Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1([CH3:8])[CH2:7][O:6][CH2:5]1.C([Li])CCC.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C1COCC1.CCCCCC>[CH3:15][Si:16]([CH3:19])([CH3:18])[C:2]#[C:3][C:4]1([CH3:8])[CH2:7][O:6][CH2:5]1
Reactant: C[Si](C)(C)Cl
Reactant: CC1(C=C(Br)Br)COC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C#C[Si](C)(C)C)COC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 93.9 %

Procedure:
A 250-mL round-bottom flask was charged with 3-(2,2-dibromovinyl)-3-methyloxetane (2.177 g, 8.51 mmol) in THF (85 mL) to give a clear solution. The flask was cooled in a dry ice/acetone bath for 15 min, then n-butyllithium (7.83 mL, 19.56 mmol) (as a 2.5 M solution in hexane) was added dropwise over five min. After stirring at −78° C. for 45 min, trimethylchlorosilane (3.81 mL, 29.8 mmol) was added over 2 min. The cooling bath was removed after 30 min and the reaction was allowed to warm to RT for 30 min. The mixture was diluted with water (50 mL) and ether (50 mL). The layers were separated, and the aqueous layer was extracted with ether (25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and evaporated. The residue was dissolved in a small amount of ether and filtered through a small pad of silica gel. The filtrate was evaporated to give trimethyl((3-methyloxetan-3-yl)ethynyl)silane (1.344 g, 7.99 mmol, 94% yield) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:3][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CC1(C)CC(C(Nc2cnc3ccc(F)cc3c2)c2ccc(C(=O)O)cc2)C1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3ccc(F)cc3c2)C2CC(C)(C)C2)cc1
Reaction time: 18 h
Yield: 53.4 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzoic acid (11.0 mg, 0.0290 mmol), was added 3-aminopropionic acid ethyl ester hydrochloride (4.90 mg, 0.0320 mmol), 1-Hydroxy-7-azabenzotriazole (4.80 mg, 0.0350 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (6.70 mg, 0.0350 mmol). Anhydrous methylene chloride (0.290 mL) was added followed by triethylamine (0.005 mL, 0.0380 mmol). After 18 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 28.6 mg of crude material. Purification by silica gel flash chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzamido)propanoate (7.40 mg, 54% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.86 (s, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.14-7.06 (m, 1H), 7.05-6.96 (m, 1H), 6.80 (t, J=5.9 Hz, 1H), 6.60 (s, 1H), 4.45 (s, 1H), 4.24 (dd, J=9.3, 4.4 Hz, 1H), 4.19-4.08 (m, 2H), 3.70 (q, J=6.0 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H), 2.58-2.44 (m, 1H), 2.06-1.96 (m, 1H), 1.75-1.67 (m, 2H), 1.67-1.55 (m, 2H), 1.28-1.22 (m, 3H), 1.13 (s, 3H), 1.09 (s, 3H). (M+1): 478.3.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.C(Cl)CCl.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][C:3]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2)=[O:5]
Reactant: O=C(O)CCl
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc2cnccc2c1
Reaction time: 4 h

Procedure:
To chloroacetic acid in DMF was added EDC, DMAP and 6-aminoisoquinoline. This mixture was stirred for 4 hours. The reaction was washed with NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave 2-chloro-N-(isoquinolin-6-yl)acetamide (E1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[C:6]([OH:12])[CH:5]=1.Cl[CH2:15][C:16]([CH3:18])=[CH2:17]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH2:17][C:16]([CH3:18])=[CH2:15])[C:7]([Br:11])=[C:6]([OH:12])[CH:5]=1
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Reactant: C=C(C)CCl
Solvent: CO
Product: C=C(C)COc1cc(C(=O)OC)cc(O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Na pieces (41.4 g, 1.82 mol) were added slowly to MeOH (3 L). The resulting mixture was stirred at room temperature for 30 min and then 4-bromo-3,5-dihydroxy-benzoic acid methyl ester (197a) (450 g, 1.82 mol) was added portion wise. The mixture was warmed to 60° C. 3-Chloro-2-methyl-propene (202.5 mL, 2 mol) was added drop wise. The mixture was refluxed for 6 h. TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (75 g, 13.6% yield). 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1 H), 7.06 (s, 1 H), 5.72 (s, 1 H), 5.11 (s, 1 H), 4.96 (s, 1 H), 4.47 (s, 2 H), 3.84 (s, 3 H), 1.79 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:30])=[C:16]([C@:18]2([CH3:29])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH2:28])=[N:19]2)[CH:17]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[O:39])=[N:36][CH:37]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[O:39])=[N:36][CH:37]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([NH:28][C:20]2[O:21][C@H:22]([C:24]([F:26])([F:27])[F:25])[CH2:23][C@:18]([C:16]3[CH:17]=[C:12]([NH:11][C:8](=[O:10])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[CH:13]=[CH:14][C:15]=3[F:30])([CH3:29])[N:19]=2)=[O:39])=[N:36][CH:37]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: O=C(c1ccc(Cl)cn1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccc(Cl)cn2)=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stock solution of (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone was prepared by adding N,N′-carbonyldiimidazole (Aldrich; 278 mg, 1.72 mmol) to a solution of 5-chloropicolinic acid (Shao Yuan; 280 mg, 1.78 mmol) in THF (5.0 mL) and heating the reaction mixture to 60° C. for 2 h. (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (4i, 50 mg, 0.172 mmol) was added to a flask containing 0.55 mL (1.1 equiv.) of the (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone stock solution. The reaction mixture was allowed to stir for 30 min at ambient temperature, after which a second aliquot of (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone solution (0.55 mL, 1.1 equiv.) was added. After 16 hs, saturated aqueous NaHCO3 (50 mL) was added to the reaction mixture and the product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4, concentrated, and purified by flash chromatography on silica gel (Gradient: 0%→50% EtOAc/hexane) to give 5-chloro-N-((4S,6S)-4-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)picolinamide (85.3 mg, 0.150 mmol) as a colorless glass. MS m/z=570 M+. Calculated for C24H17Cl2F4N5O3: 570.3
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[OH-].[K+].[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.CCO>C1(C)C=CC=CC=1.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:33]=[N:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1

Procedure:
6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (Intermediate 6) (10 g, 26.0 mmol), PEPPSI™ (1.764 g, 2.60 mmol), KOH (4.37 g, 78 mmol) and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS No. 847818-71-7 available from Milestone PharmTech USA Inc.) (11.78 g, 46.7 mmol) were combined in a mixture of toluene (80 mL), EtOH (40 mL) and water (50 mL). The mixture was degassed and then heated at reflux under a nitrogen atmosphere for 6 h. The solution was cooled, diluted with EtOAc (200 mL) and washed with water (200 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo to give a pale yellow gum. This yellow gum was purified by silica gel column chromatography (330 g column, eluting with 0-100% EtOAC/cyclohexane followed by 10% MeOH/EtOAc). The appropriate fractions were collected and the solvent evaporated in vacuo to give the crude product which was further purified by preparative HPLC (Method HpH) and then dried overnight in a vacuum oven at 55° C. to give 6-(((2S,4R)-1-acetyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (4.62 g).
Reaction SMILES: [F:1][C:2]1[C:3]([Cl:10])=[C:4](C)[C:5]([Cl:8])=[CH:6][CH:7]=1.F[C:12]1C=C(C)C=CC=1.FC1C=C(C)C(Cl)=CC=1.FC1C=C(C)C=CC=1Cl>>[F:1][C:2]1[CH:7]=[C:6]([CH3:12])[C:5]([Cl:8])=[CH:4][C:3]=1[Cl:10]
Reactant: Cc1c(Cl)ccc(F)c1Cl
Reactant: Cc1cccc(F)c1
Agent: Cc1cc(F)ccc1Cl
Agent: Cc1ccc(Cl)c(F)c1
Product: Cc1cc(F)c(Cl)cc1Cl

Procedure:
3-Fluoro-4,6-dichlorotoluene is prepared with reduced formation of 3-fluoro-2,6-dichlorotoluene by chlorinating 3-fluorotoluene in the presence of a catalyst system to give a mixture containing 3-fluoro-6-chlorotoluene and 3-fluoro-4-chlorotoluene and chlorinating this in the presence of another catalyst system to give 3-fluoro-4,6-dichlorotoluene.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8](Br)(C)[C:9](OCC=C)=O.N1C=CC=CC=1C1C=CC=CN=1.C(OCC)(=O)C>[Cu]Br.C(#N)C>[CH3:7][CH2:8][CH2:9][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4]
Reactant: C=CC(=O)OC
Reactant: C=CCOC(=O)C(C)(C)Br
Agent: [Cu]Br
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CC(=O)OCCCC
Temperature: 80 °C

Procedure:
To a 30 mL pyrex tube were added methyl acrylate (5 mL, 4.78 g, 55.5 mmole), allyl 2-methyl-2-bromopropionate(0.354 mL, 460 mg, 2.2 mmole), copper (I) bromide (318 mg, 2.22 mmole), 2,2′-bipyridyl (1.04 g, 6.66 mmole), ethyl acetate (4 mL) and acetonitrile (1 mL). The mixture was degassed by three freeze-pump-thaw cycles and then sealed. The mixture was heated to 80° C. for 3 hours and then after cooling to ambient temperature, the mixture was diluted with ethyl acetate (20 mL). An insoluble precipitate was filtered off and the filtrate was washed twice with dil. ECl and once with NaCl solution. The organic layer was dried over Na2SO4and concentrated under reduced pressure to yield a poly(butyl acrylate) having an alkenyl group at one end and a bromine atom at the other end (3.93 g, 75%). The molecular weight and the molecular weight distribution of the polymer were found to be 2700 and 1.48, respectively, by GPC analysis (based on polystyrene standard). The number of alkenyl groups introduced into the polymer was 0.81 based on 1H NMR analysis.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C@H:12]([NH:18][S:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[N:47]=[C:46]3[C:41]([CH2:42][CH2:43][CH2:44][NH:45]3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]1([S:19]([NH:18][C@@H:12]([CH2:11][N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:39]=[CH:40][C:41]4[CH2:42][CH2:43][CH2:44][NH:45][C:46]=4[N:47]=3)[CH2:34][CH2:33]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:21])=[O:20])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: c1cc2c(nc1C1CCNCC1)NCCC2
Reactant: CCOC(=O)[C@H](Cn1cnc2c(Cl)ncnc21)NS(=O)(=O)c1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NS(=O)(=O)c1cccc2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3.21 g of ethyl (2S)-3-(6-chloropurin-9-yl)-2-(naphthalene-1-sulfonylamino)propionate (Example 2) in 20 ml of abs. DMF were treated with 4.0 g of 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine and 3.88 g of diisopropylethylamine, and the mixture was stirred at 70° C. for 3 h. The solvent was distilled off in vacuo, the residue was taken up in EA and the mixture was extracted three times with water. The aqueous phases were extracted three times with DCM. The combined organic phases were dried over MgSO4 and filtered, and the solvent was distilled off in vacuo. For purification, the residue was chromatographed over silica gel (DCM/CH3OH/CH3COOH/H2O 95:5:0.5:0.5). Yield: 3.29 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:19])[C:8]([C:11]2[CH:12]=[N:13][C:14]([CH:17]=O)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:19])[C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:33][C:28]4[CH:27]=[C:26]([N:23]5[CH2:24][CH2:25][O:20][CH2:21][CH2:22]5)[CH:31]=[CH:30][C:29]=4[N:32]=3)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: Nc1ccc(N2CCOCC2)cc1N
Reactant: COC(=O)c1cnc(-c2ccc(C=O)nc2)c(Cl)c1
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
0.50 g of 3-chloro-6′-formyl-[2,3′]bipyridyl-5-carboxylic acid methyl ester (13) (1.81 mmol) prepared in Example 9 and 0.35 g of 4-morpholinobenzene-1,2-diamine(18) (1.81 mmol) prepared in Example 12 were dissolved in nitrobenzene (5.0 mL), and refluxed under heating for 2 hours. The reactant was cooled to room temperature, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: ethyl acetate/hexane=1/1) to obtain 0.55 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-carboxylic acid methyl ester (yield 68%).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]([CH3:42])[CH3:41])[C:38]([CH3:43])=[C:37]([OH:44])[C:36]3=[O:45])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]([CH3:42])[CH3:41])[C:38]([CH3:43])=[C:37]([O:44][CH3:3])[C:36]3=[O:45])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C(C)C
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: OCCO
Product: COC1=C(C)C(C(C)C)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-isopropyl-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.500 g, 1.83 mmol, 1 eq) and MeOH (10 ml); yield: 0.040 g (7.6%); MS m/z: 286.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 0.54 (d, 3H), 0.94-0.92 (q, 3H), 1.95 (t, 3H), 3.86 (s, 1H), 4.73 (s, 1H), 7.26-7.15 (m, 1H), 7.65-7.51 (m, 2H), 8.22 (d, 1H), 12.46 (d, 1H); HPLC (METHOD [A]): rt 8.32 min (96.64%)
Reaction SMILES: [H-].[Na+:2].C(O[C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:22])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](C)=[CH:16][C:15]=1[NH2:21])=[O:7])C.[CH3:23][S:24]([CH3:26])=[O:25]>>[CH3:23][S:24]([CH2-:26])=[O:25].[Na+:2].[CH3:22][N:11]1[C:12]2[NH:13][C:14]3[CH:19]=[C:18]([CH3:23])[CH:17]=[CH:16][C:15]=3[NH:21][C:6](=[O:7])[C:8]=2[CH:9]=[N:10]1
Reactant: CCOC(=O)c1cnn(C)c1Nc1ccc(C)cc1N
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2c(c1)Nc1c(cnn1C)C(=O)N2
Product: [CH2-]S(C)=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Sodium (methylsulphinyl)methanide (22.7 mmol) was prepared from sodium hydride (60% dispersion in oil, 912 mg, 22.7 mmol) and anhydrous dimethyl sulphoxide (5.5 ml) by heating at 65° C. until a solution was observed. To this was added a solution of 5-(2-amino-4-methyl-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester from Example E2.2 (3.56 g, 13.0 mmol) in anhydrous dimethyl sulphoxide (10 ml), and stirring continued at 65° C. for 30 min. The mixture was then poured into ice (200 ml), the resulting solid collected and purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to yield the title compound (1.12 g, 38%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:13]=[C:12]([O:14][Si](C)(C)C)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)(O)[O-].[Na+]>>[Br:21][CH2:22][CH2:23][CH2:24][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:14])[NH:13][C:4]1=[O:3]
Reactant: BrCCCBr
Reactant: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A mixture of 2,4-bis(trimethylsiloxy)-quinazoline (9.14 g) and 1,3-dibromopropane (30 g) was stirred for 2 hours at 130°-140° C. The reaction mixture was cooled at ambient temperature and a mixture of ice-water and saturated sodium bicarbonate aqueous solution was added to the reaction mixture and then the mixture was stirred vigorously to give precipitates. After the mixture was suspended with chloroform, the precipitates were collected by filtration. The precipitates were washed with water and with chloroform respectively and then dried to give 1-(3-bromopropyl)-2,4(1H,3H)-quinazolinedione (2.12 g) as a crystal, which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:31][CH:32]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)CCc4ccc(F)cc4)c3)c2c1
Yield: 9.8 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 3-(4-fluorophenyl)propanoic acid (0.12 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 22 mg (9% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.25 (s, 1H), 8.15 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (t, 1H), 7.4–7.3 (m, 3H), 7.2–7.1 (m, 2H), 2.85 (t, 2H), 2.65 (t, 2H); ES-MS (m/z) 403 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[N:25]1([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][OH:40])=[CH:33][CH:32]=2)[CH:29]=[N:28][N:27]=[N:26]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:40][CH2:39]/[CH:38]=[CH:37]/[C:34]2[CH:35]=[CH:36][C:31]([CH2:30][N:25]3[CH:29]=[N:28][N:27]=[N:26]3)=[CH:32][CH:33]=2)=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C/c1ccc(Cn2cnnn2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cn3cnnn3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 217 mg (1 mM) of (E)-3-{4-(1,2,3,4-tetrazol-1-ylmethyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 442 mg (83.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]=[C:6]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:7]1[N:17]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[C:10]2[N:11]=[C:12](SC)[N:13]=[CH:14][C:9]=2[CH:8]=1)[CH3:2].O[O:35][S:36]([O-:38])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[C:48]([O-])(O)=O.[Na+]>C1COCC1.CO.O>[CH2:1]([O:3][C:4](=[O:33])[CH:5]=[C:6]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:7]1[N:17]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[C:10]2[N:11]=[C:12]([S:36]([CH3:48])(=[O:38])=[O:35])[N:13]=[CH:14][C:9]=2[CH:8]=1)[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C=C(c1ccccc1Cl)c1cc2cnc(SC)nc2n1-c1c(F)cccc1F
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccccc1Cl)c1cc2cnc(S(C)(=O)=O)nc2n1-c1c(F)cccc1F

Procedure:
To a solution of 3-(2-chloro-phenyl)-3-[7-(2,6-difluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester, 13, (0.33 g, 0.68 mmol) in THF/methanol (4 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (1.46 g, 2.38 mmol) in H2O (4 mL). After stirring the reaction for 1 hour at room temperature, the solution is poured into aqueous saturated NaHCO3. The aqueous phase is extracted with CHCl3 and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to afford 0.31 g of the desired product which is used without further purification.