Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Br:13]N1C(C)(C)C(=O)N(Br)C1=O.C(O)(=O)C.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C1(Cl)C=CC=CC=1>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([O:11][CH3:12])=[CH:3][C:2]=1[CH2:1][Br:13])([O-:10])=[O:9]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: COc1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 3.2 %

Procedure:
3-Methyl-4-nitroanisole (41, 2.50 g, 15.0 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (5.00 g, 17.5 mmol) were combined in 250 mL of C6H5Cl, and acetic acid (75 μL, 1.31 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (VAZO 88, 150 mg, mmol) were added to the stirring solution. The solution was stirred at 40° C. for 72 h. The crude reaction mixture was washed three times with hot NaHCO3 solution (75 mL, 80° C.), and once with water (75 mL). The organic portion was dried over MgSO4 to give an orange solid after filtration and solvent removal. The solid was filtered through a plug of silica gel to yield a mixture of the brominated product and unbrominated starting material that was carried on to the next step without further purification. Pure material could be obtained from flash chromatography on silica (15:3:2 hexanes/EtOAc/C6H5CH3) to give a brown oil (117 mg, 3.19%). TLC Rf=0.34 (4:1 hexanes/EtOAc). 1H NMR (CDCl3, 500 MHz) δ 3.91 (3 H, s), 4.85 (2 H, s), 6.92 (1 H, dd, J=4.5, 15.0 Hz), 7.02 (1 H, d, J=5.0 Hz), 8.13 (1 H, d, , J=15.5 Hz). ). 13C NMR (CDCl3, 125 MHz) δ 630.19, 56.25, 114.11, 117.69, 127.61, 128.48, 135.72, 163.45. HRMS (ESI): Calcd for MH+, 245.9766; Found 245.9760.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].[CH3:18][N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1.O.[Na]>CS(O)(=O)=O>[CH3:18][N:19]1[CH2:23][CH2:22][CH:21]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:20]1
Reactant: CN1CCC(O)C1
Reactant: OC(c1ccccc1)c1nc2ccccc2[nH]1
Agent: CS(=O)(=O)O
Agent: [Na]
Solvent: O
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3[nH]2)C1
Temperature: 25 °C

Procedure:
272A A mixture of (1H-benzimidazol-2-yl)phenylmethanol (611 mg) and 1-methyl-3-pyrrolidinol (263 mg) in methanesulfonic acid (1.3 mL) is heated for 4 hours in a sealed tube at a temperature close to 140° C. The mixture is cooled back to room temperature, poored into water which is then made alkaline with concentrated sodium hydroxyde solution. The aqueous phase is extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to give 2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole melting at 53° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.N1C=CC=C[CH:34]=1.[C:39]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:40]1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:43]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)(=[O:44])[CH2:42][CH2:41][CH2:40][C:39]([O:45][CH3:34])=[O:46]
Reactant: O=C1CCCC(=O)O1
Reactant: c1ccncc1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)CCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydro-3-isoxazolyl]-3-pyridinyl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 60 mg, 0.13 mmol) was suspended in 2 mL of anhydrous dimethylformamide. Anhydrous pyridine (1 mL, 12 mmol), 4-dimethylaminopyridine (DMAP) (10 mg, 0.08 mmol) and glutaric anhydride (75 mg, 0.55 mmol) were added and the solution was stirred for 16 hours at room temperature during which the mixture became a clear solution. The reaction was quenched with 1 mL of methanol and purged with diazomethane generated from 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) in a diazomethane generator (Aldrich, cat. No. Z41,173–6) until all product was converted into its methylester as judged by LCMS and the solution turned yellow. The solvent was removed and the product purified by chromatography on silica using a gradient from 0–10% methanol in dichloromethane that yielded 31 mg (40%) of the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([NH2:9])=[N:17][C:15]3[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=3[CH:18]=2)[CH:2]=1
Reactant: N#CCc1cccnc1
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3cccnc3)c(N)nc2n1

Procedure:
The procedure of Example 1 was followed to react 3-pyridylacetonitrile and 2,4-diamino-5-pyrimidine-carboxaldehyde to afford the title compound; mp 317-319° C. (dec).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([CH3:13])[CH2:10][CH2:11][SH:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:12][CH2:11][CH2:10][CH:9]([CH3:13])[CH3:8])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 47.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added 3-methylbutane-1-thiol (1 ml, 8.0 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (120 mg, yield 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].[N:37]1([CH2:43][C:44]2[CH:45]=[C:46]([CH:52]=[CH:53][CH:54]=2)[O:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:25]([NH:51][CH2:50][CH2:49][CH2:48][O:47][C:46]2[CH:52]=[CH:53][CH:54]=[C:44]([CH2:43][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:45]=2)=[O:26])[CH3:18])=[CH:4][CH:3]=1
Reactant: CN(CCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN(CCCCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 1.29 g (3.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 1.04 g (4.2 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine as starting materials. Working up by chromatography (eluant: methylene chloride) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+EI-80 eV): m/z (rel. int.[%])=619 ([M])+.,<1), 230 (17) 203 (100); IR (KBr): 1634 cm-1 (C≡0).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:24](=[O:25])[C:23]3[C:18]([Cl:17])=[CH:19][CH:20]=[C:21]([CH2:28][NH:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[C:22]=3[F:27])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)(CO)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)CO)c3F)cccc12
Yield: 10.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropanamido)methyl)benzoic acid (Intermediate-59, 168 mg, 0.56 mmol), oxalyl chloride (116 mg, 0.92 mmol), DMF (1 drop) and DIPEA (178 mg, 1.37 mmol) in CH2Cl2 (2 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.41 (s, 1H), 8.68 (d, J=7.8 Hz, 1H), 8.51 (s, 1H), 8.17 (d, J=8.1 Hz, 1H), 8.11 (t, 1H), 7.52-7.38 (m, 4H), 4.91 (t, 1H), 4.33 (d, J=6.3 Hz, 2H), 3.42 (d, 2H), 1.55 (s, 9H), 1.08 (s, 6H); MS [M+H]+: 502.46.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([OH:18])=O)[C:6](=[O:15])[N:7]2[CH:12]([CH3:14])[CH3:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2([OH:45])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([NH:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]3([OH:45])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH2:34][CH2:33]1)=[O:18])[C:6](=[O:15])[N:7]2[CH:12]([CH3:13])[CH3:14]
Reactant: NCC1CCN(CC2(O)CCOCC2)CC1
Reactant: CC(C)n1c(=O)c(C(=O)O)cc2c(Cl)cccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c(C(=O)NCC2CCN(CC3(O)CCOCC3)CC2)cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (111 mg, 0.418 mmol, step 4 in preparation 1) in dichloromethane (1 mL) was added oxalyl chloride (0.11 mL, 1.26 mmol) and a drop of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 0.5 h. The solvent and excess amount of oxalyl chloride was removed in vacuo. The residue was dissolved in dichloromethane (1 mL), 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (191 mg, 0.837 mmol, step 2) was added at 0° C. and the mixture was stirred at room temperature for 1 h. Then, the mixture was quenched with water (10 mL), and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropanol to give 156 mg (78%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:29]([N:13]1[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[CH2:10][CH:11]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:12]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N=C=O
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)NC(C)(C)C)C2)cc1

Procedure:
62 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 20 mg (0.20 mmol, 1.0 eq.) of tert-butyl isocyanate were reacted according to General Method 4.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17](C(OC)=O)=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:24][Mg+].[Br-].CCO[C:30]([CH3:32])=[O:31].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:30]([OH:31])([CH3:32])[CH3:24])=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: COC(=O)c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Reactant: CCOC(C)=O
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A portion of the isolated methyl 6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carboxylate (99 mg, 0.3 mmol, 1.0 equiv) was dissolved in THF (10 mL) and transferred to a 20 dram vial. The mixture was cooled to 0° C. and MeMgBr (3M in Et2O, 0.5 mL, 1.5 mmol, 5 equiv) was added. The reaction was allowed to warm to rt and then stirred for 15 min. The reaction mixture was poured into a mixture of EtOAc (30 mL) and saturated ammonium chloride (15 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (0-20% MeOH/CH2Cl2) to give 42 mg (43%) of 2-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)propan-2-ol as a white powder. m/z=317 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=1.[C:20]([O-:23])([O-])=O.[Cs+].[Cs+].[C:26]([O-:29])(O)=O.[Na+]>CN(C=O)C>[C:14]1([C:6]2[CH:5]=[C:4]([CH2:3][O:29][C:26]3[CH:12]=[CH:13][C:4]([CH2:20][OH:23])=[CH:5][CH:6]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])O
Reactant: O=C([O-])[O-]
Reactant: ClCc1cc(-c2ccccc2)nc2ccccc12
Agent: Cl
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1ccc(OCc2cc(-c3ccccc3)nc3ccccc23)cc1
Yield: 99 %

Procedure:
A solution of Compound C1 (2.14 g, 17.23 mmol), 4-chloromethyl-2-phenyl-quinoline HCl (5.0 g, 17.23 mmol), Cs2CO3 (11.8 g, 36.2 mmol), and dry DMF (60 mL) was stirred at room temperature for 20 hours. A saturated aqueous NaHCO3 solution was added and the aqueous phase was extracted with EtOAc (300 mL). The organic phase was washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, concentrated by rotary evaporator, and dried under vacuum overnight to give [4-(2-phenyl-quinolin-4-ylmethoxy)-phenyl]-methanol (5.81 g, 99%). [4-(2-Phenyl-quinolin-4-ylmethoxy)-phenyl]-methanol (4.0 g, 11.73 mmol) was dissolved in dry CH2Cl2 (60 mL) and was cooled to 0° C. before PBr3 (1.1 mL, 11.73 mmol, in 5 mL CH2Cl2) was added. The solution was stirred overnight at room temperature. The solution was poured into a cold aqueous NaHCO3 solution (250 mL) with stirring. The aqueous phase was extracted with EtOAc (150 mL) four times. The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporator to give compound C2 (4.3 g, 91%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13]Cl)[N:8]=[C:7](C(Cl)(Cl)Cl)[N:6]=1>CO>[CH:11]1([C:9]2[N:10]=[C:5]([NH2:4])[N:6]=[C:7]([O:2][CH3:1])[N:8]=2)[CH2:13][CH2:12]1
Reactant: C[O-]
Reactant: Nc1nc(CCCCl)nc(C(Cl)(Cl)Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 60 °C
Reaction time: 1.33 h
Yield: 12.7 %

Procedure:
To a solution of 10.8 g of sodium methylate in 50 ml of methanol are added 28.9 g of 2-amino-4-(3-chloropropyl)-6-trichloromethyl-1,3,5-triazine, and the mixture is stirred at 60° C. for 80 minutes. The formed suspension is filtered under suction, diluted with 250 ml of water, and extracted 3 times with 200 ml of ethylene chloride each time. The organic phases are dried, filtered, and concentrated by evaporation. The oil which remains is purified through a silica gel column, the eluant used being methylene chloride/ether (3:1). The eluant is evaporated off to leave 2.1 g of the title product, which is recrystallised from ether/chloroform, m.p. 158°-159° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[C:19]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=4[F:36])=[N:20][O:21][C:22]=3[CH:23]3[CH2:25][CH2:24]3)=[CH:12][C:11]=2[CH3:37])=[N:7][C:6]=1[CH3:38])=[O:4].[Li+].[OH-].Cl>CO.C1COCC1.O>[CH:23]1([C:22]2[O:21][N:20]=[C:19]([C:26]3[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:27]=3[F:36])[C:18]=2[CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:38])[N:7]=3)=[C:11]([CH3:37])[CH:12]=2)[CH2:25][CH2:24]1
Reactant: COC(=O)c1sc(-c2ccc(OCc3c(-c4c(F)cccc4C(F)(F)F)noc3C3CC3)cc2C)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(-c3c(F)cccc3C(F)(F)F)noc2C2CC2)ccc1-c1nc(C)c(C(=O)O)s1
Temperature: 55 °C
Yield: 98 %

Procedure:
To a solution of 2-(4-(5-Cyclopropyl-3-(2-fluoro-6-trifluoromethyl-phenyl)-isoxazol-4-ylmethoxy)-2-methyl-phenyl)-4-methyl-thiazole-5-carboxylic acid methyl ester (0.025 g, 0.046 mmol) in 1 mL of methanol and 1 mL of THF is added a solution of LiOH (0.011 g, 0.46 mmol) in water (11 mL). The reaction is heated to 55° C. for 30 minutes. The reaction is cooled, acidified with aqueous 1M HCl, and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered, and evaporated to yield the title compound (24 mg, 99%). ES/MS m/e 533.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]([CH:17]2[CH2:19][CH2:18]2)[OH:15])=[C:4]([F:16])[CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Solvent: C1CCOC1
Product: OC(c1cnccc1-c1ccc(Cl)cc1F)C1CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (1.6 g, 6.79 mmol) (prepared as in Example 5, Part B) in THF (32 mL) cooled to −78° C., was added cyclopropylmagnesium bromide (27.2 mL, 13.58 mmol) dropwise over a period of 20 min. The reaction mixture was allowed to stir at −78° C. for 3 h. The dry ice bath was removed and reaction mixture was brought to room temperature. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (30 mL). The reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (1×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (30% ethyl acetate in pet ether) to afford (4-(4-chloro-2-fluorophenyl)pyridin-3-yl)(cyclopropyl)methanol (900 mg, 3.24 mmol, 48% yield). LCMS (ESI) m/e 278.0 [(M+H)+, calcd for C15H14ClFNO 278.1]; LC/MS retention time (Method C): tR=1.62 min.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:46])[CH2:10][C:11]1[CH:45]=[CH:44][CH:43]=[CH:42][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[CH3:21][C:20]1[C:15]([CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[CH2:10][C:9]([NH2:8])=[O:46])=[N:16][C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[N:18][CH:19]=1
Reactant: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C3CCNCC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
TFA (0.37 mL, 4.8 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A56) (64 mg, 0.12 mmol) in DCM (20 mL) under nitrogen and the resulting mixture stirred for 24 hours at room temperature. The volatiles were removed in vacuo and the residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 5 column volumes of 5% v/v aqueous ammonia in MeOH. The volatiles from the ammoniacal filtrate were evaporated under reduced pressure and the resulting solid dried under high vacuum to give the title compound 16 as a white solid (36 mg, 69%); 1H NMR (400 MHz, d6-DMSO) δ 9.28 (s, 1H), 8.15 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.44 (s, 1H), 7.25-7.13 (m, 4H), 7.10 (d, J=8.6 Hz, 2H), 6.93 (s, 1H), 3.50 (s, 2H), 3.10-2.98 (m, 4H), 2.94-2.82 (m, 2H), 2.65-2.53 (m, 3H), 2.06 (s, 3H), 1.67 (d, J=10.6 Hz, 2H), 1.49 (qd, J=12.4, 3.7 Hz, 2H). LCMS-A: rt 4.463 min; m/z 430 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[P:6]([O:10][CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])([OH:9])([OH:8])=[O:7].[CH2:17]([N:33]=[C:34]=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CNC(=O)C>[CH2:17]([NH:33][C:34](=[O:35])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[P:6]([O:10][CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])([OH:8])([OH:9])=[O:7]
Reactant: CNCCO
Reactant: CCCCCCCCCCCCCCCCN=C=O
Agent: C[N+](C)(C)CCOP(=O)(O)O
Solvent: CNC(C)=O
Product: CCCCCCCCCCCCCCCCNC(=O)N(C)CCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.5 g of 2-methylamino-ethanol-phosphocholine is dissolved in 10 ml of N-methylacetamide; the solution is mixed with 1.08 g of hexadecyl-isocyanate and stirred for 24 hours at room temperature. The solution is reduced in vacuo and the residue purified by column chromatography (silica gel//chloroform/methanol/water).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:9]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[O:31]=[C:32]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1>C1COCC1>[O:14]=[C:12]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9](=[O:22])[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]1[C:32]1([OH:31])[CH2:33][N:34]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:35]1
Reactant: O=C1CN(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(C2C(=O)N(Cc3ccccc3)CC(=O)N2Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.38 h
Yield: 49.6 %

Procedure:
To a solution of commercially available 1,4-bis(phenylmethyl)piperazine-2,5-dione (2.0 g, 6.8 mmol) in dry THF (50 mL) at −78° C. was added lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.4 mL, 6.8 mmol). The resulting reddish brown suspension was stirred for 23 min at −78° C., and then a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (770 mg, 4.5 mmol) in THF (10 mL) was added over 30 min by syringe pump. The mixture became a bright yellow solution as it was allowed to warm to room temperature over 3 hours. The mixture was quenched with saturated aqueous ammonium chloride. Water was added to dissolve precipitated salts, and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (60% ethyl acetate: 40% hexanes) to provide 1,1-dimethylethyl 3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-carboxylate as a colorless foam (1.04 g, 2.23 mmol, 50% yield). 1H NMR. (400 MHz, CDCl3): 7.39-7.29 (m, 7H), 7.23-7.19 (m, 3H), 5.34 (d, 1H), 4.82 (d, 1H), 4.58 (d, 1H), 4.37 (d, 1H), 4.37 (d, 1H), 4.22 (d, 1H), 4.15 (s, 1H), 4.08 (d, 1H), 3.97 (d, 1H), 3.75 (d, 1H), 3.74 (d, 1H), 3.67 (d, 1H), 3.64 (br s, 1H), 1.43 (s, 9H).