Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH:27]([OH:28])[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[CH:24]=4)[N:19]=[CH:18][C:17]=3[O:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[CH3:30][O:29][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:40]4[CH:41]=[CH:42][C:36]5[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)=[O:31])[CH2:9][CH2:10]3)[C:27](=[O:28])[C:26]2=1
Reactant: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2c1)C(=O)C([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 15 using [trans-4-(4-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([O:16][CH2:17][CH3:18])=[N:12][C:13](Cl)=[N:14][C:5]=3[C:4]=2[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([O:16][CH2:17][CH3:18])=[N:12][C:13]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOc1nc(Cl)nc2c1[nH]c1ccc(Br)cc12
Reactant: C1CNCCN1
Solvent: Cc1cc(C)cc(C)c1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1ccc(Br)cc12
Yield: 59.6 %

Procedure:
920 mg (2.9 mmol) 8-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole and 813 mg (9.5 mmol) piperazine were heated in 10 ml mesitylene to 150° C. for 18 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 650 mg (60%) 8-bromo-4-ethoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 376, 378 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1.O.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.047 g, 0.090 mmol) in THF (2.0 mL) was added water (2.0 mL) and lithium hydroxide (0.010 mg, 0.42 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, acidified with 2M HCl, and extracted with ethyl acetate (4×25 mL). The combined organic phase was washed with brine (25 m]L), dried over Na2SO4, and concentrated in vacuo to afford 0.044 g (89%) of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[N:6][C:7]=1[NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:17]1([NH:24]C2N=C(O)C=CC=2[N+]([O-])=O)CCCCCC1.N#CBr>C(O)C>[NH2:24][C:17]1[N:8]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:7]2=[N:6][C:5]([OH:16])=[CH:4][CH:3]=[C:2]2[N:1]=1
Reactant: Nc1ccc(O)nc1NC1CCCCCC1
Reactant: O=[N+]([O-])c1ccc(O)nc1NC1CCCCCC1
Agent: N#CBr
Solvent: CCO
Product: Nc1nc2ccc(O)nc2n1C1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-6-(cycloheptylamino)pyridin-2-ol, prepared in a similar manner as the one described in Example 1.3 from 6-(cycloheptylamino)-5-nitropyridin-2-ol (0.225 g, 0.895 mmol), was taken up in ethanol (20 mL). Cyanogen bromide (0.153 g, 1.34 mmol) was then added. The resulting solution was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.004 g). LCMS m/z=247.0 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 1.50-1.80 (m, 6H), 1.80-2.05 (m, 4H), 2.45-2.55 (m, 2H), 4.25-4.35 (m, 1H), 6.55 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.C([O-])([O-])=O.[Ca+2].II.[CH2:21]([Cl:23])Cl>CO>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:21]([Cl:23])[C:11]=1[I:12]
Reactant: ClCCl
Agent: COC(=O)c1cc(I)c(N)cc1Cl
Agent: II
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)c1ccc(N)c(I)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 4-amino-2-chloro-5-iodo-benzoate, 70n. To a suspension of compound 70m (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monchloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 70n as major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 70o as the minor product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:17])=[O:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: CC(C)=O
Reactant: OCCc1ccc(Cl)cc1C(F)(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc(Cl)cc1C(F)(F)F
Reaction time: 0.42 h

Procedure:
To a solution of 2-(4-chloro-2-trifluoromethylphenyl)-ethanol in acetone (50 mL) at 0° C. was added dropwise a solution of Jones reagent (40.3 mL of a 2.67 M solution in H2SO4). After 25 min, the mixture was poured onto Et2O/H2O and the layers were separated. The organic layer was washed with H2O and brine, dried (MgSO4) and the solvent was removed in vacuo. The resultant orange solid was crystallized from hexane and heptane to furnish the title compound as a solid which showed: 1H NMR (300 MHz, CDCl3) δ 7.67 (d, 1H, J=2.0Hz), 7.51 (dd, 1H, J=2.0, 8.0Hz), 7.34 (d, 1H, J=8.0Hz), 3.84 (s, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)(=O)C.[F:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.Cl>O1CCCC1.CO>[F:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:1])=[CH:20][CH:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
0.855 g (8.4 mmol) acetic anhydride is cooled to 0° and 0.475 g (10.3 mmol) acetic acid added dropwise. The reaction mixture is then heated to 55° for 2 hours. After cooling to room temperature the mixture is diluted with 0.5 ml dry tetrahydrofuran. A solution of 0.7 g (3.2 mmol) 4-(3-fluoro-benzyloxy)-phenylamine in 2 ml tetrahydrofuran is added dropwise at room temperature and the resulting mixture is stirred for 3 hours. Evaporation leaves a solid which is dissolved again in 2 ml tetrahydrofuran and cooled to 0°. 0.64 g (8.1 mmol) borane-methyl sulfide complex is slowly added under stirring and cooling. The mixture is stirred 1 h at 0° and 2 h at room temperature. After addition of 5 ml methanol, stirring is pursued for 1 h. The mixture is treated with 10 ml 1M aqueous hydrochloric acid and stirred overnight. The organic solvents are removed under vacuum and the aqueous phase adjusted to pH=10 bei addition of potassium carbonate. Extraction with diethyl ether, drying and evaporation yields 0.57 g (76%) of a colorless solid. MS: m/e=232.2 (M++H).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[CH2:12]([C:14]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:27][N:26]=3)[O:22][N:21]=2)[CH:17]=[C:16]([CH3:36])[C:15]=1[CH2:37][CH2:38][C:39](O)=[O:40])[CH3:13]>>[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][C:39](=[O:40])[CH2:38][CH2:37][C:15]1[C:16]([CH3:36])=[CH:17][C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][CH:33]([CH3:34])[CH3:35])=[CH:27][N:26]=3)[O:22][N:21]=2)=[CH:19][C:14]=1[CH2:12][CH3:13])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)NCCC(=O)OC(C)(C)C

Procedure:
3-(3-{2-Ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionylamino)-propionic acid tert-butyl ester is prepared in analogy to Example 37 by coupling 3-amino-propionic acid tert-butyl ester hydrochloride with 3-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid; LC-MS: tR=1.18 min, [M+H]+=535.33.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[S:7][CH2:6][CH2:5]1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[NH2:2][CH2:1][CH2:3][CH:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[S:7][CH2:6][CH2:5]1
Reactant: N#CCC1CCSc2[nH]c3ccccc3c21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: NCCC1CCSc2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
A suspension of the product of the above (2) (1.40 g) in ether (40 ml) is added dropwise to a suspension of lithium aluminium hydride (467 mg) and aluminium chloride (1.63 g) in ether. The mixture is stirred at room temperature for 2.5 hours and extracted with ether-ethyl acetate after addition of an aqueous solution of sodium hydroxide. The extract is condensed. The residue is crystallized from ethyl acetate-methanol to give the title compound as white crystals (1.13 g) melting at 136°-138° C. Yield: 79%.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5]([CH3:7])=O.C(O)C.Cl.[CH3:16][O:17][NH2:18]>N1C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5](=[N:18][O:17][CH3:16])[CH3:7]
Reactant: CC(=O)C(=NO)C(=O)N(C)C
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)C(=NO)C(=O)N(C)C
Temperature: 10 °C

Procedure:
To a stirred mixture of 336 parts of N,N-dimethyl-2-hydroxyiminoacetoacetamide (a compound of Formula III), 1500 parts ethanol and 203 parts of methoxyamine hydrochloride were added dropwise 210 parts of pyridine over one-half hour while maintaining the reaction mixture at 10° C. by external cooling. The mixture was allowed to warm slowly to 25° C. and maintained at this temperature for 18 hours. Finally, it was stirred and refluxed for one-half hour. The solvent was removed under reduced pressure (15 mm.) at 40° C. bath temperature. Approximately 2000 parts of ice water were added, which caused the residue to solidify. The solid was filtered, washed twice with ice water, filtered, and dried. There was obtained 340 parts of N,N-dimethyl-2-hydroxyimino-3-methoxyiminobutyramide (a compound of Formula II), m.p. 144-147, which is of satisfactory quality for use as an intermediate. The product was, however, recrystallized from ethyl acetate, whereupon it melted at 146°-148°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH2:14])=[O:17])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 78 °C
Yield: 101.3 %

Procedure:
To a solution of 4-benzyloxybenzonitrile (0.61 g, 2.91 mmol) in 15 ml of tert-butanol was added fine powder of KOH (1.22 g, 21.78 mmol) and the resulting reaction mixture was refluxed for 4 h at 78° C. After the completion of the reaction (TLC monitoring), added brine solution and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum, to get the product (0.67 g) that was used as such for the next step.
Reaction SMILES: [C:1]([O:11]CC)(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[O-].[Na+].Cl>O.C(#N)C.CO>[C:14]1([N:20]2[CH:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:2][C:1](=[O:11])[NH:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: NNc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: O=C1CC(c2ccccc2)N(c2ccccc2)N1

Procedure:
One hundred and seventy-six (176) grams of ethyl cinnamate, 108 g of phenylhydrazine, 200 ml of a 28% methanol solution containing sodium methoxide, and 400 ml of acetonitrile were mixed and refluxed with heating in the nitrogen atmosphere for 1 hour. The reaction solution was poured into 2 liters of water and 100 ml of concentrated hydrochloric acid was added, thereby precipitation was formed. This was filtered off and recrystallized with acetonitrile to obtain 180 g of 1-phenyl-5-phenylpyrazolidin-3-one (A) as white crystals. ##STR10## Synthesis of Compound (B)
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of Benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(3-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=476.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([C:22](=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44]>ClCCl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:43]([C:39]3[O:38][CH:42]=[CH:41][CH:40]=3)=[O:44])[C@H:18]([C:22](=[O:28])[NH:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:17]2)[N:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: COc1cc2nc(N3CCN[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 68 %

Procedure:
A mixture of 0.243 g of the above intermediate 3A, 0.17 ml of diisopropylethylamine, 0.08 ml of 2-furoyl chloride in 10 ml of dichloromethane was stirred at room temperature for 10 hours. The solution was diluted with dichloromethane (10 ml), washed with water (4×10 ml), 2N NaOH (4×10 ml), water (4×10 ml), dried (Na2SO4) and evaporated to dryness. The residue was purified by flash chromatography eluting with petroleum ether:ethyl acetate 100:2 to give 0.2 g (68%) of the title compound as an ivory solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[C:24](Cl)(=O)[CH2:25][CH2:26][CH2:27][CH3:28]>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:24]1[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Solvent: CN1CCCC1=O
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from step (iii) (1.23 g) was dissolved in NMP (25 mL) and valeryl chloride (0.46 mL) was added dropwise. The reaction mixture was stirred for 1.5 h at rt, heated to 50° C. for 24 h then heated to 80° C. for 2 days. The solvent was evaporated and the reaction mixture poured into DCM. The solid precipitate was filtered off and the filtrate was purified on silica eluting with 10% MeOH in DCM to give subtitle compound (0.9 g).
Reaction SMILES: C([NH:4][C:5]1[C:24]([Br:25])=[CH:23][C:8]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][N:16]([CH3:22])[CH2:17]3)=[O:10])=[C:7]([O:26][CH3:27])[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C.O>[CH3:22][N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[CH:21][C:12]=2[NH:11][C:9](=[O:10])[C:8]2[CH:23]=[C:24]([Br:25])[C:5]([NH2:4])=[CH:6][C:7]=2[O:26][CH3:27])[CH2:17]1
Reactant: COc1cc(NC(C)=O)c(Br)cc1C(=O)Nc1cccc2c1CCN(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(Br)cc1C(=O)Nc1cccc2c1CCN(C)C2
Yield: 7.9 %

Procedure:
To a solution of 4-acetylamino-5-bromo-2-methoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide (0.888 g, 2 mmol) in ethanol (30 ml) and water (10 ml) was added 10% aqueous sodium hydroxide (1.25 ml). The mixture was heated at reflux for 1.25h before pouring into water and extracting with chloroform. The organic layer was dried over sodium sulfate, concentrated in vacuo and the residue recrystallised from ethyl acethate to afford the title compound as a brown solid (0.062 g).
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4].[NH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:32])[CH3:31].CC(O)=O.O>CCO.CCOC(C)=O>[C:30]([NH:29][CH2:28][CH2:27][NH:26][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4])(=[O:32])[CH3:31]
Reactant: CC(=O)NCCN
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)NCCNC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol) and N-(2-amino-ethyl)-acetamide (20 mg, 0.18 mmol) in EtOH (3 mL) was refluxed for 16 h. After cooling to r.t., AcOH (0.1 mL), water (15 mL) and EtOAc (20 mL) were added. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 8.7 mg of the title compound as a light yellow solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[S:11][C:12]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:13]=2[N:14]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[S:11][C:12]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: Clc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Solid 4-bromoaniline (1.00 g, 5.81 mmol) and 2,6-dichlorobenzothiazole (1.18 g, 5.81 mmol) were heated at 140° C. for 3 days in a flask equipped with an air condenser (fusion occurred within a few minutes to give a clear liquid which solidified over the course of 3 days). The reaction mixture was allowed to cooled to ambient temperature to give N-(4-bromophenyl)-N-(6-chloro-1,3-benzothiazol-2-yl)amine (1.97 g, 5.81 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 14.65 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[C:7]([O:14]C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S].[NH:17]1[CH2:22]COC[CH2:18]1>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:17]([CH3:22])[CH3:18])=[C:7]([OH:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1cc(C(C)(C)C)ccc1C(C)=O
Agent: [S]
Solvent: O
Product: CN(C)CCc1ccc(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.76 g (27.9 mmol) of 1-(4-tert-butyl-2-methoxyphenyl)ethanone (described in patent applications WO 01/02366; WO 99/52857; WO 99/21836; WO 97/48683), 1.1 g (34.3 mmol) sulfur and 15 mL morpholine (0.172 mol) was refluxed overnight under a nitrogen atmosphere. The reaction mixture was cooled and poured into 200 mL water containing 30 g sodium hydroxide and the resulting mixture was again refluxed overnight. The reaction mixture was then cooled to room temperature, diluted with an equal volume of water, and filtered through a pad of Celite filter aid. The filtrate was then cooled with an external ice water bath and acidified. The resulting precipitate was filtered, washed with water and air dried. The residue was then suspended in EtOAc and filtered to remove insoluble material and the filtrate was concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[NH:7][CH:6]=1)=[O:4].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(=O)[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(=O)n(-c2ccccc2)c1
Yield: 55.6 %

Procedure:
Methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (6.0 g, 39.22 mmol), phenylboronic acid (5.74 g, 47.06 mmol), copper(II) acetate monohydrate (11.76 g, 58.82 mmol), pyridine (6.32 mL, 78.43 mmol) and molecular sieves (4 Å, 6.0 g) in dichloromethane (100 mL) was stirred at ambient temperature for 12 hours and filtered. Standard extractive work up provided a crude residue which was purified by silica gel column chromatography (100-200 mesh) (1-2% methanol in chloroform) to give the title compound as a brown solid (5.0 g, 56%). m.p. 100-105° C.; 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 6.63 (d, J=9.5 Hz, 1H), 7.36-7.55 (m, 5H), 7.91 (dd, J=2.5, 9.9 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H); IR (KBr) υ 3058, 2924, 2854, 1721, 1675, 1540, 1446, 1313, 1271, 1103 cm−1; MS 230 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1N.C(ON=O)(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Cu]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:4]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=2[O:2][CH3:1])=[CH:23][CH:22]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: Clc1ccccc1
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: COc1cc([N+](=O)[O-])ccc1-c1ccc(Cl)cc1

Procedure:
2-Methoxy4-nitroaniline 5 and chlorobenzene are heated in the presence of t-butylnitrite and copper powder to give 2-(4-chlorophenyl)-5-nitroanisole 6. Hydrogenation of 6 with platinum oxide in methanol (a base such as morpholine may be used) provides the desired biphenyl amine 3.