Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[NH:8][C:9](=[O:11])[CH3:10].C(O)(=O)C.[N:29]([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:12][C:5]1[N:4]=[C:3]2[N:13]([CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[N:29]=[N:1][C:2]2=[C:7]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=1
Reactant: CC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1N
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)nc2c1nnn2Cc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(3-amino-6-chloro-2-(quinolin-6-ylmethylamino)pyridin-4-yl)acetamide was added to a solution of acetic acid (2 mL) and water (2 mL) at 0° C., followed by the addition of NaNO2 (180 mg, 2.6 mmol) in H2O (0.2 mL). The reaction was stirred at 0° C. for 1 h, and then basified with 30% NaOH to pH=7. The resulting precipitate was collected by filtration to afford the title compound (80 mg), which was used for the next step without further purification. MS (m/z): 353 (M+1)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CS(C)=O.O>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of 4-fluorobenzonitrile (500 mg, 4.13 mmol, 1.00 equiv) in DMSO (5 mL), and morpholine (1070 mg, 12.30 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 120° C. in an oil bath. The resulting solution was diluted with 100 mL of H2O. The solids were collected by filtration. The product was obtained as 617 mg (79%) of a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][O:25][CH3:26])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-]>O1CCOCC1.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>[CH:27]([C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][O:25][CH3:26])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C
Yield: 48.4 %

Procedure:
To a solution of 5-bromo-3-(1-{[2-(methyloxy)ethyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (100 mg, 0.22 mmol) in dioxane (3.0 mL) and water (1.0 ml), (3-formylphenyl)boronic acid (186 mg, 1.25 mmol), Pd(PPh3)4 (25.0 mg, 10%) and cessium carbonate (200 mg, 0.45 mmol) were added. The reaction mixture was heated in a Smith synthesizer microwave at 160° C. for 20 min. All solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane, 1/1) to yield the desired product (50.0 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[N:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:16]=[N:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COc1cc(C)c(N2CCCn3c2nc2c(Cl)ccc(CO)c23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.6 %

Procedure:
Sulfur trioxide-pyridine complex (3.42 g, 21.5 mmol) was added to a stirred solution of [9-chloro-1-(6-methoxy-4-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (1.19 g, 3.31 mmol), triethylamine (3.7 mL) in dimethyl sulfoxide (10 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow solid (220 mg, 0.617 mmol, 19%).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[CH:22][CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2ccnn2)cc1
Product: O=CC=Cc1ccc(-n2ccnn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,3-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [F:1][C:2]([CH:5]=[C:6]=[CH:7][C:8]([F:11])([F:10])[F:9])([F:4])[F:3].[O:12]([CH3:14])[Na].O>CO>[C:2]([CH:5]=[C:6]([CH2:7][C:8]([F:9])([F:10])[F:11])[O:12][CH3:14])([F:4])([F:3])[F:1]
Reactant: FC(F)(F)C=C=CC(F)(F)F
Reactant: CO[Na]
Solvent: O
Solvent: CO
Product: COC(=CC(F)(F)F)CC(F)(F)F
Reaction time: 0.25 h
Yield: 88 %

Procedure:
21.1 g (0.12 mol) of bis(trifluoromethyl)allene were added to 20 mL 0.5 N NaOCH3 in methanol (8 mol % relative to allene) over 1 h with water bath cooling, keeping the reaction temperature at 10-20° C. Stirring was continued for 15 min. and the mixture poured into 80 mL cold water. The lower layer was separated and the aqueous portion extracted with 20 mL CH2Cl2. The combined organic layers were washed with 5 mL brine, dried (Na2SO4) and distilled to give 21.9 g (88% yield) of CF3CH=C(OCH3)CH2CF3, boiling point 110-111° C. IR: 1672 cm-1. Major MS fragments: 208 (75.9), 189 (30.2), 158 (31.6), 125 (60.5), 111 (82.4), 91 (100), 31 (91.2). 1H NMR:4.95 (q,1H, J=7.5 Hz), 3.65 (s, 3H), 3.18 (q, 2H, J=9.8 Hz) ppm. 19FNMR: -54.4(d,3 F), -63.9 (t, 3 F) ppm. Anal. Calcd for C6H6F6O: C, 34.61; H, 2.91. Found: C, 34.59; H. 2.85.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[O:42]1[C:46]2[CH:47]=[CH:48][C:49](B(O)O)=[CH:50][C:45]=2[CH2:44][CH2:43]1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:25]=[C:24]([C:49]3[CH:48]=[CH:47][C:46]4[O:42][CH2:43][CH2:44][C:45]=4[CH:50]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)CCO3)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 2,3-dihydrobenzofuran-5-boronic acid. LC/MS indicated a purity of 93% as measured by UV 214 nM.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][CH:14]1[CH2:20][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH:17]([CH3:28])[N:16]([CH3:29])[CH2:15]1>CN(C)C=O>[CH2:21]([N:19]1[CH2:20][CH:14]([NH:13][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:15][N:16]([CH3:29])[CH:17]([CH3:28])[CH2:18]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CC1CN(Cc2ccccc2)CC(N)CN1C
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)CN1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (2.2 g) in N,N-dimethylformamide (40 ml), N,N'-carbonyldiimidazole (2.2 g) is added, and the mixture is heated at 60° C. for 3.5 hours. A solution of 6-amino-1-benzyl-3,4-dimethylhexahydro-1H-1,4-diazepine (3.0 g) in N,N-dimethylformamide (10 ml) is added to the mixture, and the mixture is stirred at 25° C. for 2 hours. The solvent is evaporated under reduced pressure, and the residue is diluted with water and extracted with chloroform. The organic layer is washed successively with 10% aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution 10% methanol-acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.9 g) which is one isomer with lower polarity in two isomers produced in the above reaction, m.p. 203°-205° C. (recrystallized from isopropyl alcohol).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:16])[N:3]=1.P(Cl)(Cl)([Cl:19])=O>CN(C)C1C=CC=CC=1>[Cl:19][C:6]1[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:16])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CCOC(=O)CCc1c(C)nc(C)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)CCc1c(C)nc(C)nc1Cl
Yield: 72 %

Procedure:
A mixture of ethyl 3-(2,6-dimethyl-3H-pyrimidin-4-on-5-yl)propionate (3.87 g, 0.017 mol), phosphorus oxychloride (40 mL), and N,N-dimethylaniline (10 drops) was heated under reflux for 2 h. The mixture was concentrated, cooled, and ice water was added. Solid KOH was added to bring the pH to 6 and the mixture was extracted with ether. The extracts were dried (MgSO4) and concentrated to give 2.95 g (72%) of product as a brown oil.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][O:4][CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:6]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:19]([NH:26][C@H:10]1[CH2:9][CH2:8][N:7]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:6][C@H:5]1[O:4][CH2:3][CH:2]([F:18])[F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1OCC(F)F
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N1CC[C@H](NCc2ccccc2)[C@H](OCC(F)F)C1)C(F)(F)F
Yield: 79.2 %

Procedure:
The same operation as in Example (90c) was performed using 3-(2,2-difluoroethoxy)-1-(trifluoroacetyl)piperidin-4-one obtained in Example (121c) (1.1 g, 4 mmol), benzylamine (0.54 g, 5 mmol), sodium (triacetoxy)borohydride (0.85 g, 6 mmol) and 1,2-dichloroethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 1.16 g of the title compound as a yellow oily substance (79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][CH:29]([F:33])[C:30](Cl)=[O:31]>>[F:28][CH:29]([F:33])[C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: O=C(Cl)C(F)F
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)C(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and difluoroacetyl chloride (23 mg, 150 μmol). Yield 21 mg (95%).
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[N:10]([CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:26][N:31]1[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[N:10]([CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CO1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC(O)CN1CCN(C)CC1
Yield: 75 %

Procedure:
A solution of 7-(2,3-epoxypropoxy)-6-methoxy-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one (5 g, 13.8 mmol) and N-methylpiperazine (1.7 ml) in chloroform (70 ml) was refluxed for 21 hours. After cooling the mixture was poured onto a column of silica and eluted with methanol/methylene chloride/ethylacetate (5/45/50) followed by (8/42/50) followed by methanol (saturated with ammonia)/ methylene chloride/methanol (5/45/50) followed by (8/42/50). The fractions containing the expected product were combined and the volatiles were removed under vacuum. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxy-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one (4.8 g, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCNC[C@H]1C
Reaction time: 12 h

Procedure:
A solution of 2.05 g (R)-2-Methyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-ethyl ester in 15 ml dichloromethane was treated with 11.2 ml TFA and the resulting solution stirred for 12 h. The solvents were removed in vacuum and the crude hydrotrifluoroacetate transformed to the free amine by treatment with (Polystyrylmethyl)trimethylammonium bicarbonate in MeCN. Yield: 1.45 g.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16]1=[CH:22][C:23]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])=[N:24][C:25](=[O:26])[N:15]1[CH2:14][CH2:13]2.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16]1=[CH:22][C:23]([N:27]([C:37](=[O:39])[CH3:38])[C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])=[N:24][C:25](=[O:26])[N:15]1[CH2:14][CH2:13]2
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OC)-c1cc(Nc3c(C)cc(C)cc3C)nc(=O)n1CC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)-c1cc(N(C(C)=O)c3c(C)cc(C)cc3C)nc(=O)n1CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 ml of triethylamine are added first to an ice-cold solution of 9,10-dimethoxy-2-(2,4,6-trimethyl-anilino)-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one (1.6 g) in chloroform (40.0 ml), and then a solution of acetyl chloride (0.64 ml) in chloroform (10.0 ml) is added dropwise. The mixture is stirred for 2 hours. The chloroform solution is washed successively with water, sodium carbonate solution and water, and is then dried over anhydrous sodium sulfate. The solution is filtered and the filtrate evaporated to dryness in vacuo. The residue is triturated with diethyl ether to yield the desired compound in solid form. Yield 1.6 g, m.p. 210°-212° C. (dichloromethane-petroleum ether b.p. 60°-80° C.).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[O:30]=[C:21]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][CH:16]=2)[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 58, step 1, 0.92 g) in dry methylene chloride (8.8 mL) at 0° C. under N2 is treated with trifluoroacetic acid (2.2 mL) over one minute, and the resulting mixture is stirred at 0° C. for four hours and added slowly to saturated aqueous potassium carbonate (30 mL) at 0° C. to neutralize excess trifluoroacetic acid. The mixture is then diluted with water (50 mL) and saline (50 mL), extracted with methanol/methylene chloride (3×150 mL, 25/75), and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 164-166° C. (decomp.).
Reaction SMILES: C([N:8]([C@@H:24]([C:33]1[O:34][CH:35]=[C:36]([C:38]([NH:40][C:41]2[CH:42]=[N:43][C:44]3[C:49]([CH:50]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:39])[N:37]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9](=[O:23])[C@H:10]([NH2:22])[CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[NH2:22][C@H:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:9]([NH:8][C@@H:24]([C:33]1[O:34][CH:35]=[C:36]([C:38]([NH:40][C:41]2[CH:42]=[N:43][C:44]3[C:49]([CH:50]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:39])[N:37]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)c1nc(C(=O)Nc2cnc3ccccc3c2)co1
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@@H](N)C(=O)N[C@H](CCc1ccccc1)c1nc(C(=O)Nc2cnc3ccccc3c2)co1

Procedure:
2-[(1R)-1-[N,N′-Bis-Boc-(2R)-2,5-diaminovaleramido]-3-phenylpropyl]-N-(3-quinolyl)-4-oxazolecarboxamide (66 mg) was deprotected with trifluoroacetic acid to afford the title compound (68 mg) as a white powder: 1H NMR (400 MHz, D2O) δ 1.83 (m, 2H), 2.06 (m, 2H), 2.45 (m, 1H), 2.57 (m, 1H), 2.83 (m, 1H), 2.96 (m, 1H), 3.11 (t, J=8.3 Hz, 2H), 4.19 (t, J=6.0 Hz, 1H), 5.22 (t, J=7.4 Hz, 1H), 7.38 (m, 3H), 7.42 (m, 2H), 7.96 (t, J=9.0 Hz, 1H), 8.09 (t, J=9.0 Hz, 1H), 8.23 (m, 2H), 8.60 (s, 1H), 9.11 (s, 1H), and 9.48 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]5[N:31]=[CH:30][C:29]([C:32]6[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=6)=[CH:28][N:27]=5)[CH2:21]4)[N:17]=[N:18][C:13]3=[N:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][OH:47].ClCCl.CO>CN(C=O)C.CCN(CC)CC>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C@H:20]4[O:25][CH2:24][CH2:23][N:22]([C:26]5[N:27]=[CH:28][C:29]([C:32]6[CH2:33][CH2:34][N:35]([CH2:45][CH2:46][OH:47])[CH2:36][CH:37]=6)=[CH:30][N:31]=5)[CH2:21]4)[N:17]=[N:18][C:13]3=[N:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6=CCNCC6)cn5)CCO4)c3n2)ccc1F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C6=CCN(CCO)CC6)cn5)CCO4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 13 h
Yield: 18.9 %

Procedure:
(S)-2-fluoro-5-(1-((4-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile 44 mg (0.09 mmol) was dissolved in DMF 1 ml. Potassium carbonate 36 mg (0.26 mmol) and 2-bromoethanol 0.009 ml (0.13 mmol) were added, and Et3N (2 drop) were added, followed by stirring at room temperature for 13 hours under nitrogen gas. When the reaction was completed, the reaction mixture was extracted two times or more with ethyl acetate and water, and concentrated under reduced pressure. PCL using 10% dichloromethane/methanol gave (S)-2-fluoro-5-(1-((4-(5-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)morpholin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile 9 mg (0.017 mmol) with a yield of 19%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH2:11])[N:3]=1.[C:12]([OH:17])(=O)[CH2:13][CH2:14][CH3:15].C(Cl)Cl>CO.O.[NH4+].[OH-].[Pd]>[C:12]([NH:11][C:4]1[N:3]=[C:2]2[N:1]=[C:4]([CH2:5][CH2:6][CH3:7])[NH:8][C:7]2=[CH:6][CH:5]=1)(=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)O
Reactant: Nc1ccc([N+](=O)[O-])c(N)n1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc2[nH]c(CCC)nc2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
A mixture of 2,6-diamino-3-nitropyridine (878 mg, 5.7 mmol) and Pd-C (10%, 100 mg) in MeOH (100 mL) was stirred under 1 atm. H2 for 16 hours. The mixture (containing the air sensitive triamine) was filtered, evaporated, and to this flask was added polyphosphoric acid (15 mL) and butyric acid (1.05 mL, 11.5 mmol). This mixture was heated to 80° C. for 5 hours, cooled to room temperature, diluted with water and neutralized with concentrated NH4OH. Extractive workup (CH2Cl2) gave 345 mg of 5-(butyramido)-2-propylimidazo[4,5-b]pyridine: 1H NMR (300 MHz, CDCl3) δ7.94 (d, 1H, J=8.5 Hz), 7.65 (d, 1H, J=8.5 Hz), 2.96 (t, 2H J=7.5 Hz), 2.30 (t, 2H J=7 Hz), 1.98-1.84 (m, 2H), 1.68-1.55 (m, 2H), 0.99 (t, 3H, J=7.5 Hz), 0.80 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CCCCCCC>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1
Reactant: COc1cc2ncc(NC3CC4CCC3C4)nc2cc1OC
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCCC
Product: COc1cc2ncc(N[C@@H]3C[C@H]4CC[C@@H]3C4)nc2cc1OC

Procedure:
The (±)-bicyclo[2.2.1]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine of Example 17 is resolved on a chiral HPLC column (Chiralpac AD, 25×2 cm, 60% heptane/40% ethanol with 10 mM (1S)-(+)-camphorsulfonic acid, 12 mL/minute) and the above titled product is obtained as the first eluent. The fractions collected are combined and washed with 50 mL of 1 N NaOH before drying (MgSO4). The solution after filtration is concentrated on a rotovap and then dried under a high vacuum. A yellow solid is obtained. [α]d20+19.5° (c=0.20, CH2Cl2) m.p. 184-186° C. Anal. calcd for C17H21N3O2×0.3H2O; C, 66.90; H, 7.15; N, 13.77. Found: C, 66.86; H, 7.01; N, 13.86.