Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[CH:3][CH:4]=1)[CH3:15]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)O
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)NC(=O)CCC(=O)O
Temperature: 95 °C
Yield: 56.4 %

Procedure:
A mixture of (R)-4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (50 mg, 0.129 mmol), 4-fluorophenylboronic acid (27.2 mg, 0.194 mmol), Pd(Ph3P)4 (14.96 mg, 0.013 mmol) and aqueous Na2CO3 (0.129 mL, 0.259 mmol) in toluene (1 mL) is allowed to stir at 95° C. under nitrogen. After stirring for 13 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCl. The products are extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-3-(3-carboxy-propionylamino)-4-(4′-fluoro-biphenyl-4-yl)-butyric acid ethyl ester (29.2 mg). HPLC retention time=1.26 minutes (condition B); MS (m+1)=402.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7 Hz, 3 H) 2.47-2.67 (m, 6 H) 2.87 (A of ABX, Jab=13.7 Hz, Jax=7.9 Hz, 1 H) 2.99 (B of ABX, Jab=13.7 Hz, Jbx=6.6 Hz, 1 H) 4.12-4.23 (m, 2 H) 4.47-4.55 (m, 1 H) 6.52 (br d, J=8.6 Hz, 1 H) 7.08-7.14 (m, 2 H) 7.24 (d, J=8.4 Hz, 2 H) 7.46-7.55 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2sccc2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine 3, (8.68 g, 42.34 mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 as a white solid (11.04 g, 100%). 1H NMR (400 MHz, d6-DMSO) 3.74 (4H, t, J=4.9 Hz), 3.90 (4H, t, J=4.9 Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6 Hz).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:15][C:16]([C:18]1[O:19][C:20]([CH2:23][O:24][CH3:25])=[CH:21][CH:22]=1)=O.Cl>C1COCC1>[CH3:25][O:24][CH2:23][C:20]1[O:19][C:18]([C:16](=[O:15])[CH2:2][C:1]#[N:3])=[CH:22][CH:21]=1
Reactant: CC#N
Reactant: COCc1ccc(C(=O)OC)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COCc1ccc(C(=O)CC#N)o1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Following the method of Turner and Jacks (J. Org Chem. 1989, 54, 4229), to a stirred solution of 11.4 ml (216 mmol) acetonitrile in 50 ml dry THF under argon at −78° C. was added dropwise 95.0 ml (95.0 mmol) lithium bis(trimethylsilyl)amide solution (1 M in THF) and stirring continued for 30 minutes, after which a solution of 7.34 g (43.1 mmol) 5-methoxymethyl-furan-2-carboxylic acid methyl ester in 20 ml THF was added dropwise and stirring continued while the reaction mixture was allowed to warm slowly to −20° C. over 2 hours. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixtured was extracted twice with ether and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) afforded 7.73 g (99%) 3-(5-methoxymethyl-furan-2-yl)-3-oxo-propionitrile as an orange crystalline solid. EI-MS m/e (%): 179 (M+, 23), 148 ([M—OCH3]+, 40), 147 ([M—CH3OH]+, 44), 139 ([M—CH2CN]+, 45), 111 ([M—COCH2CN]+, 100).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH2:7]([C@H:9]1[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10]1)C.C[OH:20]>O>[CH3:18][O:17][C:15]([C@@H:14]1[C@H:10]([CH2:9][CH3:7])[CH2:11][C:12](=[O:20])[CH2:13]1)=[O:16]
Reactant: CO
Reactant: CC[C@@H]1CC=CC[C@@H]1C(=O)OC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CC[C@@H]1CC(=O)C[C@@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
24 g of potassium permanganate is dissolved in 15 ml of water, and 8.08 g of (1S, 6R)-6-ethyl-1-methoxycarbonylcyclohex-3-ene was added to the solution over a period of 20 minutes. The mixture was stirred for 4 hours at room temperature, and then 6 g of potassium permanganate was further added, followed by 1 hour of stirring. Methanol was added to the mixture, and the insoluble material was filtered off. Concentrated hydrochloric acid was added to the filtrate such as to adjust the pH thereof at 2, and the filtrate was extracted with a mixed solvent of ethyl acetate - tetrahydrofuran (1:1). After concentration, to the residue were added 50 ml of acetic anhydride and 2.5 g of sodium acetate, and the mixture was refluxed for 1.5 hours. The mixture was cooled down to room temperature, and a mixed solvent of hexane - ether was added thereto. The insoluble material was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ether:hexane=1:2), thereby obtaining 3.99 g of titled compound.
Reaction SMILES: O.[C:2]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1>[Fe].C(O)(=O)C>[C:2]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3ccccc23)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Oc2cccc3ccccc23)cc1

Procedure:
A mixture of 1.5 liters of water, 40 ml of glacial acetic acid and 1.0 mol of 4-(α-naphthoxy)-nitrobenzene was heated to boiling while stirring. After the boiling temperature had been reached, 200 g of iron powder were added in small portions. When the addition was finished, it was refluxed for 6 hours, while stirring.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:2]2[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1cc(F)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc(F)cc2N)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A degassed solution of 2-chloro-5-fluoro-3-amino-pyridine (3.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water then brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane/ethyl acetate 8:2) afforded 3-amino-5-fluoro-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (4.6 g) as a solid. MS (ES+) 294 (MH+), 238 (M-isoprene); 1H NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, 1H), 6.70 (dd, 1H), 7.85 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[O:18]1[CH2:19][CH2:20][N:15]([C:4]2[C:5]3[O:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:6]=3[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(N3CCOCC3)c3oc4ccccc4c3n2)cn1
Temperature: 90 °C
Yield: 4.6 %

Procedure:
Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2-d]pyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and 2-Aminopyridine-5-boronic acid pinacol ester (MW 220) (243 mg, 1.10 mmol, 4.0 eq) in 1,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 mL) for 5 min. dichioro 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90° C.) for 14 h 45 min, cooled and diluted with EtOAc (9 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (conc. 32% in water)=5:4:1 (9 mL), then NH4Cl (sat.) and brine (2×), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from=% MeOH in DCM to 5% MeOH in DCM) gave a colorless solid (4.40 mg, 5%).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:18]([NH2:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[CH2:18]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:19]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Yield: 89.2 %

Procedure:
2-(2,6-Difluoro-3-nitrophenyl)pyridine (1.00 g, 4.29 mmol), ethylamine (2.24 mL, 4.29 mmol) and then DIPEA (0.75 mL, 4.29 mmol) were added to acetonitrile (10 mL) and the resultant mixture stirred at 20° C. for 40 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to give the title compound as yellow oil (1.00 g, 90%). 1H NMR (CDCl3) δ: 8.73 (1H, ddd, J=6.6, 2.4, 1.3 Hz), 8.28 (1H, dd, J=12.6, 8.1 Hz), 7.80 (1H, td, J=10.3, 2.4 Hz), 7.45 (1H, dq, J=10.4, 1.6 Hz), 7.33 (1H, ddd, J=10.1, 6.5, 1.6 Hz), 6.51 (1H, dd, J=12.7, 10.9 Hz), 2.54-2.44 (2H, m), 1.03 (3H, t, J=9.6 Hz)
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([F:24])=[C:20](I)[CH:21]=2)[C:16]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[O:26])=[C:15]1[CH:37]([CH3:39])[CH3:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C.[Cu]I>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([F:24])=[C:20]([O:2][CH3:1])[CH:21]=2)[C:16]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[O:26])=[C:15]1[CH:37]([CH3:39])[CH3:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(I)cc2n1Cc1ccccc1
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2c(cc1F)c(C(=O)NCc1ccc(F)c(F)c1)c(C(C)C)n2Cc1ccccc1
Temperature: 110 °C

Procedure:
To a mixture of sodium methoxide (freshly prepared from 25 mg sodium and 1 ml MeOH) and CuI (30 mg, 0.16 mmol) was added a solution of 1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-6-iodo-2-isopropyl-1H-indole-3-carboxamide (Compound 179, 30 mg, 0.053 mmol) in DMF (0.5 ml). The reaction was heated to 110 ° C. for 16 h, and was filtered and concentrated. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])[N:9]=1)=[O:7])(C)(C)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Yield: 85.3 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (130) (10 g, 21.69 mmol) in a mixture of tetrahydrofuran-water (2:1, 90 mL) was added lithium hydroxide, monohydrate (4.55 g, 108.42 mmol). The mixture was refluxed for 18 h. After completion of the reaction, the volume was reduced by evaporation as much as possible, water was added, and the residue was washed with ethyl acetate to remove non-acidic impurities. The separated aqueous part was acidified with 2(N)HCl to bring the pH to approx. 5 to 6. The acidified aqueous part was extracted with dichloromethane, the separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (131) (7.5 g, 85.32%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH3:28])([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([CH:11](C(OCC)=O)[C:12](OCC)=[O:13])=[O:10])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.Cl>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O1CCCC1>[CH3:26][C:24]([CH3:25])([CH3:27])[CH2:23][CH2:22][C@@:8]1([CH3:28])[C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]([OH:13])=[CH:11][C:9]1=[O:10]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)[C@@](C)(CCC(C)(C)C)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CC[C@]1(C)C(=O)C=C(O)c2cc(F)ccc21
Temperature: 70 °C
Yield: 50.2 %

Procedure:
The compound of Example 25D (1.68 g, 4.25 mmol) was dissolved in Eaton's reagent (15 mL, 1:10 (w/w) phosphorus pentoxide in methanesulfonic acid, cf. P. E. Eaton, et al. J. Am. Chem. Soc. 1973, 38, 4071) and warmed at 70° C. for 18 h. The solution was cooled to 25° C. and added to a mixture of ice and water. The mixture was extracted with dichloromethane (3×) and the combined organic layers dried (Na2SO4) and concentrated in vacuo. The oil obtained was dissolved in tetrahydrofuran (30 mL) and treated with 1 N HCl solution, followed by warming at reflux for 18 h. The mixture was cooled and extracted with ethyl acetate (2×). The combined organic layers were extracted with water (2×) and saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a brown solid, which was triturated with ether-hexane and the resulting solid collected by filtration. These procedures afforded the title compound (590 mg, 50%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 0.32 (m, 1 H) 0.71 (m, 10 H) 1.43 (s, 3 H) 1.91 (s, 1 H) 2.05 (m, 1 H) 5.73 (s, 1 H) 7.43 (m, 1 H) 7.57 (dd, J=9.56, 2.57 Hz, 1 H) 7.71 (s, 1 H) 11.79 (s, 1 H). Specific rotation: [α]D −27.7°(c 2.11, EtOH).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C:21]2[CH:25]=[C:24]([CH:26]=O)[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]1>ClCCl>[C:15]1([C:21]2[CH:25]=[C:24]([CH2:26][N:28]3[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]3)[O:23][N:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCC1CCNCC1
Reactant: O=Cc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
Sodium triacetoxyborohydride (12.2 g) was added portionwise to a room temperature mixture of the compound prepared in Example 7 (5.00 g) and piperidin-4-ylmethanol (4.99 g) in dichloromethane (150 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with a saturated aqueous sodium bicarbonate solution and brine. The organics were dried over anhydrous magnesium sulfate and concentrated to obtain the crude title compound (8.05 g), which was used without further purification having the following physical data.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:21][CH2:20][O:19]1>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:21][CH2:20][OH:19]
Reactant: O=C1OCCO1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccccc1C(F)(F)F
Temperature: 150 °C
Yield: 19.7 %

Procedure:
A mixture of 2-trifluoromethylphenol (2.00 g, 12.3 mmol), K2CO3 (1.71 g, 12.3 mmol) and ethylene carbonate (1.20 g, 13.6 mmol) in dry DMF (30 mL) was heated at 150° C. for 1 h. After cooling, the reaction was quenched by addition of water (10 mL). The mixture was concentrated in vacuo and the residue partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with additional portions of EtOAc (3×30 mL). The combined organic layers were treated with charcoal, dried over MgSO4, and filtered through Celite. The filtrate was concentrated in vacuo and the remaining oil was purified by chromatography on silica gel using n-hexane/EtOAc (80:20) as eluent to give 0.50 g (20%) of the title product as white crystals: mp 74-77° C. Anal. (C9H9F3O2) C, H.
Reaction SMILES: N1C=CC=C([C:7]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)C=1.[Li].[CH3:19][OH:20]>>[N:12]1[CH:13]=[CH:14][CH:15]=[C:16]([C:19]([C:16]2[C:11]([C:10]([O:9][CH3:7])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:20])[CH:11]=1
Reactant: CO
Reactant: O=C(OC(=O)c1ccccn1)c1cccnc1
Agent: [Li]
Product: COC(=O)c1ncccc1C(=O)c1cccnc1

Procedure:
Synthetic Scheme 6 is yet another method of regiospecific synthesis of the methyl 3-picolinoylpicolinate 7 and 5-(pyridin-2-yl)pyrido[2,3-d]pyridazin-8(7H)-one 9. N,N-diethylpicolinamide 14, prepared as in Synthetic Scheme 5, is reacted with 1 equiv of sec-butyl lithium, and, without isolation of the lithiated intermediate, a second equivalent of N,N-diethylpicolinamide 14 is added to the reaction mixture, resulting in the condensation reaction yielding lithium 3-picolinoylpicolinate 16. Lithium 3-picolinoylpicolinate 16 is reacted with methanol to yield the methyl ester, methyl 3-picolinoylpicolinate 7, which is then reacted with hydrazine to yield 5-(pyridin-2-yl)pyrido[2,3-d]pyridazin-8(7H)-one 9. The pyridazinone 9 can be converted to the various ketone-Rilyazines 11, and then to the corresponding thione-Rilyazines 13 similarly to the methods shown in Scheme 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH3:20])[C:10]([NH:12][C:13]([NH:15]C(C)(C)C)=[O:14])=[NH:11]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH3:20])[C:10]([NH:12][C:13]([NH2:15])=[O:14])=[NH:11]
Reactant: CN(C(=N)NC(=O)NC(C)(C)C)c1c(Cl)cccc1Cl
Agent: Cl
Product: CN(C(=N)NC(N)=O)c1c(Cl)cccc1Cl

Procedure:
A mixture os 33.7 g (0.106 mole) of 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, filtered and washed with 10 ml of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain 1-(2,6-dichlorophenyl-N-methylamidino)urea.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[N-:11]=[N+:12]=[N-:13].[Na+]>>[N:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[N+:12]=[N-:13]
Reactant: COC(=O)CCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COC(=O)CCCCCN=[N+]=[N-]

Procedure:
Methyl 6-bromohexanoate was reacted with sodium azide to give methyl 6-azidohexanoate, then converted to the corresponding hydrazide using hydrazine hydrate. The linker compound 6-azidohexanehydrazide was conjugated with DOX hydrochloride in dry methanol, with a drop of acetic acid, forming the desired DOX-azide compound. The one-pot method polymerization/click method shown in the scheme was used to synthesize the new DOX-polyMPC copolymer. The polymer was characterized with NMR spectroscopy and GPC, while drug weight percent was measured using a UV method.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:5][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][N:8]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[NH2:3][C:4]1[S:5][C:6]([S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:24])=[CH:7][N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncc(Sc2ccccn2)s1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(S(=O)c2ccccn2)s1
Yield: 106.5 %

Procedure:
To a solution of 2-amino-5-(2-pyridylthio)thiazole dihydrochloride (4.0 g) in chloroform (100 ml) was dropwise added the solution of 3-chloroperbenzoic acid (5.0 g) in chloroform (100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 1.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(2-pyridylsulfinyl)thiazole (3.4 g, yield: 78.9%). mp: 200°-202° C. (dec.) IR (Nujol): 3300, 3150, 1630, 1575, 1270, 1225 cm-1
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1.C(OCC)C>[CH2:17]([O:16][C:14]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1nc(CC(=O)O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)Cc1csc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
(2-Aminothiazol-4-yl)acetic acid (10 g, 63.2 mmol) was dissolved in 1,4-dioxane (100 mL) and aqueous NaOH (6 M, 100 mL), and the solution was cooled to 0° C. Benzyl chloroformate (20 mL, 82.2 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether, and the layers separated. The water layer was cooled to 0° C., and the pH adjusted to approximately 4 with aqueous HCl (6 M). The white precipitate formed was collected by vacuum filtration, washed with water and diethyl ether, and dried under vacuum to provide (2-benzyloxycarbonylaminothiazol-4-yl)acetic acid (7.5 g, 41%).