Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5](=S)[NH:6][NH2:7])[CH:2]=[CH2:3].[Cl:9][CH:10]([C:16]([CH3:18])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>C(O)C>[ClH:9].[CH3:18][C:16]1[NH:7][N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: C=CCNC(=S)NN
Agent: Cl
Solvent: CCO
Product: C=CCNc1n[nH]c(C)c1C(=O)OCC
Reaction time: 1.5 h
Yield: 59 %

Procedure:
A mixture of 26.24 g (0.2 mole) of 4-(2-propenyl)-3-thiosemicarbazide and 32.9 g (0.2 mole) of ethyl 2-chloroacetoacetate in 150 mL of absolute ethanol was stirred under nitrogen atmosphere for 1.5 hr, treated with 100 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1.5 hr. The reaction mixture was stirred at ambient temperature for ~72 hr, heated to reflux and filtered to remove the amorphous sulfur. The filtrate was concentrated in vacuo to give a deep red oil which crystallized on trituration with acetone to give 29 g of product. Recrystallization from acetone gave 21 g of needle-like crystals with yellow. A second recrystallization from benzene gave 15.8 g of fine white needles, mp 133°-134° C. A rework of the filtrate from both recrystallizations gave an additional 7 g of crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28]C(O)=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C)(C)C.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH2:51])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCN)cc3)cc2)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1-{4′-[4-(2-Carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.825 g, 1.97 mmol), tert-butanol (0.21 mL, 2.16 mmol), diphenylphosphoryl azide (0.47 mL, 2.16 mmol), and triethylamine (0.3 mL, 2.16 mmol) were combined in toluene (8 mL) and stirred at 100° C. for 4 hours. The reaction was cooled to 80° C. and additional tert-butanol (0.21 mL, 2.16 mmol) was added. After stirring overnight at 80° C., the reaction was cooled to room temperature and submitted to aqueous workup. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes). Then, the isolated product was treated with 4 N HCl in 1,4-dioxane and stirred at 60° C. overnight. The solution was filtered and concentrated to give the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:10]([F:11])=[C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-])=O)(=O)[CH3:2].C([O-])(=O)C.[NH4+]>CC(C)=O.[Cl-].[Cl-].[Cl-].[Ti+3]>[F:11][C:10]1[C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][CH:7]=[C:6]2[C:5]=1[CH:4]=[C:1]([CH3:2])[NH:23]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(N2C(=O)c3ccccc3C2=O)c1F
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: Cc1cc2c(F)c(N3C(=O)c4ccccc4C3=O)ccc2[nH]1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
2-(Acetylmethyl)-3-fluoro-4-phthalimidonitrobenzene (4.7 g, 14 mmol) was dissolved in acetone (80 ml). Ammonium acetate (210 ml of a freshly prepared 4M aqueous solution) was added followed by titanium trichloride (140 ml, 140 mmol, 15% aqueous solution). The mixture was stirred vigorously for 30 minutes then extracted with ethyl acetate. The organic phase was washed with a hydrogen carbonate solution, brine, dried (MgSO4), filtered and the solvent evaporated off. The residue was purified by flash chromatography using 0.5% methanol in methylene chloride. Evaporation of the solvent gave 4-fluoro-2-methyl-5-phthalimidoindole (1.27 g; 31%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]
Reactant: COC(=O)c1c(N)cccc1O
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Trimethylacetyl chloride (3.69 g) was added to a mixture of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128, 3.99 g) and sodium bicarbonate (2.57 g) in ethyl acetate (77 mL) and water (18 mL). The reaction mixture was stirred at room temperature for 1 hour. A further amount of trimethylacetyl chloride (1.85 g) was added and the mixture was stirred for 1 hour. A further amount of trimethylacetyl chloride (0.920 g) was added and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, the layers were separated and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25% to give methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (5.79 g) as a white solid.
Reaction SMILES: C(O)(=[O:3])C.S(=O)(=O)(O)O.O.[C:11]([C:13]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:17])[CH:14]([CH3:16])[CH3:15])#N>C(OCC)(=O)C>[C:20]1([C:19]2[O:26][C:11](=[O:3])[C:13]([CH:14]([CH3:16])[CH3:15])([CH3:17])[N:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)O
Reactant: CC(C)C(C)(C#N)NC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C1(C)N=C(c2ccccc2)OC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
40 ml of glacial acetic acid, 3.92 g (0.038 mole) of concentrated sulfuric acid and 0.36 g (0.02 mole) of water were added to 8.6 g (0.04 mole) of N-(1-cyano-1,2-dimethylpropyl)benzamide. The mixture was stirred at 80° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled. Thereto were added 100 ml of water and 100 ml of ethyl acetate for layer separation. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and concentrated to obtain 7.2 g (0.033 mole) of 2-phenyl-4-isopropyl-4-methyl-1,3-oxazol-5-one (yield=83%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([C@@:11]23[CH2:20][C@H:15]([CH2:16][C:17](=[O:19])[CH2:18]2)[N:14]([CH3:21])[CH2:13][C@H:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)[CH3:3].[BH4-].[Na+]>C(O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([C@@:11]23[CH2:20][C@H:15]([CH2:16][CH:17]([OH:19])[CH2:18]2)[N:14]([CH3:21])[CH2:13][C@H:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1cccc([C@]23CC(=O)C[C@@H](C2)N(C)C[C@H]3C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1cccc([C@]23CC(O)C[C@@H](C2)N(C)C[C@H]3C)c1
Yield: 95 %

Procedure:
To a solution of 15 (1 eq) dissolved in absolute ethanol (7 mL/g of 15) was added solid sodium borohydride slowly over 10 minutes. This mixture was allowed to stir at room temperature for 24 hours after which time the ethanol was removed under aspirator vacuum and the residue carefully dissolved in 0.5N HCl (6 mL/g of 15). This solution was washed twice with ether (3 mL/g of 15 for each wash) and then the aqueous solution is made basic with 50% NaOH solution (pH=14) and the ether layers discarded. This solution was then saturated with sodium chloride and extracted five times with 3:1, methylene chloride:THF, (3 mL/g of 15 for each extraction) and the combined organic layers were dried over magnesium sulfate and the solvent removed under aspirator vacuum to provide 16 as a yellow oil in 95% yield from 15 as a mixture of 7-hydroxy diastereomers. This material is used in the next step without purification. 1H NMR (CDCl3): δ0.46-0.48(d, J=6.90 Hz, 3H), 1.32-1.34 (d, J=6.02 Hz, 6H), 1.47-1.58(m, 2H), 1.87-1.93(dd, J=14.16, 5.09 Hz, 2H), 2.27-2.47 (m, 8H), 2.69-2.75 (dd, J=11.64, 5.26 Hz, 1H), 3.09 (br s, 1H), 4.02-4.05 (t, J=4.83 Hz, 1H), 4.47-4.59 (septet, J=6.07 Hz, 1H)5.30 (br s, 1H), 6.68-6.81 (m, 3H), 7.7.16-7.62 (in, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41].[OH-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:12]([CH:11]1[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[N:1]1[CH2:37][CH2:38][CH2:39][C:40]1=[O:41])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(N)CC3)c1
Reactant: O=C(Cl)CCCCl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(N2CCCC2=O)CC3)c1
Temperature: 45 °C

Procedure:
N-((7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide (271 mg, 0.66 mmol, cf. 173) was dissolved in dichloromethane (10 mL). Pyridine (0.191 mL, 2.357 mmol) was added. 4-Chlorobutanoyl chloride (0.116 mL, 1.038 mmol) was added dropwise. After 2 h N,N-dimethyl-4-aminopyridine (46 mg, 0.378 mmol) was added and stirring was continued over night. 1 N sodium hydroxide solution was added and the mixture extracted with dichloromethane. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was suspended in dry tetrahydrofuran and a suspension of sodium hydride (60% in oil, 179 mg, washed twice with pentane prior to addition) in tetrahydrofuran (3 mL) was added. The reaction mixture was heated to 45° C. for 1 h. Water was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 98 mg (0.205 mmol, 46%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(Cl)(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([O:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:6]=1
Reactant: Oc1ccccc1
Reactant: Brc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Brc1nnc(Oc2ccccc2)s1
Temperature: 25 °C

Procedure:
A solution of 2,5-dibromo-1,3,4-thiadiazole (1.00 g, 4.10 mmol; prepared as described in Yasuda, T.; Imase, T.; Sasaki, S.; Yamamoto, T. Macromolecules 2005, 38, 1500) and phenol (188 mg, 2.00 mmol; Aldrich) in anhydrous tetrahydrofuran (4 mL) was treated with cesium carbonate (2.0 g, 6.0 mmol) and heated to reflux for 5 hours. The mixture was cooled to room temperature, diluted with chloroform, filtered through Celite, and the residue was purified by flash chromatography (Analogix 40×120 mm 80 g silica gel column, chloroform) to afford the title compound: 1H NMR (300 MHz, chloroform-D) δ ppm 7.28-7.35 (m, 3H), 7.41-7.49 (m, 2H) MS (+ESI) m/z=257/259 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[O:37])=[C:34]([CH3:45])[NH:33][C:32]=1[CH:46]=O>N1CCCCC1.C(O)C>[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[O:37])=[C:34]([CH3:45])[NH:33][C:32]=1/[CH:46]=[C:23]1\[C:24](=[O:29])[NH:25][C:26]2[C:22]\1=[CH:21][C:20]([S:17]([CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:19])=[O:18])=[CH:28][CH:27]=2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1C(=O)N1CCN(C)CC1
Yield: 50.2 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (46 mg, 0.12 mmol) was condensed with 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (30 mg, 0.12 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solid was collected by vacuum filtration and purified on a silica gel column to give 39 mg (55%) of the titled compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[C:15](OC(=O)C)(=O)C.C(Cl)(=O)C>ClCCl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([OH:3])=[O:2]
Reactant: O=C(O)CCc1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COC(=O)CCc1ccccc1C(=O)O

Procedure:
2-carboxybenzenepropanoic acid (9.7 g., 0.05 mole), acetic anhydride (15.5 g., 0.15 mole) and acetyl chloride (0.5 g) in dichloromethane (200 ml) was boiled at reflux under nitrogen for 16 hr. The solvents were removed at high vacuum and the residual cyclic anhydride was heated at reflux with methanol (250 ml) for 2 hrs. Evaporation of solvent gave the sub-title compound as an oil which crystallised with petroleum ether (b.p.60°-80°) to a solid (6.3 g) mp 76°-79°. This was further purified by continuous extraction of the crude product with boiling petroleum (b.p.40°-60°) in a Soxhlet apparatus. The pure compound, mp 79°-81° separated from the extracts on cooling.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH2:46][CH2:47][C:48]1[CH:57]=[CH:56][C:51]2[O:52][CH2:53][CH2:54][O:55][C:50]=2[CH:49]=1>CN(C=O)C>[CH2:54]1[CH2:53][O:52][C:51]2[CH:56]=[CH:57][C:48]([CH2:47][CH2:46][NH:45][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:3]4[CH:4]=[C:5]([C:8]5[O:9][C:10]([CH3:13])=[N:11][N:12]=5)[CH:6]=[CH:7][C:2]=4[CH3:1])=[CH:19][CH:18]=3)=[O:22])=[CH:49][C:50]=2[O:55]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCCc1ccc2c(c1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCCc4ccc5c(c4)OCCO5)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 6-(2-aminoethyl)-1,4-benzodioxan (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-[2-(3,4-ethylenedioxyphenyl)ethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.30 min, MH+ 456.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:14](OC(=O)C)(=[O:16])[CH3:15].CC([O-])=O.[K+]>>[C:14]([NH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [K+]
Product: CC(=O)Nc1cc(C(=O)O)cc(C(=O)O)c1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
5-Aminoisophthalic acid (30.33 g, 0.167 mol) was charged into a 250 mL round bottom flask with acetic anhydride (56.24 g, 0.551 mol) and KOAc (0.88 g). The reaction temperature was 60°-110° C. for 45 minutes. The resulting white solid was filtered after the reaction was allowed to cool to room temperature (about 20° C.). Yield 31.98 g (86%). 1H NMR (d-6 DMSO)--10.30, 8.41, 8.14, 2.06. 13C NMR (d-6 DMSO)--69.17, 166.82, 140.16, 131.92, 124,61, 123.59, 24.05.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:25][CH2:26][CH2:27][O:28][C:29]1[C:36]([CH3:37])=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[CH3:38]>C(O)C.[Cu](Cl)Cl>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[C:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=3)[N:1]=[C:33]2[C:32]2[CH:35]=[C:36]([CH3:37])[C:29]([O:28][CH2:27][CH2:26][OH:25])=[C:30]([CH3:38])[CH:31]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2cc(S(C)(=O)=O)ccc2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccc(S(C)(=O)=O)cc3c2=O)cc1

Procedure:
To a solution of 2-amino-N-(4-sec-butyl-phenyl)-5-methanesulfonyl-benzamide (0.21 g, 0.58 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.13 g, 0.64 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.440 g, 3.27 mmol) and the reaction mixture was refluxed for 48 hours. The solvent was evaporated in vacuo and the product was extracted with dichloromethane. The solvent was evaporated in vacuo and the residue was triturated with ether and methanol/ethyl acetate and filtered off, to obtain the title compound as a white solid. Yield: 0.13 g (43%). MP 258.8-260.2° C. 1H-NMR (400 MHz, CDCl3): δ 8.94 (s, 1H), 8.28 (d, 1H), 7.94 (d, 1H), 7.19 (m, 2H), 7.03 (m, 2H), 7.01 (s, 2H), 3.91 (m, 2H), 3.79 (d, 2H), 3.17 (s, 3H), 2.58 (m, 1H), 2.18 (s, 3H), 2.03 (m, 1H), 1.60 (m, 2H), 1.21 (d, 3H), 0.78 (t, 3H). MS (ES+) m/z: 521.66 (M+1).
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:28]([S:30][C:31]1([CH2:42][CH2:43]O)[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=2)[NH:33][C:32]1=[O:41])[CH3:29]>>[CH2:28]([S:30][C:31]1([CH2:42][CH2:43][N:14]2[CH2:15][CH2:16][N:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:13]2)[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=2)[NH:33][C:32]1=[O:41])[CH3:29]
Reactant: CCSC1(CCO)C(=O)Nc2ccc(F)cc21
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCSC1(CCN2CCN(c3cccc4ccccc34)CC2)C(=O)Nc2ccc(F)cc21

Procedure:
The product is obtained by following the procedure described under 1.3, starting with 31.6 g (0.148 mole) of 1-naphthylpiperazine and 30.5 g (0.074 mole) of 3-(ethylthio)-5-fluoro-3-(2-hydroxyethyl) -1,3-dihydro-2(2H)-indolone tosylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][CH2:28][NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:16][C:15]=1[C:32]([F:35])([F:34])[F:33])#[N:13].N1C=CC=CC=1>ClCCl>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][CH2:28][N:29]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:25][CH:24]=2)=[O:22])=[CH:16][C:15]=1[C:32]([F:35])([F:33])[F:34])#[N:13]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: N#Cc1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
3-Chloro-benzenesulphonyl chloride (55 mg, 0.26 mmol, 1.1 equiv.) was added to a mixture of crude 2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (70 mg, 0.24 mmol, 1 equiv.) in dichloromethane (2 ml) and pyridine (0.15 mL, 1.9 mmol, 8 equiv.) and the mixture stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by column chromatography (SiO2, dichloromethane). Fractions were combined to afford 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, 81 mg (67% yield). LC @215 nm; Rt 1.74: 94%, m/z (ES+): 547 (M+H+.), δH (400 MHz; d6-DMSO) 11.04 (1H, s), 8.55 (1H, s), 8.36 (1H, d), 8.12-8.26 (5H, m), 7.92 (1H, t), 7.79 (1H, d), 7.45 (1H, d), 4.15 (2H, t), 3.07 (2H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1Br)[CH3:9].[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:25]1[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=1)[CH3:9]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(OC(=O)Nc1ccncc1Br)c1ccccc1Cl
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: COCCOC
Solvent: O
Product: CC(OC(=O)Nc1ccncc1-c1ccc(O)cc1)c1ccccc1Cl
Temperature: 80 °C

Procedure:
(3-Bromo-pyridin-4-yl)-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.180 g, 0.51 mmol), 4-hydroxyphenylboronic acid (0.104 g, 0.76 mmol) and potassium carbonate (0.245 g, 1.78 mmol) were suspended in DME:H2O (2:1, 3 mL). The suspension was purged with N2 (g) for 5 minutes then tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.051 mmol) was added and the N2 (g) purge continued for 5 additional minutes. The reaction vessel was sealed and heated to 80° C. for 1 hour then allowed to cool. The reaction mixture was submitted to EtOAc/H2O workup then purified on silica gel to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][CH2:27][CH3:28])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C)C=O>[NH2:24][C:21]1[N:20]=[C:19]([NH2:25])[C:18]([CH2:17][C:11]2[CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH:3]=3)=[C:9]([O:26][CH2:27][CH3:28])[CH:10]=2)=[CH:23][N:22]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-(3′-Amino-2,6-diethoxy-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine (228 mg; 0.6 mmol) is dissolved in dimethylformamide (6 ml; dried over a molecular sieve), triethylamine (0.090 ml; 0.66 mmol) is added at room temperature, and the mixture is cooled to 0° C. and a solution of methanesulphonyl chloride (0.051 ml; 0.66 mmol) in dimethylformamide (1.0 ml) is added in the course of 5 minutes. After 1 hour at 0-5° C. the reaction mixture is concentrated and the residue is taken up in water, after which the pH is adjusted to 10 by addition of NH4OH conc. After stirring for 15 minutes the mixture is filtered with suction and the residue is dried under a high vacuum and chromatographed over silica gel (60 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05).