Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:54])[NH:22][CH:23]([C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[CH:37][N:38]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:19][O:20][C:21](=[O:54])[NH:22][CH:23]([C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([C:14]3[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:12][CH:13]=3)=[CH:43][CH:44]=2)=[CH:37][N:38]=1)=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CNC(=O)OC(C)(C)C)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
A mixture of [2-(4-Bromo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (1 g, 3.2 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (1.57 g, 3.2 mmol), tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.15 mmol), potassium carbonate (878 mg, 6.5 mmol), 1,2-dimethoxyethane (25 mL) and water (2.5 mL) was stirred at 80° C. for 16 hours. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dichloromethane (100 mL) and washed with water (25 mL) and saturated sodium chloride (25 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide [1-(2-{5-[4′-(2-tert-butoxycarbonylamino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (869 mg, 1.4 mmol, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:36][NH:35][CH2:34][CH:33]([CH3:37])[N:32]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH2:26][N:35]3[CH2:36][C@@H:31]([CH3:30])[N:32]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C@H:33]([CH3:37])[CH2:34]3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CC1CNCC(C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)C[C@@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 520 mmol), tert-butyl 2,6-dimethylpiperazine-1-carboxylate (335 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBCNH3 (129 mg, 2.08 mmol) was added and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (72 mg, 24%). LC-MS (ESI) m/z: 584 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]#[C:12][I:13])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=O)[N:7]=1.CO.Cl.[NH2:17][OH:18]>C(N(CC)CC)C>[CH3:1][N:2]([CH2:10][C:11]#[C:12][I:13])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=[N:17][OH:18])[N:7]=1
Reactant: NO
Reactant: CN(CC#CI)c1nc(C=O)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CC#CI)c1nc(C=NO)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2-(N-methyl-3-iodo-2-propynylamino)-4-formylthiazole (No. 21) (72 mg) were added methanol (5 ml), triethylamine (0.2 ml) and hydroxylamine hydrochloride (24 mg) and the mixture was stirred at room temperature for 4 hours and evaporated to remove the solvent. After addition of a 5% aqueous solution of potassium carbonate, the residue was extracted with chloroform. The extract was washed with water, dried and evaporated to remove the solvent. The crystalline residue was treated with acetone to give 2-(N-methyl-3-iodo-2-propynylamino)-4-hydroxyiminomethylthiazole (No. 22) melting at 155°-156° C. (decomp.).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:7][N:6]=1.Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[CH3:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:6]=1
Reactant: Clc1ncccn1
Reactant: CCOC(=O)c1c[nH]nc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ncccn2)nc1OC
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
Sodium hydride (60% in mineral oil, 528 mg, 13.2 mmol) is added portion wise to a solution of ethyl 3-methoxy-1H-pyrazole-4-carboxylate (1.5 g, 8.81 mmol) in 40 mL of THF at RT. Evolution of H2 (g) is observed. After about 5-10 min, 2-chloropyrimidine (1.0 g, 8.81 mmol) is added, and the resulting reaction mixture is stirred at reflux for 15 h. After cooling to RT, the reaction is quenched with 10 mL of sat. NH4Cl and 10 mL of water and extracted with CH2Cl2 (2×40 mL). The combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a brown solid. Purification by silica gel column chromatography (gradient from 50% EtOAc/hexane to EtOAc) affords the title compound as a fluffy white solid.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[CH3:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1>CCO>[CH3:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]([O:14][CH2:1][CH3:2])=[O:13])[CH2:7]1
Reactant: CC(=O)Cl
Reactant: C[C@H]1CCN[C@H](C(=O)O)C1
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@@H](C)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of dry EtOH (65 mL) and acetyl chloride (6.52 mL added dropwise at 0° C.) was added (2S, 4S)-4-methyl pipecolic acid (2.8 g, 19.6 mmol at room temperature. The reaction was stirred at room temperature for 16 hrs and then concentrated it vacuo to give the title compound, (3.01 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl[CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=4)=[O:28])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 81 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (30 mg, 0.084 mmol), prepared as described in Example 1, 2-chloro-N-(4-(trifluoromethyl)phenyl)acetamide (22 mg, 0.092 mmol), K2CO3 (35 mg, 0.25 mmol) in DMF (1 ml), was heated at 80° C. for 1 hour. After this time, the solution was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (38 mg, 81%) as a yellow solid. MS M+H=558; 1H NMR (CDCl3) δ 8.26 (1H), 7.60 (2H), 7.38-7.20 (8H), 7.11 (2H), 5.07 (2H).
Reaction SMILES: Br.[NH:2]1[C:6]([C:7]2[C:15](=N)[N:14]3[C:10]([S:11][C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=43)=[N:9][CH:8]=2)=[N:5][N:4]=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].N1C=CC=CC=1>O>[NH:2]1[C:6]([C:7]2[C:15](=[S:22])[N:14]3[C:10]([S:11][C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=43)=[N:9][CH:8]=2)=[N:5][N:4]=[N:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: N=c1c(-c2nnn[nH]2)cnc2sc3ccccc3n12
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: S=c1c(-c2nnn[nH]2)cnc2sc3ccccc3n12

Procedure:
- The product of Example 24, 0.02 mole, and 12.0 g. (0.054 mole) of P2S5 in 125 ml. of pyridine is heated at reflux for 5 hrs. and then poured into 1 l. of ice and water mixture. The product is collected by filtration, the solid dissolved in dilute NaOH, treated with decolorizing carbon, filtered and the filtrate acidified whereupon the purified product precipitated and was collected on a filter.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.N([O-])=O.[Na+].[BrH:14]>O.[Cu]Br>[Br:14][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1
Reactant: Cc1ccc(N)cc1O
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-2-methylphenol (10 g, 81.2 mmol) in hydrobromic acid (40 mL, 48% solution) and water (50 mL) at 0° C. was added a solution of sodium nitrite (5.6 g, 81.2 mmol) in water (15 mL) and the mixture stirred at this temperature for 30 minutes. To this was added copper (I) bromide (11.6 g, 81.2 mmol) in hydrobromic acid (15 mL, 48% solution) and the reaction was subsequently heated at reflux for 2 hours. Upon cooling to room temperature the resulting mixture was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with aqueous potassium hydroxide solution (˜1 M, 200 mL), dried (magnesium sulphate) and concentrated under reduced pressure. The crude product was purified by column chromatography [SiO2; light petroleum to 4:1 light petroleum-ethyl acetate] to give the title compound as a colourless oil, which crystallised to give fine colourless needles upon standing overnight (4 g, 26%). Rf=0.26 [4:1 light petroleum-ethyl acetate]. 1H NMR δ 2.21 (3 H, s), 4.89-4.95 (1 H, br, s), 6.96-6.97 (1 H, br, m), 6.99-7.00 (2 H, m).
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH2:57]([O:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][N:61]=1)[CH3:58]>O1CCOCC1>[CH2:57]([O:59][C:60]1[N:61]=[CH:62][C:63]([C:10]2[N:9]=[C:8]3[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]3=[CH:12][CH:11]=2)=[CH:64][CH:65]=1)[CH3:58]
Reactant: CCOc1ccc(B(O)O)cn1
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOc1ccc(-c2ccc3c(C#N)c[nH]c3n2)cn1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-ethoxy-5-pyridineboronic acid (205 mg, 1.23 mmol, Eq: 1.3) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and stirred for O/N h. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (167 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].IC.[C:14]([O-])(=O)C.[Na+]>C1COCC1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][CH3:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CNc1cc(OC)cc(OC)c1
Yield: 29.9 %

Procedure:
A solution of 3,5-dimethoxyaniline (13.8 g, 90 mmol), Iodomethane (12.7 g, 90 mmol), and sodium acetate (7.4 g, 90 mmol) in 100 ml of anhydrous THF was stirred under nitrogen atmosphere for 10 hr. Then, THF was removed by rotary evaporation. The crude product was partitioned between water and ethyl ether. The ethereal extraction was separated and washed with water, brine, and dried over Na2SO4. Filtration and removal of solvent provided 13.6 g of crude product. The crude product was chromatographed on silica gel (33% acetone-petroleum ether) to afford the expected product 4.5 g (27% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:33]=[N:32][CH:31]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1cncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)c1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-methoxypyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 243. NMR (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.00 (3H, s), 4.05-4.10 (4H, m), 7.35 (1H, s), 8.23 (1H, s), 8.38 (1H, s), 9.26 (1H, s). MS (ESI+): MH+505.19 (100%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:36]([CH:33]4[CH2:35][CH2:34]4)(=[O:38])=[O:37])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cn2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(S(=O)(=O)C4CC4)CC3)cn2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10 g of 4-(5-(piperazin-1-yl)pyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in a 500 ml round-bottomed flask. 126 ml of dichloromethane are added, followed by 4.23 ml of triethylamine and, finally, 2.7 ml of cyclopropylsulphonyl chloride. The reaction mixture is stirred at ambient temperature for 16 h, then washed with water and once with a saturated sodium chloride solution, dried over magnesium sulphate and then evaporated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol in dichloromethane varying from 0% to 10%. 10.9 g of 4-[5-(4-(cyclopropylsulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][C:22]([Br:29])=[CH:23][CH:24]=3)[C:19](=[O:30])[C:18]=2[CH:17]=1>C(OCC)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]1([OH:30])[C:18]2[CH:17]=[C:16]([Br:15])[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][C:22]([Br:29])=[CH:23][CH:24]=2
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2ccccc2-c2ccccc2)c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 3 h

Procedure:
A Grignard reagent prepared from 0.72 g (30 mmol) of magnesium turnings and 5.1 ml (30 mmol) of 2-bromobiphenyl in 15 ml of diethyl ether is added dropwise over the course of 2 hours while stirring (in an ultrasonic bath) to a boiling suspension of 10.0 g (29.6 mmol) of 2,7-dibromo-9-fluorenone in 1 00 ml of dry diethyl ether. After addition is complete, the mixture is boiled for a further 3 hours. After cooling overnight, the precipitate formed is filtered off with suction and washed with cold ether. The magnesium complex filtered off is hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice water. After 1 hour, the 9-(2-biphenylyl)-2,7-dibromo-9-fluorenol formed is filtered off with suction, washed with water and sucked dry. For the ring closure reaction, the dried fluorenol is boiled in 100 ml of glacial acetic acid, after addition of 3 drops of concentrated hydrochloric acid, for 6 hours. The mixture is allowed to crystallize overnight, the product formed is filtered off with suction and washed with glacial acetic acid and water.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[S:26][C:27]([N:30]2[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[N:31]2)=[CH:28][N:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:24][C:25]3[S:26][C:27]([N:30]4[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[N:31]4)=[CH:28][N:29]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(-c2cnc(N)s2)c1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cnn(-c2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Yield: 49.7 %

Procedure:
The compound of example A5 was obtained by similar method described in example A1 using 2-(4-cyclopropanesulfonyl-phenyl)-2-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 4; 1.1 g, 3.23 mmol), ethyl 1-(2-aminothiazol-5-yl)pyrazole-4-carboxylate (Preparation 41; 0.924 g, 3.88 mmol), HOBt (0.524 g, 3.88 mmol), and EDCl (0.741 g, 3.88 mmol), N-methyl morpholine (0.815 g, 0.88 mmol) in DCM (20 mL) to provide the title compound (0.9 g).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28](N(CC)CC)C.CI>CO>[CH3:28][N:11]([CH2:12][CH2:13][CH:14]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(C(CCNCCCSc2ccccc2)c2ccccc2)cc1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CO
Product: CN(CCCSc1ccccc1)CCC(c1ccccc1)c1ccc(O)cc1

Procedure:
To a solution of 0.8 g (0.0021 moles) of N-(3-phenylthiopropyl)-3-p-hydroxyphenyl-3-phenylpropylamine in 20 ml methanol and containing 0.3 ml triethylamine are added gradually 0.13 ml (0.0021 moles) methyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[CH:9]=[N:10][C:11]4[C:16]([C:7]=3[C:6](=O)[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[NH2:21][OH:22].Cl>C(OC(O)C)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[CH:9]=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:21][OH:22])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: COc1ccc2c(c1)C(=O)c1c-2cnc2ccccc12
Reactant: NO
Agent: CCOC(C)O
Agent: Cl
Product: COc1ccc2c(c1)C(=NO)c1c-2cnc2ccccc12
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a suspension of compound 5d (0.26 g, 1 mmol) in ethoxyethanol (30 mL) was added NH2OH·HCl (0.20 g, 3 mmol). The reaction mixture was heated with stirring under microwave irradiation (100 W) for 30 min (by TLC monitoring), followed by concentration in vacuo. A solid thus obtained was recrystallized from MeOH to give the title compound 6a (0.20 g, 73% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6]O.S(Cl)(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCc1nccs1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cc1nccs1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 11 h

Procedure:
To a chloroform (15 ml) solution of thiazole-2-methanol (171 mg, 1.49 mmol) was added thionyl chloride (0.33 ml, 4.47 mmol) and the resulting mixture was stirred at 50° C. for 11 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in butanol (10 ml). To the resulting solution were added sodium 4-chlorobenzenesulfinate (296 mg, 1.49 mmol) and potassium acetate (292 mg, 2.98 mmol). The mixture was stirred at 70° C. for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure, whereby the title compound (169 mg, 41%) was obtained as a pale yellow solid.