Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:33][Si:34]([CH3:40])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:33][Si:34]([CH3:40])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:42]4[CH2:43][CH2:44][CH2:45][CH2:46][O:41]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(C)(O)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To a 0.2M solution of the tertiary alcohol of Step 4 in CH2Cl2 were added 5 equiv. of dihydropyran and 0.1 equiv. of triphenylphosphonium bromide and the mixture was stirred at reflux for 1 day. Then, the same amount of dihydropyran and triphenylphosphonium bromide were added and the mixture stirred at reflux another day. Toluene was added and the resulting solution was filtered through silica with EtOAc:toluene 0:100 to 2:98 to afford the title product.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.N12CCN(CC1)CC2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:35]([CH:36]([OH:40])[CH2:37][CH:38]=[CH2:39])=[CH:34][C:33]2[C:28](=[C:29]([CH3:41])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.[H-].[Na+]>CS(C)=O.O>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([O:40][CH:36]([C:35]2[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:41])[CH2:37][CH:38]=[CH2:39])=[N:7][CH:6]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C=CCC(O)c1cc2cccc(C)c2nc1-c1ccccc1Cl
Agent: C1CN2CCN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC(Oc1ncnc2[nH]ccc12)c1cc2cccc(C)c2nc1-c1ccccc1Cl
Reaction time: 5 h

Procedure:
Prepared according to procedure L. A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (474 mg, 3.1 mmol) and 1,4-diazabicyclo[2.2.2]octane (694 mg, 6.2 mmol) in anhydrous DMSO (4.5 mL) was stirred at it for 5 h and then added via cannula to a mixture of 1-(2-(2-chlorophenyl)-8-methylquinolin-3-yl)but-3-en-1-ol (500 mg, 1.5 mmol) and sodium hydride, 60% dispersion in mineral oil (180 mg, 4.5 mmol) in DMSO (3 mL) that had been stirred for 30 min at rt and 30 min at 50° C. prior to the addition. The mixture was stirred at rt for 6 h before addition of water (10 mL), and the mixture was extracted with EtOAc (4×20 mL). The combined organic layers were washed with water, brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH, 50/1) to provide 3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)but-3-enyl)-2-(2-chlorophenyl)-8-methyl-quinoline [PI3Kδ IC50=28 nM] as a white solid. 1H-NMR (CDCl3) δ 10.20 (s, br, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.15-7.64 (m, 8H), 6.59-6.62 (m, 1H), 6.34-6.37 (m, 1H), 5.64-5.79 (m, 1H), 4.93-5.01 (m, 2H), 2.74 (t, J=8.7 Hz, 2H), 2.70 (s, 3H). Mass Spectrum (ESI) m/e=441 (M+1).
Reaction SMILES: [Cl-].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.NC1C=CC=CC=1O.CC1C=CC(C)=C(N)C=1O.[H-].[Na+].[CH2:51]([O:58][C:59]1[N:66]=[C:65]([CH2:67][O:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:64]([CH2:76][CH3:77])=[CH:63][C:60]=1[CH:61]=O)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>O1CCCC1.C(O)(=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=[CH:61][C:60]1[C:59]([O:58][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[N:66][C:65]([CH2:67][O:68][CH2:69][C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)=[C:64]([CH2:76][CH3:77])[CH:63]=1
Reactant: CCc1cc(C=O)c(OCc2ccccc2)nc1COCc1ccccc1
Reactant: c1ccc([P+](Cc2nc3ccccc3o2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(C)c(O)c1N
Agent: Nc1ccccc1O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1cc(C=Cc2nc3ccccc3o2)c(OCc2ccccc2)nc1COCc1ccccc1

Procedure:
To a suspension of [(benzoxazol-2-yl)methyl]triphenylphosphonium chloride (1.77 g, 4.12 mmol) (prepared using substantially the same procedures described in Example 5, but substituting 2-aminophenol and the intermediate thereof for the 2,5-dimethyl-6-aminophenol and its corresponding intermediate used therein), in dry tetrahydrofuran (20 mL), under a nitrogen atmosphere, was added 60% NaH/mineral oil (0.42 g, 10 mmol). After 0.5 hour a solution of 2-benzyloxy-5-ethyl-6-benzyloxymethylnicotinaldehyde (1.44 g, 4.0 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was refluxed for 23 hours. The reaction was cooled, neutralized with acetic acid and partitioned between water and chloroform. The chloroform layer was washed with NaHCO3 solution, dried, filtered through a pad of charcoal and evaporated. This material was dissolved in chloroform and flash chromatographed through silica gel to give pure product as a yellow oil. The product was a mixture of cis and trans olefins.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([O:26][CH3:27])[C:18]=2[CH2:28][CH2:29][CH3:30])=[CH:8][CH:7]=1)C.[OH-].[Na+]>CO>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([C:5](=[O:31])[C:4]([OH:32])=[O:3])=[CH:7][CH:8]=2)=[C:18]([CH2:28][CH2:29][CH3:30])[C:19]=1[O:26][CH3:27])(=[O:25])[CH3:24]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(C)=O)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)O)cc2)ccc(C(C)=O)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
As in example 10, a solution of 4-[3-[4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.4 g) in methanol (30 mL) was treated with 2N sodium hydroxide (0.25 mL) was stirred at room temperature for 4 hours. Most of the solvents were removed in vacuo, water was added, then the mixture was acidified with 3N hydrochloric acid and extracted with dichloromethane-tetrahydrofuran (1:1). The dried (MgSO4) extracts were evaporated and the crude oil was purified by flash chromatography over silica gel (toluene-ethyl acetate-acetic acid; 75:25:0.5 increasing to 74:25:1) and crystallized from diethyl ether-hexane to provide 0.13 g of 4-[3-[4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid, mp 94°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1.Cl>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])=[O:28])=[CH:22][CH:21]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)Cc2ccc(Cl)cc2)c(OC)c1
Temperature: 25 °C

Procedure:
To 3.56 g (20 mmol) of 2,4-dimethoxyaniline and 2.53 g (25 mmol) of triethylamine in 50 ml of methylene chloride are added dropwise, whilst cooling with ice, 3.97 g (21 mmol) of 4-chlorophenylacetyl chloride. The mixture is stirred for a further hour at ambient temperature, added to dilute hydrochloric acid and extracted with methylene chloride. The extracts are dried and evaporated down. The evaporation residue is triturated with petroleum ether and suction filtered. Yield: 5.2 g (85.0% of theory), Melting point: 134-135° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([C:22](=[O:26])[CH2:23][O:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19].[CH3:27]OC(OC)N(C)C>>[F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:27]=[C:23]([O:24][CH3:25])[C:22](=[O:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[N:16]1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccc(N2CCOCC2)c(F)c1F)C(=O)OC
Product: COC(=O)c1nn(-c2ccc(N3CCOCC3)c(F)c2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of methyl 2-[(2,3-difluoro-4-morpholin-4-ylphenyl)hydrazono]-4-methoxy-3-oxobutanoate (4.7 g, 13 mmol) in N,N-dimethylformamide dimethyl acetal (20 mL) was stirred at 100° C. for 80 min. After cooling to room temperature, the precipitate was collected by filtration and washed with iPr2O to give the title compound (4.1 g, 84% yield) as a brown powder: NMR (300 MHz, DMSO-d6): δ ppm 3.13 (4H, dt, J=4.4, 2.5 Hz), 3.49-4.05 (10H, m), 7.03 (1H, td, J=8.8, 2.5 Hz), 7.51 (1H, td, J=8.5, 2.3 Hz), 8.53 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 382 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:9]([OH:13])[CH2:10][NH:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)(C)C>[CH2:1]([C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C@H:9]([OH:13])[CH2:10][NH:11][N:12]=[C:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNN
Reactant: O=C1CCCC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNN=C1CCCC1
Reaction time: 18 h
Yield: 13.9 %

Procedure:
A solution of tert-butyl N-[(1S,2R)-1-benzyl-3-hydrazino-2-hydroxypropyl]carbamate (500 mg, 1.695 mmol) in 5 mL of isopropanol under Argon was treated with cyclopentanone (180 μL, 2.034 mmol). After stirring for approximately 18 hours, the reaction solvent was removed in vacuo and the residue was triturated with diethylether. The slurry was filtered and the solid was dried under high vacuum to provide tert-butyl N-[(1S,2R)-1-benzyl-3-(2-cyclopentylidenhydrazino)-2-hydroxypropyl]carbamate (85 mg, 14%) as a white solid. H1-NMR (chloroform-D3) 1.34 (s, 9H), 1.54 (b, 2H), 1.73 (m, 2H), 1.83 (m, 2H), 2.22 (m, 2H), 2.35 (m, 2H), 2.90 (m, 1H), 3.02 (m, 1H), 3.14 (m, 1H), 3.38 (m, 1H), 3.64 (bm, 1H), 3.84 (bm, 1H), 4.52 (m, 1H), 7.25 (m, 5H). MS(APCI): 361(M+Na).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([F:21])([F:20])[F:19])[O:17][CH:11]2C(OCC)=O)=[CH:6][CH:5]=1>C(O)C.O>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=[O:17])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1OC1(c1ccc(C)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(C=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a solution of 4.8 g of potassium hydroxide in 20 ml of ethanol and 5 ml of water, 8.0 g or ethyl 3-(4-methylphenyl)-2,3-epoxy-4,4,4-trifluorobutyrate was added with ice-cooling. The reaction solution was stirred at room temperature for 3 hours. Thereafter, the reaction solution was poured into ice water. The resulting solution was washed with diethyl ether and adjusted to pH 3 with 10% HCl and extracted twice with diethyl ether. The ether layers were combined and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to distillation under a reduced pressure by heating in an oil bath (140°-160° C.) to obtain 3.0 g of the desired aldehyde (b.p. 110°-120° C./110-120 mmHg).
Reaction SMILES: N([O-])=[O:2].[Na+].[F:5][C:6]([F:15])([F:14])[C:7]1[N:8]=[CH:9][C:10](N)=[N:11][CH:12]=1>S(=O)(=O)(O)O>[F:5][C:6]([F:15])([F:14])[C:7]1[N:8]=[CH:9][C:10](=[O:2])[NH:11][CH:12]=1
Reactant: O=N[O-]
Reactant: Nc1cnc(C(F)(F)F)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1cnc(C(F)(F)F)c[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
Concentrated sulfuric acid (2.38 mL) was stirred in an ice bath. Sodium nitrite (199 mg) was added in one portion, and the mixture was stirred for 5 minutes and allowed to warm to room temperature over 5 minutes. It was then heated to 40° C. for 10 minutes and then cooled 0° C. A solution of 5-(trifluoromethyl)-pyrazin-2-amine (313 mg) in 3.4 mL concentrated sulfuric acid was added drop-wise over 5 minutes. The reaction was allowed to stir in the ice bath for 10 minutes, then at room temperature for 10 minutes, then at 40° C. for 20 minutes. The reaction was then pipetted into stirring ice water. The aqueous layer was extracted twice with ethyl acetate, which was then washed with water and brine and dried over MgSO4. Purification by flash column chromatography (40 g, 0-100% ethyl acetate in heptanes) gave 0.239 g of Intermediate (1 h) as a white solid. MS 163.1 (M−1, APCI-).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[O:5][C:6]([C:9]23[CH2:16][N:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][CH2:10]3)=[CH:7][N:8]=1.[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][CH2:3][C:4]1[O:5][C:6]([C:9]23[CH2:16][N:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][CH2:10]3)=[CH:7][N:8]=1
Reactant: C[O-]
Reactant: ClCc1ncc(C23CCCN(CC2)C3)o1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ncc(C23CCCN(CC2)C3)o1
Yield: 79 %

Procedure:
A solution of (±)5-(2-chloromethyl-1,3-oxazol-5-yl)-1-azabicyclo[3.2.1]octane hydrochloride (D25) (75 mg, 0.28 mmole) in dry methanol (2 ml) was added dropwise over 2h to a solution of sodium methoxide in methanol (15 ml of a 25 wt % solution, 66 mmole), under nitrogen, cooled in ice. After evaporation of the solvent in vacuo the residue was treated with saturated aqueous potassium carbonate solution (10 ml) and extracted with chloroform. The combined extracts were dried over sodium sulphate then concentrated in vacuo. The residue was chromatographed on neutral alumina in a gradient of 0-0.5% methanol in chloroform. This afforded the title compound (E11) as an oil (50 mg, 79%) which was converted into the hydrochloride salt m.p. 129°-131° C. (from acetone-ether).
Reaction SMILES: C([NH:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][CH:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O>C(O)(=O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:27][CH:28]=1
Reactant: CC(=O)Nc1ccc(CC2c3ccccc3-c3[nH]c(=O)c4nccn4c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(CC2c3ccccc3-c3[nH]c(=O)c4nccn4c32)cc1
Temperature: 98 °C
Yield: 101.5 %

Procedure:
A mixture of 0.1 g of 10-(4-acetylamino-benzyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 5 ml of 1N sodium hydroxide and 5 ml of water is heated at 98° C. for 16 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is acidified with 1 ml of acetic acid, filtered and the precipitate formed is washed with 1 ml of methanol and air-dried. 90 mg of 10-(4-aminobenzyl)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a yellow solid melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 3.19 and 3.42 (2dd, J=15 and 7 Hz and J=15 and 5 Hz respectively, 1H each: Ar--CH2); 4.41 (dd, J=7 and 5 Hz, 1H: --H10); 4.80 (broad mult., 1H: --NH2); 6.22 and 6.40 (2d, J=7.5 Hz, 2H each: aromatic --H); 7.32 (m, 2H: --H7 and --H8); 7.45 and 7.75 (2 broad d, J=7.5 Hz, 1H each: --H6 and --H9); 7.64 and 8.13 (2 broad s, 1H each: --H of the imidazole); 12.23 (broad s, 1H: --CO--NH--)).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O

Procedure:
28.75 g of the carbobenzoxy compound of 25, dissolved in 1 liter of methanol, are hydrogenated at room temperature in the presence of 2.9 g of 10 % strength palladium-charcoal. After complete decarbobenzoxylation the catalyst is filtered off and the filtrate is evaporated to dryness. The product melts at 160°- 161°C. Rf = 0.15 in chloroform-methanol (8:2).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1=[O:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:24][C:25]([NH2:27])=[S:26])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[N:21][C:20]([CH3:23])=[N:19]1>C(O)C.CCOC(C)=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:24][C:25]2[S:26][C:7]3[CH2:6][CH2:5][CH2:4][C:3](=[O:9])[C:2]=3[N:27]=2)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[N:21][C:20]([CH3:23])=[N:19]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)n1
Reactant: O=C1CCCC(Br)C1=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3=O)ccc1-n1cnc(C)n1
Yield: 43.5 %

Procedure:
A mixture of 3-bromocyclohexane-1,2dione (158 mg, 0.827 mmol, from preparation AAE) and 1-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (109 mg, 0.414 mmol, from step 4 of preparation F) was heated in ethanol (1.4 mL) at 80° C. for 12 h. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (80% acetone/hexanes) to afford 2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one (64 mg, 44% yield) as a yellow solid. LC-MS (M+H)+ 356.3. 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (s, 1 H) 7.68 (d, J=8.56 Hz, 1 H) 7.31 (d, J=2.27 Hz, 1 H) 6.96 (dd, J=8.56, 2.52 Hz, 1 H) 3.95 (s, 3H) 3.00 (t, J=6.04 Hz, 2 H) 2.59-2.68 (m, 2 H) 2.45-2.52 (m, 3H) 2.20-2.31 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:7]=3[N:8]([CH2:11][CH3:12])[C:9]=2[CH:10]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:7]=4[N:8]([CH2:11][CH3:12])[C:9]=3[CH:10]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CCn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 48.1 %

Procedure:
Prepared from tert-butyl 7-bromo-5-ethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (500 mg, 1.32 mmol) and 4-benzyloxypyridone (265 mg, 1.32 mmol), according to the procedure of Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) gave the title compound (317 mg, 48%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.2 Hz, 1H), 7.44-7.37 (m, 5H), 7.32-7.29 (m, 2H), 7.04 (d, J=8.0 Hz, 1H), 6.10-6.03 (m, 2H), 5.08 (s, 2H), 4.66 (br s, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.86 (br m, 2H), 2.84 (br m, 2H), 1.53 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11][C:12]1[CH:13]=[C:14]([CH:20]=O)[C:15]([O:18][CH3:19])=[N:16][CH:17]=1.N1CCCCC1>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:20]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[C:15]([O:18][CH3:19])=[N:16][CH:17]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ncc(Br)cc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ncc(Br)cc1C=C1C(=O)Nc2ccccc21
Temperature: 80 °C
Yield: 55.5 %

Procedure:
To a solution of indolinone (130 mg, 0.98 mmol) in ethanol (5 mL) was added 5-bromo-2-methoxypyridine-3-carbaldehyde (J. Het. Chem, 1985, (22), 1583-1592) (200 mg, 0.98 mmol, 1 eq), followed by piperidine (0.194 mL, 1.9 mmol, 2 eq). The reaction mixture was heated at 80° C. for 2 hours and then allowed to cool to room temperature. The precipitate that formed was collected by filtration and washed with ethanol to give the title compound (180 mg, 55%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]1[C:15]([OH:16])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][C:12]=2[NH2:17].[CH2:26]([O:28][P:29]([CH3:33])[O:30]CC)[CH3:27]>O1CCOCC1>[NH2:17][C:12]1[N:11]=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[N:9]=[C:8]2[C:13]=1[N:14]=[C:15]([OH:16])[N:7]2[CH2:6][C:5]1[CH:4]=[C:3]([CH2:2][P:29]([CH3:33])(=[O:30])[O:28][CH2:26][CH3:27])[CH:25]=[CH:24][CH:23]=1
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CBr)c3)c2n1
Reactant: CCOP(C)OCC
Solvent: C1COCCO1
Product: CCOP(C)(=O)Cc1cccc(Cn2c(O)nc3c(N)nc(OCCOC)nc32)c1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A solution of Compound (9) (0.148 mmol) and diethylmethylphosphonite (1 mL) in dioxane (2.5 mL) was placed in an oil bath preheated to 100° C. for 30 minutes. The progress of the reaction was monitored by LCMS at 10 minute intervals. Once the reaction was observed to be complete, all of the solvent and phosphonite reagent were evaporated under high vacuum, and the remaining product was purified by HPLC. Lyophylization of the crude product gave Compound (10) (8.9 mg, 14%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.22 (t, J=6.9, 14.1 Hz, 2H), 1.36 (d, J=14.1 Hz, 3H), 3.20 (d, J=17.7 Hz, 2H), 3.38 (s, 3H), 3.69 (t, J=4.8, 9.6 Hz, 2H), 3.95 (m, 3H), 4.39 (t, J=4.8, 9.6 Hz, 2H), 4.97 (s, 2H), 7.24 (s, 1H), 7.31 (m, 3H). LCMS: m/z for C19H26N5O5P++H observed 436.1 at 1.29 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc(Nc2ccc3[nH]ccc3c2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 2-amino-4,6-dichloropyrimidine (1.64 g, 10 mmol), 5-aminoindole (1.32 g, 10 mmol), diisopropylethylamine (5.23 ml, 30 mmol) and N,N-dimethylformamide (30 ml) was heated at 60° C. and stirred overnight under nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate and water after cooled to room temperature; and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off; the obtained residue was dissolved in tetrahydrofuran (100 ml); 10% Palladium on carbon (50% wet, 1.0 g) was added thereto under nitrogen atmosphere; and the reaction mixture was stirred for 4 days under hydrogen atmosphere at atmospheric pressure. The reaction system was purged with nitrogen; the catalyst was filtered off; the filtrate was concentrated under reduced pressure; the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate:methanol=95:5); diethyl ether was added to the residue to crystallize; and the crystals were filtered off, and dried under aeration to yield the title compound (852 mg, 3.8 mmol, 38%) as pale brown crystals.