Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[C:29]([F:37])[CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1.N>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[C:29]([F:37])[CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)c(F)c3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1F

Procedure:
The title compound was prepared according to the method of Example 346, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-fluorophenol in place of isobutanol mp 168-170° C. 1H NMR (300 MHz, DMSO-d6) δ 3.39 (s, 3H), 7.15 (d, 4H), 7.51 (m, 1H), 7.6 (m, 1H), 7.6 (m, 1H) 7.75 (m, 3H), 7.97 (t, 1H); 8.4 (s, 1H). MS (DCI/NH3) m/z 491 (M+H)+, 508 (M+NH4)+. Anal. calc. for C23H14F4N2O4S: C, 56.33; H, 2.88; N, 5.71. Found, C, 56.07; H, 2.94; N, 5.33.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].BrBr.[Br:10][C:11]1[CH:12]=[C:13]([C:21](=[S:23])[NH2:22])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])O.[Na+].[CH2:29](OCC)[CH3:30]>C(O)C>[Br:10][C:11]1[CH:12]=[C:13]([C:21]2[S:23][C:6]([CH3:7])=[C:2]([C:3]([O:5][CH2:29][CH3:30])=[O:4])[N:22]=2)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=1
Reactant: NC(=S)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCC(=O)C(=O)O
Reactant: CCOCC
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc(-c2cc(Br)cc(C(F)(F)F)c2)sc1C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (30 mL) of 2-oxobutyric acid (3.0 g, 29 mmol) in diethyl ether was slowly added dropwise a solution (20 mL) of bromine (2.6 g, 33 mmol) in diethyl ether over 30 min, and the mixture was stirred at the same temperature for 3 hr. The solvent was evaporated under reduced pressure, and to a solution (50 mL) of the residue in ethanol was added the compound (3.2 g, 11 mmol) obtained in Example 77b, and the mixture was stirred at 80° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=90/10) to give a crude title compound (5.9 g) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH3:16])([CH3:15])[CH2:9]1.[C-:28]#[N:29].[Na+].[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([NH:31][C:11]2([C:28]#[N:29])[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]4=[O:27])=[CH:3][C:2]=3[F:1])[CH2:9][C:10]2([CH3:15])[CH3:16])[CH:33]=1
Reactant: [C-]#N
Reactant: Nc1cccnc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccnc4)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 48 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)—N-{3-[3-fluoro-4-(4-oxo-3,3-dimethylpiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 3-aminopyridine the compound was obtained in 48% yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: O=C(O)CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(F)cc4n3)cc21
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(F)cc4n3)cc21

Procedure:
2-(7-Fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:6]=1)=[NH:4].[S:25]([C:29]1[S:30][C:31]([C:34](O)=O)=[CH:32][CH:33]=1)(=[O:28])(=[O:27])[NH2:26]>>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:34]([C:31]3[S:30][C:29]([S:25]([NH2:26])(=[O:28])=[O:27])=[CH:33][CH:32]=3)[O:1][N:2]=2)[N:10]=1
Reactant: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)s1
Product: NS(=O)(=O)c1ccc(-c2nc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)no2)s1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxamidine (example C.2) (0.176 g, 0.5 mmol) and commercially available 2-sulfamoyl-thiophene-5-carboxylic acid [CAS-No. 7353-87-9] (0.104 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.12 g, 46%). MS (ISN) 520.1 [(M−H)−]; mp 258.5° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:13][C:12]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:11]=3[O:10]2)[CH2:6][CH2:5]1)(=O)C.[ClH:21]>CCOCC>[ClH:21].[N+:18]([C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:7]3([CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[CH2:13][C:12]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: CC(=O)N1CCC2(CC1)Cc1cc([N+](=O)[O-])ccc1O2
Agent: Cl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3.4 g of 2,3-dihydro-1'-acetyl-5-nitrospiro[benzofuran-2,4'-piperidine] in 150 ml of 6 N hydrochoric acid is refluxed for 45 hours and then stirred at ambient temperature for 16 hours. Thereafter, the reaction mixture is successively extracted once with ether, basified with 6 N sodium hydroxide and extracted thrice with ether. The combined ether extracts are dried and the solvent is removed, leaving a yellow residue. The residue is dissolved in ether where it is converted to its hydrogen chloride salt. The salt is collected, dried and finally recrystallized twice from ethyl alcohol to give the product, 2,3-dihydro-5-nitrospiro[benzofuran-2,4'-piperidine]hydrochloride, mp 265°-266° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].[CH2:23]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:24][CH2:25][CH3:26]>CC#N.CCOC(C)=O>[CH2:23]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:16])[CH2:29][CH2:28]1)[CH2:24][CH2:25][CH3:26]
Reactant: Cc1cccc2c1ccc(=O)n2CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCC1CCN(CCCn2c(=O)ccc3c(C)cccc32)CC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-5-methyl-1H-quinolin-2-one (0.053 g, 0.23 mmol), KI (0.083 g, 0.5 mmol), K2CO3 (0.069 g, 0.50 mmol) and 4-butylpiperidine (50 μl, 0.30 mmol) in CH3CN (2 mL). The mixture was shaken at 50° C. for 72 h and then diluted with EtOAc (25 mL) and washed with water (15 mL). The water phase was extracted (2×25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 1:4) to give the title compound (0.058 g, 74%). 1H NMR (CD3OD) δ 8.13 (d, J=9.8 Hz, 1H), 7.56-7.46 (m, 2H), 7.15 (brd, 6.8 Hz, 2H), 6.67 (d, J=9.8 Hz, 1H), 4.38 (t, J=7.2 Hz, 2H), 3.10-3.03 (m, 2H), 2.68-2.61 (m, 2H), 2.57 (s, 3H), 2.25-2.15 (m, 2H), 2.04-1.95 (m, 2H), 1.78-1.69 (m, 2H), 1.36-1.16 (m, 9H), 0.89 (t, J=7.0 Hz, 3H); 13C NMR (CD3OD) δ 162.3, 138.7, 136.6, 136.2, 130.4, 123.6, 119.4, 118.9, 112.4, 54.7, 52.9, 39.9, 35.3, 34.5, 30.7, 28.2, 23.7, 22.1, 17.3, 12.6; HPLC-MS (ammonium acetate) [M+H]+=341.3.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1[CH:18]=[CH:17][CH:16]=[C:9]2[C:10]([O:12][C:13](=[O:15])[NH:14][C:8]=12)=[O:11].S(=O)(=O)(O)O>>[CH3:6][C:7]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[CH:16]=[C:9]2[C:10]([O:12][C:13](=[O:15])[NH:14][C:8]=12)=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])cc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium nitrate (1.43 g, 14.1 mmole) was added in small portions at <30° C. with external water-bath cooling to a solution of 3-methyl isatoic anhydride (2.50 g, 14.1 mmole) and concentrated sulfuric acid (8 mL). The resulting mixture was stirred at 25° C. for 1.5 hours and then was poured into approximately 200 g of ice with stirring. After the ice had melted, the solid product was isolated by filtration and washed with dilute aqueous HCl and then air-dried. The product was suspended in acetonitrile (50 mL) and concentrated in vacuo to give 2.75 of a yellow solid. 1H NMR (DMSO-d6): δ 11.6 (br s, 1H), 8.45 (d, 1H), 8.42 (d, 1H), 2.43 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])[CH2:3]1.[OH-].[Li+].CO>O>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:13]=2)=[O:7])[CH2:5]1
Reactant: CCOC(=O)c1cc(C(=O)N2CC(O)C2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylate (2.0 g, 5.9 mmol), lithium hydroxide (0.56 g, 24 mmol), methanol (100 mL), and water (10 mL) was stirred at rt for 4 h. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH 2-3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to yield a white solid. LC-MS: 312.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6): 13.30 (bs, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.64 (d, 2H, J=8.0 Hz), 7.32 (d, 2H, J=8.0 Hz), 5.79 (bs, 1H), 4.52 (s, 2H), 4.30 (bs, 1H), 4.10 (bs, 1H), 3.84 (d, 1H, J=9.6 Hz), 2.37 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([I:8])=[N:6][CH:7]=1.C1COCC1.CCN(C(C)C)C(C)C.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl.[Cl:31]CCCl>>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:5]([I:8])=[N:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:5]([Cl:31])=[N:6][CH:7]=1
Reactant: ClCCCl
Reactant: COCCOCCl
Reactant: Oc1cc(Br)cnc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCOc1cc(Br)cnc1Cl
Product: COCCOCOc1cc(Br)cnc1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A dry, 100 mL one neck round bottom flask was charged with 5-bromo-2-iodopyridin-3-ol (2.30 g, 7.67 mmol), 15 mL dry THF, a stirbar and n,n-diisopropylethylamine, 99.5% (1.74 ml, 9.97 mmol). The flask was fitted with an inert atmosphere inlet, and swept with Ar for several minutes. To the stirring solution was added 2-methoxyethoxymethyl chloride (0.955 ml, 8.44 mmol) over 5 minutes. The reaction was stirred at room temperature for 24 h, and poured onto 100 mL DCE. The solution as washed with 5% NaHCO3 (2×25 mL) and the DCE solution was passed through an unbuffered Varian Chem elute CE1010 (100 mL, PN 12198010). The tube was extracted with DCE (2×40 mL), and the combined DCE solution was concentrated in vacuo. The residue was purified using 80 g of SiO2 wet packed with 5% THF in hexanes and eluted with 500 mL 10% THF, followed by 500 mL 15% THF in hexanes. A band that eluted with Rf=0.33 (15% THF in hexanes) was isolated. The solvent was removed in vacuo to afford 5-bromo-2-iodo-3-((2-methoxyethoxy)methoxy)pyridine as the major component of a 70:30 mixture with 5-bromo-2-chloro-3-((2-methoxyethoxy)methoxy)pyridine (2.0846 g). Data for 5-bromo-2-iodo-3-((2-methoxyethoxy)methoxy)pyridine: 1H NMR (300 MHz, chloroform-d) δ ppm 3.38 (s, 3H) 3.57 (dd, J=6.43, 2.70 Hz, 1H) 3.57 (t, J=4.46 Hz, 1H) 3.87 (ddd, J=6.34, 2.76, 1.94 Hz, 2H) 5.36 (s, 2H) 7.50 (d, J=2.05 Hz, 1H) 8.14 (d, J=2.05 Hz, 1H). 13C NMR (75 MHz, chloroform-d) δ ppm 59.04 (s, 1 C) 68.53 (s, 1 C) 71.28 (s, 1 C) 94.17 (s, 1 C) 110.02 (s, 1 C) 120.28 (s, 1 C) 124.12 (s, 1 C) 144.61 (s, 1 C) 153.67 (s, 1 C). NMR data for 5-bromo-2-chloro-3-((2-methoxyethoxy)methoxy)pyridine: 1H NMR (300 MHz, chloroform-d) δ ppm 3.38 (s, 3H) 3.57 (dd, J=6.43, 2.70 Hz, 1H) 3.57 (t, J=4.46 Hz, 1H) 3.87 (ddd, J=6.34, 2.76, 1.94 Hz, 2H) 5.36 (s, 2H) 7.71 (d, J=2.12 Hz, 1H) 8.12 (d, J=2.12 Hz, 1H). 13C NMR (75 MHz, chloroform-d) δ ppm 59.04 (s, 1 C) 68.53 (s, 1 C) 71.28 (s, 1 C) 94.24 (s, 1 C) 118.90 (s, 1 C) 126.44 (s, 1 C) 140.18 (s, 1 C) 142.57 (s, 1 C) 149.75 (s, 1 C).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([OH:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[O:21][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)cc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)nc1
Product: O=Cc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)nc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 6-fluoronicotinaldehyde and 3-chloro-5-(trifluoromethyl) phenol.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].O>Br(O)(=O)=O.C(O)(=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: [O-][Br+2]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccccc1[N+](=O)[O-]

Procedure:
In the same manner as in Example 3, the operation was conducted, except that 0.61 g (4 mmols) of o-nitrobenzyl alcohol was used in place of m-methoxybenzyl alcohol and 2 ml of water and one drop of 47% bromic acid were used in place of 2 ml of acetic acid. With respect to the components in the reaction solution, the intended o-nitrobenzaldehyde was produced in an area ratio, as determined by gas chromatography, of 75.2% and 24.2% of o-nitrobenzyl alcohol as a raw material was remained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:5]2=[O:20].[C:21](OC(=O)C)(=[O:23])[CH3:22].[CH3:28][C:29](CC(O)=O)=[O:30]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:21](=[O:23])[CH3:22])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:29](=[O:30])[CH3:28])=[CH:15][CH:14]=1)[C:5]2=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)c(Cl)cc12
Reactant: CC(=O)CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2coc3cc(OC(C)=O)c(Cl)cc3c2=O)cc1
Temperature: 107.5 °C
Yield: 75 %

Procedure:
A mixture of 6-chloro-4′,7-dihydroxyisoflavone (1.25 g, 4.3 mmol), acetic anhydride (7.5 ml) and pyridine (1.4 ml) was heated in an oil bath at 105-110° C. for 1 h. After cooling the mixture to room temperature, it was stirred for a further 30 min during which time the diacetate crystallised from the solution. The product was filtered, washed thoroughly with aqueous methanol (50%) and dried to yield 6-chloro-4′,7-diacetoxyisoflavone (1.2 g, 75%) as colourless prisms. 1H NMR (CDCl3): δ 2.32 (s, 3H, OCOCH3), 2.41 (s, 3H, OCOCH3), 7.16 (d, 2H, J 8.6 Hz, ArH), 7.36 (s, 1H, H8), 7.57 (d, 2H, J 8.6 Hz, ArH), 8.00 (s, 1H, H5), 8.37 (s, 1H, H2).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[NH2:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15].[NH2:18][C:19]1[C:20]([CH3:27])=[N:21][N:22]([CH3:26])[C:23]=1[C:24]#N.[OH-].[NH4+]>C(Cl)(Cl)Cl>[CH3:26][N:22]1[C:23]2[C:24]3[N:17]([C:14]([CH3:16])([CH3:15])[CH2:13][N:12]=3)[C:1]([CH3:2])=[N:18][C:19]=2[C:20]([CH3:27])=[N:21]1
Reactant: Cc1nn(C)c(C#N)c1N
Reactant: CC(C)(N)CN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1=Nc2c(C)nn(C)c2C2=NCC(C)(C)N12

Procedure:
The requisite 2-(4-amino-1,3-dimethyl-5-pyrazolyl)-3,3-dimethylimidazoline is prepared as follows. p-Toluenesulfonic acid (10 g, 0.055 mol) is added to 5 g (0.057 mol) of 1,2-diamino-2-methylpropane and to the resulting hot (100°) melt is added 7 g (0.05 mol) of 4-amino-5-cyano-1,3-dimethylpyrazole. The mixture is heated in an oil bath at 185°-195° C. for six hours. The residue, an amorphous yellow solid is dissolved in 250 ml of chloroform and stirred with 40 ml of conc. ammonium hydroxide. The organic layer is separated, dried (MgSO4), and evaporated in vacuo to give 9 g (90%) of slightly crude title compound as a viscous purple oil.
Reaction SMILES: [CH3:1][C:2]1([NH:15][C:16]([NH2:18])=[S:17])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:19][I:20]>CCO>[IH:20].[CH3:1][C:2]1([NH:15][C:16]([S:17][CH3:19])=[NH:18])[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: CI
Reactant: Cc1cc(N2CCC(C)(NC(N)=S)CC2)ncn1
Solvent: CCO
Product: CSC(=N)NC1(C)CCN(c2cc(C)ncn2)CC1
Product: I
Temperature: 75 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 1-(4-methyl-1-(6-methylpyrimidin-4-yl)piperidin-4-yl)thiourea (1.28 g, 4.82 mmol) in EtOH (11.7 mL) was added MeI (332 L, 5.31 mmol) and the reaction mixture was stirred under Argon at 75° C. for 3 hours. The reaction mixture was then evaporated and the residue (white foam) stirred with diethylether (15 mL) at room temperature for 1 hour. The solid was then washed with diethylether and dried to afford the title compound (1.89 g, 96%) as a white solid. MS ISP (m/e): 190.3 [(M+H)+].
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)=[N:10][C:8]=2[N:9]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[CH2:1]([S:3]([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]([C:20]3[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=3)=[N:10][C:8]=2[N:9]=1)=[O:33])[CH3:2]
Reactant: CCSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine-7-yl]benzaldehyde (1.0 g, 2.69 mmol) in CH2Cl2 (30 mL) was added m-chloroperoxy benzoic acid (0.660 g, 3.0 mmol). The solution was stirred for 1 hr then quenched with sat. NaHCO3 and 10% Na2S2O3 and stirred for 30 min. The reaction mixture was diluted with CH2Cl2, extracted, dried with MgSO4, and filtered to afford the title compound. LRMS m/z (M+H) Calcd: 388.1 found: 388.1
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:35].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2](=[O:35])[NH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:31][CH:30]=1
Reactant: O=N[O-]
Reactant: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (400 mg, 0.88 mmoL) was dissolved in 3.5 M H2SO4 (10 mL), and 2 M NaNO2 (6 mL) was added at 0° C. The reaction mixture was stirred at rt for 20 min. The reaction mixture was then treated with aqueous NaOH solution (8%), and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (350 mg, 0.78 mmol). 1H NMR (CDCl3): δ=1.10-1.25 (m, 8H), 1.37 (m, 1H), 1.42-1.55 (m, 2H), 1.78-1.93 (m, 2H), 2.10-2.38 (m, 2H), 2.87 (m, 2H), 3.52-3.58 (m, 1H), 3.31-3.97 (m, 1H), 4.12-4.19 (m, 1H), 5.53-5.63 (m, 1H), 6.85-7.15 (m, 3H), 7.35-7.55 (m, 1H), 7.75-7.89 (m, 1H), 8.10-8.12 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].Br[CH2:14][CH2:15][CH2:16][Cl:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([C:10](=[O:12])[CH3:11])=[CH:5][C:6]=1[F:9]
Reactant: ClCCCBr
Reactant: CC(=O)c1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cc(F)c(OCCCCl)c(F)c1
Temperature: 25 °C
Yield: 110.4 %

Procedure:
A mixture of 1-(3,5-difluoro-4-hydroxyphenyl)ethanone (8.1 g, 47 mmol), 3-bromo-1-chloropropane (14.7 g, 93 mmol) and K2CO3 (21.3 g, 154 mmol) in acetone (120 mL) was stirred at reflux for 20 h. The reaction was cooled to rt and concentrated at reduced pressure, then partitioned between water and methylene chloride. The aqueous layer was extracted twice with methylene chloride to obtain 1-[4-(3-chloropropoxy)-3,5-difluoro-phenyl]ethanone (12.9 g, quantitative yield); MS m/z 249 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[O:17]=[C:18]1[C:23]([CH:24]=O)=[CH:22][CH:21]=[CH:20][NH:19]1.C(Cl)Cl>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[CH:24][C:23]3[C:18](=[O:17])[NH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=Cc1ccc[nH]c1=O
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]cccc1C=C1c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of 2-nitrofluorene (326 mg, 1.54 mmol) and 2-oxo-1,2-dihydro-pyridine-3-carbaldehyde (19 mg, 1.54 mmol) in 10 mL of methanol was added KF—Al2O3 (224 mg, 1.38 mmol). The resulting mixture was stirred at 85° C. After 24 hrs, TLC indicated that a new product was produced and lots of starting material was still remained. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was purified by silica gel column; eluting with 60% EtOAc in hexane afforded 26 mg of CYD-1-93 as a yellow solid. 1H-NMR (600 MHz, d6-DMSO) δ 12.18 (br s, 2H), 8.77 (d, 1H, J=1.8 Hz), 8.52 (d, 1H, J=1.8 Hz), 8.28 (m, 2H), 8.15 (m, 2H), 8.10 (d, 1H, J=7.8 Hz), 8.06 (m, 2H), 7.97 (m, 2H), 7.86 (m, 2H), 7.80 (s, 1H), 7.63 (m, 1H), 7.59 (m, 1H), 7.49 (m, 3H), 7.37 (m, 1H), 6.40 (m, 2H). 13C-NMR (150 MHz, CDCl3) δ 161.2, 161.1, 146.9, 146.2, 146.1, 143.6, 142.1, 141.7, 140.5, 139.6, 138.3, 137.3, 136.1, 136.0, 133.6, 133.4, 129.3, 129.1, 129.0, 128.8, 127.9, 127.4, 126.1, 125.9, 124.0, 123.9, 123.5, 121.9, 121.5, 121.1, 120.7, 120.5, 119.0, 105.1, 105.0.