Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:19][C:20]([OH:22])=[O:21])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(=O)O)C(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of (R)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-4,4-dimethylpentanoic acid, 3a, (0.08 g, 0.14 mmol) in MeOH (2.6 mL) was added sodium methanolate (2.91 mL of 25% w/v, 13.46 mmol). The reaction was stirred at room temperature for 30 min and then quenched by dilution into aqueous saturated ammonium chloride solution. The MeOH was evaporated in vacuo and the resulting aqueous phase diluted with EtOAc, then extracted with EtOAc (3×). The organics were dried (Na2SO4), filtered and concentrated in vacuo. Recrystalization from MeOH provided 52 mg of the desired product 1 as a white powder: 1H NMR (d6-DMSO) δ 12.25 (s, 1H): 12.0 (bs, 1H): 8.8 (s, 1H): 8.3 (s, 1H): 8.25 (s, 1H); 8.1 (s, 1H): 7.45 (d, 1H); 4.75 (t, 1H); 2.5 (m, 2H), 1.0 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.06 minutes (M+H) 392.21.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:36]=[CH:35][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([CH2:26][C:25]2[CH:35]=[CH:36][C:22]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)=[CH:16][CH:15]=[CH:14][N:13]4[N:17]=3)=[CH:23][CH:24]=2)[CH2:28][CH2:29]1
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nc23)cc1

Procedure:
N-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.039 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.7 Hz, 1H), 8.23 (d, J=7.4 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.67 (d, J=6.9 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.04 (t, J=7.2 Hz, 1H), 6.94 (s, 1H), 3.62 (s, 2H), 3.10 (s, 3H), 3.08-3.03 (m, 4H), 3.02-2.97 (m, 4H). MS=512 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1ccccc1Br
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])c(Br)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
2-Bromopyridine-N-oxide (28.36 g) was carefully dissolved in concentrated sulphuric acid (43 ml) with stirring. A mixture of concentrated sulphuric acid (65 ml) and concentrated nitric acid (43 ml) was added dropwise, and the mixture refluxed for 3 hours and allowed to cool to room temperature. The mixture was then poured on to ice and the precipitate removed by filtration , washed with water and air dried leaving a fine yellow powder of 2-Bromo-4-nitro-pyridine-N-oxide (14.08 g, 63%), m.p. 145-147° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][NH:14][CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:16]=O.[BH4-].[Na+]>CO.O>[I:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Cn1c2c(c3cccc(I)c31)CNCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCc2c(c3cccc(I)c3n2C)C1
Temperature: 0 °C
Yield: 15 %

Procedure:
6-Iodo-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.85 g, 12.3 mmol) was suspended in methanol (40 mL). Formaldehyde (14 mL of 37%) was added and heated at reflux for 2 h. The reaction was cooled to 0° C. in an ice bath and sodium borohydride (1.7 g, 46 mmol) was added slowly over 15 minutes and stirred for two h at 0-10° C. The reaction was diluted with water (200 mL) and extracted with CH2Cl2 (3×150 mL). The organics were collected, washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (3% MeOH/CH2Cl2) to give 6-iodo-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.6 g, 15%). 1H NMR (CDCl3 300 MHz) δ 7.59 (d, 1H, J=7.4 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.73 (t, 1H, J=7.7 Hz), 3.98 (s, 3H), 3.62 (s, 2H), 2.83 (s, 4H), 2.55 (s, 3H) ppm.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:35][CH:36]([C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=2)[C:37]([OH:39])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[CH:28]1([CH2:35][CH:36]([C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=2)[C:37]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution of triphenylphosphine (116 mg, 0.44 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (78 mg, 0.44 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid (72 mg, 0.22 mmol) in methylene chloride (2 mL). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (66 mg, 0.66 mmol), and the resulting suspension was stirred for 20 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×10 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and a saturated aqueous sodium chloride solution (1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (68 mg, 76%) as an amorphous solid: EI-HRMS m/e calcd for C21H26N2O3S2 (M+) 406.1426, found 406.1424.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13]C)=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:3]=1.[BrH:22]>C(O)(=O)C>[Br:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:3]=1
Reactant: Br
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1F
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(O)c(F)cc3c(Br)n2)n[nH]1
Temperature: 160 °C

Procedure:
To a solution of (1-Chloro-7-fluoro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (1.0 g) in 10 mL acetic acid was added hydrobromic acid (1 mL, 40%). The mixture was heated at 160° C. for 30 min under microwave irradiation. Most of the solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried with anhydrous sodium sulfate and concentrated to give oil (0.92 g), which was used for the next reaction without further purification. LC-MS m/e 338 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.Cl.[CH3:26]O>>[CH3:26][O:23][C:22](=[O:24])[C@H:2]([CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)[NH2:1]
Reactant: CO
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1

Procedure:
Thyroxine (20 g) was suspended in dry methanol (500 ml). The suspension was saturated with hydrogen chloride gas, cooled and saturated again. The crystals were collected, washed with methanol and ether, and then dried. The resulting thyroxine methyl ester hydrochloride crystals were added to 500 ml of methanol and an equimolar concentration of concentrated sodium hydroxide was added with stirring. Deionized distilled water (500 ml) was added to this solution. The solution was chilled to recrystallize the thyroxine methyl ester from the solution. The crystals were then collected and air dried.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=O)=[CH:18][CH:17]=1.CC[N:31](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]([C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[C:23](=[O:28])[CH2:24][C:25]([NH2:31])=[O:27])=[CH:20][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(Oc2ccncc2)cc1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)CC(=O)N(c1ccc(F)cc1)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A solution of 4-(4-aminophenoxy)pyridine (93 mg, 0.50 mmol) in DMF was treated with 3-(4-fluorophenylamino)-3-oxopropanoic acid (99 mg, 0.50 mmol), DIPEA (113 μL, 0.65 mmol) and TBTU (209 mg, 0.65 mmol) and the mixture was stirred at RT for 2 h. The mixture was concentrated to remove the DMF and the residue partitioned between EtOAc and saturated sodium bicarbonate solution. The EtOAc phase was washed with saturated sodium bicarbonate solution, brine, dried (MgSO4) and concentrated to give the title compound as an off-white foam (140 mg, 76%). 1H NMR (DMSO-d6) δ 10.30 (s, 1H), 10.24 (s, 1H), 8.43 (dd, 2H, J=5.5, 1.5 Hz), 7.70 (d, 2H, J=9.1 Hz), 7.63-7.60 (m, 2H), 7.17-7.14 (m, 4H), 6.89 (dd, 2H, J=5.5, 1.5 Hz), 3.46 (s, 2H); MS(ESI+) m/z 365.9 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([NH:17][C:18]2[N:23]=[CH:22][C:21]([CH:24]([CH3:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C.N1CCCCC1>ClCCl>[OH:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([NH:17][C:18]2[N:23]=[CH:22][C:21]([CH:24]([CH3:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(OC(C)=O)c2)nc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
A solution of (RS) Methyl 3-{6-[2-(3-acetoxy-4-nitrophenyl)-acetylamino]-pyridin-3-yl}-butanoate (1.5 g, Reference Example 16) in dichloromethane (50 mL) was treated with a piperidine (5.0 mL). After stirring at room temperature for 1.5 hours the reaction mixture was washed with aqueous acetic acid (1M), then and dried over magnesium sulphate and then evaporated. The residual light brown oil was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound (1.26 g) as a pale yellow solid.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:32])[CH2:14][C@@H:13]1[C:33]([O:35][CH3:36])=[O:34])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:32])[CH2:14][C@@H:13]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Yield: 90.8 %

Procedure:
A solution of methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 35) (595 mg, 1.19 mmol) in methanol (10 mL) was hydrogenated over palladium on carbon (10%, wet) at normal pressure and room temperature for 30 minutes. It was filtered through a 0.45 μm membrane, washed with methanol and the wash and filtrate were concentrated under reduced pressure to give 395 mg (91%) of the product as a colorless hard foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:7][CH2:6]2.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:16])=[O:17])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1N)N(S(=O)(=O)c1ccc(C)cc1)CC2
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A yellow slurry of 5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-6-nitro-2,3-dihydro-1H-indole (16.1 g, 46 mmol) and NiCl2.6H2O (3.29 g, 13.9 mmol) in THF (150 mL) and MeOH (300 mL) was treated with NaBH4 (5.2 g, 139 mmol) in small portions. The resulting mixture was stirred for 1 h, concentrated onto Celite and purified by column chromatography using 0-10% MeOH (containing 0.2% NH3)/CH2Cl2to obtain 5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-indol-6-amine as white solid (11.94 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3H), 2.63 (t, J=8.15 Hz, 2H), 3.66 (s, 3H), 3.77 (t, J=8.06 Hz 2H), 4.79 (s, 2H), 6.58 (s, 1H), 6.94 (s, 1H), 7.34 (d, J=7.87 Hz, 2H), 7.62 (d, J=7.87 Hz, 2H); ESIMS (M+H)+=320.12.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[C:24]1[O:25][C:26]2[C:31]([C:32](=[O:34])[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2.C([N-]C(C)C)(C)C.[Li+].[C:50](=[O:52])=[O:51]>O1CCCC1>[CH3:41][O:40][C:36]1[CH:35]=[C:23]([CH:22]=[C:21]([O:20][CH3:19])[C:37]=1[O:38][CH3:39])[C:24]1[O:25][C:26]2[C:31]([C:32](=[O:34])[C:33]=1[C:50]([OH:52])=[O:51])=[CH:30][CH:29]=[CH:28][CH:27]=2
Reactant: COc1cc(-c2cc(=O)c3ccccc3o2)cc(OC)c1OC
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Temperature: -60 °C

Procedure:
9.9 ml Diisopropylamine were reacted with 12 ml tetrahydrofuran under a nitrogen atmosphere, and 44.5 ml 1.6 n butyllithium/n-hexane were added at 0° C. to this mixture, and the mixture was cooled to -60° C. Then a further 50 ml of absolute tetrahydrofuran were added, and the solution was cooled to -78° C. A solution of 15 g 3',4',5'-trimethoxyflavone in 500 ml of absolute tetrahydrofuran cooled to about -60° C. was then quickly added to the lithium diisopropylamide solution. After three minutes 10 g of freshly crushed dry ice (CO2, -7820 C.) were added. Then the cooling was removed, and the mixture was allowed to warm to room temperature, excess gaseous carbon dioxide being stirred out of the solution. The reaction mixture was worked up by adjusting to pHl with half-concentrated hydrochloric acid and extracted with dichloromethane. The dichloromethane phase was shaken with an aqueous saturated sodium bicarbonate solution (about 100 ml). The aqueous phase was separated and carefully brought to pH1 with concentrated hydrochloric acid, whereby the resulting 3',4',5'-trimethoxyflavone-3-carboxylic acid precipitated out. The precipitated product was extracted from the reaction mixture with dichloromethane. The dichloromethane phase was separated, dried over sodium sulfate and concentrated, whereupon the product crystallized. 14.75 g of 3',4',5'-trimethoxyflavone-3-carboxylic acid were obtained.
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:34][C:35]1[CH:47]=[CH:46][C:38]([C:39]([C:41]2[CH:45]=[CH:44][O:43][N:42]=2)=[O:40])=[CH:37][CH:36]=1.[Cl:48][C:49]1[CH:59]=[C:58]([O:60][CH2:61][CH:62]=[C:63]([Cl:65])[Cl:64])[CH:57]=[C:56]([Cl:66])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54]O>O1CCCC1>[Cl:48][C:49]1[CH:59]=[C:58]([O:60][CH2:61][CH:62]=[C:63]([Cl:65])[Cl:64])[CH:57]=[C:56]([Cl:66])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54][O:34][C:35]1[CH:47]=[CH:46][C:38]([C:39]([C:41]2[CH:45]=[CH:44][O:43][N:42]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(c1ccc(O)cc1)c1ccon1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1)c1ccon1
Reaction time: 0.5 h

Procedure:
0.93 ml of azodicarboxylic acid diisopropyl ester is added at 0° C. to 1.26 g of triphenylphosphine in 30 ml of tetrahydrofuran and stirring is carried out for 30 minutes. 0.76 g of 3-(4-hydroxybenzoyl)isoxazole and 1.38 g of 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propan-1-ol in 10 ml of tetrahydrofuran are then added dropwise and stirring is carried out at room temperature for 24 hours. After the reaction mixture has been concentrated and purified over silica gel, (4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-isoxazol-3-yl-methanone is obtained in the form of a colourless oil.
Reaction SMILES: [Na:1][Na].[P:3]([OH:33])([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:20][CH:19]=1)([O:5][C:6]1[CH:11]=[CH:10][C:9](OP(O)(O)=O)=[CH:8][CH:7]=1)=[O:4]>>[P:3]([O-:33])([O:5][C:6]1[C:11]2[C:10](=[CH:11][CH:6]=[CH:7][CH:8]=2)[CH:9]=[CH:8][CH:7]=1)([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:22][CH:23]=1)=[O:4].[Na+:1]
Reactant: [Na][Na]
Reactant: CC(C)(c1ccccc1)c1ccc(OP(=O)(O)Oc2ccc(OP(=O)(O)O)cc2)cc1
Product: CC(C)(c1ccccc1)c1ccc(OP(=O)([O-])Oc2cccc3ccccc23)cc1
Product: [Na+]

Procedure:
disodium salt of 4-dihydroxyphosphinyloxyphenyl 4-(1-phenyl-1-methylethyl)phenyl hydrogen phosphate
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[CH:18]=[C:8]([C:9](OC2C=CC=CC=2)=[O:10])[C:7]([OH:19])=[CH:6][CH:5]=1.Cl.[NH2:21]O>CO>[Br:3][C:4]1[CH:18]=[C:8]([C:9]([NH:21][OH:1])=[O:10])[C:7]([OH:19])=[CH:6][CH:5]=1
Reactant: O=C(Oc1ccccc1)c1cc(Br)ccc1O
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=C(NO)c1cc(Br)ccc1O
Reaction time: 4 h

Procedure:
A methanol solution of 127 g of KOH was gradually added to a methanol solution of 210 g of phenyl 5-bromosalicylate prepared as in (2-1) above and 105 g of hydroxylamine hydrochloride. After stirring for 4 hours, the precipitate formed was collected by filtration. The precipitation was then suspended in water, and 60 ml of conc. hydrochloric acid (35%) was added thereto, followed by stirring for two hours to collect the precipitate by filtration followed by drying. Yield: 136 g.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=2)=[CH:10]3)=[CH:4][CH:3]=1.Cl.[CH3:25][NH:26][O:27][CH3:28].CC1(C)C2[C:51](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:50]C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:28][O:27][N:26]([CH3:25])[C:51]([C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=2)=[CH:10]3)=[CH:4][CH:3]=1)=[O:50]
Reactant: CNOC
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 80 °C
Yield: 246.1 %

Procedure:
To a round bottom flask was added 13-bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (1.6 g, 4.3 mmol), N,O-dimethylhydroxylamine hydrochloride (0.62 g, 6.4 mmol), Pd(OAc)2 (95 mg, 0.43 mmol), Xantphos (0.49 g, 0.85 mmol), TEA (1.3 g, 13 mmol) and toluene (20 mL). After being purged with CO three times, the mixture was heated at 80° C. overnight. The solid was filtered off. The filtrate was concentrated and purified by silica gel chromatography using 50% EtOAc in petroleum ether as eluant to give the desired product (800 mg, 50% yield) as a yellow solid. LCMS m/z [M+H]+ 383.3
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[F:14].C([Li])CCC.Cl[C:21]1[C:26]([N:27]=[C:28]=[S:29])=[CH:25][CH:24]=[C:23]([Cl:30])[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CN(C=O)C>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:28]2[S:29][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([Cl:30])[N:22]=3)=[C:3]([F:14])[CH:4]=1
Reactant: S=C=Nc1ccc(Cl)nc1Cl
Reactant: Fc1cc(C2OCCCO2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(Cl)nc2s1
Reaction time: 0.33 h

Procedure:
To a solution of 2-(4-bromo-3-fluorophenyl)-1,3-dioxane (7.65 g, 29.3 mmol) in 75 mL THF under argon at −78° C. was added 1-butyllithium 2.5M in hexanes (12.9 mL, 32.2 mmol) in portions over ˜20 min. The reaction mixture was allowed to stir 20 min, and was yellow. A solution of 2,6-dichloro-3-isothiocyanatopyridine (6.01 g, 29.3 mmol) in 20 mL THF was added dropwise via cannula. The resulting dark brown solution was allowed to stir 15 min, then was quenched by addition of sat'd aq. NH4Cl. The reaction mixture was partitioned between sat'd aq. NH4Cl and Et2O. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give an orange solid. The solid was treated with sodium carbonate (4.66 g, 44.0 mmol) and approximately 15 mL DMF, and stirred under nitrogen at 90° C. The reaction was heated overnight, and in the morning was a solid mass. The reaction was diluted with water, stirred rapidly for several hours, and filtered, rinsing with water and MeOH. The resulting solid was dried in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-chlorothiazolo[5,4-b]pyridine. MS (ESI) m/z: Calculated: 350.0; Observed: 350.9 (M++1).