Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([CH2:15][CH2:16]C2C=CC=CC=2O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: Oc1ccccc1CCC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Brc1cccc(OCCC2CCCCC2)c1
Yield: 93.7 %

Procedure:
To a solution of 3-bromophenol (15.0 g, 86.7 mmol), 2-cyclohexylethylphenol (12.0 ml, 86.7 mmol) and triphenylphosphine (23.0 g, 86.7 mmol) in tetrahydrofuran (200 ml) was added slowly a 40% solution of diethyl azodicarboxylate in toluene (38.0 ml, 86.7 mmol) in portions at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 7 hours. After stirring, the reaction mixture was evaporated in vacuo, and hexane was added to the residue. After filtration, the filtrate was evaporated in vacuo once again, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:100) as the eluent to afford 1-bromo-3-(2-cyclohexylethoxy)benzene (23.0 g, yield: 94%).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:15][C:16]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:12](=[O:13])[CH2:11][C:1]12[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(O)cc1Cl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc(O)cc1Cl

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (2.9 g) and 2-chloro-4-hydroxyaniline to give the title compound as a white solid. (0.15 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:14]=1>C(O)CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:14]=1
Reactant: Cc1cc(-c2cccs2)nc(Cl)n1
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: OCCO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cccs2)nc(Nc2ccc(C(C)C)cc2Br)n1
Yield: 25.8 %

Procedure:
Part C: 2-Bromo-4-(1-methylethyl)aniline (0.26 g) and 2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g) in ethylene glycol were heated at reflux for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with aq. sodium hydroxide solution (10%, 3×100 mL) and the organic phase was dried. Solvent removal gave a crude brown oil, which was purified on silica gel using 20% ethyl acetate in hexanes (Rf 0.5) as eluent to provide N-(2-bromo-4-isopropylphenyl)-4-methyl-6-(2-thienyl)-2-pyrimidinamine (0.1 g) as a solid, mp 98-101° C. Mass spec (NH3 --CI/DDIP); 390 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([C:24]([O:26][CH2:27][CH3:28])=[O:25])#N>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CCOC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of ethyl 2-(4-bromophenyl)acetate (5.0 g, 21 mmol) in dry THF (40 mL) at −78° C. was added a 2.0M solution of lithium diisopropylamide in THF (11 mL, 22 mmol). After stirring for 30 minutes at −78° C., ethyl cyanoformate (2.0 mL, 21 mmol) was added and the mixture was allowed to warm to room temperature. After stirring for 48 h at room temperature, the mixture was quenched with water (10 mL). The reaction was partitioned between 1 N HCl (50 mL) and dichloromethane (50 mL), and the organic layer was separated. The organic layer was washed with 1 N HCl (50 mL), dried over Na2SO4 and evaporated. The crude material was purified by silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to give diethyl 2-(4-bromophenyl)malonate (2.6 g, 41%) 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.58 (m, 2H), 7.36-7.34 (m, 2H), 5.03 (s, 1H), 4.21-4.09 (m, 4H), 1.20-1.16 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:4][C:5]([N:15]2[C:19]3[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=3[N:17]=[CH:16]2)=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:30](C1NC=CN=1)(C1NC=CN=1)=[O:31]>C1COCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[CH:16][N:15]([C:5]3[N:6]=[C:7]4[C:2]([NH:1][C:30](=[O:31])[N:8]4[CH:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)=[C:3]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:4]=3)[C:19]=2[CH:20]=1
Reactant: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc(NC2CCOCC2)c1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 70.4 %

Procedure:
To a solution of ethyl 5-amino-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-carboxylate (800 mg, 2.0 mmol) in dry THF (10 mL) was added carbonyl diimidazole (2.0 g) and the mixture was stirred at 60° C. for 48 h in a sealed tube. The solvent was evaporated and water (25 mL) was added to the residue. Filtration and drying of the white solid gave 600 mg (51% yield) of desired product. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 11.89 (s, 1H), 9.09 (s, 1H), 8.84 (dd, J=2.8, 2.4 Hz, 1H), 7.78 (dd, J=5.2, 5.2 Hz, 1H), 7.23 (m, 1H), 4.63 (m, 1H), 4.49 (q, J=6.8 Hz, 2H), 4.40 (dd, J=4.0, 3.0 Hz, 2H), 3.51 (t, J=11.6 Hz, 2H), 2.52 (m, 2H), 1.80 (d, J=2 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H); LCMS (EI) m/z 427 (MH)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)cc1CCc1ccc(F)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2CCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.86-2.98 (4H, m), 5.05 (2H, s), 5.73 (1H, d, J=2.0 Hz), 6.90-78.01 (6H, m), 7.33-7.39 (2H, m), 7.59 (1H, d, J=1.6 Hz), 7.95 (1H, s), 8.56 (1H, d, J=4.4 Hz). [M+H] Calc'd for C24H18F2N4O, 417. Found, 417.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([S:18][C:19]4[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C1(O)C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][C:19]4[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccc(Br)cc3)CS[C@H]12
Solvent: Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Sc3ccc(Br)cc3)CS[C@H]12
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of (7R)-7-[(phenylacetyl)amino]-3-(4-bromophenylthio)-3-cephem-4-carboxylate, benzhydryl ester (80 mg, 0.12 mmol) in phenol (230 mg) at 45° was added trifluoroacetic acid (9 μL). After 1.5 h, the volatiles were removed with a rotary evaporator, and the residue was triturated with isopropanol/hexane. The resulting white solid was washed with ether and dried in vacuo, affording 48 mg (79%) of the title compound. 1H NMR (acetone-d6) δ3.67 (d, 1H, J=16), 3.75 (d, 1H, J=16), 3.64 (d, 1H, J=18), 3.67 (d, 1H, J=18), 5.25 (d, 1H, J=5), 5.92 (d, 1H, J=5), 7.2-7.7 (m, 9H); IR (KBr) 1347, 1386, 1606, 1756, 3276 cm-1.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:5]=[N:4][CH:3]=1.CC(C)=[O:23].OS(O)(=O)=O.O=[Cr](=O)=O>C(O)(=O)C>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13](=[O:23])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([CH3:1])=[CH:3][N:4]=[CH:5]1
Reactant: CC(C)=O
Reactant: Cc1cncn1-c1ccccc1Cc1ccccc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cncn1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Preparation 44, 5-methyl-1-[α-(o-chlorophenyl)-o-tolyl]imidazole in acetic acid is heated with Jones reagent to give 2'-chloro-2-(5-methylimidazol-1-yl)benzophenone.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH:16]([CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([NH:15][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=1)[CH2:24][CH3:25])[CH:21]([CH3:22])[CH3:23]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc(C(F)(F)F)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-trifluoromethylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:3].[Cl:10][C:11]1[C:17](Cl)=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:10][C:11]1[C:17]([N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[CH2:4][N:2]([CH3:3])[CH3:1])=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: CN(C)CC1CCCN1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CC1CCCN1c1cc(N)c([N+](=O)[O-])cc1Cl

Procedure:
The sub-title compound was prepared from 2-dimethylaminomethyl-pyrrolidine (270 mg, 2.1 mmol), 4,5-dichloro-2-nitroaniline (300 mg, 1.5 mmol) and potassium carbonate (300 mg, 2.2 mmol) in DMSO (3 mL) in analogy to the method described in example 3 step (a).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:18][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1.Cl[CH2:20][C:21]([NH2:23])=[O:22]>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:20][C:21]([NH2:23])=[O:22])[C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][CH:5]=1
Reactant: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Under nitrogen flow, sodium hydride (0.96 g, 0.0234 mole, 60% in oil) was washed with hexanes (~70 ml) and decanted. Dimethylformamide was added (100 ml) and the 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine (5.0 g, 0.022 mole) was added in portions. The reaction mixture was heated at 70°-85° C. for 11/2 hours. Chloroacetamide (2.06 g, 0.022 mole) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was added to water (~600 ml) and the precipitate was collected by filtration, washed with water, and dried under high vacuum overnight at 50° C. NMR indicated a 14% yield of the isomer: 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide and an 86% yield of the title compound. The solid was dissolved in pyridine, filtered, and diluted with water to produce crystalline produce with refrigeration. The solid was collected by filtration, washed with water and dried under high vacuum at 90° C. overnight to give 2.3 g (36.5%) of the title compound, mp 280°-283° C. with decomposition.
Reaction SMILES: [CH2:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH2:4][NH:3][CH2:2]1.Cl.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)=O>[N+:18]([C:17]1[C:12]([N:3]2[CH2:2][CH:1]=[C:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4]2)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=C(O)C1=CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: O=C(O)C1=CCN(c2ncccc2[N+](=O)[O-])CC1
Yield: 43.8 %

Procedure:
A well homogenised mixture of isoguvacine hydrochloride (497 mg, 3.04 mmol), 2-chloro-3-nitro-pyridine (482 mg, 3.04 mmol) and potassium carbonate (882 mg, 6.38 mmol), was stirred at 60° C. for 1.5 h. The reaction mixture was cooled, poured into a solution of water and formic acid (pH=3) and extracted with dichloromethane. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether-Acetic Acid 20:80:0.05) affording the title product (332 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:35]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:33])([CH3:34])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:35])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: CI
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.0 g, 4.1 mmol) and methyl iodide (7.6 mL, 123 mmol) in dry DMF (20 mL) at 0° C. was added NaH (60% suspension in oil, 328 mg, 8.2 mmol) in portion wise. The reaction mixture was stirred for 90 min at 0° C. under nitrogen. The reaction mixture was quenched by addition of aqueous HCl (2N). After extraction with EtOAc, the organic fraction was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane-EtOAc (80:20) as eluent affording the 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)amino]-thiophene-2-carboxylic acid methyl ester 950 mg (46%) as a solid.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=O)[O:14][C:15](O)([CH3:23])[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[C:13](=[O:14])[NH:2][N:3]=[C:15]([CH3:23])[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(O)OC(=O)C(c2c(F)cccc2F)=C1c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(=O)c(-c2c(F)cccc2F)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
0.60 g of hydrazine monohydrate was added dropwise to a mixture of 2.83 g of 3-(2,6-difluorophenyl)-5-hydroxy-5-methyl-4-phenyl-2(5H)-furanone and 15 ml of 1-butanol, followed by stirring at a bath temperature of 110° C. for 2.5 hours. Next, the reaction mixture was cooled to 0° C. The obtained solid was collected by filtration. The collected solid was washed with a mixed solvent (1:1) of hexane and t-butyl methyl ether, and dried under reduced pressure, thereby obtaining 1.70 g of 4-(2,6-difluorophenyl)-6-methyl-5-phenyl-2H-pyridazine-3-one. 1H-NMR (DMSO-d6, TMS) δ (ppm): 2.02 (3H, s), 6.92-6.98 (2H, m), 7.11-7.12 (2H, m), 7.27-7.36 (4H, m), 13.2 (1H, br s)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccncc1
Temperature: 0 °C
Yield: 63 %

Procedure:
1-(3-Nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (12.0 g, 42.2 mmoles) was added into 2 liters of acetone and warmed with stirring until a solution was formed. To the solution was added powdered potassium carbonate (23.4 g, 169.3 mmoles) and 4-chloromethylpyridine hydrochloride (10.4 g, 63.4 mmoles). The solution was stirred at reflux temperature for 18 hours. The solution was filtered while hot. Three quarters of the solvent was removed resulting in the formation of a precipitate. The solution was cooled to 0° C. and the precipitate was removed by filtration. The precipitate was washed with ethyl ether and air dried yielding 10.0 g (26.6 mmole, 63% yield) of 1-(3-nitrophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (mp 207°-209° C.).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3]2=[CH:16][S:15][CH:14]=[C:4]2[C:5]1=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A mixture of 0.35 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one, 65 mg. of 57% sodium hydride-mineral oil dispersion and 0.3 ml. of benzylbromide in 10 ml. of dimethylformamide is stirred at room temperature for 3 hours, quenched by dropwise addition of water, diluted with 100 ml. of water and extracted several times with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil which is chromatographed on silica gel with benzene-methanol (19:1) to give an oil which crystallizes on trituration with acetonitrile. Recrystallization from methanol-water gives off-white crystals, m.p. 137°-138.5°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([OH:24])[CH3:23])=[CH:18][CH:17]=3)[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH2:3][CH2:2]1.O=[C:26]([CH3:40])[CH2:27][CH2:28][N:29]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:29][CH2:28][CH2:27][CH:26]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([OH:24])[CH3:23])=[CH:20][CH:21]=3)[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11]2)[CH2:5][CH2:6]1)[CH3:40]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CC(O)c1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Product: CC(O)c1ccc(C2(C3CCN(C(C)CCN)CC3)Oc3ccccc3O2)cc1

Procedure:
Using general procedure B with the above amine (166 mg, 0.510 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (222 mg, 1.03 mmol) and then using general procedure D afforded 1-(4-{2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-2-yl}-phenyl)-ethanol as a colourless oil (139 mg, 69% over 2 steps).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(#N)C.O>[C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3cccnc3Cl)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(Nc2nccc(-c3cccnc3Cl)n2)c1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-3-pyridyl)-2-pyrimidineamine (1.15 g, 3.24 mmol), sodium hydroxide (300 mg, 7.5 mmol) in acetonitrile (15 mL) and water (5 mL) is heated to reflux for 4 hours. The reaction mixture is then cooled to room temperature and concentrated. The residue is dissolved in water and acidified with 10% hydrochloric acid. The solid is collected by filtration and washed with water, methanol and dried to give N-[3-carboxy-phenyl]-4-(2-chloro-3-pyridyl)-2-pyrimidineamine (600 mg); ESI-MS (m/z): 327.0 (M++H).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]2[CH2:27][CH2:28][CH2:29][CH:25]2[CH3:24])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC1CCCN1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCCC2C)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 89.7 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 85 mg of 2-methylpyrrolidine was added therein, and the mixture was stirred for 7 hours at 60° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 207 mg of 4-(2-butynyloxy)-6-(2-methyl-pyrrolidin-1-yl)pyrimidine (hereinafter, referred to as Compound (21)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCCCO
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with 1-amino-4-hydroxybutane under substantially similar conditions to those described under Example 11 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(4'-hydroxybutyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(4'-hydroxybutyl)-2-methylpyrid-4-one as white crystals, m.p. 126°-128° C.; νmax (nujol) 1630, 3350 cm-1 ; δ(d6DMSO) 1.5 (m, 4H), 2.45 (s, 3H) 3.35 (t, 2H), 4.30 (t, 2H), 7.25 (d 1H), 8.2 (d, 1H).