Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:26]=[CH:25][N:24]=2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1.ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[C:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:26]=[CH:25][N:24]=2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]([CH3:36])[CH3:37])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)N1CCn2c(Cc3ncccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.23 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (166) in tetrahydrofuran (20 mL) were added triphenyl phosphine (66 mg, 0.25 mL) and DTAD (58 mg, 0.25 mmol) at room temperature. A yellow clear solution was formed, which was sonicated for 20 min. It was stirred at room temperature for 24 h. Silica thin layer chromatography was performed (5% methanol in dichloromethane, Rf=0.2). The mixture was concentrated under reduced pressure to get a crude product, which was purified by a preparative thin layer chromatography plate (mobile phase 5% methanol in dichloromethane) to get pure 9-benzyloxy-2-isopropyl-6-(3-phenyl-pyridin-2-ylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (167) (17 mg, 35.23%) as a yellow sticky solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:12])=[C:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: Cc1cc(Br)c(C)c(C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CI
Product: COc1c(C)cc(Br)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2,3,6-trimethyl phenol (66.2 g; 0.294 mol) in acetone (2 L) was added potassium carbonate (203 g; 1.47 mol) at ambient temperature. Then MeI (91.4 ml; 1.47 mol) was added dropwise over 30 mins. Reaction was stirred overnight at ambient temperature. After this time the mixture was filtered, washing with acetone (2×200 ml) and the filtrate evaporated to give a red solid. The solid was taken up in DCM (1.2 L) and washed with 1M sodium thiosulfate (2×400 ml), half sat. brine (800 ml), dried (anh. MgSO4), filtered and the solvent evaporated to give a red oil (53.8 g; 80%). 1H NMR (300 MHz, CDCl3), δ/ppm; 2.23 (3H, s, Ar—CH3), 2.25 (3H, s, Ar—CH3), 2.32 (3H, s, Ar—CH3), 3.66 (3H, s, Ar—OCH3), 7.23 (1H, s, Ar—H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]([NH2:18])=[C:5]([N+:19]([O-])=O)[CH:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:19])[C:6]([NH2:18])=[CH:7][C:8]=1[O:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: COc1cc([N+](=O)[O-])c(N)cc1OCN1CCC(C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(N)cc1OCN1CCC(C)CC1
Reaction time: 4 h
Yield: 100.5 %

Procedure:
A mixture of 4-Methoxy-5-(4-methyl-piperidin-1-ylmethoxy)-2-nitro-phenylamine (0.9 g, 3.0 mmol) and 10% palladium on carbon (90 mg) in MeOH (20 ml) was shaken under an atmosphere of hydrogen for 4 hours. The reaction mixture was filtered through GF/A paper directly into saturated EtOAc/HCl to give a purple solution, which was reduced in vacuo to yield 4-Methoxy-5-(4-methyl-piperidin-1-ylmethoxy)-benzene-1,2-diamine as a purple foam (0.8 g), (LC/MS (acidic method): Rt 0.34, [M+H]+ 266)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(C(C)=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 92.2 %

Procedure:
6.6 g (30 millimols) of 4-(4'-chlorophenoxy)phenol, 4.14 g (30 millimols) of potassium carbonate, 60 ml. of methyl ethyl ketone and 5.0 g (45 millimols) of methyl chloroacetate were treated in the same way as in Referential Example 2 to afford 8.1 g of oily methyl 4-(4'-chlorophenoxy)phenoxyacetate in a yield of 92%.
Reaction SMILES: C([Li])CCC.[C:6](=[N:19][C:20]1[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=1[F:27])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:28][S:29]C.[Cl-].[NH4+]>O1CCCC1.O>[C:6](=[N:19][C:20]1[CH:25]=[C:24]([S:29][CH3:28])[CH:23]=[CH:22][C:21]=1[F:27])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Fc1ccc(Br)cc1N=C(c1ccccc1)c1ccccc1
Reactant: CSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(F)c(N=C(c2ccccc2)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
2.2 mL n-butyl lithium (2.66 M hexane solution) was added dropwise to a solution of 1.85 g benzhydrylidene-(5-bromo-2-fluorophenyl)-amine (compound in Production Example 336) in 10 mL tetrahydrofuran at −70° C., then the mixture was stirred for 15 minutes, a solution of 0.53 mL methyl sulfide in 5 mL tetrahydrofuran was added dropwise thereto, and the mixture was stirred at 0° C. for 2 hours. An aqueous saturated ammonium chloride solution was added thereto, and the reaction mixture was diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1.24 g of the title compound (colorless oil).
Reaction SMILES: [CH:1]1([C:4](=[O:29])[CH2:5][C:6]2[CH:7]=[N:8][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>CN(C=O)C>[CH:1]1([C:4](=[O:29])/[C:5](/[C:6]2[CH:7]=[N:8][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:10][CH:11]=2)=[CH:32]/[N:33]([CH3:35])[CH3:34])[CH2:3][CH2:2]1
Reactant: O=C(Cc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1)C1CC1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C(/C(=O)C1CC1)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
100 mg (0.26 mmol) of 1-cyclopropyl-2-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]-pyridin-3-yl]-5-pyrimidinyl}ethanone (example XXVI, step 1) are added to a solution of 123 mg (1.03 mmol) of N-(dimethoxymethyl)-N,N-dimethylamine in 1 ml of DMF. The reaction mixture is stirred at 110° C. for 2 hours and then poured into distilled water. The precipitated solid is filtered off, washed with distilled water and dried. 93 mg (64% of theory) of the product are obtained and are directly reacted further without further purification.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(=O)=O.C([O:15][C:16]([C:18]1[C:19]([CH:34]2[CH2:36][CH2:35]2)=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1)=O)C>C1(C)C=CC=CC=1.C1COCC1.CCOCC>[CH:34]1([C:19]2[C:18]([CH2:16][OH:15])=[CH:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=3)[N:20]=2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Within 10 min was dropped 31.6 ml (37.9 mmol) of 1.2 M DIBALH solution in toluene to a dry ice cooled (−50° C.) solution of 4.25 g (12.64 mmol) 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 50 ml of THF. The reaction mixture was stirred 30 min at −50° C. and after letting rise the temperature to RT, the reaction was stirred for 1 h at RT. The reaction mixture was taken up in ether and washed with 1N HCL and water. The solvent was removed under reduced pressure to give 3.72 g of pure [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1.[CH:12](=O)[C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1>O.CO>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=2)=[N:8][CH:9]=1
Reactant: NNc1ccc(N)cn1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(C=NNc2ccc(N)cn2)cc1OC
Reaction time: 0.8 h

Procedure:
A solution of 5.0 g (0.025 mole) of the compound of Example I in a mixture of 13 ml of H2O and 20 ml of CH3OH was treated rapidly with a solution of 4.7 g (0.027 mole) of veratraldehyde in 40 ml of methanol using mechanical stirring. The reaction mixture was stirred rapidly for 0.8 hr and filtered. The yellow-brown solid was washed with 40 ml of methanol, ether and air dried, m.p. 232°-233°dec. yield: 7.2 g (83%). Recrystallization from methanol raised the melting point to 235°-236°, dec.
Reaction SMILES: CO[C:3](=[O:26])[C@H:4]([CH2:24][OH:25])[NH:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.[NH2:28][NH2:29]>CO>[C:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([NH:28][NH2:29])=[O:26])[CH2:24][OH:25])=[O:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: NN
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)NN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
18.3 g of tert-butyloxycarbonyl-L-phenylalanyl-L-serine methyl ester were dissolved in 50 ml of methyl alcohol, and to this solution 7.5 ml of 80% hydrazine mono hydrate were added. The mixture was stirred for 15 hours at room temperature and then the reaction mixture was concentrated under reduced pressure to give a solid substance. The solid substance was allowed to re-crystallization with ethyl alcohol and thereby tert-butyloxycarbonyl-L-phenylalanyl-L-serine hydrazide was obtained.
Reaction SMILES: C(C1[C:12]2[C:7](=[CH:8][C:9](C)=[CH:10][CH:11]=2)[C:6](C)(C)C1C)(C)C.[CH2:17]([Cl:21])[C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:20][C:18]([C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=1)([CH3:19])[CH2:17][Cl:21]
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C)(C)CCl)cc1
Temperature: 40 °C

Procedure:
To prepare the 1-isopropyl-2,3,3,5-tetramethylindane, the procedures of Traas et al., U.S. Pat. No. 4,352,748 are substantially followed. Specifically, methallyl chloride (24 g) is added to a mixture of toluene (92 g) and concentrated sulfuric acid (49 g), while maintaining the temperature at about 40° C. The reaction mixture is stirred for half an hour, after which time the layers are separated. The organic layer is washed neutral with soda solution, dried on magnesium sulfate and evaporated. The residue is distilled under diminished pressure to obtain 2-methyl-2 (para-tolyl)propyl chloride. A mixture of 2 methyl-2-(para-tolyl)propyl chloride (18 g) and tert-amyl chloride (10 g) is added to aluminum chloride (10 g) dissolved in nitromethane (50 ml), at a temperature of between about 5° C. and 10 ° C. The reaction mixture is allowed to warm to room temperature, with stirring, over a period of about one hour. The reaction mixture is then poured over ice, and extracted three times with ether. The solution in ether is washed to neutrality, dried on magnesium sulfate and evaporated. The residue is distilled under diminished pressure to yield 1-isopropyl-2,3,3,5-tetramethylindane.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.C1OC2C=CC(C3C4C(=CC=CC=4)C(C4C=CC5OCOC=5C=4)=C3C(OCC)=O)=CC=2O1>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Solvent: CO
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Ethyl (1RS,3RS)-1,3-Di-(3,4-methylenedioxy-phenyl)indane-2-carboxylate. Ethyl(RS)-1,3-di-(3,4-Methylenedioxyphenyl)indene-2-carboxylate (163 mg, 0.38 mmol) was placed in MeOH (0.05 ml), and to this was added SmI2 (10 ml of 0.1M solution in THF, 1.0 mmol). The resulting mixture was stirred under an argon atmosphere overnight, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional SmI2 (5ml of 0.1M solution in THF, 0.5 mmol) was added, and stirring was continued for 2 h. The reaction mixture was partitioned between Et2O and 5% aqueous Na2S2O3. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with 10% EtOAc/ hexanes to afford the title compound as a colorless, glassy solid (120 mg, 75%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.Cl.Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:21][CH2:20]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(CC)CC)C>CN(C)C=O.C(N(CC)CC)C>[C:28]1([CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:20][CH2:21]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NC1CCN(CCCc2ccccc2)CC1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A suspension of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.2 g), 4-amino-1-(3-phenylpropan-1-yl)piperidine dihydrochloride (1.5 g), triethylamine (1.5 ml), 1-hydroxy-1H-benzotriazole monohydrate (0.8 g), and 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (1.0 g) in N,N-dimethylformamide (15 ml) was stirred at 50° C. for 2 hours. After spontaneous cooling, this reaction mixture was extracted with ethyl acetate/tetrahydrofuran (4/1; 90 ml). The organic layer was washed with 1N-aqueous solution of sodium hydroxide (10 ml) and water (30 ml) and concentrated. The resulting crystal crop was rinsed with diisopropyl ether (20 ml) and dried to provide the title compound (2.0 g, 95%).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12](=[O:13])[N:11]([C:14]2[S:15][C:16]([C:20](=[O:29])[NH:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([CH3:19])[N:18]=2)[CH:10]=[N:9]1)(=O)=O.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CO>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][CH2:6][CH2:7][N:8]2[C:12](=[O:13])[N:11]([C:14]3[S:15][C:16]([C:20]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[O:29])=[C:17]([CH3:19])[N:18]=3)[CH:10]=[N:9]2)=[CH:33][CH:32]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Solvent: CO
Product: Cc1nc(-n2cnn(CCNCc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 66 %

Procedure:
A solution of 2-(4-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)thiazol-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl methanesulfonate (0.10 g, 0.23 mmol) and (4-fluorophenyl)methanamine (0.09 g, 0.69 mmol) in anhydrous methanol (5 mL) was heated at reflux for 6 hours. The solvent was removed in vacuo and the residue was purified by column chromatography eluted with ethyl acetate to afford the title compound as a white solid in 66% yield (0.07 g): mp 106-107° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.59 (br s, 1H), 8.56-8.47 (m, 1H), 8.25 (s, 1H), 7.73-7.65 (m, 1H), 7.32-7.18 (m, 3H), 7.00-6.89 (m, 2H), 6.44 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.98 (t, J=5.8 Hz, 2H), 3.77 (s, 2H), 3.00 (t, J=5.8 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 468.2 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[N:12]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C@H:27]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:20]=2)=[O:10])[CH2:6][C@H:5]2[CH2:37][C@@H:3]1[C:4]2([CH3:39])[CH3:38].[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([OH:49])=[C:45]([CH:48]=1)[CH:46]=O>>[CH3:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[N:12]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH2:46][C:45]3[CH:48]=[C:41]([Cl:40])[CH:42]=[CH:43][C:44]=3[OH:49])[C@H:27]([CH2:33][N:34]([CH3:35])[CH3:36])[CH2:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH:20]=2)=[O:10])[CH2:6][C@H:5]2[CH2:37][C@@H:3]1[C:4]2([CH3:38])[CH3:39]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN[C@H](CN(C)C)CC(C)(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN(Cc3cc(Cl)ccc3O)[C@H](CN(C)C)CC(C)(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Yield: 17.8 %

Procedure:
Using Method A, 2-{3-[((S)-1-Dimethylaminomethyl-3,3-dimethyl-butylamino)methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (Intermediate 6, 0.200 g, 0.360 mmol) and 5-chloro-2-hydroxy-benzaldehyde (available from Aldrich; 0.066 g, 0.430 mmol) were reacted to form 2-(3-{[(5-Chloro-2-hydroxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.0450 g, 18%). Mass spectrum: m/Z: 701.5 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](Br)[C:11]([CH3:14])([CH3:13])[CH3:12].[I-].[Na+]>>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Product: CC(C)(C)COc1ccc(C=O)cc1
Yield: 99.9 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and neopentyl bromide (495 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-(neopentyloxy)benzaldehyde (315 mg, quant. crude) as a yellow oil that was used without further purification or characterization.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:37](O)(=[O:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:37]([C:38]2[CH:46]=[CH:45][C:44]3[O:43][CH2:42][O:41][C:40]=3[CH:39]=2)=[O:47])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(c1ccc2c(c1)OCO2)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and piperonylic acid (19.9 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:6][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:2][CH2:3][CH2:4][CH3:5].B(F)(F)F.CC[O:31]CC.[OH-].[Na+].OO.C([O-])([O-])=O.[K+].[K+]>[BH4-].[Na+].COCCOCCOC.O>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:18][C:13]([CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:31])=[CH:14][CH:15]=1
Reactant: C=CCCCC(OCCCCC)c1ccc(-c2ccccc2)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: OO
Solvent: COCCOCCOC
Solvent: O
Product: CCCCCOC(CCCCCO)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
4-(1-pentyloxyhex-5-enyl)-biphenyl (1 g) was dissolved in 0.5 M NaBH4 in diglyme (8 ml) and chilled in an ice bath. BF3.OEt2 (1 ml) in diglyme (4 ml) was added with vigorous stirring. Stirring was continued for 1 hour and water (1 ml) was added. 3M NaOH (2 ml) was added followed by 30% H2O2 (3 ml). Anhydrous K2CO3 (5 g) was added and the solvent decanted. The K2CO3 was washed with ethyl acetate and the combined organics dried (Na2SO4) and evaporated. Distillation under vacuum removes most of the remaining diglyme. The residue was purified by column chromatography (ethyl acetate/petrol) to give an oil. δC (CDCl3, 62.9 MHz): 14.1, 22.6, 25.7, 25.8, 28.4, 29.7, 32.7, 34.4, 63.0, 69.0, 82.0, 126.9, 127.1, 127.2, 128.8, 140.2, 141.0 and 142.4. δH (CDCl3, 250 MHz): 0.88 (3H, m), 1.16-1.55 (14H, m), 3.30 (2H, m), 3.62 (2H, t, J 6.1), 4.21 (1H, t, J 6.1), 7.34 (3H, d, J 7.6), 7.43 (2H, t, J 7.3) and 7.58 (4H, t, J 7.3).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][C:28](=O)[NH:27][C:26]=4[CH:32]=3)[CH2:17][CH2:16]2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][NH:27][C:26]=4[CH:32]=3)[CH2:19][CH2:20]2)[N:3]=1
Reactant: Cc1ccc2c(OCCN3CCN(Cc4ccc5c(c4)NC(=O)CO5)CC3)cccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(OCCN3CCN(Cc4ccc5c(c4)NCCO5)CC3)cccc2n1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
6-(4-(2-(2-Methylquinolin-5-yloxy)ethyl)piperazin-1-ylmethyl)-4H-benzo[1,4]oxazin-3-one (0.139 g, 0.32 mmol) was dissolved in dry tetrahydrofuran (10 mL) under argon and treated with a solution of lithium aluminium hydride in tetrahydrofuran (1 M, 0.32 mL, 0.32 mmol) and the reaction stirred at ambient temperature. More lithium aluminium hydride solution (1 M in tetrahydrofuran, 0.32 mL, 0.32 mmol) was added after 18 h and the mixture stirred for 1 h before being quenched with 10% potassium sodium tartrate aq. and extracted with ethyl acetate. The combine organic extracts were washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with a gradient of 10% 0.880 ammonia/methanol in dichloromethane, gave the title compound (0.073 g, 54%) as a yellow foam.