Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[OH-:12].[Na+].O=[C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19]>O.C(O)C.C1COCC1.O>[CH3:21][S:18]([NH:17][C:16]1[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:1][C:11]2[C:6]([C:4]=1[C:2]([OH:12])=[O:3])=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:20])=[O:19]
Reactant: [OH-]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CS(=O)(=O)NCC(=O)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
To isatin (441 mg, 3 mmol) was added a solution of sodium hydroxide (1.15 g, 29.0 mmol) in water (2.5 mL). The resulting brown precipitate was stirred vigorously at RT for 20 minutes before being heated to 85° C. A solution of N-(2-oxo-2-phenylethyl)methanesulfonamide (1b) (639 mg, 3.0 mmol) in ethanol/THF/water (6.3 mL/1.25 mL/6.3 mL was then added dropwise over 30 minutes. The reaction mixture was stirred at 85° C. for further 4 h before cooling to RT. All organic solvents were removed in vacuo and the aqueous residue reduced to a volume of approximately 6 mL. The aqueous residue was washed with ether (3×10 mL) and then the aqueous residue were acidified with cooling to pH 4 with acetic acid. The precipitate formed were collected, washed with water and dried to give the title compound as a solid (721 mg, 70.3%). 1H NMR (300 MHz, CDCl3) δ 3.11 (s, 3H), 7.05 (d, 1H), 7.39 (d, 2H), 7.64 (m, 2H), 7.78 (m, 1H), 8.06 (m, 1H), 8.19 (m, 1H), 8.47 (m, 1H), 10.03 (b, 2H). MS APCI, m/z=343 (M+1). LCMS: 1.07 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CC1C=CC([CH:17]=[S:18])=CC=1.[C:21]1([CH2:27]C(=O)C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.BrC1C=CC(C=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:27][C:21]2[CH:26]=[CH:25][C:24]([S:18][CH3:17])=[CH:23][CH:22]=2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: CC(=O)Cc1ccc(Br)cc1
Reactant: Cc1ccc(C=S)cc1
Agent: O=Cc1ccc(Br)cc1
Product: CSc1ccc(C=C(C(C)=O)c2ccc(Br)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 190 using (4-bromophenyl)acetone and 4-methylthiobenzaldehyde, instead of phenylacetone and 4-bromobenzaldehyde.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:36][C:37]#[N:38]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:36][C:37]#[N:38])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCBr
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and bromoacetonitrile in N,N-dimethylformamide, to give the desired product as a light brown foam (42%).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.C([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)(=[O:29])=[O:28])(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.FC(F)(F)C(O)=O>[CH:17]1([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:7]3[NH:6][C:5]4[CH:20]=[CH:21][C:2]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[S:27]([NH2:26])(=[O:29])=[O:28])=[CH:3][C:4]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:19][CH2:18]1
Reactant: Brc1ccc2[nH]c(COc3ccc(C4CC4)cc3)nc2c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C4CC4)cc3)nc2c1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-2-(4-cyclopropyl-phenoxymethyl)-1H-benzoimidazole (0.030 g, 0.0874 mmol), 2-(tert-butylamino)sulfonylphenylboronic acid (0.029 g, 0.114 mmol), sodium carbonate (0.079 g, 0.524 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.006 g, 0.00874 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product. It was then dissolved in trifluoroacetic acid (3 mL) and heated to 60° C. for 2 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a light brown solid. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.14 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.77 (s, 1H), 7.73 (d, 1H, J=9.2 Hz), 7.65 (td, 1H, J=8.2 Hz, J=1.6 Hz), 7.50 (td, 1H, J=8.4 Hz, J=1.6 Hz), 7.51 (dd, 1H, J=8.8 Hz, J=1.2 Hz), 7.41 (dd, 1H, J=6.0 Hz, J=1.2 Hz), 7.08-6.99 (m, 4H), 5.50 (s, 2H), 1.90-1.84 (m, 1H), 0.92-0.90 (m, 2H), 0.62-0.58 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H22N3O3S: 420.5 (M+H), Found 420.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][OH:39]>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
A mixture of 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and methanol (1.0 ml) in DMSO (0.5 ml) is heated using a microwave source at 180° C. for 5 min. The resulting mixture is diluted with CH2Cl2 (5 ml), washed with water, dried over Na2SO4 and concentrated. Purification of the residue by column chromatography on silica gel (50% EtOAc in hexane) gives 3-fluoro-N-{4-[(2-methoxypyrimidin-4-yl)oxy]-1-naphthyl}-5-morpholin-4-ylbenzamide as a white solid (31 mg). Mp: 216-217° C.; 1H NMR (300 MHz, CDCl3) δ 3.25(t, J=4.8 Hz, 4H), 3.84(s, 3H), 3.87(t, J=4.8 Hz, 4H), 6.53(d, J=5.7 Hz, 1H), 6.77(d, J=12 Hz, 1H), 7.06(d, J=8.4 Hz, 1H), 7.31-7.34(m, 2H), 7.49-7.60(m, 2H), 7.89-7.97(m, 3H), 8.15(s, 1H), 8.36(d, J=5.7 Hz, 1H);
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]#[N:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[NH2:15]/[C:14](=[N:17]\[OH:18])/[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C#N
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCCC1/C(N)=N/O
Yield: 95 %

Procedure:
In a 16 mL vial, N-boc-2-cyanopiperidine (500 mg, 2.38 mmol) was dissolved in ethanol (6.7 mL), then hydroxylamine hydrochloride (231 mg, 3.33 mmol) and triethylamine (0.56 mL, 4.05 mmol) were added. The reaction mixture was stirred at reflux for 5 h, cooled and concentrated. The residue was taken up in EtOAc and water. The two layers were separated and the aqueous phase extracted with EtOAc. The combined organics were dried on Na2SO4 and concentrated to give the product as a white solid (550 mg, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:24](O)=[O:25])[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C[O-].[Na+].Cl>C(Cl)Cl.CCOC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[N:15]=[C:16]([CH3:17])[C:11]3=[C:10]([CH:24]=[O:25])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a suspension of 3.80 g of 6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 100 ml of DCM were added 5.5 ml of Hünig's base, 6.48 g of BEP and 2.41 g of (2R,5S)-dimethyl-1-benzylpiperazine. The reaction was stirred overnight at r.t. Then 3 ml of sodium methanolate (30% in methanol) were added, and the reation was stirred for 30 min. The pH was then brought to 5 by the addition of 2 M aqueous hydrochloric acid. The mixture was then diluted with EtOAc and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 2.10 g (36%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22](=[O:32])[NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[CH:30]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:14]([O:21][C:22](=[O:32])[NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[CH2:30][NH:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CN)Cc1ccc(F)cc1
Reactant: O=CC1CCCCC1NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNCC1CCCCC1NC(=O)OCc1ccccc1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
3-(4-Fluorophenyl)-2,2-dimethylpropylamine (253 mg, 1.39 mmol) and (2-formylcyclohexyl)carbamic acid benzyl ester (363 mg, 1.39 mmol) were dissolved in methanol (6 mL) and stirred at room temperature for 4 h. Sodium borohydride (84 mg, 2.22 mmol) was added, and the mixture was stirred for 30 min. 1.0 M aqueous sodium hydroxide was added, and the mixture was extracted with ether. The organic phase was washed with saturated aqueous sodium chloride and dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, to provide a colorless gum (450 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.IC.[C:11](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (0.18 g, 1.03 mmol) in DMF (5 mL) was added iodomethane (0.2 mL, 3.1 mmol) and potassium carbonate (0.8 g, 6.2 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, the residue dissolved in ethyl acetate (200 mL), washed with water (50 mL) and brine solution. The organic layers were combined and dried over sodium sulfate, filtered and concentrated under vacuum to afford 5-bromo-1-methylpyridin-2(1H)-one [Albrecht, US Patent Application Publication No. 2009/0318436] as yellow solid (40 mg, 21%). 1H NMR (DMSO-d6): δ 8.01 (d, 1H), 7.49 (dd, 1H), 6.34 (d, 1H), 3.38 (s, 3H); LC-MS m/z calculated for [M+H]+ 187.96, found 188.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:20]=[C:19]([CH3:31])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:31][C:19]1[CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[C:17]([CH3:16])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH2:6][O:7][C:8]=3[CH:13]=2)[CH:33]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.348 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20) to give the title compound (0.442 g, yield 82%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]2.[C:29]([O:46][CH:47]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:48][S:49][CH2:50][CH2:51][C:52](O)=[O:53])(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:29]([O:46][CH:47]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:48][S:49][CH2:50][CH2:51][C:52]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]2)=[O:53])(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CCC(C(=O)OC(C)(C)C)N1Cc2cc(N)ccc2C1=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc2c(c1)CN(C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2=O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of 5-amino-2-(1,3-bis-(t-butyloxycarbonyl)propyl)isoindolin-1-one (178 mg) in pyridine (2.3 ml), phosphorus trichloride (0.020 ml) was added, followed by stirring at room temperature for 2 hours. To this mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid (150 mg) was added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate =2:1) to yield the title compound (208 mg, yield 91%) as a wax-like substance.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:25].[K+].CS(C)=O>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([F:25])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2F)cc1
Temperature: 120 °C

Procedure:
A round bottom flask is charged with 2-tert-butyl-4-chloro-5-(4-tert-butylbenzyl)thio 3(2H)-pyridazinone (100 mg, 0.27 mmol) and to it is added potassium fluoride (23.4 mg, 0.40 mmol) and 2 ml dimethyl sulfoxide. This is heated to 120° C. for 6 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. This is washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) gave the above mentioned compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:15]([OH:17])=O)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].CCN(C(C)C)C(C)C.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:15](=[O:17])[NH:36][CH2:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:29][CH:30]=1)[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)NCCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the compound of example 70 (1.55 g, 5.96 mmol) in anhydrous DMF (5 mL) was treated successively with DIEA (5.2 mL), 4-biphenylethyl amine (2.40 g, 11.92 mmol) and TBTU (2.76 g, 8.34 mmol). The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was treated with HCl (1M, excess) and the mixture was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed with 30% ethyl acetate in hexanes and the desired product was obtained as a white solid. 1H-NMR(CDCl3, 400 MH: 1.22(t, J=7.2, 3H); 1.42(s, 9H); 2.32–2.42(m, 2H); 2.60–2.75(m, 2H); 2.83(t, J=7.1 Hz, 2H); 3.02(m, 1H); 3.53(m, 2H); 4.11(m, 2H); 6.25(m, t, 5.1 Hz, 1H); 7.30(m, 3H); 7.43(m, 2H); 7.57(m, 4H).
Reaction SMILES: Cl.CN(C)C.[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:17][O:18][CH2:19][C@H:20]([OH:22])[CH3:21].C(N(CC)CC)C.CN(C)CCCN.Cl>O.C1(C)C=CC=CC=1>[CH3:13][C:12]1[CH:14]=[CH:15][C:9]([S:6]([O:22][C@H:20]([CH3:21])[CH2:19][O:18][CH3:17])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: COC[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 4.5 h

Procedure:
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) under a nitrogen atmosphere and the reaction mixture agitated to form an oily slurry. The slurry was cooled to −5° C., then (2R)-1-methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a line wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature <8° C. Further toluene (2.5 vols) was added as a line wash and the reaction mixture held at −5° C. to 5° C. for 4.5 hours. N,N-dimethyl-1,3-propane-diamine, (0.3 eq) was added over 10 minutes at −5° C. The reaction mixture was agitated at −5° C. to 5° C. for 30 minutes, then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The reaction mixture was agitated for 30 minutes at 22° C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to an oil to give the title compound as a dry light brown oil. Yield corrected for assay 93-97%. 1H NMR δ (400 MHz CDCl3): 7.78-7.75 (d, 2H), 7.45-7.43 (d, 2H), 4.66-4.62 (m, 1H), 3.35-3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13-1.11 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1>COCCOC.[Cu]I>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(I)cnc(N)c23)cc1
Agent: [Cu]I
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(-c4ccccn4)cnc(N)c23)cc1
Temperature: 90 °C
Yield: 66.3 %

Procedure:
A suspension of Example 77A (734 mg, 1.6 mmol) and pyridyl-2-trimethylstannane (418 mg, 1.72 mmol) in DME (12 mL) was degassed with nitrogen, and PdCl2(o-tol3P)2 (62 mg, 0.078 mmol) and CuI (15 mg, 0.078 mmol) were added. The reaction vessel was sealed and the reaction was heated to 90° C. for 16 h. After cooling, the mixture was partitioned between EtOAc and H2O. The extracts were dried (Na2SO4) and concentrated, and the residue was purified by flash chromatography on silica gel, eluting with 40–75% EtOAc/hexanes to give the desired product (222 mg). MS (ESI(+)) m/e 419.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].O.[NH4+:14]>O1CCOCC1>[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:14])=[O:5]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.025 g (15 mmol) of (2R)-2-amino-2-phenylethanoate hydrochloride were suspended in 45 ml of dioxane and 45 ml of aqueous ammonium hydrate were added. After 8 hours at room temperature under stirring the solvent was evaporated and the residue redissolved with chloroform and washed with water. The organic layer was concentrated to afford 1.7 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>>[O:18]=[C:17]1[N:7]2[CH:6]=[C:5]([C:8]([NH2:10])=[O:9])[CH:4]=[CH:3][C:2]2=[N:11][C:12]2[S:13][C:14]([CH2:22][CH2:23][CH3:24])=[CH:15][C:16]1=2
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Reactant: NC(=O)c1ccc(Cl)nc1
Product: CCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 312 %

Procedure:
From 4.6 g (0.0029 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 8.6 g (0.040 mol) of 2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester, following the procedure of Example 22 there is obtained 2.6 g of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 260°-264° C. after recrystallization from pyridine.