Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:51]([NH2:59])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:59][CH2:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (75 mg, 0.20 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at ambient temperature was added phenethylamine (28 μL, 0.22 mmol) and N,N-diisopropylethylamine (105 μL, 0.60 mmol). The resulting yellow solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (5 mL), then dried over sodium sulfate and concentrated to afford ethyl 6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as an off-white solid (89 mg, 93% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].[H-].[Na+].Br[CH:20]([CH3:35])[C:21]([C:23]1[C:24]([CH:32]([CH3:34])[CH3:33])=[N:25][N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12)=[O:22].[Cl-].[NH4+]>O.CN(C=O)C>[CH2:15]([O:14][C:12]([C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])([CH:20]([CH3:35])[C:21]([C:23]1[C:24]([CH:32]([CH3:34])[CH3:33])=[N:25][N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12)=[O:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:13])[CH3:16]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(Br)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C(C)C(=O)c1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Triethoxycarbonylmethane (1.53 g) was dissolved into DMF (20 ml), and, after adding sodium hydride (0.28 g), the mixture was stirred for 0.5 hours at room temperature. 3-(2-Bromo-propionyl)-2-isopropylpyrazolo[1,5-a]pyridine (1.77 g) was added and the mixture was stirred for 1 hour at room temperature, and then further stirred for 7 hours by heating to 80 to 100° C. Saturated aqueous solution of ammonium chloride was added to the reaction liquor, which was diluted with water, then extracted with ether. After the organic layer was washed with water and with saturated brine and dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure and the residue was purified by means of silica gel column chromatography (developing solvent, ethyl acetate:n-hexane=1:2) to obtain aimed product (0.67 g) as a yellow oily product.
Reaction SMILES: Cl[CH:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH3:10])=[C:4]([CH3:11])[NH:3]1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>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.CCO>[Cl:8][C:6]1[CH:7]=[C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=2)[N:3]=[C:4]([CH3:11])[C:5]=1[CH2:9][CH3:10]
Reactant: CCC1=C(C)NC(Cl)C=C1Cl
Reactant: OB(O)c1cccc(Cl)c1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c(Cl)cc(-c2cccc(Cl)c2)nc1C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A 50-mL round bottomed flask was charged with 2,4-dichloro-5-ethyl-6-methyl-1,2-dihydropyridine (94 mg, 0.49 mmol, 1 eq.), (3-chlorophenyl)boronic acid (77 mg, 0.49 mmol, 1 eq.), tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.09 mmol, 0.09 eq.), and K2CO3 (200 mg, 1.45 mmol, 3 eq.). Toluene (4 ml), EtOH (1.6 ml) and water (1.6 ml) were added. The resulting mixture was stirred under Ar at 90° C. for 3 hr. until the starting chloride was consumed. After cooling to room temperature, the aqueous layer was separated and the organic layer was concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using hexane/dichloromethane (49:1, then 9:1 and 8:1) as eluent to afford 4-chloro-6-(3-chlorophenyl)-3-ethyl-2-methyl-pyridine, which was converted into its corresponding HCl salt by treating with 4N HCl in dioxane (120 mg, 81% yield).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([P:17]([CH2:27][CH:28]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:29]([NH:31][C@H:32]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:30])([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[NH:9][C:10]([O:12]C(C)(C)C)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)=O>[CH:10]([OH:12])=[O:11].[NH2:9][CH:8]([P:17]([CH2:27][CH:28]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:29]([NH:31][C@H:32]([C:40]([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:41])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)P(=O)(CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: O=CO
Product: NC(Cc1ccccc1)P(=O)(CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 97 %

Procedure:
Phenylmethyl N-[2-[[[2-phenyl-1-[[(tert-butoxy)carbonyl]amino]ethyl]phenylmethoxyphosphinyl]methyl]-1-oxo-3-phenylpropyl]-L-phenylalaninate is stirred for 2 hours in the presence of formic acid. The mixture is evaporated to dryness. The product is precipitated using diethyl ether. The product is recovered in a yield of 97%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C)[C@@H:28]([O:29]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@H:18]3[O:19]C(=O)C)=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:46]([O:53]CCCBr)[C:47]1C=CC=C[CH:48]=1.[OH-].[Na+]>C(#N)C.O.CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:28]([OH:29])[C@H:23]([OH:24])[C@H:18]3[OH:19])=[N:12][N:13]([CH2:48][CH2:47][CH2:46][OH:53])[C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CCCO)c2C)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-[(4-ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.030 g) and cesium carbonate (0.091 g) in acetonitrile (0.4 mL) was added benzyl(3-bromopropyl)ether (0.039 mL), and the mixture was stirred at 80° C. for 30 minutes. To the reaction mixture were added methanol (0.4 mL) and 2 mol/L aqueous sodium hydroxide solution (0.55 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). To the resulting eluent was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 days. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by liquid chromatography on ODS (eluent: methanol/water=40/60) to give 4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-1-(3-hydroxypropyl)-5-methyl-1H-pyrazole (0.0080 g).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][S:8][CH2:9][CH2:10][S:11]([NH:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1)(=[O:13])=[O:12]>C(O)(=O)C>[CH3:7][S:8]([CH2:9][CH2:10][S:11]([NH:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1)(=[O:13])=[O:12])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCCS(=O)(=O)NCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)CCS(=O)(=O)NCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
An aqueous solution (25 ml) containing 3.20 g of sodium metaperiodate was added dropwise to an acetic acid suspension (100 ml) containing 5.36 g of 6-[4-(3-(2-methylthioethyl)sulfonylaminopropyl)phenyl]pyridazin-3(2H)-one, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water, and precipitated crystal was collected by filtration and dried to obtain 5.00 g of 6-[4-(3-(2-methylsulfinylethyl)sulfonylaminopropyl)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][CH2:21][CH3:22]>C(O)(=O)C.CO>[CH2:21]([C:22]1[N:11]([C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1)[CH3:20]
Reactant: CCC
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (115 mg, 0.412 mmol) in acetic acid (1.1 mL) was added propane, 1,1,1-triethoxy- (265 μL, 1.32 mmol). The resulting mixture was stirred at 120° C. for 30 min. After cooling to room temperature, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (74.8 mg, 57%). LCMS calculated for C16H20N3O2S (M+H)+: m/z=318.1. Found: 318.1.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([CH2:24][CH2:25][N:26]=3)[C:10]3[C:15]([N+:16]=2[O-:17])=[CH:14][CH:13]=[C:12]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](O)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:27]([N:21]1[CH2:20][CH2:19][N:18]([C:12]2[CH:11]=[C:10]3[C:15]([N+:16]([O-:17])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]4[N:9]3[CH2:24][CH2:25][N:26]=4)=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Reactant: CCCCCCCC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)N1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a stirred suspension of 1,2-dihydro-4-phenyl-8piperazinylimidazo [1,2-a]quinoxaline 5-oxide (1.5 g, 0.0043 mol) in dimethylformamide (20 ml) under an atmosphere of nitrogen and cooled in an ice-bath, was added octanoic acid (0.67 g, 0.0043 mol.) and diphenylphosphorylazide (1.29 g, 0.0047 mol). The reaction mixture was allowed to stand for 15 minutes. Triethylamine (0.95 g, 0.0047 mol) was added to the reaction mixture and the resulting mixture was allowed to stand for 1 hr, then warmed to room temperature over an additional 1 hr period. The solvent was removed in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and then water, dried over anhydrous magnesium sulphate and concentrated in vacuo to yield an orange solid. The orange solid was recrystallized from chloroform:ethyl acetate to yield 1,2-dihydro-8-(4-octanoylpiperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 5-oxide, (1.6 g) as yellow crystals, m.p. 212°-213° C. (Found: C,70.72; H,7.44; N,14.77%; C28H35N5O2 requires C,71.01; H,7.45; N,14.78%), represented by the structural formula: ##STR25##
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=O)[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:28]>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([Cl:28])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Yield: 98.5 %

Procedure:
2-(biphenyl-4-ylmethyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (25 mg, 0.075 mmol) is refluxed in POCl3 (10 mL) for 60 hours, and the mixture is evaporated to dryness. The residue is purified by silica gel flash chromatography to give 26 mg product as white solids (Yield: 98.5%). 1H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 5.45 (s, 2H), 7.39 (m, 3H), 7.43 (m, 2H), 7.59 (m, 4H), 8.01 (s, 1H). MS (FAB) m/z 351.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccc(-n2ccnc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Yield: 87.3 %

Procedure:
A 2-L three-necked flask equipped with a stirrer, a thermometer, a condenser tube and a nitrogen inlet tube was charged with 150.7 g (0.560 mol) of 2,5-dichloro-4′-fluorobenzophenone, 114.4 g (1.68 mol) of imidazole, 100.6 g (0.728 mol) of potassium carbonate and 840 ml of N,N′-dimethylacetamide. The reaction solution was heated under a nitrogen atmosphere in an oil bath at 110° C. for 2 hours. After thin layer chromatography confirmed that the materials showed no peaks, the reaction liquid was allowed to cool to room temperature. The reaction liquid was slowly added to 3 L of water, and the product was precipitated. The liquid was then filtered. The product obtained by the filtration was dissolved in THF (1.2 L), and toluene (4 L) was added to the solution. The mixture was washed with salt solution until the water phase became neutral. The organic phase was dried over magnesium sulfate, and the solvent was evaporated with an evaporator. A crude product weighing 180 g was obtained. The crude product was subjected to recrystallization using 1 L of toluene and 20 ml of methanol in combination at 80° C., and the resultant crystal was isolated. As a result, 155 g of a white solid was obtained with a yield of 87%. A 1H-NMR spectrum of the compound is shown in FIG. 1.
Reaction SMILES: Cl.C([O:5][CH2:6][CH2:7][N:8]([CH2:12][CH2:13][N:14]1[C:22]2[CH:21]=[CH:20][C:19]([NH2:23])=[C:18]3[S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:16]([C:17]=23)=[N:15]1)C(=O)C)(=O)C.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36]C1=O>C(Cl)Cl.CO>[ClH:31].[OH:36][CH2:37][CH2:38][NH:34][CH2:33][CH2:32][NH:23][C:19]1[CH:20]=[CH:21][C:22]2[N:14]([CH2:13][CH2:12][NH:8][CH2:7][CH2:6][OH:5])[N:15]=[C:16]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[S:24][C:18]=1[C:17]=23
Reactant: CC(=O)OCCN(CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2)C(C)=O
Reactant: O=C1OCCN1CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: OCCNCCNc1ccc2c3c(nn2CCNCCO)-c2ccccc2Sc13
Temperature: 150 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
A mixture of 5.1 g (0.012 mol) of N-[2-(acetyloxy)ethyl]-N-[2-(5-amino-2H[1]benzothiopyrano[4,3,2-cd]indazol-2-yl)ethyl]acetamide, hydrochloride salt and 11.6 g (0.077 mol) of 3-(β-chloroethyl)-2-oxazolidinone was stirred at 150° C. for 2 hours, dissolved in 20 ml of a CH2Cl2 /MeOH (20/1) mixture, and flash chromatographed over silica gel, eluting with a CH2Cl2 /MeOH (20/1) mixture. The appropriate fractions were combined and concentrated to dryness in vacuo. The residue was treated with 20 ml of 2N KOH in MeOH, 10 ml of H2O, and 10 ml of THF, and the mixture was heated under reflux under a N2 atmosphere for 16 hours. The mixture was treated with 100 ml of H2O and 100 ml of CH2Cl2 and the layers were separated. The aqueous phase was extracted twice with CH2Cl2 and the Ch2Cl2 extracts were combined, dried (MgSO4), and concentrated to dryness in vacuo. The residue was dissolved in 50 ml of EtOH and treated with an excess of i-PrOH saturated with gaseous HCl. The precipitate was collected and recrystallized from MeOH to give 6.0 g of product, mp 222°-225° C.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[C:9]([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)([CH3:14])[C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C>[C:5]([CH:4]([C:3]#[N:7])[C:9]([CH3:14])([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:6]
Reactant: N#CCC#N
Reactant: COC(=O)C(C)(Br)c1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1cnccn1)C(C#N)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A DMF (15 mL) solution of sodium hydride (0.38 g, 9.4 mmol, 60%) was added to malononitrile (0.62 g, 9.4 mmol) in DMF (3 mL) at 0° C. After 10 minutes the intermediate from Step C (2.1 g, 8.6 mmol) was added. After stirring for 2 hours at room temperature the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate and the organic layer concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR δ (ppm) (CHCl3-d): 8.85 (1H, s), 8.65 (1H, d, J=2.6 Hz), 8.58 (1H, s), 5.12 (1H, s), 3.81 (3H, s), 2.09 (3H, s). m/z=231.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[S:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.NC1C(C(C2C(OC)=CC=C(F)C=2F)=S)=CN=C(NC2CCC(S(C[CH2:61][CH2:62][N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)(=O)=O)CC2)N=1.NC1C(C(C2C(OC)=CC=C(F)C=2F)=O)=CN=C(NC2CCC(S(CCCN3CCOCC3)(=O)=O)CC2)N=1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[S:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:61][CH2:62][N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)(=[O:28])=[O:29])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=S)c1cnc(NC2CCC(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N
Reactant: COc1ccc(F)c(F)c1C(=S)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Agent: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCC(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=S)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N

Procedure:
By a similar procedure to the preparation of the compound of Example 1, {4-Amino-2-[4-(3-morpholin-4-yl-propane-1-sulfonyl)-cyclohexylamino]-pyrimidin-5-yl}(2,3-difluoro-6-methoxy-phenyl)-methanethione was made from {4-Amino-2-[4-(3-morpholin-4-yl-propane-1-sulfonyl)-cyclohexylamino]-pyrimidin-5-yl}(2,3-difluoro-6-methoxy-phenyl)-methanone (prepared in accordance with US 2004/0162303 A1, 60 mg). LC/MS (m+H)+: 570.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2Br)[CH:10]=1)=[O:4].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]2=[O:21])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(NC(=O)Cc2ccccc2Br)cc(-c2ccc(C)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(N2C(=O)Cc3ccccc32)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The 5-[2-(2-bromo-phenyl)-acetylamino]-4′-methyl-biphenyl-3-carboxylic acid methyl ester from step 1 was dissolved in toluene (3 mL) and CsCO3 (325 mg, 1 equive.), Pd(OAc)2 (15 mg) and XANTPHOS (59 mg) were added. The reaction mixture was stirred overnight at 100° C., then cooled and partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (2:1 hexanes:ethyl acetate) to give 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid methyl ester, which was used directly in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:2].BrN1C(=[O:22])CCC1=O>ClCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]([OH:22])=[O:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 134.3 %

Procedure:
A solution of 4-(2-formylphenyl)toluene (2 g, 10.2 mmol), N-bromosuccinimide (1.8 g, 10.1 mmol) and dibenzoyl peroxide 75% (0.26 g, 0.8 mmol) in 22 ml of dichloromethane is stirred at the temperature of reflux for 5 hours. Reaction mixture is filtered and evaporated to dryness under reduced pressure. Oily residue is suspended in 20 ml of brine and extracted with 20 ml of ethyl acetate. Organic layer is evaporated to dryness under reduced pressure to obtain 2.88 g of oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=Cc1cc(Br)cc(Cl)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: Clc1cc(Br)cc(CNC2CC2)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2,3-dichlorobenzaldehyde from the previous step (1 eq.), cyclopropylamine (1 eq.) and sodium cyanoborohydride (1.5 eq.) were combined in MeOH (0.2 M). At 0° C., acetic acid (3 eq.) was added dropwise and the reaction mixture was slowly warmed to RT over 16 h. The reaction mixture was then diluted with ether and quenched with 1N aq. NaHCO3. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→80:20 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.