Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([OH:7])[CH2:2]1.CC(C)([O-])C.[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN1C(=O)CCC1>[CH2:15]([O:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([OH:8])[CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O[C@@H]1CCC[C@H](O)C1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O[C@H]1CCC[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
150.0 g (1.29 mol) of cis-1,3-cyclohexanediol were dissolved in 1.5 l of NMP, admixed with 111.6 g (0.99 mol) of potassium tert-butoxide (KOtBu) and stirred at 25–27° C. After about 30 minutes, the mixture was cooled to 0° C. and admixed dropwise with 78.1 g (0.46 mol) of benzyl bromide. The mixture was stirred at approx. 0° C. for 15 min and then 1.5 l of water were added. After washing three times with 700 ml of n-heptane and discarding the n-heptane solutions, the aqueous solution was extracted four times with 500 ml of MTBE. The combined MTBE phases were washed twice with in each case 1 l of water, dried (Na2SO4) and subsequently concentrated by evaporation under reduced pressure. 48.0 g of the desired compound were obtained as a clear, yellow oil; 1H NMR (CDCl3), δ =1.29 (m, 1H), 1.43–1.93 (m, 6H), 2.06 (m, 1H), 2.55 (s (br.), 1H), 3.56 (m, 1H), 3.74 (br, 1H), 4.55 (dd, 2H), 7.25–7.36 (m, 5H).
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3CCOCC3)=O)C)=CN=2)=CC=1.[NH2:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29].[Cl:45][C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48](O)=[O:49]>>[Cl:45][C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48]([NH:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29])=[O:49]
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3Cl)nn2)cc1
Yield: 80.7 %

Procedure:
In a similar manner as described for Intermediate 50, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 2-chlorobenzoic acid (70 mg, 0.45 mmol) to give 2-chloro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (127 mg) as a yellow solid. MS m/z 384 (M+1).
Reaction SMILES: O[C@H:2]1[CH2:11][N:10]2[C@H:4]([CH2:5][O:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]2=[O:12])[CH2:3]1.C(N(S(F)(F)[F:23])CC)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[F:23][C@@H:2]1[CH2:11][N:10]2[C@H:4]([CH2:5][O:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]2=[O:12])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1c2ccccc2OC[C@@H]2C[C@@H](O)CN12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2OC[C@@H]2C[C@H](F)CN12
Temperature: 25 °C
Yield: 29.8 %

Procedure:
A solution of the material prepared in Example 25 (200 mg; 0.91 mmol) in dry ethyl acetate (10 ml) was cooled to −50° C. and (diethylamino)sulphur trifluoride (191 mg; 1.19 mmol) was added dropwise. The resultant solution was stirred at −50° C. for 1 h and then allowed to slowly warm to room temperature over a period of 3 h. The mixture was then poured onto a saturated aqueous NaHCO3 solution (50 ml) and further ethyl acetate (50 ml) added. After thorough mixing the organic layer was separated, washed sequentially with water (50 ml) and brine (50 ml), and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography to give the title compound as a pale yellow crystalline solid (60 mg). 1H NMR (CDCl3) δ 2.13 to 2.48 (m, 2H), 3.79 (qd, 1H), 4.09 (t, 1H), 4.25 to 4.35 (m, 2H), 4.43-4.49 (m, 1H), 5.333 (d, 1H), 7.04 (d, 1H) 7.15 (t, 1H), 7.41 (dd, 1H), 7.88 (dd, 1H); EIMS: m/z=222.2 [M+H]+
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:46]1N=N[C:48]2[CH:49]=CC=C[C:47]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:46][CH2:47][CH2:48][CH3:49])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCN
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cccc(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and propylamine (7.40 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.8 mg, 63%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][CH:48]([CH3:52])[CH:49](O)[CH3:50]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH:49]([CH3:50])[CH:48]([CH3:52])[CH3:47])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: CC(C)C(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OC(C)C(C)C)cccc2[nH]1
Reaction time: 72 h

Procedure:
DEAD (5.3 ml, 34.1 mmol) is slowly added to a solution of 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (5 g, 24.36 mmol), triphenylphosphine (8.95 g, 34.1 mmol) and 3-Methyl-butan-2-ol (3.58 ml, 33.13 mmol) in 50 ml of THF, so that the temperature always remained below 30° C. Stirring is continued for 3 days and the solvent is then evaporated. The crude mixture is purified by chromatography on silicagel using first cyclohexane as eluent, then increasing amounts of EtOAc (from 5% to 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8][CH2:7]1.Cl[C:19]1[N:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([N:12]([CH3:13])[C:19]2[N:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:10][CH2:11]1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CNC1CCN(Cc2ccc(F)c(F)c2)CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(C(F)(F)F)nn1)C1CCN(Cc2ccc(F)c(F)c2)CC1

Procedure:
A solution of D5 (480 mg, 2 mmol), 3-chloro-6-trifluoromethylpyridazine (182 mg, 1 mmol) and diisopropylethylamine (260 mg, 2 mmol) in n-butanol (4 ml) was heated at 190° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 2 h. After this period, the reaction mixture was evaporated in vacuo and the residue extracted with dichloromethane. The organic layer was washed with a saturated solution of sodium hydrogen carbonate, dried (MgSO4) and the solvents evaporated in vacuo. Purification by reverse phase HPLC (conditions as previously described) gave E12 (210 mg, 54%). C18H19F5N4 requires 386; Found 387 (MH+). 1H NMR (CDCl3) δ 1.74 (br.d, J=12.0 Hz, 2H), 1.88 (qd, J=12.0, 3.9 Hz, 2H), 2.17 (td, J=11.8, 2.5 Hz, 2H), 2.96 (br.d, J=11.6 Hz, 2H), 3.00 (s, 3H), 3.47 (s, 2H), 4.85 (t, J=12.1 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 6.99-7.05 (m, 1H), 7.10 (dt, J=10.2, 8.1 Hz, 1H), 7.20 (ddd, J=11.4, 7.8, 2.1 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H)
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([Cl:25])[C:18]=2[Cl:26])=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:14])[F:13].O>ClCCl>[Cl:5][C:6]1[C:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:25])[C:18]=2[Cl:26])=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:13])[F:14]
Reactant: COc1ccc(Cc2nn(C)c(OC(F)F)c2Cl)c(Cl)c1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1nc(Cc2ccc(O)c(Cl)c2Cl)c(Cl)c1OC(F)F
Temperature: 20 °C
Reaction time: 72 h

Procedure:
18.1 ml (18 mmol) of a 1-molar solution of boron tribromide in dichloromethane were added to a solution of 3.37 g (9 mmol) of 4-chloro-3-(2,3-dichloro-4-methoxybenzyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 45 ml of dichloromethane which had been cooled to (−78)° C. After 3 days of stirring at approximately 20° C., the mixture was admixed with 100 ml of water. The undissolved fraction was subsequently filtered off and washed with 100 ml of dichloromethane. The aqueous phase was extracted again with 100 ml of dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate and subsequently concentrated. Yield: 1.1 g; m.p.: 127—128° C.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([O:10][C:11]([C:13]1[N:17]2[CH2:18][C:19](=O)[N:20]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:16]2=[NH+:15][C:14]=1[CH3:31])=[O:12])[CH3:9].P(Cl)(Cl)([Cl:34])=O>>[CH2:8]([O:10][C:11]([C:13]1[N:17]2[CH:18]=[C:19]([Cl:34])[N:20]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:16]2=[N:15][C:14]=1[CH3:31])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1c(C)[nH+]c2n1CC(=O)N2c1c(C)cc(C)cc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1c(C)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12

Procedure:
A solution of 3-ethoxycarbonyl-2-methyl-6-oxo-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazolium trifluoroacetate (22.2 mg, 0.050 mmol) in phosphorus oxychloride (1 mL) was heated at 150° C. for 48 h. The excess of phosphorus oxychloride was removed under reduced pressure, the residue was dissolved in saturated aqueous solution of sodium bicarbonate (20 mL) and extracted with ethyl acetate (5×20 mL). The combined organic extracts were dried with MgSO4. The solvent was removed under reduced pressure and the crude product was dried under pump vacuum overnight. Yield—23.3 mg (99%). LC/MS: tR=1.93 min., MS: [M+H]=346.
Reaction SMILES: CO[C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9].[NH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:13]([C:10]([C:11]#[N:12])=[C:3]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:14]
Reactant: COC(=C(C#N)C#N)c1occc1C
Reactant: CC(C)(C)OC(=O)NCCN
Product: Cc1ccoc1C(NCCNC(=O)OC(C)(C)C)=C(C#N)C#N

Procedure:
N-(2-{[2,2-dicyano-1-(3-methyl(2-furyl))vinyl]amino}ethyl)(tert-butoxy)carboxamide was synthesized in the same manner using [methoxy(3-methyl(2-furyl))methylene]methane-1,1-dicarbonitrile and tert-butyl N-(2-aminoethyl)carbamate. The NMR and ESI/MS data for this compound are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:17][N:18]([CH3:24])[CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH:19]([N:18]([CH3:24])[CH3:17])[CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)C1CCNC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 4-bromobenzoyl chloride (2.2 g, 10 mmol) and pyridine (1 mLl) in CH2Cl2 at 0° C. is added 3-(dimethylamino)pyrrolidine (1.14 mL, 10 mmol). The reaction is stirred at room temperature for 2 h, diluted with ether and filtered. The filtercake is washed with ether, treated with 0.1 N sodium hydroxide, stirred and filtered. This filtercake is washed with ether and recrystallized from petroleum ether to give 1-(4-bromobenzoyl)-3-dimethylaminopyrrolidine as a white powder (1.5 g), identified by NMR analysis.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[CH2:7][NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[OH-].[Na+].Cl>O1CCCC1.O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:9]([NH:8][CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:21])=[O:2])=[O:20])=[O:19])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)O
Reaction time: 16 h

Procedure:
Add to a solution of t-butoxycarbonyl-glycyl-glycyl-glycine methyl ester (4.1 g.) in tetrahydrofuran (30 ml.) and water (30 ml.) dropwise with stirring 1 N sodium hydroxide (13.6 ml.). Stir the reaction mixture for 16 hours, acidify to pH 3 with dilute hydrochloric acid and then evaporate to dryness under reduced pressure. Suspend the residue in acetone, filter and evaporate the filtrate to dryness to afford the title product (m.p. 115°-120° C.).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH:31]=[C:30]([N+:32]([O-])=O)[N:29]=[CH:28]3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CO.CC(O)=O.[H][H].[Pt]>[NH2:32][C:30]1[N:29]=[CH:28][N:27]([CH2:26][CH2:25][O:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([NH:13][C:11]([NH:10][C:8]3[N:7]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:12])=[CH:15][CH:16]=2)[CH:31]=1
Reactant: [H][H]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc([N+](=O)[O-])c3)c3ccccc23)cc1
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc(N)c3)c3ccccc23)cc1
Yield: 113.2 %

Procedure:
A solution of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-(4-nitro-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)urea (30) (158 mg, 0.253 mmol) in DCM/MeOH/AcOH (1:1:2, 6.0 mL) was passed through a Thales H-cube (10% Pt/C Cat-Cart., 30 mm) at 1.0 ml·min−1 in full hydrogen mode at 50° C. The solvents were evaporated under reduced pressure to give 1-(4-(2-(4-amino-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate I) as a light brown oil (150 mg, 100%): m/z 524 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13]O.P(Br)(Br)[Br:17]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13][Br:17]
Reactant: COC(=O)COc1ccc(Cl)cc1CO
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)COc1ccc(Cl)cc1CBr
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of (4-chloro-2-hydroxymethyl-phenoxy)-acetic acid methyl ester (5 g, 0.022 mmol) in DCM (50 mL) under an inert atmosphere of nitrogen is added phosphorus tribromide (1.03 mL, 0.011 mol) and the mixture is stirred at 0° C. for 90 minutes. The reaction mixture is diluted with water (15 mL) and allowed to warm to RT. The mixture is then washed with water (2×25 mL) and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo to yield the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](C2N3C=CC(C(F)(F)F)=NC3=NC=2)=[CH:4][C:3]=1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=1.Br[C:29]1[N:33]2[CH:34]=[CH:35][C:36]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:37][C:32]2=[N:31][CH:30]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]2[N:33]3[CH:34]=[CH:35][C:36]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:37][C:32]3=[N:31][CH:30]=2)=[CH:4][C:3]=1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ncccc1F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ncccc4F)c3)cnc2n1

Procedure:
4-Fluoro-3-(3-fluoropyridin-2-yl)phenylboronic acid (prepared according to Example 80) was coupled with 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol by the method of Example 78. Purification by chromatography on silica gel, eluting with dichloromethane containing 3.5% methanol, gave 2-[3-(4-fluoro-3-(3-fluoropyridin-2-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol which was converted to its hydrochloride salt by treatment with methanolic hydrogen chloride, evaporation, and crystallisation of the residue from isopropanol/ethyl acetate: δH (400 MHz, DMSO) 1.56 (6H, s), 7.62-7.71 (1H, m), 7.70 (1H, dd, J 9 and 2), 7.87 (1H, d, J 7.4), 7.92-8.00 (3H, m), 8.54 (1H, s), 8.61 (1H, m), 9.25 (1H, d, J 7); m/z (ES+) 367 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22].[S-:24][C:25]#[N:26].[K+]>CS(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][S:24][C:25]#[N:26])=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22]
Reactant: CCCc1c(OCc2ccc(CBr)cc2)ccc(C(C)=O)c1O
Reactant: N#C[S-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1c(OCc2ccc(CSC#N)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[2-Hydroxy-3-propyl-4-(4-bromomethylphenylmethoxy)phenyl]ethanone (6.4 g; 0.017 m) and potassium thiocyanate (3.3 g; 0.034 m) were dissolved in dry dimethylsulphoxide (60 ml) and stirred at room temperature for 4 hours. The solution was then poured onto water, stirred and filtered to give a white solid; dried at 60° C. under reduced pressure. Recrystallised from ethanol to give a white crystalline solid m.p. 110°-111° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH3:9].O.[OH-].[Li+].O.CO>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH3:9]
Reactant: COC(=O)c1ccc(C(C)Oc2ncccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(Oc1ncccn1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
A mixture of methyl 4-(1-(pyrimidin-2-yloxy)ethyl)benzoate (400 mg, 1.6 mmol), lithium hydroxide monohydrate (326 mg, 7.8 mmol), water (4 mL) and methanol (4 mL) in tetrahydrofuran (12 mL) was stirred at 20° C. for 5 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(1-(pyrimidin-2-yloxy)ethyl)benzoic acid as a white solid (300 mg, 88%). LRMS (M+H+) m/z: 244.08. found 244.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[CH:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1ccc(N)cc1
Reactant: Cc1ncnc(Cl)c1C
Product: Cc1ncnc(Nc2ccc(C(C)C)cc2)c1C
Yield: 23.2 %

Procedure:
To 3.6 g (0.025 mole) of 4-chloro-5,6-dimethylpyrimidine were added 3.4 g (0.025 mole) of p-isopropylaniline; the mixture was then heated at 100°-150° C. for about 3 minutes. The reaction mixture quickly became a solution and soon produced a precipitate, which was separated and then made alkaline by the addition of 50 ml of a dilute aqueous solution of sodium hydroxide. The mixture was then extracted with ethyl acetate and the extract was washed, in turn, with water and with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous sodium sulphate and then the ethyl acetate was distilled off under reduced pressure, to give crystals, which, on recrystallisation froma 3:1 by volume mixture of benzene and hexane, gave 1.4 g (yield 23%) of the desired product in the form of very fine colourless needles melting at132°-133° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH2:17][CH2:16][C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15](=[O:25])[CH2:16][CH2:17]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3cc(Cl)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCc2cc(Cl)ccc2N1C1CCNCC1
Yield: 149.7 %

Procedure:
4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 3.28 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 1.3 g (93%) of a white solid. MS (electrospray): exact mass calculated for C13H17ClN2O, 264.10. m/z found, 265.1 [M++H].
Reaction SMILES: C([O:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[C:10]#[N:11])(=O)C.[OH-].[Na+]>C(O)C.O>[OH:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[C:10]#[N:11]
Reactant: CCCCCC(CCCN(C#N)CCCCCC(C)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)CCCN(C#N)CCCCCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl 7-[N-(4-acetoxynonyl)cyanamido] -2-methylheptanoate (7.6 g., 0.02 mole) in ethanol (50 ml.) is added a solution of sodium hydroxide (1.6 g., 0.04 mole) in water (15 ml.) and the reaction is stirred at ambient temperature for 20 hours. Then most of the ethanol is removed in vacuo and the residue taken up in water (150 ml.). The solution is extracted once with ether then acidified with hydrochloric acid (dil.). The oil that separates is extracted into ether, the ether is washed with brine, dried over sodium sulfate, then removed under vacuum to give 7-[N-(4-hydroxynonyl)cyanamido]-2-methylheptanoic acid as a yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:29])[N:7]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17](CC3C=CC=CC=3)[C:16](=[O:28])[CH:15]=[CH:14]4)[C:8]2=[O:10])[CH2:4][CH2:3]1>CO.[H][H].[OH-].[OH-].[Pd+2]>[OH:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:29])[N:7]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16](=[O:28])[CH:15]=[CH:14]4)[C:8]2=[O:10])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=C1[C@@H]2[C@H](O)CCN2C(=O)N1c1ccc2c(ccc(=O)n2Cc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1[C@@H]2[C@H](O)CCN2C(=O)N1c1ccc2[nH]c(=O)ccc2c1
Yield: 26.7 %

Procedure:
Compound 46E (80 mg, 0.20 mmol) was dissolved in MeOH (5 mL) and hydrogenated at 1 atmosphere of hydrogen for 24 h in the presence of 20 mg Pd(OH)2. The reaction was then filtered, concentrated under reduced pressure, and subsequently purified by silica gel flash chromatography eluting with a gradient of 5%-10% MeOH in CH2Cl2 to give the title compound (16 mg) as a white solid. HPLC: 98% at 0.79 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O-10% MeCN-0.1% TFA and B=10% H2O-90% MeCN-0.1% TFA); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 300 [M+H]+.