Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]([CH3:17])=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:15]([CH3:17])[CH3:14])[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (1 equiv.) in methanol (5 mL), acetone (5 equiv.) and acetic acid (2 equiv.) were added and reaction mixture stirred at room temperature for 2 h. Then NaBH3CN (3 equiv.) was added at 0° C. The resulting reaction mixture was stirred further for 16 h at room temperature. On completion, solvent was evaporated and water added to the residue and the extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford crude product which was used in next step without further purification (yield 80-90%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=O.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([NH2:27])[CH3:26])[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([NH:27][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH3:26])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CC(N)c1ccc(F)c(F)c1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cccs1
Product: CC(NC(c1cccc([N+](=O)[O-])c1)c1cccs1)c1ccc(F)c(F)c1
Yield: 95 %

Procedure:
Following a similar procedure to that described in Example (1a), 3.03 g of 3-nitrophenyl thiophen-2-yl ketone and 2.52 g of 1-(3,4-difluorophenyl)ethylamine were reacted, to obtain 4.62 g of the title compound as a reddish orange oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18].C1(C)C=CC=CC=1>ClCCl>[Cl:19][C:17]([N:14]1[CH2:15][C@H:12]([NH:11][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[C:13]1=[O:16])=[O:18]
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(N[C@H]1CN(C(=O)Cl)C1=O)OCc1ccccc1
Temperature: -10 °C

Procedure:
(S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone was suspended in 5 ml of dichloromethane and cooled to -10° C. A solution of 12.5% phosgene in toluene (2.9 ml, 3.4 mmol) was added dropwise to the rapidly stirring mixture. After stirring at -10° C. for 2 hours, the volatiles were evaporated without external heating. The residue was cooled to -10° C. and dissolved in 5 ml of dichloromethane to give (S)-1-chlorocarbonyl-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The compound was not characterized, but was used as a crude intermediate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:4]([CH2:14][CH2:15][CH3:16])[CH:3]=1.[F:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:24]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[N:23]=2)=[O:25])=[C:4]([CH2:14][CH2:15][CH3:16])[CH:3]=1
Reactant: O=C(O)c1cccc(F)n1
Reactant: CCCc1cc(Cl)nnc1CNCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCc1cc(Cl)nnc1CN(CC(C)C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (6-chloro-4-propyl-pyridazin-3-ylmethyl)-isobutyl-amine (940 mg, 3.89 mmol) and 6-fluoro-pyridine-2-carboxylic acid (663 mg, 4.7 mmol) in CH2Cl2 (10 ml) is added EDCI (783 mg, 4.7 mmol) and DMAP (244 mg, 2 mmol). The mixture is stirred at room temperature overnight. Water (10 ml) is added and the layers are separated. The organic layer is washed with brine (10 ml), then dried (Na2SO4) and evaporated. Flash column purification of the residue (2:1 of hexane: ethyl acetate) provides the title product. 1H NMR (CDCl3) (mixture of rotamers) 7.89 (q, 0.7H), 7.81 (q, 0.3H), 7.69 (dd, 0.3H), 7.53 (dd, 0.7H), 7.34 (s, 0.7H), 7.20 (s, 0.3H), 6.99 (dd, 0.7H1), 6.91 (dd, 0.3H), 5.19 (s, 0.6H), 5.07 (s, 1.4H), 3.41 (d, 0.6H), 3.31 (d, 1.4H1), 2.75 (t, 1.4H1), 2.48 (t, 0.6H), 2.08-2.17 (m, 1H), 1.69-1.75 (m, 1.4H1), 1.54-1.60 (m, 0.6H), 1.02 (t, 2.11H), 0.99 (d, 1.8H), 0.97 (t, 0.9H), 0.80 (d, 4.2H).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:23])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2.C([O:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:23])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:22][CH2:21][N:20]([CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCCc2cc(-c3csc(C4CCNC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCCc2cc(-c3csc(C4CCN(CCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out starting from 4-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-pyrrolidin-3-ylthiazole hydrobromide and 4-bromobutyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2ccccn2)c(F)cc1Cl
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Product: N#Cc1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1

Procedure:
The title compound was prepared according to the method described for Example 99 using 2-chloro-4-fluoro-5-(pyridin-2-yl)benzoic acid (Preparation 22) and 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53). The residue was purified using silica gel column chromatography eluting with 10% MeOH in EtOAc followed by a second chromatography eluting with 50% EtOAc in heptanes.
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.C[Al](C)C.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]=1[OH:27]>C1(C)C=CC=CC=1>[OH:27][C:16]1[CH:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:19]=[CH:20][C:15]=1[C:14]([NH:2][CH3:1])=[O:13]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1O
Reactant: CN
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(N2CCOCC2)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a cooled (0° C.), stirred solution of methylamine in dry tetrahydrofuran (1.27 mL of 2.0 M solution; 2.52 mmol) was slowly added a solution of trimethylaluminum in dry toluene (1.27 mL of 2.0 M solution; 2.52 mmol) via syringe under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stir for 2 hours. To the resulting solution, a solution of the 2-hydroxy-4-morpholin-4-yl-benzoic acid methyl ester (100 mg; 0.42 mmol) in dry toluene (4.0 mL) was added via cannula and the resulting solution was heated to reflux for 2 hours. After cooling to room temperature, the reaction was quenched with the careful addition of 1 N aqueous hydrochloric acid to pH 4. The mixture then was extracted with EtOAc (3×10 mL), and the combined organic layers washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from CH2Cl2—hexanes to provide the amide (93 mg; 93%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[OH:28][C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:33]([C:29]3([OH:28])[CH2:32][CH2:31][CH2:30]3)=[O:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)C1(O)CCC1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3(O)CCC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F) and 1-hydroxy-cyclobutanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=377.4 [M+H]+.
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].CO>O>[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2([CH:1]([NH2:22])[CH3:2])[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: [BH3-]C#N
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (2.2 g) prepared as described in Example 1, ammonium acetate (7 g), sodium cyanoborohydride (0.4 g) and methanol (28 ml) was stirred at room temperature for four days. The reaction mixture was poured into a mixture of ice and water and the resulting mixture extracted with ether. The ether extract was washed with water, dried and the ether removed to leave 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine as an oil which was identified by standard analytical techniques as the compound of Example 1 in the form of its free base.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4][C:3]1=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].[C:17]([CH2:21][CH:22]([CH3:26])[C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18]>C(=S)=S>[C:17]([CH2:21][CH:22]([CH3:26])[C:23]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:12])[NH:4][CH2:5]2)=[O:24])([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: CN1C(=O)NCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)CNC(=O)N2C
Temperature: 25 °C

Procedure:
3,4-Dihydro-1-methyl-2(1H)-quinazolinone (2.5 g) is added to a stirred suspension of anhydrous aluminum chloride (10.5 g) in carbon disulfide (120 ml) under nitrogen. 3-Carbomethoxy-2-methyl-propionyl chloride (2.5 g) is added dropwise to the stirred suspension, which is refluxed for about 18 hours and cooled to RT. The liquid phase is decanted and the residue treated with ice/H2O and 6N HCl (25 ml). The aqueous mixture is extracted with methylene chloride, the organic extract dried, filtered and concentrated in vacuo, affording the desired product as an oil which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.C(O)(=O)C.S(=O)(=O)(O)O.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[C:7]([Br:24])[CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
A vigorously stirred solution of 1,3-bis(trifluoromethyl)benzene (107 g) in a mixture of glacial acetic acid (22 mL) and concentrated sulfuric acid (142 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (77.25 g) at 25° C. The exothermic reaction raised the temperature to approximately 40° C. After aging at 45° C. for 4.5 h, the mixture was cooled to approximately 0° C. and poured into cold water (250 mL). After washing with 5N NaOH (75 mL) the organic layer contained 137 g of the desired 3,5-bis(trifluoromethyl)-1-bromobenzene by assay (94% yield). This product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH:22]=1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1cccnc1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cccnc2)c(=O)[nH]c1=O
Yield: 33 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (120 mg, yield: 33.0%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]([NH:11][NH2:12])=[O:10].[Cl:13][C:14]1[CH:31]=[CH:30][C:17]2[O:18][C:19]3[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=3[CH2:21][N:22]([C:23](Cl)=[O:24])[C:16]=2[CH:15]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]([NH:11][NH:12][C:23]([N:22]1[CH2:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=2[O:18][C:17]2[CH:30]=[CH:31][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])=[O:10]
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: NNC(=O)COCc1cccs1
Product: O=C(COCc1cccs1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(2-thienylmethoxy)acetyl]hydrazide (21) was prepared in the manner described in Example 6 from 1 mmol of 2-(2-thienyl-methoxy)acetic acid, hydrazide (20), prepared as described above in Example 20, and 1.0 mmol of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, to yield 0.28 g (64%) of product. Analysis calculated for C21H18N3O4SCl (M.W. 443.91): C, 56.82; H, 4.09; N, 9.47. Found: C, 56.55; H, 4.08; N, 9.28.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]1[CH:20]=[C:19]([C:21]2[CH2:25][C:24]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=3)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=2)[O:18][C:17]=1[CH3:39])(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:39][C:17]1[O:18][C:19]([C:21]2[CH2:25][C:24]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=3)([C:26]([F:28])([F:27])[F:29])[O:23][N:22]=2)=[CH:20][C:16]=1[CH2:15][NH2:14]
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CN
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
Trifluoroacetic acid (6.0 ml) is added to a solution of {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-carbamic acid tert-butyl ester (2.05 g) in dichloromethane (20 ml). After 45 min at room temperature, an aqueous solution of NaOH (2M) is added until pH 12 is reached and the reaction mixture is extracted three times with dichloromethane. The combined organic phases are washed with a saturated solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield C-{2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-yl}-methylamine (1.64 g, compound 2.5 in Table 2) as a light yellow foam. The crude product obtained is used without further purification. MS (HPLC/MS): 410 (MH), Retention time: 1.27 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH2:10]([N:7]1[CH:8]=[N:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ncn(Cc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ncn(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (4.11 g) in THF (30 mL) in methanol (30 mL), was added sodium hydroxide solution (1.0 N, 28 mL, 28 mmol). The solution was stirred at room temperature for 3 hours. The organic solvents were removed by evaporation. The aqueous phase washed with diethyl ether one time. The aqueous solution was acidified by adding 2 N HCl and then filtered to yield 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid as a white solid.
Reaction SMILES: C(OS([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O)CCCCCCCCCCC.[Na].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[C:25]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Brc1ccccc1
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: c1ccccc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
The procedure of Example 15 is repeated except that the 4 parts of sodium diisopropyl naphthalene sulphonate are replaced by 4 parts of sodium dodecylbenzene sulphonate. Again all the bromobenzene is reduced, but mainly to benzene, so that only 0.94 parts of biphenyl are isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[N:14][N:13]([CH2:32][CH3:33])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)cc4)c3c2cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(C#N)cc2)c2c3cc(OC)c(OC)cc3ncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 34000 %

Procedure:
4-(7,8-Dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (132 mg, 400 μmol) is dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (111 mg, 800 μmol) and ethyl iodide (37 μl, 440 μmol) is subsequently added. The reaction mixture is stirred at room temperature for 3 h. The mixture is subsequently poured into water (100 ml) and extracted twice with ethyl acetate (100 ml each time). The combined organic phases are washed once with water (50 ml), dried over Na2SO4, filtered with suction, and the filtrate obtained is evaporated to dryness in vacuo. The residue is chromatographed over flash silica gel (solvent gradient n-heptane/0-100% by vol. of ethyl acetate/ethanol 0-30% by vol.). After evaporation of the product fractions, the residue is dissolved in a little tetrahydrofuran, and 2-propanol (5 ml) is added, and the mixture is evaporated. The precipitate obtained is filtered off with suction and dried in a high vacuum, giving the title compound 4-(7,8-dimethoxy-3-ethyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (49 mg, 136 mmol) as a solid having a melting point of 227.4° C. MS: 359.0 (M+H+), TLC (HPTLC): Rf=0.51 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=O)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:19]1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: O=C(C=Cc1ccccc1)Nc1ccccc1Cl
Product: Clc1ccccc1-n1c(/C=C/c2ccccc2)nc2ccccc21
Yield: 21.2 %

Procedure:
The title compound was prepared with the analogous procedure described in example 7 (one pot reaction) using 1-iodo-2-nitrobenzene (124.5 mg, 0.5 mmol) and N-(2-chloro-phenyl)-3-phenylacrylamide (154 mg, 0.6 mmol) as starting materials to yield the title compound as a solid (35 mg, 21%). 1H NMR (DMSO) δ 6.73 (d, 1 H), 7.03 (d, 1H), 7.31 (t, 1H), 7.39 (m, 4H), 7.58 (d, 2 H), 7.70 (m, 1H), 7.75 (m, 1H), 7.79 (m, 2H), 7.88 (dd, 2H). [M+H+]: 331.08.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:6]=1.N.[CH3:21][N:22]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[CH:6]=1)#[N:22]
Reactant: CN1CCCC1=O
Reactant: Cc1cc(-n2cc(I)nc2C)cc2ccc(=O)[nH]c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Product: Cc1cc(-n2cc(C#N)nc2C)cc2ccc(=O)[nH]c12
Reaction time: 2 h

Procedure:
A mixture of 6-(4-Iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.55 g), cuprous cyanide (0.27 g) and palladium acetate (0.03 g) in 1-methyl-2-pyrrolidone (5 cm3) was heated and stirred at 175° for 2 hours. The cooled mixture was poured into aqueous ammonia solution (30 cm3 ; S.G. 0.880) and extracted with dichloromethane (3×100 cm3). The combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform. Combination and evaporation of the appropriate fractions afforded the title compound, m.p. >350°, (0.22 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:31]1(Br)[CH2:35][CH2:34][CH2:33][CH2:32]1.[H-].[Na+]>CN(C=O)C>[CH:31]1([N:28]2[CH:27]=[C:26]([CH2:25][N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:11]([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[CH2:16][CH2:15][CH2:14]3)=[O:12])[CH:30]=[N:29]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: BrC1CCCC1
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)cc1)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cnn(C3CCCC3)c1)c1ccc(C(C)C)cc1)CCC2
Reaction time: 0.5 h

Procedure:
N-(4-Isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) and cyclopentyl bromide (0.12 mL) were dissolved in DMF (5 mL), and sodium hydride (0.09 g) was added under ice-cooling. The mixture was stirred at the same temperature for 30 min and then at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-[(1-cyclopentylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.38 g).
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:10][CH:11]=1
Reactant: CCOC(=O)NCCCl
Reactant: CC(C)=CCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-methyl-2-butenoxy)phenol (1.64 g, 9.2 mmol), ethyl 2-chloroethylcarbamate (1.81 g, 11.9 mmol), and potassium carbonate (2.54 g, 18.4 mmol) in 20 ml of dimethylformamide (DMF) is heated at 85° for 18 hours. The reaction mixture is cooled to room temperature (RT), poured into water and extracted with ether. The combined ether extracts are washed with water until neutral followed with brine and dried over calcium sulfate. The solvent was removed in vacuo and the residue was placed under high vacuum at 80° for ca. 2 hours to remove the excess ethyl 2-chloroethylcarbamate. Purification by preparative thin layer chromotography (prep. TLC) gave ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl }-carbamate (compound 1, Table A).