Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[O:26]=[C:27]([CH:29]=[C:30]([CH3:32])[CH3:31])[CH3:28]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:30]([CH3:32])([CH3:31])[CH2:29][C:27](=[O:26])[CH3:28])=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: CC(=O)C=C(C)C
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)CC(C)(C)P(=O)(O)CCCCc1ccccc1
Yield: 37.8 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.0025 mole) in chloroform (15 ml) was added triethylamine (0.77 ml, 0.005 mole), trimethyl silylchloride (0.70 ml, 0.005 mole) and mesityl oxide (0.32 ml, 0.0025 mole). The reaction mixture was stirred at reflux temperature for 18 hours. CHCl3 was removed in vacuo. The residue was diluted with ether and washed with 5% aqueous NaHCO3 solution. The aqueous layer was acidified with concentrated HCl and extracted twice with ether and once with EtOAc. Organic layers were combined and extracted with brine, dried over Na2SO4 and solvent was removed to give 0.28 g of the product an an oil.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6](=[O:12])[N:5]3[C@H:13]([CH2:15][N:16]4[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22]C(=O)C(F)(F)F)[CH2:17]4)[CH2:14][N:3]1[C:4]=23.C(=O)([O-])[O-].[K+].[K+]>CO.O.CO.C(Cl)Cl>[NH2:22][CH2:21][C@@H:18]1[CH2:19][CH2:20][N:16]([CH2:15][C@H:13]2[N:5]3[C:4]4[N:3]([C:2](=[O:1])[CH:11]=[CH:10][C:9]=4[CH:8]=[CH:7][C:6]3=[O:12])[CH2:14]2)[CH2:17]1
Reactant: O=C(NC[C@@H]1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: NC[C@@H]1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)C1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a 25 mL round-bottomed flask was added N-[((3S)-1-{[(1R)-4,9-dioxo-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridin-1-yl]methyl}-3-pyrrolidinyl)methyl]-2,2,2-trifluoroacetamide (85 mg, 0.214 mmol) in methanol (9 ml) and water (1.00 ml) to give a yellow solution. Potassium carbonate (59.3 mg, 0.429 mmol) was added and the reaction was stirred overnight. LCMS indicated a complete reaction. The reaction was diluted with 20% MeOH/DCM (100 mL), dried over Na2SO4, filtered and concentrated to give the product (60 mg, 0.200 mmol, 93% yield) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].C([O-])=O.[NH4+].[CH:18]([NH2:20])=O>CCOC(C)=O>[CH:10]1[C:11]([F:13])=[CH:12][C:2]2[NH:1][CH:18]=[N:20][C:4](=[O:5])[C:3]=2[CH:9]=1
Reactant: NC=O
Reactant: CCOC(=O)c1ccc(F)cc1N
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: O=c1nc[nH]c2cc(F)ccc12

Procedure:
To a suspension of ethyl 2-amino-4-fluorobenzoate (1.73 g, 9.45 mmol) in formamide (8 mL) was added ammonium formate (0.9 g, 14 mmol). The reaction mixture was stirred at 140° C. for 24 hr, with additional ammonium formate (0.92 g, 15 mmol) at 6 hr. The reaction was dilute with EtOAc, washed with water, back-extracted with EtOAc, dried and concentrated in vacuo to give 7-fluoro-3-hydroquinazolin-4-one (2.82 g) which contains some formamide. ES-MS (M+H)+=165.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].CS(C)=O.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[CH2:22]([O:21][C:19](=[O:20])[C:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([CH3:25])[CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A mixture of 4-hydroxyindole (0.100 g, 0.75 mmol, 1.0 eq), powdered potassium hydroxide (0.046 g, 0.83 mmol, 1.1 eq), and DMSO (2 mL) was stirred at room temperature for 1 hour and then ethyl 2-bromo-2-methylpropionate (0.161 g, 0.12 mL, 0.83 mmol, 1.1 eq) was added to the above mixture dropwise. The reaction mixture was stirred at room temperature for another 2 hours before 15 mL of water was added. The mixture was extracted with ethyl acetate (2×30 mL). The organic layer was collected, combined, washed with water (6×25 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo. The residue thus obtained was purified by flash chromatograph over silica gel using hexane/ethyl acetate (95/5) as an eluant to afford 2-(1H-indol-4-yloxy)-2-methylpropionic acid ethyl ester (0.144 g, yield: 80%).
Reaction SMILES: [C:1]([CH2:4][C:5]([C:7]1C=C[CH:10]=[CH:9][CH:8]=1)=O)(O)=O.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15].[C:20]([OH:23])(=[O:22])[CH3:21].C([O-])(=O)C.[Na+]>O>[C:20]([C:21]1[CH:1]=[CH:4][CH:5]=[CH:7][C:8]=1[C:9](=[C:19]1[S:13][C:14](=[S:15])[NH:16][C:17]1=[O:18])[CH3:10])([OH:23])=[O:22]
Reactant: O=C1CSC(=S)N1
Reactant: CC(=O)O
Reactant: O=C(O)CC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=C1SC(=S)NC1=O)c1ccccc1C(=O)O

Procedure:
To a hot stirred solution of 2-carboxyacetophenone (1.91 g., 11.65 mM) and 1.57 g. (11.75 mM) of rhodanine in 8 ml. of acetic acid is added 3.12 g. (38.1 mM) of sodium acetate. The solution is refluxed for 3.5 hours, cooled, and poured into water, whereupon a gum forms. The gum crystallizes and is collected and recrystallized from methanol to give 5-(2-carboxy-α-methylbenzylidene) rhodanine as yellow-brown crystals, m.p. 193°-195°.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH2:25])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH:25][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=4)=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1
Reactant: COc1c(OCCCN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCCN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
8-{3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (200 mg, 0.52 mmol) was dissolved in DMF (2.0 mL), and nicotinic acid (76 mg, 0.62 mmol) was added. PYBOP (322 mg, 0.62 mmol) and diisopropylethylamine (0.33 mL, 1.55 mmol) were subsequently added, and the mixture was stirred at room temperature overnight. EtOAc was added, and the precipitate was isolated by vacuum filtration to give the title compound (156 mg, 61%): HPLC MS RT=1.34 min, MH+=493.3; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.53 (1H, s), 9.03 (1H, d), 9.00 (1H, d), 8.07 (1H, d), 8.01 (1H, dd), 7.49 (1H, d), 4.58 (2H, m), 4.34 (2H, t), 4.27 (2H, m), 4.03 (3H, s), 3.81 (2H, m), 3.53 (2H, d), 3.29 (2H, m), 2.69 (2H, m), 2.27 (2H, m), 1.15 (6H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCC(N)c1nc(-c2ccc(F)cc2)c[nH]1
Reactant: O=C1CCCCC1
Product: CCCCCCC(NC1CCCCC1)c1nc(-c2ccc(F)cc2)c[nH]1
Yield: 15 %

Procedure:
This compound was obtained according to a protocol analogous to that of stage 13777.4 of example 13777, using 1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-heptanamine (0.5 g; 0.0014 mol) as starting amine and cyclohexanone (0.17 ml; 0.0014 mol) as starting ketone. A white powder was obtained with a yield of 15%. Melting point: 190-192° C. MH+=358.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg) and triethylamine (0.1 ml) in dichloromethane (4 ml) was added 2-furoyl chloride (0.05 ml). The mixture was stirred at room temperature for 20 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 2-benzyl-4-[3-(2-furoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (145 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)=[CH:4][C:3]=1[F:34].[CH3:35]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.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>[F:34][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)[CH:6]=[N:7][C:2]=1[CH3:35]
Reactant: CB1OB(C)OB(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnc(Cl)c(F)c2)c1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cc1F
Temperature: 110 °C

Procedure:
(R)-6′-Chloro-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Example 53, 139 mg, 0.28 mmol) and trimethyl-boroxine (34.4 mg, 0.274 mmol) were dissolved in dioxane (1.5 mL). K2CO3 (104 mg, 0.756 mmol) was added, the RM was flushed with argon and Pd(PPh3)4 (32.4 mg, 0.028 mmol) was added. The RM was heated overnight at 110° C. After cooling to RT, the RM was dissolved in EtOAc treated with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH). Further purification by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10 to 41% MeCN+0.1% formic acid). The combined pure fractions were neutralized with NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH and evaporated under reduced pressure to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=5.16 min, UPLC-MS (Condition 7) m/z=477.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 1H) 1.78-1.88 (m, 1H) 2.42-2.56 (m, 3H) 2.87 (d, J=11.73 Hz, 1H) 3.14-3.28 (m, 2H) 3.33-3.43 (m, 1H) 4.18 (br. s, 1H) 4.84 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.71 (dd, J=10.17, 1.56 Hz, 1H) 7.79-7.90 (m, 2H) 8.02 (d, J=2.35 Hz, 1H) 8.34 (s, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][S:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27](O)[CH3:28]>S(=O)(=O)(O)O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][S:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=3)[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)CCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 80 %

Procedure:
To a mixture of 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionic acid (365 mg) and ethanol (10 ml) was added concentrated sulfuric acid (one drop) and heated for 4 hours under reflux. The reaction mixture was concentrated, to which was added saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give crystals of ethyl 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionate (310 mg, 80%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 77-78° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:23][CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:23][CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cncs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cncs2)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), 4-(morpholinomethyl)-benzaldehyde (0.017 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained as a solid after trituration with diethyl ether (0.022 g, 26%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.41 (m, 4H), 2.61-2.67 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.8 Hz, 4H), 3.63-3.69 (m, 4H), 3.87 (s, 2H, NCH2), 7.48 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.82 (s, 1H, thiazole H-4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.05 (s, 1H, thiazole H-2), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.10 min—554/556 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 554.1342, calculated for C25H29BrN7OS (M+H)+: 554.1338.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[NH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cnc(N[N+](=O)[O-])[nH]c1=O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (1.64 g) and 2-nitroamino-5-methoxypyrimidin-4-one (1.12 g) were stirred under reflux, for 40 hours, in ethanol (15 ml). The ethanol was replaced by pyridine (15 ml) and the solution stirred under reflux for a further 10 hours to complete the reaction. The reaction mixture was cooled and evaporated under reduced pressure to give a residue. This was partitioned between water (25 ml) and chloroform (25 ml), the aqueous layer being further extracted with chloroform (2×25 ml). The combined chloroform extracts were dried (MgSO4), evaporated under reduced pressure and subjected to medium pressure chromatography using chloroform: methanol (95 : 5) to give the title compound. The fractions containing the title compound were dissolved in isopropanol and treated with maleic acid (0.6 g) in isopropanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-5-methoxypyrimidin-4-one maleate (0.96 g), m.p. 148°-149.5° C (recrystallisation from ethanol).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1)=O.Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27](/[CH:30]=[C:31]2/[C:32]([NH:37][CH2:38][C:39]#[CH:40])=[N:33][C:34](=[O:36])[S:35]/2)[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[O:36]=[C:34]1[N:33]=[C:32]([NH:37][CH2:38][C:39]#[CH:40])/[C:31](=[CH:30]/[CH:27]2[CH2:26][CH2:25][N:24]([CH2:8][C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=3)[CH2:29][CH2:28]2)/[S:35]1
Reactant: N#Cc1ccc(C=O)cc1C(F)(F)F
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of triethylamine (1.38 mL) and 4-formyl-2-(trifluoromethyl)benzonitrile (593 mg) in DMF (10 mL) was added (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (800 mg). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (2.1 g) was added. The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (250 mg).
Reaction SMILES: [Br-:1].[Cl:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][CH2:8][N+:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]([C:29]#[N:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[H][H]>CO.[Pt]=O>[BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH2:15][C:16]([C:29]#[N:30])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:31][CH:32]=1
Reactant: N#CC(Cc1cccc[n+]1CCc1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Reactant: [Br-]
Agent: O=[Pt]
Solvent: CO
Product: Br
Product: N#CC(CC1CCCCN1CCc1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of 1-(4-chlorophenethyl)-2-(2-cyano-2,2-diphenylethyl)pyridinium bromide (252 mg, 0.50 mmol) (see Preparation 4) in methanol (3 ml) was stirred at room temperature under one atmosphere of hydrogen in the presence of platinum oxide (20 mg) for 3 hours, filtered and evaporated to give the title compound (255 mg, 100%) as a colourless foam.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10](N)[C:11](=[CH:15][CH:16]=1)[C:12]([OH:14])=[O:13].N([O-])=O.[Na+].[Na+].[I-:23]>O>[I:23][C:10]1[CH:9]=[C:8]([O:7][CH3:6])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a mixture of 50% sulfuric acid (150 ml) and 4-methoxyanthranilic acid (12 g) at 5°-10° C. is added sodium nitrite (5.5 g) in water, followed 10 minutes later by NaI (16.5 g) in water (30-50 ml). The reaction mixture is warmed to room temperature and stirred for 2 hours, then is heated at 60°-70° C. for 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture is extracted with ether (4×125 ml) and the combined ether extracts are washed with water (50 ml×2), dried over MgSO4, filtered and evaporated. The residue is purified by column chromatography on silica gel eluting with ether to afford 12 g of 2-iodo-4-methoxybenzoic acid.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6](O)=[O:7])(=[O:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:16]([O:15][CH:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([Cl:21])=[O:7])[CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Reaction time: 48 h

Procedure:
The 2,3,4-triacetoxy-butyric acid (25 g, 0.095 mol) was stirred in thionyl chloride (15.3 mL) at room temperature with a condenser fitted. The reaction was stirred for 48 hours and then the thionyl chloride was removed under reduced pressure to give an oil which was the desire material (26.1 g, 98%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:9]=1.C(N(CC)CC)C.[Br:30][C:31]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:32]=1[NH2:33]>CN(C)C=O.C(Cl)Cl.CN(C)C1C=CN=CC=1.C(=O)=O>[Br:30][C:31]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:32]=1[NH:33][C:13]([C:11]1[N:10]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:9]=[C:8]([Br:7])[CH:12]=1)=[O:15]
Reactant: Nc1c(F)cc(F)cc1Br
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c(F)cc(F)cc1Br)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (0.043 mL, 0.5 mmol) was added to a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the product of Step D) (200 mg, 0.66 mmol) and two drops of N,N-dimethylformamide (DMF) in 30 mL of methylene chloride at room temperature and the reaction was stirred for 10 minutes. After this time a catalytic amount of 4-(dimethylamino)pyridine was added, followed by dropwise addition of a mixture of triethylamine (184 mL, 1.4 mmol) and 2-bromo-4,6-difluoroaniline in 10 mL of methylene chloride. The reaction was stirred overnight and then concentrated to near dryness. Chromatography on silica gel with hexane/ethyl acetate gradient as eluent (9:1 to 1:1) afforded an oil. The oil was then cooled in dry ice and triturated with ether/hexane to provide the title compound (0.22 g), a compound of the present invention, as a solid melting at 138-139° C.