.656 g, 1.27 mmol) and trifluoro-methanesulfonic acid 4-isopropyl-[1,2,5]thiadiazol-3-yl ester (0.26 g, 0.942 mmol) in 6 mL of dry THF. The reaction mixture was heated to reflux for 70 hours. The reaction mixture was cooled to room temperature and ice water was added. After one hour the mixture was extracted with EtOAc and the combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (17:1 EtOAc/hexanes) to give 0.118 g of 3-(4-isopropyl-[1,2,5]thiadiazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=354.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)ccc1O
Product: COC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Methyl 2-hydroxy-5-aminobenzoate (10 g, 60 mmole) was mixed with acetic anhydride (10 ml) and heated with stirring to 100° C. for 5 minutes. Subsequently the reaction mixture was cooled and concentrated to dryness, in vacuo. The remaining material was recrystallized from ethanol-water (1:1) with activated carbon, to give the title compound (9.7 g, 74%), m.p. 147°-148° C. Found (Calc. for C10H11NO4) C 57.01 (57.42), H 5.27 (5.26), N 6.76 (6.70).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.[CH:12](O)=[O:13]>C1(C)C=CC=CC=1>[CH:12]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][CH2:3]1)=[O:13]
Reactant: O=CO
Reactant: c1ccc2c(c1)CNCCS2
Solvent: Cc1ccccc1
Product: O=CN1CCSc2ccccc2C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4.56 g), formic acid (20 ml) and toluene (60 ml) was heated under reflux at 90° C. for four hours and then at 120° C. for a further three hours. The solvent was removed from the mixture by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 3.73 g (m.p. 84°-87° C.).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([O:20][CH2:21][C:22]4([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23]4)=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:7][CH:6]=1.[C:34]([O:38][C:39](=[O:42])[CH2:40]Br)([CH3:37])([CH3:36])[CH3:35].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:34]([O:38][C:39](=[O:42])[CH2:40][O:27][CH2:26][C:22]1([CH2:21][O:20][C:18]2[C:19]3[C:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=4)=[C:12]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:13][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:25][CH2:24][CH2:23]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4(CO)CCC4)c23)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4(COCC(=O)OC(C)(C)C)CCC4)c23)cc1
Temperature: 70 °C

Procedure:
Add 0.6 ml of an 11.25N sodium hydroxide solution to a solution of 285 mg (0.68 mmol) of [1-({[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}methyl)cyclobutyl]methanol in 5 ml of toluene. After adding 23 mg (0.07 mmol) of tetra-n-butylammonium hydrogensulphate and 267 mg (1.37 mmol) of bromoacetic acid tert-butyl ester, stir the reaction mixture at 70° C. for20 h. After cooling to room temperature, adjust to pH 7 with conc. hydrochloric acid. Extract three times with 20 ml each time of dichloromethane. Wash the combined organic extracts with satd. aqueous sodium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate under reduced pressure. Purify the crude product by means of preparative RP-HPLC (gradient: water/acetonitrile). 260 mg (72% of theory) of the desired product are obtained.
Reaction SMILES: [OH:1][CH:2]([C:29]1[CH:38]=[C:37]([CH3:39])[C:32]2[NH:33][C:34](=[O:36])[O:35][C:31]=2[CH:30]=1)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:21][CH2:20][C:19]4[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=4[NH:17][C:16]3=[O:28])[CH2:11][CH2:10]2)[N:6]=[N:7][CH:8]=1.CO>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:18]2[NH:17][C:16](=[O:28])[N:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:5]4[N:6]=[N:7][CH:8]=[C:3]([C:2]([C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)=[O:1])[CH:4]=4)[CH2:14][CH2:13]3)[CH2:21][CH2:20][C:19]=2[CH:22]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(O)c4cc(C)c5[nH]c(=O)oc5c4)cnn3)CC1)C(=O)N2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)cnn3)CC1)C(=O)N2
Reaction time: 20 h

Procedure:
0.13 g (0.049 mmol) 3-(1-{5-[hydroxy-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl]-pyridazin-3-yl}-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 1.0 g (12 mmol) manganese(IV)-oxide in 100 mL DCM were stirred overnight at RT. Then 500 mg manganese(IV)-oxide were added and the mixture was stirred for a further 20 h. Then the reaction mixture was combined with 10 mL MeOH, filtered off and evaporated down. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([OH:33])[CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:26]([O:25][C:23]1[CH:24]=[C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:20]=[C:21]([OH:33])[C:22]=1[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Oc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: OCC=Cc1ccccc1
Product: Oc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C/C=C/c1ccccc1
Yield: 62 %

Procedure:
Following the procedure in the literature (Li, L.; Chan, T. H. Org. Lett. 2001, 5, 739), cinnamyl alcohol was reacted with 3,5-dibenzyloxyphenol to yield (#a) as a white solid (62% yield); mp 76-78° C.; 1H NMR. (CDCl3, 400 MHz) δ 7.40-7.24 (m, 15H), 6.48 (A of AB, J=15.9 Hz, 1H), 6.35 (B of ABt, J=15.9, 5.5 HZ, 1H), 6.27 (d, j=2.1 Hz, 1H), 6.16 (d, J=2.1 Hz, 1H), 5.07 (s, 1H), 5.02 (s, 2H), 4.99 (s, 2H), 3.59-3.57 (d, J=5.5 Hz, 2H); 13C NMR (CDCl3, 400 MHz) δ 158.5, 157.6, 155.4, 137.0, 136.8, 136.6, 130.2, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 127.3, 127.0, 126.8, 125.8, 106.6, 94.8, 93.4, 70.1, 69.9, 26.2; HRMS (ESI) calcd for C29H26O3Na (M+Na) 445.1780. found 445.1793.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(-c2ncc(-c3cnc(C4CCNCC4)[nH]3)cn2)cc1
Yield: 20.7 %

Procedure:
Solid tert-butyl 4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (Example 17, 122 mg, 0.30 mmol) was treated with trifluoroacetic acid 2.0 mL) at room temperature for 15 minutes. Three times the reaction mixture was diluted with toluene and concentrated under reduced pressure to provide a dark semi-solid. The crude material was chromatographed on silica (12 g) eluted with 1:5:85 v/v acetic acid-methanol-dichloromethane. Some clean fractions were collected, concentrated, and the purified material was three times diluted with toluene and concentrated then promoted to solidify under hexane with scratching to afford the title compound (19 mg) as a light-pink acetate salt. The remaining fractions were collected, concentrated, three times diluted with toluene and concentrated to afford a semi-solid; Rf 0.17 with 1/10/90 v/v acetic acid/methanol/dichloromethane; 1H-NMR (400 MHz; DMSO-d6) δ 9.20 (s, 2H), 8.6-8.8 (br d, 1H), 8.3-8.5 (m, 3H), 7.83 (s, 1H), 7.45-7.55 (m, 3H), 3.2-3.5 (m, 2H), 2.95-3.2 (m, 3H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 5H); MS (ESI+) m/z 306 (M+1); H-PGDS FPBA IC50: 1 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[C:16]([CH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)#[N:17]>>[C:16]([CH2:18][CH2:19][CH2:20][N:21]([C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[C:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1)=[O:15])#[N:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCCCC#N)cc1
Product: COc1ccc2c(c1)C(C(=O)N(CCCC#N)c1ccc(C(C)C)cc1)CCC2
Yield: 52.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.56 g) and (3-cyanopropyl) (4-isopropylphenyl)amine (1.79 g) as starting materials, N-(3-cyanopropyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.56 g) was obtained. melting point: 74-750° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.[C-]#N.[K+].[CH3:27][N:28](C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:27]#[N:28])=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC#N)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl chloride (6.4 g), powdered potassium cyanide (4.0 g) and N,N-dimethylformamide (50 ml) was stirred for two hours at 60° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off to leave 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl cyanide (5.2 g, 81%). The product was recrystallized from ethyl acetate--hexane to afford colorless needles, m.p.109°-110° C.