Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+]>[C].[Pd].CO>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][CH2:7][C:4]1[S:3][CH:2]=[N:6][CH:5]=1
Reactant: Clc1ncc(COC2CCCCO2)s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ncc(COC2CCCCO2)s1
Temperature: 60 °C
Reaction time: 10 h
Yield: 78.6 %

Procedure:
A mixture of 2-chloro-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole (10.4 g), 10% palladium carbon (containing 50% water, 2.0 g), potassium carbonate (6.2 g) and methanol (10 mL) was stirred under hydrogen atmosphere (5 atm) at 60° C. for 10 hr. The insoluble material was filtered off, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (6.97 g, yield 79%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](=[O:15])[CH3:14])=[C:11]([CH3:16])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Br:41]Br>C(Cl)(Cl)Cl>[Br:41][CH2:14][C:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[N:10][C:11]=1[CH3:16])=[O:15]
Reactant: CC(=O)c1c(C)nnn1-c1ccc(F)cc1
Reactant: BrBr
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: ClC(Cl)Cl
Product: Cc1nnn(-c2ccc(F)cc2)c1C(=O)CBr
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A solution of 1-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-ethanone (3.62 g, 17 mmol) was dissolved in chloroform (28 mL) and acetic (0.5 mL) was heated to reflux and then a solution of bromine (0.89 mL, 17 mmol) in chloroform (9 mL) and heated under reflux for 2 h. After cooling to room temperature the mixture was poured onto ice-water and the mixture extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 60% ethyl acetate in heptane) afforded the title compound (3.34 g, 68%) as an off white solid. MS: m/e=298.3/300.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[C:16](OC)(OC)(OC)[CH3:17].N>C(O)(=O)C>[CH3:16][C:17]1[NH:8][C:7]2[C:6]([CH3:9])=[CH:5][C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:3][C:2]=2[N:1]=1
Reactant: Cc1cc(-c2ccccc2)cc(N)c1N
Reactant: COC(C)(OC)OC
Agent: N
Solvent: CC(=O)O
Product: Cc1nc2cc(-c3ccccc3)cc(C)c2[nH]1
Temperature: 110 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
[step 4] 3,4-Diamino-5-methylbiphenyl (150 mg, 0.64 mmol) obtained in step 3 was suspended in acetic acid (4 mL), trimethyl ortho acetate (0.14 mL, 0.76 mmol) was added, and the mixture was stirred at 110° C. for 18 hr. Under ice-cooling, 28% aqueous ammonia solution (5 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (137 mg, 96%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17](O)=[C:16]([Cl:22])[C:15]=1[OH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([O:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:16]([Cl:22])[C:15]=1[OH:23]
Reactant: CN1CCN(CCO)CC1
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1O
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)c(OCCN2CCN(C)CC2)c(Cl)c1O
Reaction time: 16 h

Procedure:
To a solution of 2-(4-methylpiperazin-1-yl) ethanol (14.42 g) and 3,5-dichloro-2,4-dihydroxybenzoic acid methyl ester (52.15 g) in chloroform (400 ml) were added triphenylphosphine (28.85 g) and azodicarboxylic acid diisopropyl (21.7 ml) at room temperature, and the mixture was stirred for 16 hours, 1N Hydrochloric acid (300 ml) was added to the reaction mixture for extraction to give a crude product of the title compound. Step 4) 3,5-Dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]-benzoic acid (VII)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:11][C:12]([F:18])([F:17])[O:13][CH2:14][CH2:15][NH2:16]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:16][CH2:15][CH2:14][O:13][C:12]([F:18])([F:17])[F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: NCCOC(F)(F)F
Product: N#Cc1cnc(N)cc1NCCOC(F)(F)F

Procedure:
From intermediate 21 and 2-(trifluoromethoxy)ethanamine, reacted in an analogous manner to the preparation of intermediate 102. (UPLC-MS 3) Rt=0.54 min; MS m/z [M+H]+ 247.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23]C)[CH:19]=2)[C:14]=1[O:25][C:26]1[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:28][CH:27]=1.Cl.B(Br)(Br)Br.CO>C(OCC)(=O)C.C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]([O:25][C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)c(Cl)c3Cl)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c(Cl)c1Cl
Temperature: 0 °C
Yield: 30 %

Procedure:
Dissolve the product of Example 33 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.5 mL, 1.0 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1 hour. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting the 6-(2,3-dichloro-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and add 2M HCl in diethyl ether (0.5 mL, 1.0 mmol). Collect the precipitate on filter paper, rinse with diethyl ether to give 38 mg of the title compound (30%): mass spectrum (ion spray): m/z=586.2.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[C:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[CH:20]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])C1C=CC=CC=1.FC(F)(F)C(O)=O>O>[C:27]1(=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[CH:20]=2)[C:15]2[CH:14]=[CH:13][C:12]([S:9]([NH2:8])(=[O:10])=[O:11])=[CH:17][CH:16]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1ccc(C(=C2CCCC2)c2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)cc1F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=C2CCCC2)c2ccc(S(N)(=O)=O)cc2)cc1F
Temperature: 60 °C
Yield: 70.2 %

Procedure:
A solution of 6.5 g of N,N-dibenzyl-4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulfonamide, prepared in Example 10, in ml of trifluoroacetic acid is heated for 10 hours at 60° C. The mixture is poured into iced water and extracted with dichloromethane. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel in a dichloromethane/acetone mixture (95/5) to give 3 g of 4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulfonamide in the form of a semicrystalline oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:7]=2[CH:24]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N+:19]=3[O-:33])[C:7]=2[CH:24]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C2CC(C)(C)Oc3ccc(C#N)cc32)nc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2CC(C)(C)Oc3ccc(C#N)cc32)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
237 mg of methyl 6-(6-cyano-3,4-dihydro-2 2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylate were dissolved in 30 ml of dichloromethane and 180 mg of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature overnight and then washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The resulting oil was triturated with diethyl ether to give a solid which was recrystallized from t-butyl methyl ether. There were obtained 60 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-(methoxycarbonyl)pyridine N-oxide of melting point 135°-137° C.
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[N+:23](/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-:25])=[O:24]>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:26]1[N+:23]([O-:25])=[O:24])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCc2ccccc2)[C@@H](c2ccccc2)[C@@H]1[N+](=O)[O-]
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 6-benzyl 1-ethyl 5-acetylhex-2-enedioate 4b (0.3 mmol, 1.0 eq) and 1-((E)-2-nitrovinyl)benzene (0.45 mmol, 1.5 eq) in diethylether (0.4 mL) was added catalyst VI (Q-NH2) (0.045 mmol, 0.15 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 16 hours, then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Ethyl acetate:Hexane=1:10 to 1:4) in 91% yield.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C1COCC1>[C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH:23][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc(N)cc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-phenyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (69 mg, 0.207 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2 h. THF was evaporated and the residue was washed ethanol to obtain 40 mg of N1-phenyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 252° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:16][CH:15]3[NH:17][CH:12]([CH2:13][CH2:14]3)[CH:11]=2)=[CH:2]1>[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:16][CH:15]3[NH:17][CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2
Agent: [Pd]
Product: c1ccc2c(C3CC4CCC(C3)N4)c[nH]c2c1

Procedure:
The 3-(indol-3-yl)-8-azabicyclo[3.2.1]oct-2-ene may be hydrogenated over a precious metal catalyst, such as palladium on carbon, to give the corresponding 3-(indol-3-yl)-8-azabicyclo[3.2.1]octane. For those compounds of the invention where the indole moiety is substituted with bromo, a hydrogenation catalyst such as sulfided platinum on carbon, platinum oxide, or a mixed catalyst system of sulfided platinum on carbon with platinum oxide is used to prevent hydrogenolysis of the bromo substituent during reduction of the octene double bond. The hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of 20-80 p.s.i., preferably from 50-60 p.s.i., at 0-60° C., preferably at ambient temperature to 40° C., for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate. The compounds prepared in this manner are isolated by removal of the catalyst by filtration followed by concentration of the reaction solvent under reduced pressure. The product recovered may further purified by chromatography, or by recrystallization from a suitable solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]=[C:14]=[O:15]>C1(C)C=CC=CC=1>[CH3:12][NH:13][C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:15]
Reactant: CN=C=O
Reactant: COC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of methyl 4-aminobenzoate (15 g, 99 mmol), and methyl isocyanate (11.8 mL, 200 mmol) in toluene (400 mL) was heated at 100° C. under N2 for 3 hours during which time a precipitate formed slowly. Additional methyl isocyanate (11.8 mL, 200 mmol) was added and heating was continued for 2 hours. The reaction mixture was cooled to 0° C. and filtered. The precipitate was washed with ether and vacuum-dried to give methyl 4-(N-methylaminocarbonyl)aminobenzoate as a colorless solid (17.5 g, 85%).
Reaction SMILES: [N+](C1C=C(C=C([N+]([O-])=O)C=1)C([O:9][C@H:10]([CH2:14][C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]#[C:12][CH3:13])=O)([O-])=O.[OH-].[Na+]>CO>[CH3:22][C@H:15]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][C@@H:10]([OH:9])[C:11]#[C:12][CH3:13]
Reactant: CC#C[C@@H](C[C@H](C)CCCC(C)C)OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC#C[C@H](O)C[C@H](C)CCCC(C)C
Yield: 98.3 %

Procedure:
6.65 g (0.0171 mol) of 6(R),10-dimethyl-undecan-2-yn-4(R)-ol 3,5-dinitrobenzoate and 35 ml of 6 N aqueous NaOH in methanol (300 ml) were refluxed for 11/2 hr. It was worked up as in Example 45 to give 3.30 g (98.8%) of pure 6(R),10-dimethyl-undecan-2-yn-4(R)-ol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[N:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[N:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: FC(F)(F)c1cnc(NC2CCCc3c2[nH]c2ccc(Br)cc32)nc1

Procedure:
6-Bromo-N-[5-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 2-chloro-5-(trifluoromethyl)-pyrimidine (0.5 mL) in a similar manner as described in Example 22 to give 5 mg (4%) of a yellow solid. 1H-NMR (DMSO-d6) taken at 80° C.: δ 10.94-10.88 (m, 1H), 8.69-8.62 (m, 1H), 8.30-8.24 (m, 1H), 7.55 (s, 1H), 7.21 (d, 1H), 7.13-7.10 (m, 1H), 7.02 (d, 1H), 5.40-5.27 (m, 1H), 2.62-2.58 (m, 2H), 2.08-1.96 (m, 2H), 1.87-1.76 (m, 2H); MS m/z (M−1) 409, 411.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][O:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([N:19]=[C:20]=[S:21])=[O:18])=[CH:15][CH:14]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[S:21])[NH:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccc(C(=O)N=C=S)cc1
Solvent: CCOCC
Product: COc1ccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)cc1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a stirred mixture of 7.5 g of 2-aminobenzamide and 150 ml of ether was added dropwise, a mixture of 10 g of 4-methoxybenzoyl isothiocyanate in ether over 15 minutes. After stirring overnight the solid was collected, giving 14.2 g of N-[[[2-(aminocarbonyl)phenyl]amino]thioxomethyl]-4-methoxybenzamide.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:38])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:11]([OH:39])[C@@H:10]1[OH:40].CCN(C(C)C)C(C)C.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>C1COCC1>[Cl:38][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([NH:8][C:50](=[O:53])[CH2:51][CH3:52])[C@@H:10]([OH:40])[C@H:11]2[OH:39])=[C:19]([NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1
Reactant: CCC(=O)Cl
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S,2R,3S,5R)-3-Amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol trifluoroacetate (9.50 g, 16.42 mmol) and DIPEA (6.36 g, 49.27 mmol) are placed in a flask with dry THF (150 mL). Propionyl chloride (1.52 g, 16.42 mmol) is added dropwise and the reaction mixture is stirred at RT. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between DCM (250 mL) and water (250 mL). The organic layer is washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and the solvent is removed in vacuo. The solid is re-crystallised from 1,2-dichloroethane to give the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:29]1([C:35]2[CH:40]=[CH:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17]([C:38]4[CH:37]=[N:36][C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:40][CH:39]=4)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:3])=[O:4]
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccccc2)nc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CSC
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(-c5ccccc5)nc4)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (90 mg) in 1,2-dimethoxyethane (10 mL) was added 2-phenyl-5-tributylstannanyl-pyridine (180 mg) and copper(I)bromide-dimethyl sulfide (84 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (12 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 387. NMR: (CDCl3): 2.65-2.69 (4H, m), 2.82 (3H, s, Me), 3.28-3.32 (4H, m), 3.84 (2H, s, CH2), 3.90-3.93 (4H, m), 4.00-4.02 (4H, m), 7.18 (1H, s, Ar), 7.45-7.53 (3H, m, Ar), 7.85 (1H, d, J 8.5, Ar), 8.09-8.12 (2H, m, Ar), 8.76 (1H, d, J 8.5, Ar) and 9.72 (1H, d, J 1.2, Ar). MS: (ESI+): MH+ 551.14
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:20])[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH2:6][CH2:5]1.[CH3:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:11]([NH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:27]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:35][CH:34]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:5][CH2:6]1)=[O:20]
Reactant: O=C(NC1CCN(CCCl)CC1)c1c(Cl)cccc1Cl
Reactant: Cc1ccc(CNc2ccccn2)cc1
Product: Cc1ccc(CN(CCN2CCC(NC(=O)c3c(Cl)cccc3Cl)CC2)c2ccccn2)cc1

Procedure:
The title compound is prepared in a manner similar to Example 11 using 1-(2-chloroethyl)-4-(2,6-dichlorobenzamido)piperidine and 2-(p-methylbenzyl)aminopyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:26][O:27][CH2:28][CH2:29][OH:30]>>[CH3:26][O:27][CH2:28][CH2:29][O:30][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:25])=[O:19]
Reactant: COCCO
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Product: COCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 31 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one (200 mg, 0.6 mmol) in 6 mL of 2-methoxyethanol was stirred at room temperature for 20 h and partitioned between water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified on a silica gel column eluting with ethyl acetate-hexane (1:3) to give 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-methoxy-ethyl ester (63 mg, 31%) as an red solid. 1H NMR (400 MHz, CDCl3) δ 12.71 (s, 1H, NH-1′), 7.85 (d, J=7.05 Hz, 1H), 7.50 (d, J=7.05 Hz, 1H), 7.40 (s, 1H, H-vinyl), 7.16–7.23 (m, 2H), 6.03 (s, br, 1H, H-4′), 4.62 (t, J=4.70 Hz, 2H, CH2), 3.81 (t, J=4.70 Hz, 2H, CH2), 2.38 (s, 3H, CH3), and 2.34 (s, 3H, CH3). MS m/z (relative intensity, %) 341 (100, [M+1]+.).