Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].O.[CH3:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][S+:15]([O-:27])[C:16]2[NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:25][CH3:26])=[CH:22][C:23]=3[N:24]=2)=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12]>CO>[CH3:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][S+:15]([O-:27])[C:16]2[N-:17][C:18]3[CH:19]=[CH:20][C:21]([O:25][CH3:26])=[CH:22][C:23]=3[N:24]=2)=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 31 °C
Yield: 52.6 %

Procedure:
50 ml of methanol was taken into a round bottom flask and a mixture of 12.75 g sodium hydroxide and 11 ml of water was added to it and stirred for clear dissolution at 31° C. 110 g of esomeprazole was dissolved in 550 ml of methanol and the solution was added to the above methanolic sodium hydroxide solution. The mass was subjected to stirring at a temperature of 30° C. for 40 minutes, followed by the addition of 5.5 g of carbon with simultaneous stirring. The reaction mass was filtered through a Celite bed, and washed with 550 ml of methanol. The filtrate was subjected to distillation at a temperature of 30° C. under a vacuum of 200 torr. The residue was co-distilled with 1650 ml of acetone in three equal lots at 35° C. To the obtained residue, 220 ml of acetone was added and stirred for one hour. The separated solid was filtered and dried at 34° C. for 12 hours to afford 61.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([OH:16])[C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC(C)=O>[Cl:1][C:2]1[C:3]([C:10]2[C:11]([Cl:18])=[CH:12][C:13]([Cl:17])=[C:14]([CH:15]=2)[O:16][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]
Reactant: CSc1c(Cl)c(-c2cc(O)c(Cl)cc2Cl)nn1C
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1cc(-c2nn(C)c(SC)c2Cl)c(Cl)cc1Cl

Procedure:
A mixture of 4-chloro-3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-5-methylthio-1H-pyrazole (3.50 g, 10.8 mmoles), 50 ml acetone, anhydrous K2CO3, and ethyl 2-bromopropionate (2.06 g, 11.4 mmoles) was subjected to reaction under reflux for 2 hours. Then the resulting solution was filtered to remove acetone-insoluble matter, and the filtrate was concentrated and purified by silica gel column chromatography, give the title compound as oily substance; Yield 70.0 nD(28.8° C.): 1.5763.
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([N+:19]([O-:21])=[O:20])=[C:4]([O:22][CH3:23])[CH:3]=1.O.[NH2:25][NH2:26]>COCCOC>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[C:4]([O:22][CH3:23])[CH:3]=[C:2]2[C:7]=1[CH:8]=[N:25][NH:26]2
Reactant: NN
Reactant: COc1cc(F)c(C=O)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Solvent: O
Solvent: COCCOC
Product: COc1cc2[nH]ncc2c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A biphasic mixture of 6-fluoro-2-(2-fluoro-4-iodo-phenylamino)-4-methoxy-3-nitro-benzaldehyde (1.5 g, 3.46 mmol) in hydrazine hydrate (10 mL) and DME (10 mL) was stirred at room temperature for 4 hours, then heated at 50° C. for 3 hours. The reaction mixture was concentrated in vacuo, the residue treated with water and the resultant solid precipitate collected by filtration to give a red/orange solid. The solid was recrystallised from IMS to give the title compound as a yellow solid (956 mg, 64%). LCMS (Method B) RT=3.62 min, [M+H]+=429 [M−H]−=427.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2)=[O:5])C.[NH2:20][CH2:21][C:22]([OH:24])=[O:23].Cl.O>C[O-].[Na+].CO>[C:18]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:5])[N:7]=1)#[N:19]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2cc(O)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(O)cc12
Yield: 86 %

Procedure:
[(1-Cyano-4,7-dihydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid was prepared by heating a mixture of 42 mg (0.162 mmol) of 1-Cyano-4,7 dihydroxy-isoquinoline-3-carboxylic acid ethyl ester and 97 mg (1.29 mmol) of glycine in 2.25 mL of 0.5 N NaOMe in methanol at reflux temperature for 26 hours. The reaction mixture was cooled and acidified with 3 mL of 1 N HCl and water. A white solid was collected on a medium glass fritted filter to provide 40 mg of the title compound; MS (ESI+): 288.2 e/z (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:34][CH2:33][C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:17]=[CH:18][C:13]=2[C:12]1=[O:35].C1COCC1>[Pd].CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N:11]2[CH2:34][CH2:33][C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[N:17]=[CH:18][C:13]=3[C:12]2=[O:35])[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
To a solution of 6-(2-Methyl-5-nitro-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (100 mg, 0.211 mmol) in the mixed solvent of THF (5 ml) and methanol (5 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 6-(5-Amino-2-methyl-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [45] (Yield: 86.45 mg, 92.3%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH:10]=[N:11][O:12][CH3:13])=[O:8])=[C:5]([CH3:16])[CH:4]=1)=O.Cl.[OH:18][NH2:19]>CO.O>[OH:18][N:19]=[CH:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH:10]=[N:11][O:12][CH3:13])=[O:8])=[C:5]([CH3:16])[CH:4]=1
Reactant: NO
Reactant: CON=CNC(=O)c1ccc(C=O)cc1C
Agent: Cl
Solvent: O
Solvent: CO
Product: CON=CNC(=O)c1ccc(C=NO)cc1C
Yield: 102.4 %

Procedure:
In a solution of 64 mg of 4-formyl-N-(methoxyiminomethyl)-2-methyl benzoic acid amide in 4 mL of methanol and 1 mL of water, 30 mg of hydroxyamine hydrochloride was added at room temperature with stirring, and continued to stir at the same temperature for 1.5 hour. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:1) to obtain 70 mg of the aimed product as white crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.F[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.CC(C)([O-])C.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([O:22][C:25]5[CH:30]=[N:29][CH:28]=[CH:27][N:26]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: Fc1cnccn1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cnccn5)cc43)sc2C(=O)N1
Temperature: 150 °C
Yield: 40.5 %

Procedure:
To a solution of Example 57 (70 mg, 0.211 mmol) in THF (4 mL) was added 2-fluoropyrazine (41 mg, 0.423 mmol) and sodium tert-butoxide (81 mg, 0.846 mmol). The reaction was heated to 150° C. under microwave irradiation for 50 minutes then cooled to r.t. The resulting precipitate was collected, washed with water (4×10 mL), Et2O (3×10 mL) and dried in vacuo to yield the title compound (35 mg, 41%) as an off-white solid. δH (CDCl3) 8.44 (1H, d, J 1.3 Hz), 8.26 (1H, d, J 2.6 Hz), 8.12 (1H, dd, J 2.8 and 1.5 Hz), 8.02 (1H, d, J 2.6 Hz), 7.01 (1H, d, J 8.9 Hz), 6.86 (1H, dd, J 8.9 and 2.6 Hz), 5.26 (1H, s), 4.42-4.30 (2H, m), 4.15-4.10 (2H, m), 2.86 (2H, s), 1.38 (6H, s). LCMS (ES+) 410.0 (M+H)+, RT 3.04 minutes (Method 2).
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[CH2:3][C:4]1[C:5]([CH3:14])=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7]2.N1C=CN=C1.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.C(Cl)Cl>[Si:26]([O:16][CH2:15][CH:2]([OH:1])[CH2:3][C:4]1[C:5]([CH3:14])=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7]2)([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(CC(O)CO)ccc2c1COC2=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(CC(O)CO[Si](C)(C)C(C)(C)C)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-(2,3-dihydroxypropyl)-4-methylisobenzofuran-1(3H)-one (2.00 g, 9.0 mmol) in dry DMF (20 mL) was added imidazole (1.20 g, 18.0 mmol) and TBSCl (1.50 g, 9.9 mmol). After stirring at 25° C. for 2.5 h, the reaction mixture was diluted with CH2Cl2 (50 mL) and washed with H2O (3×20 mL) and saturated NaHCO3 (3×20 mL). The combined aqueous layers were extracted five times with CH2Cl2 (20 mL). The combined organic layers were washed with brine (3×30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([Cl:12])=[CH2:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: C=C(Cl)c1ccc(Br)cc1

Procedure:
Initially, 4-bromoacetophenone (3) can be treated with powdered phosphorous pentachloride to produce 1-(4-bromophenyl)-1-chloroethylene (4). Compound 4 was then treated with potassium hydroxide to produce 4-bromophenylacetylene (5) at a 60% yield. Treatment of compound 5 with ethyl magnesium bromide was followed by reaction with chlorotrimethylsilane. The resulting product (4-bromophenylethynyl) trimethylsilane (6) was recovered with a 90% yield. Compound 6 was then treated with ethyl magnesium bromide, followed by reaction with carbon dioxide to produce (4-carboxyphenylethynyl) trimethylsilane (7) in 89% yield. Compound 7 was then deprotected using KOH in methanol to form 4-ethynylbenzoic acid (8) in 96% yield. Compound 8 is a useful building block for forming a variety of molecular switches in accordance with the present invention, and was used in forming molecular switches of the following examples.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Product: CN1CCN(c2cccc(Nc3nc4cccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1
Yield: 43.2 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75 mg, 0.26 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (73 mg, 0.29 mmol) in a manner analogous to Example 77 to yield [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (52 mg, 43%) as a yellow powder following purification on a 12 g Isco silica gel column using methanol in dichloromethane (0-10%) as eluent. MP=251° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.52 (s, 1H), 8.33 (d, J=8.6 Hz, 2H), 8.12 (d, J=8.6 Hz, 2H), 7.61-7.72 (m, 2H), 7.53 (s, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.07 (t, J=15.0 Hz, 8.6 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.45 (d, J=7.5 Hz, 1H), 3.33 (s, 3H), 3.04 (s, 4H), 2.44 (s, 4H), 2.22 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([S:15][C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[C:9]=2[N:8]=[CH:7][C:6]=1[CH3:25])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([S:15]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[O:34])[C:9]=2[N:8]=[CH:7][C:6]=1[CH3:25])[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1c(C)cnc2c1CCCC2Sc1nc2ccccc2[nH]1
Solvent: ClCCl
Product: C=CCOc1c(C)cnc2c1CCCC2S(=O)c1nc2ccccc2[nH]1
Reaction time: 0.33 h

Procedure:
0.7 Gram of 4-allyloxy-8(2-benzimidazolyl)thio-3-methyl-5,6,7,8-tetrahydroquinoline was dissolved in 30 ml of methylene chloride, then this solution was cooled to -50° to -60° C., next to this solution was added dropwise a solution prepared by dissolving 0.43 g of 80%-meta-chloroperbenzoic acid in 10 ml of methylene chloride, and the reaction mixture was stirred for 20 minutes at the above-mentioned temperature. After the reaction was completed, the reaction mixture was washed with as aqueous solution of sodium carbonate, and dried with anhydrous magnesium sulfate. Methylene chloride was removed by evaporation under reduced pressure, the residue thus obtained was recrystallized from diethyl ether to obtain 0.4 g of 4-allyloxy-8-(2-benzimidazolyl)sulfinyl-3-methyl-5,6,7,8-tetrahydroquinoline. White powdery crystals. Melting point: 100°-102° C. (decomposed)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([O:27][CH3:28])[CH:11]=1>CO>[CH3:28][O:27][C:12]1[CH:11]=[C:10]([CH2:9][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: Oc1ccccc1
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(CBr)cc1OC
Solvent: CO
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(COc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of phenol (130 mg, 138 mmol) and methyl 4-[4′-(bromomethyl)-2′-methoxy-5′-nitrophenoxy] butanoate (7) (500 mg, 138 mmol) in anhydrous methanol (5 cm3) was added KTOBu (186 mg, 166 mmol). The resulting green mixture was stirred at r.t. for 30 mins after which time a white precipitate had formed. The precipitate was filtered and recrystallised from methanol affording the desired compound 9 as a pure white solid (319 mg, 61%). m.p. 96–98° C.; Found C, 61.0; H, 5.8; N, 4.0; C19H21NO7 requires C, 60.8; H, 5.6; N, 3.7%; Rf 0.64 (SiO2, hexane:EtOAc 2:1 v/v); νmax (KBr disc)/cm−1 3000–2800 (m), 1720 (s), 1610, 1580, 1520, 1280, 1220; δH (300 MHz, CDCl3) 2.21 (2H, q, J 6.7 Hz, CH2), 2.57 (2H, t, J 6.7 Hz, CH2), 3.71 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.14 (2H, t, J 6.7 Hz, CH2), 5.50 (2H, s, CH2), 6.98–7.02 (3H, m, ar), 7.29–7.34 (3H, m, ar), 7.77 (1H, s, ar) ppm; δc (100 MHz, CDCl3) 24.7 (CH2), 30.4 (CH2), 51.7 (OCH3), 56.3 (OCH3), 67.0 (CH2), 68.2 (CH2), 109.4 (CH), 109.6 (CH), 115.0 (CH), 121.5 (CH), 129.6 (CH), 129.7 (CH), 138.9, 147.0, 154.3, 158.1, 173.2 (COOCH3) ppm; m/z (FAB) 376 [(MH+), 20%], 282 [(M-C6H5O), 80%].
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[C:3]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:20][CH2:21]1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccc3ncnc(N4CCOCC4)c3n2)cc1
Yield: 97 %

Procedure:
A mixture of 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (56 mg, 0.2 mmol) and morpholine (200 μl) in dioxane (5 ml) was refluxed for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:60, yielding the title compound (60 mg, yield 97%) as a white solid which was characterised by its mass spectrum as follows: MS (m/z): 311 ([M+H]+, 100).
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[Cl-:12].[Li+]>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([Cl:12])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: [Cl-]
Agent: [Li+]
Product: O=[N+]([O-])c1cc(Br)cnc1Cl

Procedure:
5-Bromo-2-chloro-3-nitropyridine was prepared according the method described by K. Jouve and J. Bergman, J. Heterocyclic Chem., 40, 261 (2003) from 2-amino-5-bromo-3-nitropyridine except that one equivalent of lithium chloride was added and the yield was improved to 84%. The required product gave the characterising data:—1H NMR Spectrum: (CDCl3) 8.70 (1H, d); 8.37 (1H, d).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(NCc3ccccc3)c2)c1
Yield: 85 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 1.24 g, 0.0044 mol) and benzylamine (40 mL) was heated at 180° C. for 20 hours The excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 1.33 g (85% yield) of the titled compound as a clear oil, which solidified upon standing: mp: 73-75° C. Anal. Calc'd. for C23H22N40.2H2O: C, 76.83; H, 6.39; N, 15.06. Found: C, 76.88; H, 6.37; N, 14.92.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:22]3[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]3[CH3:16])[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 125 °C
Yield: 60.1 %

Procedure:
To a solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (0.75 g, 3.3 mmol) in NMP (10 mL) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol). The mixture was heated to 125° C. for 60 hours. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give (S)-tert-butyl 4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.775 g, 60%). 1H NMR (CDCl3, 400 MHz) δ 8.60-8.59 (d, 1H), 6.07-5.89 (m, 1H), 4.73-4.60 (m, 1H), 4.30-3.80 (m, 3H), 3.60-3.35 (m, 1H), 3.22 (m, 1H), 3.02 (br, 1H), 2.78 (m, 1H), 2.35-1.60 (m, 5H), 1.49 (s, 9H), 1.32-1.20 (m, 6H). MS (APCI+) [M+H] +391. The resulting mixture of diastereomers was purified by chiral separation by HPLC (Chiralcel ODH column, 250×20 mm, 15 mL/min, Hexane/EtOH 50:50). The first peak (RT=3.864 min) gave (S)-tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.281 g, 36%) and the second peak (RT=5.064 min) gave (S)-tert-butyl 4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.389 g, 50%). Treatment of the (S)-tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate with HCl in dioxane (4M, 2 ml) gave the (5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride in quantitative yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[NH4+].[OH-].[BrH:16].CC(O)=O>>[Br:16][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: Br
Reactant: CCc1nc2nc(Cl)cc(C)c2[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nc2nc(Br)cc(C)c2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 22.2 g (0.113 mol) of the product of Step B in 30% HBr-HOAc was heated to 100° C. for 19 hours. The mixture was poured onto ice, neutralized with NH4OH, extracted (5×EtOAc), and the organic layers were concentrated to give 15 g (1st crop) of the title compound as a solid after crystallization from EtOAc.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1([C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[N:13]1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([N:12]4[CH:16]=[CH:15][CH:14]=[N:13]4)[CH:22]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: Clc1ccn2c(Br)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccn2c(-c3cccc(-n4cccn4)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo-[1,2-a]-pyridine (1 eq, 2.59 mmol, 600 mg) and 3-(1H-pyrazolyl)-phenylboronic acid (1.2 eq, 1.04 mmol, 195 mg) are dissolved in DME (5 ml) and water (1.5 ml) and Na2CO3 (0.65 eq, 1.68 mmol, 209 mg) is added. PdCl2(PPh3)2 (0.04 eq, 0.104 mmol, 72.8 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 7-chloro-3-(3-pyrazol-1-yl -phenyl)-imidazo[1,2-a]pyridine as a brown solid; [M+H]+=295
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH:5]=[C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=O)[O:7]1.O.[NH2:21][NH2:22]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=[O:7])[NH:22][N:21]=1
Reactant: O=C1OC(=Cc2ccc(F)c(Br)c2)C2=C1CCCC2
Reactant: NN
Solvent: O
Product: O=c1[nH]nc(Cc2ccc(F)c(Br)c2)c2c1CCCC2
Temperature: 85 °C

Procedure:
To 3-(3-bromo-4-fluoro-benzylidene)-4,5,6,7-tetrahydro-3H-isobenzofuran-1-one (8) (cis l trans mixture) (20.78 g, 64.3 mmol) suspended in water (150 ml) was added hydrazine hydrate (12.5 ml, 257.2 mmol). The reaction was heated to 85° C. for 18 hours and then cooled to room temperature. A beige suspension was isolated by filtration and washed with water (1×50 ml), hexane (1×50 ml), and ether (1×25 ml) before being dried overnight in a vacuum oven. Main peak in LC-MS, (19.1 g, 91% purity) and required no further purification; m/z (LC-MS, ESP), RT=3.92 mins (M+H 337 & 339).