Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:5]=2[CH:6]=[O:7])[CH2:3][CH2:2]1.Cl([O-])=[O:15].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:5]=2[C:6]([OH:15])=[O:7])[CH2:2][CH2:3]1
Reactant: CCc1cccc(C2CC2)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1cccc(C2CC2)c1C(=O)O
Temperature: 25 °C

Procedure:
2-Cyclopropyl-6-ethyl-benzaldehyde (CAS 945408-11-7) (500 mg, 2.9 mmol) was dissolved in 3.5 mL tert butanol and 1.7 mL 2-methyl-2-butene. At 0° C. a solution of sodium chlorite (80% purity, 422 mg, 3.8 mmol) and sodium dihydrogenphosphate (452 mg, 3.8 mmol) in 3 mL water was added slowly. The reaction mixture was stirred at room temperature over night. The solvents were evaporated off. The residue was taken up in 1N sodium hydroxide solution and was extracted with tert butyl methylether. The aqueous phase was adjusted at pH 1 with 25% HCl and extracted twice with tert butyl methylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was used without any further purification, white solid (412 mg, 75%), MS: m/e=189.3 [(M−H)−].
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[CH:21])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.I[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:19]([C:20]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:18][C:5]([C:6]([N:8]=[S:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Reactant: Oc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=NC(=O)c1cnc(N)c(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of (S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (60 mg, 0.2 mmol), 3-iodophenol (66 mg, 0.3 mmol), triethylamine (0.07 mL, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol), triphenylphosphine (1.3 mg, 0.005 mmol) in 1.8 mL DMF at room temperature was degassed using a H2/N2 (1:1) mixture and then copper(I) iodide (2 mg, 0.01 mmol) added. The reaction was heated at 60° C. for 15 minutes and then partitioned between EtOAc and saturated NaHCO3. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to a brown oil. Before chromatography a different lot of product (23 mg) was added and the combined lots were purified by chromatography (silica gel, EtOAc/EtOH) to the title compound as an off-white solid (91 mg, 89%).
Reaction SMILES: C[Mg+].[Br-].CCOCC.[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[C:19]#[N:20]>C1(C)C=CC=CC=1>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[C:19](=[NH:20])[C:18]1[C:17]([Cl:16])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:25])([CH3:11])[CH3:10]
Reactant: N#Cc1c(Cl)cccc1Cl
Reactant: CC(C)NC(C)C
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)N(C(=N)c1c(Cl)cccc1Cl)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
A solution of MeMgBr in ether (10 mL, 3.0 M, 30 mmol) was added to a solution of diisopropylamine (3.38 g, 33.5 mmol) in toluene (50 mL) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and 2,6-dichlorobenzonitrile (5.0 g, 29 mmol) was added. The mixture was allowed to warm to room temperature and the mixture was stirred for 16 h subsequently. The conversion, determined by GC, appeared to be 100%. The mixture was quenched with an aqueous NH4Cl solution (1%, 150 mL). The organic phase was separated from the aqueous phase and the latter was extracted with CH2Cl2 (250 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure resulting in a sticky residue. Pure product 2.50 g (31%) was obtained by rinsing the residue with ligroin. A second portion of pure ligand (5.20 g (65%)) was obtained by evaporating the solvent slowly. Total yield: 7.70 g (97%). The ligand was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.3 (m, 2H), 7.1 (m, 1H), 3.6 (p, 1H), 3.2 (p, 1H), 1.6 (d, 6H), 1.1 (d, 6H) and by 13C-NMR (75.5 MHz) (CDCl3) δ (ppm) 160.7, 138.5, 132.7, 129.5, 128.6, 52.7, 46.2, 21.5, 20.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[C:4]2[O:13][C:12]([C:15]([OH:17])=[O:16])([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:8][C:7]1[C:2]([CH3:1])=[C:3]([CH3:18])[C:4]2[O:13][C:12]([C:15]([O:17][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:16])([CH3:14])[CH2:11][CH2:10][C:5]=2[C:6]=1[CH3:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(C(=O)OCc1ccccc1)O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
To a solution of Trolox® (10 g, 39.1 mmol) at) at 0° C. in DMF (50 mL), was added sodium hydride (60% dispersion in oil, 3.5 g, 87.9 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and then benzyl bromide (17.1 g, 99.9 mmol) was added drop wise. The reaction mixture was allowed to warm to room temperature and stirred for overnight. DMF was evaporated under high vacuum and then the residue was dissolved in ethyl acetate (200 mL) and washed with 1 N aqueous HCl (100 mL) and brine (100 mL) to give 10.1 g (58.7%) of an oil of the intermediate, benzyl (6-benzyloxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carboxylate. 1H NMR (CDCl3) δ1.57 (s, 3H), 1.82 (m, 1H), 2.02 (s, 3H), 2.08 (s, 3H), 2.15 (s, 3H), 2.44 (m, 3H), 4.61 (s, 2H), 5.00 (q, 2H), 7.00-7.45 (m, 10H). MS(ES) m/z 431.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[CH2:22][NH:21][CH2:20][CH2:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C>>[Cl:32][C:31]1[C:26]([N:21]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][N:18]=[C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([S:3]([C:2]([F:1])([F:23])[F:24])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[C:14]=3[CH2:22]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Clc1cccnc1Cl
Reactant: O=S(=O)(c1ccc(Nc2ncnc3c2CNCC3)cc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cc1)C(F)(F)F
Yield: 18.9 %

Procedure:
The title compound was prepared according to the procedure given for Compound 4C using 5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[4,3-d]pyrimidin-4-amine (160 mg, 0.45 mmol), 2,3-dichloropyridine (135 mg, 0.9 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.9 mmol) to give the desired compound as an off-white powder (40 mg, 19%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15]([Cl:18])(Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:18][C:15]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: O=C(Cl)Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-methylpiperazine (0.65 ml) and triethylamine (1.3 ml) in toluene (25 ml) at 0° C. was added dropwise a solution of phosgene in toluene (20%, 5.1 ml) over a period of 15 min. The reaction was allowed to warm to room temperature, stirred for 3 hr, filtered and concentrated to approximately 10 ml under reduced pressure to give a solution of 1-chlorocarbonyl-4-methylpiperazine which was reacted with 5-oximino-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide (Example 5) (300 mg), triethylamine (1101) and 4-dimethylaminopyridine (5 mg) in dichloromethane (10 ml) at room temperature according to the method described in Example 45. Purification of the desired material was achieved by chromatography on silica (Kieselgel 60, 230-400 mesh, Merck) (35 g) eluting with dichloromethane. Appropriate fractions were combined and evaporated to dryness under vacuum to give a material (53 mg) which was further purified by high pressure liquid chromatography on a Dynamax (trade mark) column (21.2×250 mm, 5 μm, ODS-silica, Rainin) eluting at 20 ml per minute with a methanol-water 95:5 mixture. Appropriate fractions were combined and evaporated under vacuum to yield the title compound as a white powder. Mass and NMR spectra were fully consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccc(C(F)(F)F)cc3)c2c1
Yield: 76 %

Procedure:
This compound was prepared from 6b using 4-trifluoromethylphenylboronic acid according to method P. Yellow crystals; Yield: 76%; mp 299–300° C.; 1H-NMR (400 MHz, DMSO-d6) δ 7.07 (dd, J=8.8, 8.8 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.94 (dd, J=8.4, 2.1 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 8.07 (dd, J=13.0, 2.0 Hz, 1H), 9.91 (s, 1H), 10.21 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.58 (dd, J=13.2, 9.3 Hz), −61.43 (s); MS (ESI) m/z 398 ([M−H]−), 400 ([M+H]+); Anal. Calcd for C22H13F4NO2: C: 66.17, H: 3.28, N: 3.51. Found: C: 66.09, H: 3.41, N: 3.45.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O>[CH:1]([C:4]1[C:12]([C:13](=[O:15])[CH3:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2ccccn2n1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
2-Isopropyl-pyrazolo[1,5-a]pyridine (10.00 g, 66.7 mmol), acetic anhydride (100 ml), and concentrated sulfuric acid (10 drops) were combined and stirred for 3 hours at reflux. The reaction mixture was cooled to room temperature and poured into ice water (300 ml). The mixture was quenched with 2 N sodium hydroxide until the pH>10, and the quenched solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (0 to 40% ethyl acetate in hexanes) to give 11.8 g (87%) of 1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-ethanone. 1H-NMR (250 MHz, DMSO-d6) δ 8.47 (d, J=6.8 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.38 (t, J=7.3 Hz, 1H), 6.89 (t, J=6.0 Hz, 1H), 3.76 (sept, J=6.9 Hz, 1H), 2.60 (s, 3H), 1.39 (d, J=6.8 Hz, 6H); LC/MS 203.3 m/z (M+H+).
Reaction SMILES: [CH:1]([OH:3])=O.N1(C(N2C=CN=C2)=O)C=CN=C1.C(OC([N:23]1[C:27]2[N:28]=[CH:29][N:30]=[C:31]([N:32]3[CH2:39][C:36]4([CH2:38][CH2:37]4)[N:35]([S:40](=[O:43])(=[O:42])[NH2:41])[CH2:34][CH2:33]3)[C:26]=2[CH:25]=[CH:24]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:28]1[C:27]2[NH:23][CH:24]=[CH:25][C:26]=2[C:31]([N:32]2[CH2:33][CH2:34][N:35]([S:40]([NH:41][CH:1]=[O:3])(=[O:43])=[O:42])[C:36]3([CH2:38][CH2:37]3)[CH2:39]2)=[N:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Reactant: O=CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=CNS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Formic acid (0.24 mmol) was dissolved in dry THF (0.5 mL), added di(imidazol-1-yl)methanone (0.29 mmol) and then stirred at 50° C. for 30 min. before being cooled to rt and added 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (Intermediate 2) (0.24 mmol) and DBU (0.29 mmol). The reaction mixture was stirred at rt for 16 h. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:12]N1C(=O)CCC1=O>O1CCCC1.S(=O)(=O)(O)O>[Br:12][C:8]1[C:9]([NH2:11])=[CH:10][C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Nc1cc2c(cc1Br)OCCO2
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (1 g, 6.6 mmol) in tetrahydrofuran (15 ml) was cooled to −78 deg C. then treated with 1 drop of concentrated sulphuric acid followed by N-bromosuccinimide (1.2 g, 6.6 mmol). The mixture was allowed to warm to room temperature over 1 hour then evaporated. The residue was dissolved in ether, washed with water then brine, dried and evaporated to afford an oil (1.4 g, 93%).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1ccc(-c2cncs2)cc1
Product: Clc1ccc(Br)cc1Cc1ncc(-c2ccccc2)s1

Procedure:
The above 5-phenylthiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 100 to give 5-bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene as a yellow solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2].FC(F)(F)C([O-])=O.[C:33](Cl)(=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([CH2:22][CH3:23])[C:33](=[O:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc(C)cnc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)CCc2ccccc2)c1

Procedure:
[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, trifluoroacetate (0.36 mmol) was reacted with hydrocinnamoyl chloride (0.06 mL, 0.44 mmol) and triethylamine (0.15 mL, 1.09 mmol) in CH2Cl2 to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[NH:15][C:14](=[S:16])[NH:13][C:12]2=[O:17])=[CH:2]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[OH-].[Na+].CO>[CH2:18]([S:16][C:14]1[NH:13][C:12](=[O:17])/[C:11](=[CH:10]/[C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)/[N:15]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NC(=S)NC1=Cc1c[nH]c2ncccc12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(SCc2ccccc2)=N/C1=C\c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxoimidazolidin-4-one (500 mg, 2.05 mmol) in 12.6% aq. NaOH (1 mL) and methanol (5 mL), benzyl bromide (430 mg, 2.5 mmol) was added and the reaction mixture stirred at RT for 18 h. Most of the solvent was distilled out and the precipitate was filtered and washed first with water, then with diethylether and dried. The crude material was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 15:1). Obtained the desired (5Z)-2-(benzylthio)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,5-dihydro-4H-imidazol-4-one, as a yellow solid (700 mg, 2 mmol).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:36])([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[C:10]([CH3:36])[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OC(C)(C)C(=O)O
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-methylphenoxy}-2-methylpropionic acid ethyl ester (11.8 mmol) in THF (30 mL) and methanol (60 mL) was treated with 5N aqueous NaOH (20 mL). The solution was heated at 55° C. for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (20 mL), acidified with 5N aqueous HCl (25 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (40 mL), dried (Na2SO4), and concentrated to yield the desired product. mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.62 (dt, J=6.8, 1.2 Hz, 2H), 7.45 (tt, J=6.8, 1.2 Hz, 2H), 7.37 (tt, J=7.2, 2.0 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 6.71 (d, J=3.2 Hz, 1H), 6.57 (dd, J=8.8, 3.2 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 3.82 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 2.21 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([CH3:18])=[CH:16][C:15](=[O:19])[NH:14]1)=[O:12].Cl[Si](C)(C)C.C(Br)C=C>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[CH2:18])[CH:16]([CH2:3][CH:1]=[CH2:2])[C:15](=[O:19])[NH:14]1)=[O:12]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C=C1C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1C(=C)C(C(=O)OC)(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
Lithium diisopropylamide solution (0.695 M solution in tetrahydrofuran, 5.66 ml, 3.93 mmol, 1.0 equiv) was added dropwise via syringe to a stirred solution of 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (1.5 g, 3.93 mmol, 1.0 equiv) in tetrahydrofuran (45 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Chlorotrimethylsilane (0.5 ml, 427 mg, 3.93 mmol, 1.0 equiv) was added and the resultant solution was stirred at −78° C. for 3 h. Another equiv of lithium diisopropylamide solution (0.695 M solution in tetrahydrofuran, 5.66 ml, 3.93 mmol, 1.0 equiv) was added dropwise at −78° C. The reaction mixture was stirred −78° C. for 30 min. Allyl bromide (0.68 ml, 0.951 g, 7.86 mmol, 2.0 equiv) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 2 h. A buffer solution (pH=7, 100 ml) was added at −78° C. The mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to furnish 4-allyl-2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methylene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (0.757 g, 46%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH2:26]([O:28]C(C1C=CNC=1C)=O)C.COC1C=CC(CBr)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:28][CH3:26])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: COc1ccc(CBr)cc1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1

Procedure:
Prepared similarly according to a reaction sequence in Example 117 steps (a), (b), (c) and (d) for the synthesis of 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, 4-methoxybenzyl bromide. The title compound, ESI MS (m/z): 483 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5](/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[C:4]([CH3:18])[N:3]=1.C1CCN2C(=NCCC2)CC1>O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[CH:12][C:13](=[O:14])[N:8]([CH2:9][CH3:10])[C:6]=2[N:7]=1
Reactant: CCNc1nc(N)nc(C)c1/C=C/C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCn1c(=O)ccc2c(C)nc(N)nc21
Temperature: 165 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
(E)-Ethyl 3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (4.50 g, 18.0 mmol) was added to DBU (10.95 g, 4.0 equiv.) and the mixture was heated to 165° C. and stirred for 24 h. After that, the mixture was cooled to 70° C. followed by the addition of H2O (20 mL) to precipitate crystal and stirred for 1 h at room temperature. The crystal was collected and washed with H2O and acetone and dried under vacuum to afford 2.70 g (73.5% yield of 2-amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a light yellowish brown solid. LC/MS: Calculated for C10H12N4O (204.2). Found: 205.31 (MH+); HPLC analytical purity: 98.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CO>[CH3:23][N:24](/[CH:26]=[C:11]1\[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[C:10]\1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:25]
Reactant: COC(OC)N(C)C
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Solvent: CO
Product: CN(C)/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (2.5 g, 8.1 mmol) was dissolved in methanol (3 mL), treated with N,N-dimethylformamide dimethylacetal (1.2 g, 9.7 mmol, 1.2 equiv) and placed into a preheated oil bath at 60° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.