Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Mg].[CH3:11][C:12]([CH3:14])=[O:13].Cl>CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]([CH3:14])([OH:13])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(Cl)cc1
Yield: 70 %

Procedure:
A solution of 4-chlorobenzyl chloride (165 g; 1.02 mole) in ether (500 ml) was added dropwise during one hour to magnesium (24.3 g; 1.00 mole) in a three-necked flask equipped with stirrer and reflux condenser. The spontaneous reflux was allowed to continue for another hour and the solution was cooled. Acetone (60.0 g, 1.30 mole) was added dropwise and the solution heated to reflux for three hours. After cooling, the reaction mixture was poured out on ice (500 ml) and concentrated hydrochloric acid (92 ml). The phases were separated. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was fractionated affording 1-(4-chlorophenyl)-2-methyl-2-propanol (b.p. 123°-124° C./12 mm Hg; nD25 =1.5300; 128.5 g, 70% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:33])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[O:33])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1nc(CCO)cs1)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 12B-a, 86 mg, 0.18 mmol) in diethyl ether (5 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (10 mg, 0.27 mmol). The reaction mixture was slowly warmed to 25° C. where it was stirred for 16 h. At this time, the reaction mixture was slowly diluted with water (5 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-[4-(2-hydroxy-ethyl)-thiazol-2-yl]-2-(4-phenoxy-phenyl)-propionamide (21 mg, 27%) as an off-white solid: FAB-HRMS m/e calcd for C25H28N2O3S (M+H)+ 437.1899, found 437.1900.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](OC(=O)C)(=[O:49])[CH3:48].O.[OH-].[Na+]>C(O)(=O)C>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:49])[CH3:48])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reaction time: 3 h

Procedure:
To a solution 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazole-3-yl}phenylamine (0.200 g, 0.63 mmol), in acetic acid (6.0 mL) was added acetic anhydride (0.178 mL, 1.89 mmol). The reaction mixture was heated to reflux temperature for 12 hours. Water was added (10 mL) and the mixture was neutralized with 2.0 N aqueous sodium hydroxide. The product was extracted with ethyl acetate and concentrated to dryness. The crude oil was dissolved in 4 mL of ethanol and treated with 4 mL of commercial solution of hydrogen peroxide and 0.200 mL of 2.0 N aqueous sodium hydroxide. After 3 hours, the solvent was removed under reduced pressure. The resulting oil was dissolved in 5 mL of dimethoxy dimethyl formamide acetal and the solution was heated to reflux temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in 10 mL of acetic acid and treated with 1 mL of anhydrous hydrazine. The reaction mixture was heated to reflux temperature for 12 hours. After neutralization with aqueous sodium hydroxide (2.0 N), the crude was extracted with ethyl acetate and purified by preparative HPLC (15-80% acetonitrile in water) (0.040 g, 20% over 5 steps): 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 10.1 (s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.2 (s, 1H), 8.1 (d, 1H), 7.7 (t, 3H), 7.5 (t, 1H), 2.1 (s, 3H); ES-MS (m/z) 319 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17]Cl)[CH3:14]>CN(C=O)C>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Reaction time: 20 h

Procedure:
To a cold solution of 41.8 g of 4-nitrophenol in 250 ml of DMF was added 16.0 g of a 57% dispersion of sodium hydride in mineral oil, followed by 46.0 g of 2-diethylaminoethyl chloride. After 20 hours, the mixture was filtered, freed of solvent by evaporation under reduced pressure, the residue dissolved in ether and washed with water. Extraction with 2N hydrochloric acid and basification of the extract gave N,N-diethyl-2-(4-nitrophenoxy)ethanamine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH3:2].[CH3:11][S:12](O)(=[O:14])=[O:13].P(Cl)(Cl)(Cl)=O>>[CH2:1]([C:3]1[C:4]([CH2:9][CH3:10])=[C:5]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)O
Reactant: CCc1ccccc1CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cccc(S(C)(=O)=O)c1CC
Temperature: 90 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
An isomeric mixture of diethyl benzene (268.44 g, 2.0 moles), anhydrous methane sulfonic acid (96.1 g, 1.0 mole) and phosphorus oxychloride (25.6 g, 2.17 moles) were heated at 90° C. with stirring for 8 hours. Treatment of the reaction mixture after cooling was the same as in Example 1 and 25 g (12% yield) of methyl diethylphenyl sulfone was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[C:42](=[O:45])([O-])[O-].[K+].[K+].O>C(COC)OC>[OH:45][CH2:42][C:7]1[CH:15]=[CH:14][C:13]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:12][CH:8]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(CO)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 128.1 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (9.6 mL), and the solution was treated with 4-(hydroxymethyl)phenylborate (62.0 mg, 0.405 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (22 mg, 0.027 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.098 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-[4-(hydroxymethyl)phenyl]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (47.7 mg, yield 64%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[C:11]3[C:16]([C:17](=O)[C:3]1=2)=[CH:15][C:14]([CH3:19])=[CH:13][CH:12]=3.O.NN.[OH-].[K+]>C(O)COCCO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[C:11]3[C:16]([CH2:17][C:3]1=2)=[CH:15][C:14]([CH3:19])=[CH:13][CH:12]=3
Reactant: Cc1ccc2c(c1)C(=O)c1c-2c2ccccc2n1C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Cc1ccc2c(c1)Cc1c-2c2ccccc2n1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 1.04 g (0.0042 mol) of 5,8-dimethylindeno[2,1-b]indol-6(5H)-one and 1.12 mL (0.0224 mol) of hydrazine monohydrate in 20 mL of diethylene glycol was stirred at 80° C. for 1 h and then refluxed for 1 h. The resulting mixture was cooled to r.t., treated with a solution of 1.2 g (0.0214 mol) of KOH in 5 mL of water and then it was refluxed for 2 h. The resulting mixture was poured into 100 mL of water, the precipitate was filtered, washed 5 times with 50 mL of water and dried. Yield 0.84 g (86%) of greenish solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][OH:8])[C:3]([CH3:6])([CH3:5])[CH3:4].O.[CH2:10]([O:12]C(Cl)=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:3]([C@@H:2]1[CH2:7][O:8][C:10](=[O:12])[NH:1]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)[C@@H](N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[C@@H]1COC(=O)N1
Temperature: 65 °C
Yield: 79.9 %

Procedure:
73 g (containing 0.25 mole (R)-tert-leucinol) of the filtrate cited in example 6 was taken up with 27 ml water and 200 ml toluene. 25 ml (0.26 mole) chloroformic acid ethyl ester were then added dropwise at 20°-25° C., during which the pH was maintained at 7-8.5 by the addition of 10 M sodium hydroxide solution. The mixture was then heated to 60°-65° C. at pH 8.0 and the aqueous phase separated. The toluene phase was dehydrated on a water separator under a slight vacuum and slowly heated after the addition of 0.4 g finely granulated sodium hydroxide at 70° C. A total of 40 ml distillate which contained the ethanol produced during the reaction was separated from 70°-100° C . After cooling of the batch to 65° C. a solution of 0.6 ml glacial acetic acid in 10 ml water was added, the mixture briefly agitated, the aqueous phase separated and the toluene phase compounded again with 15 ml warm water which was separated again after a brief agitation at 65° C. After distilling the organic phase on a water separator the phase was concentrated to 120 ml, filtered hot and slowly cooled off under agitation, during which the product separated in colorless crystals. These crystals were filtered off after 30 min agitation at 5° C., washed with cold toluene and dried in a vacuum at 50° C. 28.6 g (R)-4-tert-butyl-2-oxazolidinone (80% yield) was obtained. A 1H-NMR spectrum corroborated the structure of the product.
Reaction SMILES: [OH:1][CH:2]([CH2:32][OH:33])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:31])=[C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[CH3:27])=[CH:15][C:14]=2[N+:28]([O-])=O)=[O:12])[CH:10]=1>CO.[Pd]>[NH2:28][C:14]1[CH:15]=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])[CH:17]=[CH:18][C:13]=1[C:11]([C:9]1[CH:10]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:32][OH:33])[CH:6]=[CH:7][C:8]=1[CH3:31])=[O:12]
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(OCC(O)CO)ccc2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(OCC(O)CO)ccc2C)c(N)c1
Reaction time: 1 h

Procedure:
Compound 302 (0.025 g, 0.055 mmol) was dissolved in MeOH (2 mL). A catalytic amount of palladium on charcoal was added and the mixture was stirred under a hydrogen atmosphere for 1 h. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC. This afforded the title compound. 1H NMR (CDCl3) δ 7.19 (dd, 1H), 7.13 (d, 1H), 7.05-6.82 (m, 4H), 6.76 (d, 1H), 6.46 (bs, 2H), 5.89 (dd, 1H), 5.75 (d, 1H), 5.56 (bs, 1H), 4.15-3.93 (m, 3H), 3.80 (dd, 1H), 3.71 (dd, 1H), 2.65 (bs, 1H), 2.23 (s, 3H), 2.19 (s, 3H), 2.10 (bs, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>[Cu].C1(C)C=CC=CC=1>[O:15]([C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: Brc1cccc(Br)c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1cccc(Oc2ccccc2)c1
Temperature: 210 °C
Yield: 36.8 %

Procedure:
A mixture of 1,3-dibromobenzene (15.7 g), phenol (8.0 g), potassium hydroxide (3.8 g, mortar-ground) and copper powder (0.1 g) was heated at reflux for 18 hours at 210° C. After cooling, the reaction mixture was mixed with toluene and successively washed with 10% aqueous sodium hydroxide and water. The toluene was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane), thereby giving 6.1 g of the desired compound.
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CS(C)=O>[C:6]([C:5]1[CH:8]=[C:9]([CH3:10])[C:2]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:3][CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)cnc1F
Reactant: CC(C)(C)OC(=O)CCCN
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)cnc1NCCCC(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 6-fluoro-5-methylnicotinonitrile (10.0 g, 73.4 mmol), tert-butyl 4-aminobutanoate (Bachem F-3755, 17.4 g, 88.1 mmol) and TEA (25.6 mL, 183.6 mmol) was prepared in DMSO (100 mL) under nitrogen, and the heated at 150° C. for 4 hours. The reaction mixture was cooled to 100° C., and then water was added (100 mL) drop wise. The resulting mixture was stirred at RT for 2 hours, and then the precipitate was filtered off, washed with water and dried under reduced pressure to afford the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (1H, s), 7.53 (1H, s), 6.95 (1H, m), 3.40 (2H, t), 2.23 (2H, t), 2.03 (3H, s), 1.75 (2H, m), 1.37 (9H, s).
Reaction SMILES: [CH3:1][CH:2]1O[CH:5]([CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[H][H]>O>[C:13]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCOC(=O)CCCC(=O)CCC1CCC(C)O1
Reactant: [H][H]
Solvent: O
Product: CCCCCCCCCCCC(=O)OCC

Procedure:
Neat ethyl 7-(5-methyltetrahydrofuran-2-yl)-5-oxoheptanoate was flowed at a pressure of 470 psig, and temperature of 240° C. under flowing hydrogen gas for 28 hours. The liquid flow rate and hydrogen gas flow rates were kept constant relative to each other, e.g. 0.03 mL/min liquid flow and 30 mL/min gas flow; 0.06 and 60 mL/min; or 0.09 and 90 mL/min The effluent was primarily organic with a small spontaneously separating water layer beneath the organic phase. Not counting the startup and shutdown, 62.9 g of organic phase was collected out of a theoretical 68.5 g, or 91.9%. GCMS analysis revealed an initial high concentration of 58.2% ethyl dodecanoate, 28.7% dodecanoic acid, and 13% intermediates, possibly ethyl 7-(5-methyltetrahydrofuran-2-yl)heptanoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][NH2:13])[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:17]([C:24](O)=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][NH:13][C:24]([C:17]1[C:16]([NH2:15])=[N:21][C:20]([NH2:22])=[C:19]([Cl:23])[N:18]=1)=[O:25])[CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ((S)-1-aminomethyl-butyl)-carbamic acid tert-butyl ester (1.70 g, 8.40 mmol), 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (1.59 g, 8.43 mmol), N-methylmorpholine (3.8 mL, 34.5 mmol) and HATU (3.2 g, 8.42 mmol) in anhydrous DMF (50 mL) is stirred at RT for 16 h. The reaction mixture is concentrated in vacuo and the resulting residue is purified by column chromatography (basic alumina, MeOH:DCM) to afford the title compound as yellow solid. [M+H]+ 333.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([Br:23])[CH:25]=3)[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(Cc3cccc(Br)c3)c2n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 38 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.65 mmol). The mixture was heated at 50° C. for 20 minutes resulting in a clear solution. The heating mantle was removed, and 3-bromobenzyl bromide (240 μL, 0.96 mmol) was added. After 10 minutes, the reaction mixture was poured onto 30 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate, then dried in vacuo to provide 178 mg (58%) of 2-amino-8-(3-bromobenzyl)-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp softens at 195° C., melts at 215° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2)cc1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of 4-phenylimidazole (7.49 g, 51.9 mmol) in DMF (30 mL) cooled to 0° C. under nitrogen add portionwise NaH (95%, 2.56 g, 101 mmol). After 10 minutes, add p-methoxybenzyl chloride (PMBCl) (7.50 mL, 55.3 mmol) dropwise. Stir for 5 hours, quench with MeOH (5 mL), dilute with water (100 mL), and extract with CH2Cl2 (2×100 mL). Dry the combined organic layers (Na2SO4) and concentrate in vacuo to a volume of 80 mL, affording 12.2 g (89% yield) after crystallization. MS(ES+): m/z=265 (M+H)+
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([OH:7])[CH2:4][CH2:5][Br:6].N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>CN(C)C=O>[Br:6][CH2:5][CH2:4][C@@H:3]([CH2:2][Br:1])[O:7][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O[C@H](CBr)CCBr
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@H](CBr)CCBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of (S)-1,4-dibromo-2-butanol (5.0 g) in N,N-dimethylformamide (30 mL) were added imidazole (1.91 g) and tert-butylchlorodiphenylsilane (7.1 mL) under ice-cooling, followed by stirring the mixture at room temperature for 13 hours. To the reaction mixture were further added imidazole (0.59 g) and tert-butylchlorodiphenylsilane (1.77 mL), followed by stirring the mixture at room temperature for 7 hours To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:50) to give ((S)-3-bromo-1-bromomethyl-propoxy)-tert-butyldiphenylsilane (8.56 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH2:1]([N:8]([CH2:24][C:23]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=1[F:21])[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 8A and 2,4-difluorobenzaldehyde were processed as described in Example 1C to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.40-7.18 (m, 6H), 7.11 (m, 2H), 6.92 (m, 1H), 6.72 (m, 2H), 6.07 (s, 1H), 4.07 (s, 4H), 2.93 (s, 3H), 2.30 (s, 3H); MS(ESI+) m/z 417 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>CC(N(C)C)=O.N1C=CC=CC=1>[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:8](=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([NH2:2])=[CH:13][CH:12]=2)[C:9]([OH:11])=[O:10])=[O:20])=[CH:17][CH:16]=1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Nc1ccc(C=C(C(=O)O)C(=O)c2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 90 %

Procedure:
Para-aminocinnamic acid hydrochloride (0.1 mol, 19.96 g) was dissolved in 100 milliliters (ml) of dimethylacetamide and 30 ml pyridine, then 0.1 mol of para-fluorobenzoylchloride was added dropwise while the solution was maintained at 0° C. The solution was allowed to react for about 5 hours at room temperature, and then neutralized to a pH of 6 to 7 with hydrochloric acid. The solution was filtered to obtain a reaction intermediate. The intermediate was washed with water, dried under a vacuum and recrystallized in a solution of dimethylacetamide (10%) and water (90%). A yield of 90% N (para-fluorbenzoyl)-para-aminocinnamic acid in was obtained. Thionyl chloride (1.2 equivalents) and 50 ml of methylene chloride were added. The solution was allowed to react until clear. After the reaction, the solvent and thionyl chloride were removed under a vacuum, and the remaining product was dried. N-(para-fluorbenzoyl)- para-aminocinnamic acid was obtained.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[F:9][C:10]([F:28])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[N:16]=1>C(#N)C>[F:28][C:10]([F:9])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])[N:16]=1
Reactant: NCCCCc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: NC(=NCC(F)(F)F)Nc1ccnc(CCCCNC(=S)NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 25.5 %

Procedure:
2,2,2-Trifluoroethylisothiocyanate (0.31 g.) was added to a solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine (0.58 g.) in acetonitrile (5 ml.), and the solution kept at room temperature for 18 hours and then evaporated to dryness. The residual gum was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-(2,2,2-trifluoroethyl)thioureido)butyl]pyrimidine (0.22 g.) characterised as the hydrogen maleate, m.p. 142°-145° (after recrystallisation from acetonitrile).