Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[O:22]1[CH:26]=[CH:25][C:24](B(OC(C)C)OC(C)C)=[CH:23]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:24]3[CH:25]=[CH:26][O:22][CH:23]=3)=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: Fc1ccc(Nc2ncnc3cc(Br)ccc23)cc1Cl
Reactant: CC(C)OB(OC(C)C)c1ccoc1
Agent: Cl
Product: Fc1ccc(Nc2ncnc3cc(-c4ccoc4)ccc23)cc1Cl
Yield: 37 %

Procedure:
Using an analogous procedure to that described in Example 1, 7-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 3-furylboronate to give 4-(3-chloro-4-fluoroanilino)-7-(3-furyl)quinazoline in 37% yield, m.p. 249°-250° C.;
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](O)(=O)[CH2:13][OH:14].[NH4+].[OH-]>>[N+:9]([C:5]1[CH:6]=[C:7]2[N:8]=[C:12]([CH2:13][OH:14])[NH:1][C:2]2=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: O=C(O)CO
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2[nH]c(CO)nc2c1
Temperature: 145 °C
Reaction time: 0.62 h
Yield: 57.9 %

Procedure:
Solid 2,3-Diamino-5-nitropyridine (prepared according to J. Med. Chem. 1997, 40, 3679-3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145° C. and stirred for approx. 30-45 min (solid fuses together, liquifies then re-solidifies). After allowing to cool to rt the solid was extracted with 1N HCl. The aqueous mixture was concentrated under vacuum to leave a crude solid that was basified using conc. NH4OH solution. The ammonia solution was concentrated under vacuum to leave a crude solid that was dry-loaded on to silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) that was used directly in the next step.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[CH:25]1([C:28]2[C:29]([O:38][CH2:39][C:40]34[CH2:50][C:44]5([F:51])[CH2:45][C:46]([F:49])([CH2:48][C:42]([F:52])([CH2:43]5)[CH2:41]3)[CH2:47]4)=[CH:30][C:31]([F:37])=[C:32]([CH:36]=2)[C:33](O)=[O:34])[CH2:27][CH2:26]1.CS(N)(=O)=O.[N:58]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60][CH2:59]1>>[N:58]1([S:62]([NH:65][C:33](=[O:34])[C:32]2[CH:36]=[C:28]([CH:25]3[CH2:26][CH2:27]3)[C:29]([O:38][CH2:39][C:40]34[CH2:50][C:44]5([F:51])[CH2:43][C:42]([F:52])([CH2:48][C:46]([F:49])([CH2:45]5)[CH2:47]3)[CH2:41]4)=[CH:30][C:31]=2[F:37])(=[O:64])=[O:63])[CH2:61][CH2:60][CH2:59]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Yield: 47 %

Procedure:
Following the procedure as described in Example 150 step 5 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acid and to replace methyl sulfonamide with azetidine-1-sulfonamide. Purification by silica gel column chromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.10 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 11.61 (br s, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.7 Hz, 1H), 4.01 (t, J=7.6 Hz, 4H), 3.93 (s, 2H), 2.25-1.99 (m, 9H), 1.80 (s, 6H), 0.93-0.85 (m, 2H), 0.67-0.60 (m, 2H); MS (ES−) m/z 515.1 (M−1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 78.8 %

Procedure:
The title compound was prepared from methyl 3-(2-(7-phenylheptanoyl)oxazol-5-yl)benzoate (29 mg, 0.074 mmol) following General Procedure E. Preparative thin layer chromatography (EtOAc) yielded the title compound as a white solid (22 mg, 79%): 1H NMR (THF-d8, 500 MHz) δ 8.55 (s, 1H), 8.16 (d, 1H, J=7.5 Hz), 8.09 (d, 1H, J=8.0 Hz), 7.88 (s, 1H), 7.66 (t, 1H, J=8.0 Hz), 7.32-7.29 (m, 2H), 7.25-7.24 (m, 2H), 7.20-7.18 (m, 1H), 3.15 (t, 2H, J=7.0 Hz), 2.70 (t, 2H, J=7.5 Hz), 1.84-1.81 (m, 2H), 1.77-1.71 (m, 2H), 1.54-1.49 (m, 4H); 13C NMR (THF-d8, 125 MHz) δ 187.2, 166.9, 158.0, 153.4, 142.9, 133.1, 130.9, 129.4, 128.9, 128.5, 128.4, 127.8, 126.4, 125.7, 124.8, 38.9, 36.1, 31.8, 29.4, 29.4, 24.2; MALDI-FTMS m/z 378.1699 (M+H+, C23H24NO4, requires 378.1700).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C@@:17]1([CH2:30]O)[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[F:16][C@@:17]1([CH2:30][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(COS(=O)(=O)C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
Triflic anhydride (24.06 ml, 142 mmol) was added to a solution of 1,1-dimethylethyl (3S)-3-fluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (30.2 g, 129 mmol) and triethylamine (23.46 ml, 168 mmol) in DCM (100 ml) at −10° C. over 20 min. The mixture was stirred for 2 h, allowing to warm to 0° C., then washed with water and brine, dried and evaporated to give 1,1-dimethylethyl (3S)-3-fluoro-3-({[(trifluoromethyl)sulfonyl]oxy}methyl)-1-piperidinecarboxylate as a dark brown oil (50.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C@@H:20]([NH:22]C(OC(C)(C)C)=O)[CH3:21])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:30])=[O:4].Cl.Cl[C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][N:37]2[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1.CCN(C(C)C)C(C)C>CO.O1CCOCC1.C(O)CCC>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11]([C@@H:20]([NH:22][C:33]3[N:41]=[CH:40][N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][N:37]4[CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[CH3:21])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:30])=[O:4]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c12
Temperature: 45 °C
Yield: 86.2 %

Procedure:
To a solution of 2-((S)-1-tertbutoxycarbonylaminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carboxylic acid methyl ester (1.1 g, 2.7 mmol) in MeOH (20 mL) was added 4N HCl in dioxane (5 mL) and the reaction mixture was heated at 45° C. for 3 h. The volatiles were removed under reduced pressure and the resulting residue was treated with 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (825 mg, 3.46 mmol) and DIPEA (1.8 mL, 10.6 mmol) in n-butanol (10 mL). The reaction mixture was heated in a sealed vial for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (1.2 g, 87%). LCMS (Method C): RT 3.11 min [M+H]+ 516.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[N:11](C(OC(C)(C)C)=O)[C:10]=1[C:26]([O:28][CH3:29])=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1c(NCCC(=O)c2ccc(F)c(F)c2)c2ccc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccc(F)c(F)c1
Yield: 62 %

Procedure:
Dissolve 3-[(3,4-difluorophenacyl)methylamino]-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (5 mL) and stir for 4 hours at room temperture. Dilute with ethyl acetate (50 mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography (30% ethyl acetate/hexane) and recrystallize from ethyl acetate/hexane to yield the title compound (1.0 g, 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.[CH3:22][CH:23]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:22]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:21])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)[CH3:23]
Reactant: CC1(C)OB(c2ccc(C3CCNCC3)cc2)OC1(C)C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine in THF was added MeCHO (40%, 0.17 mL, 1.48 mmol) and AcOH (45 mg, 0.74 mmol), the mixture was stirred at room temperature for 20 minutes. Then the NaBH(OAc)3 (157 mg, 0.74 mmol) was added and stirred overnight. The reaction solution was poured to NaHCO3, extracted with EA, dried and concentrated to give product as white solid. MS (m/z): 316 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[N:6][CH:7]=1.[CH3:16][N:17]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1)[C:18](=[O:28])[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:15][C@H:10]1[O:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:5]2[N:4]=[CH:3][C:2]([C:32]3[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=3)[CH2:29][N:17]([CH3:16])[C:18](=[O:28])[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:7][N:6]=2)[CH2:9]1
Reactant: C[C@@H]1CN(c2ncc(Br)cn2)C[C@H](C)O1
Reactant: CN(Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C(=O)CNC(=O)OC(C)(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H]1CN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)C[C@H](C)O1
Temperature: 80 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
rel-(2R,6S)-4-(5-Bromopyrimidin-2-yl)-2,6-dimethylmorpholine (118 mg) and tert-butyl (2-{methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]amino}-2-oxoethyl)carbamate (175 mg) were dissolved in DME (2 ml) and water (1 ml), and tetrakis(triphenylphosphine)palladium (15 mg) and sodium carbonate (137 mg) were added thereto, followed by stirring at 80° C. for 24 hours. The obtained residue was subjected to liquid separation with CHCl3 and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl rel-{2-[(3-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl]carbamate (190 mg) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br.CC(O)=O>>[C:20]1([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[CH:11][CH:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(Nc2ccc(-c3ccccc3)c3ccccc23)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Nc2ccc(-c3ccccc3)c3ccccc23)cc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with N-(4-methoxyphenyl)-4-phenylnaphthalen-1-amine (600 mg, 1844 μmol) and 6 mL 1:1 HBr (100 μl, 1844 μmol) and HOAc (106 μl, 1844 μmol). The flask was fitted with a reflux condenser and the mixture was heated at 140° C. After 1 h, LCMS showed ˜50% conversion to desired product. Heating was continued for another 5 h. Upon cooling, the mixture was brought to neutral pH by addition of 6 N NaOH and extracted with DCM. The organic portion was dried, filtered and concentrated. The crude material was purified by silica gel chromatography, 0-50% EtOAc/hex to provide 4-(4-phenylnaphthalen-1-ylamino)phenol. MS: [M+H]=312.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].[CH:47](=O)[CH3:48].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH2:47]([N:27]([CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@@H:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10][CH2:9]3)=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:40][CH:41]=2)=[CH:30][CH:29]=1)[CH3:48]
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(OCc5ccc(OC(F)(F)F)cc5)cc4)CC3)cc1)CC2
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: CCN(c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1)C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-{1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine (0.47 g) was suspended in 1,2-dichloroethane (5 ml). Acetaldehyde (0.41 ml) and sodium triacetoxyborohydride (0.46 g) were added to the suspension, and the mixture was stirred at room temperature for 3 days. A potassium carbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) and recrystallized from methanol to afford the title compound as a yellow powder (0.25 g).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][NH2:10])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:4]=1)[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:28])=O)=[CH:22][CH:21]=1>C(O)C>[CH2:1]([C:3]1[N:8]=[C:7]([NH:9][N:10]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[CH3:28])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:4]=1)[CH3:2]
Reactant: CCc1nc(NN)cc(-c2ccccc2OC)n1
Reactant: CC(=O)c1ccc(C)cc1
Solvent: CCO
Product: CCc1nc(NN=C(C)c2ccc(C)cc2)cc(-c2ccccc2OC)n1

Procedure:
The title compound was prepared from [2-ethyl-6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazine (100 mg, 0.41 mmol) and 4-methylacetophenone (55 μL, 0.41 mmol) in 1.0 mL of ethanol by a procedure similar to example 1, step 4 yielding 117 mg (79%) of a yellow solid. HPLC Purity: 95%.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:6](OC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+].O.ClCCl>CO>[OH:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1
Reactant: COC(=O)C(CN1CCN(C)CC1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC(CO)CN1CCN(C)CC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
A solution under inert atmosphere of 3.27 g of methyl (acetylamino)-3-(4-methyl-piperazin-1-yl)propanoate in 100 mL of anhydrous methanol is cooled at a temperature of about 10° C., then 0.76 g of sodium borohydride are added using a spatula. The reaction medium is stirred for 5 hours at a temperature of about 20° C., then are added again 0.26 g of sodium borohydride and the stirring is carried out for 38 hours. Then, 5 mL of water is dropped into the reaction mass which is heated and concentated under reduced pressure (2 kPa) at a temperature of about 30° C. The obtained residue is taken up with dichloromethane and the insoluble matter is removed by filtration. The filtrate is concentrated under reduced pressure (2 kPa) at a temperature of about 20° C. The residue is purified by chromatography under argon pressure (60 kPa), on a column of silica gel (particle size 40–63 μm; diameter 5 cm; height 19 cm), eluting with successive mixtures of 20% dichloromethane/methanol/aqueous ammonia (98/2/0, 95/5/0.1, 90/10/0.2, 80/20/0.25, 50/50/0.25 by volume). The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 40° C. About 0.92 g of N-[2-hydroxy-1-(4-methyl-piperazin-1-ylmethyl)ethyl]acetamide are obtained in the form of a yellow-colored liquid. [Infrared spectrum CH2Cl2 3621; 3429; 3352; 2944; 2803; 1657; 1513; 1460; 1284; 1050; 1011 and 816 cm−1].
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([NH2:12])[C:9](Cl)=[CH:8][C:5]=1[NH:6][CH3:7])([O-:3])=[O:2].[SH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>>[N+:1]([C:4]1[CH:11]=[C:10]([NH2:12])[C:9]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:8][C:5]=1[NH:6][CH3:7])([O-:3])=[O:2]
Reactant: Oc1ccc(S)cc1
Reactant: CNc1cc(Cl)c(N)cc1[N+](=O)[O-]
Product: CNc1cc(Sc2ccc(O)cc2)c(N)cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
11.5 g (0.057 mol) of 2-nitro-4-amino-5-chloro-N-(methyl)aniline and 11.9 g (0.085 mol) of 4-mercaptophenol were used as the starting materials to give brown-orange crystals (11.3 g) recrystallized from 96° ethanol and melting at 206° C., whose elemental analysis calculated for C13H13N3O3S was:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[NH:51][C:52]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:54]=1>CN(C=O)C>[N:50]1[NH:51][C:52]([C:55]2[CH:56]=[C:57]([NH:61][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:54]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccn[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccn[nH]4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 6.8 %

Procedure:
DIEA (0.011 mL, 0.062 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.012 g, 0.057 mmol) and HATU (0.024 g, 0.062 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2H-pyrazol-3-yl)-phenylamine (0.009 g, 0.057 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.0014 g of product in 7% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: N[C@@H](C(O)=O)CC1C=NC=CC=1.C1C=C[C:16]2NC=[C:19]([CH2:22][C@@H:23]([NH2:27])[C:24]([OH:26])=[O:25])[C:17]=2C=1.N[C@@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.NCCC1N=CNC=1>>[N:27]1[CH:16]=[CH:17][CH:19]=[CH:22][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: NCCc1c[nH]cn1
Agent: N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: N[C@H](Cc1cccnc1)C(=O)O
Product: O=C(O)c1ccccn1

Procedure:
D-PicLys was substituted by D-3Pal, D-Trp, D-PzcLys, D-2-Nal and D-NicLys. Peptides 7 and 10 with D-3-Pal and D-2-Nal, respectively, were inactive at 0.25 μg. D-Trp is neutral and D-PzcLys is less basic than D-PicLys. These amino acids might be a good choice for lowering histamine release. Analog 11 with D-NicLys showed 67% AOA/0.25 μg which confirms past results that picolinic acid is superior to nicotinic acid for acylation of lysine.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:38])[N:9]([CH3:37])[C:10]=3[N:17]=[CH:16][C:15]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)=[CH:31][CH:32]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.091 mmol) in THF (2 ml) and water (2 mL) was added LiOH.H2O (7.6 mg, 0.183 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 40.5% yield) as a white solid. 1H NMR (CD3OD) δ: 8.52 (s, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.15-7.07 (m, 3H), 6.79 (d, J=8.4 Hz, 2H), 4.67 (s, 2H), 4.10 (t, J=6.8 Hz, 2H), 3.74 (s, 3H), 3.57 (t, J=6.4 Hz, 2H), 1.86-1.81 (m, 2H). LCMS: MH+ 520 and TR=3.195 min.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[CH2:20][C@H:19]([OH:23])[C@@H:18]2[CH2:24][CH3:25])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].IC.C(O)(=O)C>O1CCCC1.O>[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[C@@H:20]([CH3:1])[C@H:19]([OH:23])[C@@H:18]2[CH2:24][CH3:25])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Reactant: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: CI
Product: CC[C@H]1[C@@H](O)[C@H](C)C(=O)N1c1ccc(C#N)c(Cl)c1
Reaction time: 1 h
Yield: 13 %

Procedure:
To absolution of diisopropylamine (0.111 mL) in tetrahydrofuran (5 mL) was added dropwise n-butyllithium-hexane solution (0.472 mL, 1.6 mol/L) at −78° C., the mixture was stirred for 1 hr, and a solution of 2-chloro-4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]benzonitrile (80 mg) in tetrahydrofuran (3 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, iodomethane (0.100 mL) was added dropwise at −78° C., and the mixture was stirred at 0° C. for 2 hr. Acetic acid (0.500 mL) was added dropwise to the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/3) to give the title compound as a colorless solid (yield: 10.8 mg, 13%).