Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[C:16]([OH:18])([CH3:17])[CH:10]([CH2:11][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:18][C:16]1([CH3:17])[CH:14]2[CH2:15][NH:8][CH2:9][CH:10]1[CH2:11][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC(C1)C2(C)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CNCC(C1)C2(C)O

Procedure:
A solution of tert-butyl 7-benzyl-9-hydroxy-9-methyl-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate (from step (iii) above; 450 mg, 1.3 mmol) in aqueous ethanol (50 mL of 95%) was hydrogenated over 5% Pd/C at 1 atm until tlc indicated that the reaction was complete. The catalyst was removed by filtration through a pad of Celite®, and the filtrate concentrated under reduced pressure to give the sub-title compound in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1.Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1cccc(N=C=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COc1cccc(NC(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 3-Methoxyphenyl isocyanate (0.03 mL, 0.24 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 30 (28 mg, 30% yield) as a yellow solid. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:15]=[C:16]([OH:22])[C:17]2=[O:18])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: O=c1c(O)nc2ccccc2n1-c1ccc(Cl)cc1

Procedure:
N-(4-Chlorophenyl)benzene-1,2-diamine (11.2 g) was added to diethyl oxalate (50 ml) and the mixture heated under reflux for 2 hours. The mixture was cooled and ethanol (40 ml) was added. The precipitated solid was filtered off and recrystallised from ethanol giving the title compound (11.2 g) mp>300° C.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:15]=[C:16]2[NH:22][C:21](=[O:23])[S:20][C:17]2=[N:18][CH:19]=1.O>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[C:16]2[N:22]([CH2:2][C:3]([O:5][CH3:6])=[O:4])[C:21](=[O:23])[S:20][C:17]2=[N:18][CH:19]=1
Reactant: O=c1[nH]c2cc(Cl)cnc2s1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(=O)sc2ncc(Cl)cc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
Methyl chloroacetate (9.6 g) and potassium carbonate (11.1 g) were added to a solution of 6-chloro-2-oxo-1,2-dihydrothiazolo[5.4-b]pyridine (15.0 g ) in dry N,N-dimethylformamide (50 ml). The mixture was stirred for 30 minutes at 80° C. and then poured into cold water. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give white powder of 6-chloro-1-methoxycarbonylmethyl-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (20.52 g).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]1([C:11]2(C(O)=O)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O.ClCCl>[C:5]1([C:11]2([NH2:1])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: NC1(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Following the procedure described in N. W. Werner et.al., J. Org. Syn. Coll. Vol. 5, 273-276, sodium azide (0.915 g, 14.1 mmol) is slowly added to a solution of 1-phenyl-cyclopropanecarboxlic acid (1.0 g, 6.1 mmol) in concentrated sulfuric acid (5 ml) and dichloromethane (10 ml). The sodium sulfate precipitated out of solution. The reaction mixture is heated to 50 degrees C. for 17 hours and then cooled to 0 degrees C. The mixture is basified to pH=11 with sodium hydroxide (1N) and extracted with dichloromethane (2×). The organic layers are combined, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography (silica gel; isopropyl alcohol/chloroform/ammonium hydroxide 4/95/1) to give the title compound, MS (ESI+) for C9H11N m/z (M+H)+=134.
Reaction SMILES: O[C@H:2]([CH:22]([CH3:24])[CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].O[C@@H](C(C)C)[C@@H](NC(OCCCCCC1C=CC=CC=1)=O)C(O)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[CH:22]([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CC(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4-methyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid and (2R*,3S*)-3-hydroxy-4-methyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.076 g, 0.24 mmol) in dry CH2Cl2 (10.0 mL), at 0° C., Et3N (0.2 mL, 1.44 mmol) and subsequently TBTU (0.091 g, 0.28 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 100:0 to 80:20) to afford the pure title compound (0.041 g, 56%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 337 [M−NH4]+; (ESI) m/z: 318 [M−H]−. 1H NMR (DMSO-d6) δ 0.87 (d, J=6.75 Hz, 3H), 0.95 (d, J=6.55 Hz, 3H), 1.27-1.43 (m, 2H), 1.49-1.69 (m, 4H), 1.87-2.08 (m, 1H), 2.57 (t, J=7.67 Hz, 2H), 3.99 (t, J=6.59 Hz, 2H), 4.22 (dd, J=4.39, 9.13 Hz, 1H), 4.73 (dd, J=4.40, 8.18 Hz, 1H), 7.10-7.35 (m, 5H), 8.06 (d, J=8.16 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:5](=[CH:10][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH2:15]([NH:14][C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][CH:12]=1)[C:3]([OH:22])=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(NCc2ccccc2)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A mixture of 4-benzylamino-phthalic acid dimethyl ester (1.11 g, 3.71 mmol) and 3N sodium hydroxide (50 mL) in ethanol (100 mL) was refluxed for one hour. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with CH2Cl2 (2×100 mL) and acidified (HCl), and resulting mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (2×100 mL), and dried (MgSO4) and evaporated under vacuum. The resulting solid was stirred in ether for 2 hours. The solid was filtered and dried, providing 0.50 g of 4-benzylamino-phthalic acid, in 74% yield; 1H NMR (DMSO-d6) δ 4.35 (d, J=5.7 Hz, 2H), 6.59-6.62 (m, 2H), 7.10-7.34 (m, 6H), 7.54-7.57 (m, 1H), 12.48 (br, 2H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(O)=O>ClCCCl>[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C1CN(C2CCC3(CC2)OCCO3)CCO1
Temperature: 12 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Sodium triacetoxyborohydride (382 g, 1.8 mol) was added in one portion to a mixture of 1,4-dioxaspiro[4.5]decan-8-one (200.0 g, 1.28 mol), morpholine (111.4 g, 1.28 mol) and glacial AcOH (73.2 mL, 1.28 mol) in 1,2-dichloroethane (4 L). A slightly exothermic reaction occurred accompanied by increase in temperature by 12° C. Then the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 10% aqueous NaOH (1.8 L) over a period of 20 min. The organic layer was separated, washed with brine (1 L), dried over MgSO4 and concentrated to afford 1 (237.66 g) as white solid. The aqueous layer was extracted with AcOEt (4×300 mL). Combined extracts were washed with brine (1 L), dried over MgSO4 and concentrated to furnish additional portion of 1 (44 g) as an off-white solid. Total yield of 1 (281.66 g, 97%). 1H NMR data identical with the data obtained earlier.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][NH:11][C:10](=[O:17])[C:9]=3[C:8]([C:18]3[N:22](C4CCCCO4)[N:21]=[CH:20][CH:19]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:29].C(OCC)(=O)C>C(O)C>[ClH:29].[CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][NH:11][C:10](=[O:17])[C:9]=3[C:8]([C:18]3[NH:22][N:21]=[CH:20][CH:19]=3)=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1c[nH]c(=O)c2c(-c3ccnn3C3CCCCO3)cn(C3CCCC3)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1c[nH]c(=O)c2c(-c3ccn[nH]3)cn(C3CCCC3)c12

Procedure:
A solution of 1-cyclopentyl-4-oxo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile and 4N hydrogen chloride/ethyl acetate solution (1.31 mL) in ethanol (2 mL) was stirred overnight at 50° C., and the solvent was evaporated under reduced pressure. The residue was crystallized from ethanol and diisopropyl ether to give the title compound (136 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][CH:20]([OH:24])[CH2:21][O:22][CH3:23])[CH:18]=1)=[CH:9][CH:8]=2.I[CH3:26]>C1COCC1>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][CH:20]([O:24][CH3:26])[CH2:21][O:22][CH3:23])[CH:18]=1)=[CH:9][CH:8]=2
Reactant: CI
Reactant: COCC(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1)OC
Reaction time: 0.25 h

Procedure:
NaH (60%, 3.5 mg) was added to a solution of racemic 1-(4-(3-chloroisoquinolin-6-yl)-1H-pyrazol-1-yl)-3-methoxypropan-2-ol (Preparation 36, 20 mg, 0.063 mmol) in THF (4 mL). After stirring for 15 minutes, iodomethane (20 uL, 0.32 mmol) was added. The resulting solution was stirred at 60° C. under microwave irradiation for 60 minutes. The reaction mixture was extracted with EtOAc, dried over sodium sulphate and concentrated in vacuo. The residue was used in the next step without further purification.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[NH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1>>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][C@@H:3]([CH2:1][N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)[NH:4]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Product: OC1CCN(C[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and piperidin-4-ol (26 mg, 0.26 mmol) provided a crude oil which was used without purification in the preparation of Example 110. MS(ESI+) m/z 247.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:35]1([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: CCOC(=O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)CCCCNC(=O)OC(C)(C)C)c1ccccc1
Yield: 48.1 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 7.8 g at a yield of 48.1% in the same manner as in Example 1 except that 10 g (45.8 mmol) of 5-(N-t-butoxycarbonylamino)pentanoic acid instead of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 70 ml of THF and 11.1 g (68.7 mmol) of CDI was added; 9.5 ml (72 mmol) of diisopropylamine and 40 ml of THF were added and 42 ml (69 mmol) of 1.63N BA solution was added dropwise; 10.6 g (68.7 mmol) of ethyl phenylacetate instead of methyl phenylacetate was dissolved in 20 ml of THF; and 30 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 70 g of 4N hydrochloric acid was added, and 100 ml of ethylacetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.C([O-])([O-])=O.[K+].[K+].Cl[C:26]1[C:35]([CH3:36])=[C:34]([Cl:37])[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C=O)C>[Cl:37][C:34]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[C:35]=1[CH3:36]
Reactant: C=CCCC(=O)OCC
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1nc2ncccc2c(Cl)c1C
Temperature: 75 °C
Reaction time: 10 h

Procedure:
To a solution of ethyl 4-pentenoate (2.5 g, 20 mmol) in 60 mL THF was added 9-BBN (0.5 M in THF, 47 mL, 23 mmol) gradually at room temperature. After stirring for 10 hours, it was treated with Pd(OAc)2 (0.4 g, 2.0 mmol), 1,1′-bis(diphenylphosphino)-ferrocene (DPPF) (1.1 g, 2.0 mmol), K2CO3 (powder, 8.1 g, 58 mmol), 2,4-dichloro-3-methyl-naphthyridine (L) (3.6 g, 20 mmol) and 50 mL DMF. The reaction mixture was purged with argon for 5 minutes and then refluxed at 75° C. for 24 hours. It was cooled to room temperature and treated with 10 mL ethanolamine and stirred for 30 minutes. The mixture was diluted with 400 mL H2O and extracted with EtOAc(×3). The combined organic layers were washed with brine and dried. After solvent removal, the residue was purified by silica gel chromatography using EtOAc/hexanes (1:1) to give the desired product 3-3 as a liquid.
Reaction SMILES: [N:1]1[CH:6]=C[CH:4]=[C:3]([O:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:2]=1.OC1C=[N:16]C=NC=1.C(=O)CCC1C=CC=CC=1>>[N:1]1[CH:2]=[C:3]([O:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:4]=[N:16][CH:6]=1
Reactant: c1cncc(OC2=NOCC2)c1
Reactant: Oc1cncnc1
Agent: O=CCCc1ccccc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(Pyrimidin-5-yloxy)-4,5-dihydroisoxazole III-54 was prepared in 3 steps from compound III-9 starting with the synthesis of 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-53 from compound III-9 and 5-hydroxypyrimidine using Method 5. Compound III-53 is then deprotected using analogous conditions to Example 11 and then converted to desired product III-54 using the analogous procedure as Example 13 except that hydrocinnamaldehyde was used in the place of benzoyl chloride. [M+H]+=367.6 m/z. Activity: B
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:6]2[N:7]([N:24]=[CH:25][CH:26]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:9]([C:11](N(OC)C)=[O:12])[CH:10]=1>O1CCCC1>[Cl:4][C:5]1[C:6]2[N:7]([N:24]=[CH:25][CH:26]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:9]([C:11](=[O:12])[CH3:1])[CH:10]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
3.0 M Methylmagnesium bromide in tetrahydrofuran (0.87 mL) was added dropwise to a solution of 4-chloro-7-(3-fluorophenyl)-N-methoxy-N-methylpyrazolo[1,5-a]pyridine-6-carboxamide (0.25 g, 0.75 mmol) in tetrahydrofuran (3.038 mL) under N2 cooled to 0° C. The solution was stirred at 0° C. for 30 minutes. The reaction solution was quenched at 0° C. with 1.0 M hydrogen chloride in water (2.996 mL), poured into 25 mL of water saturated sodium bicarbonate solution and was extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 1-[4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethanone (0.15 g, 68%) as an oil. LCMS calculated for C15H11ClFN2O (M+H)+: m/z=289.1. found: 288.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[CH:17]=[CH:18][CH:19]=1.Cl>>[F:13][C:14]1[CH:15]=[C:16]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3cccc(F)c3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(3-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.79 (s, br, 1H), 7.63-6.82 (m, 11H), 5.24-5.15 (m, 1H), 3.70-3.56 (br, 2H), 3.04-2.84 (br, 2H), 2.82-2.60 (m, br, 4H), 2.60-2.42 (m, br, 2H), 2.20-1.83 (m, br, 6H), 1.70-1.44 (m, br, 2H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 589.3 (M+H)+.
Reaction SMILES: [Mg].BrCCBr.[Br-].[F:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][CH:9]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17].[NH4+].[Cl-]>O1CCCC1.[Cu]I.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[CH2:19][C@H:18]([OH:20])[CH2:16][Cl:17]
Reactant: Fc1ccc(F)c(F)c1
Reactant: ClC[C@@H]1CO1
Agent: [Cu]I
Agent: [Br-]
Agent: [Cl-]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O[C@H](CCl)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Magnesium (Mg) (1.26 g) was suspended in tetrahydrofuran (THF) (10 ml), and a drop of 1,2-dibromoethane was added thereto. To the resulting mixture, 2,4,5-trifluorobenzene bromide (0.55 g) was added dropwise slowly and then stirred for 30 min. 2,4,5-trifluorobenzene bromide (9.0 g) dissolved in THF (50 ml) was added slowly dropwise to the resulting mixture for 30 min and then stirred at room temperature for 1 hour. CuI (0.72 g) was added to the resulting mixture and the reaction temperature was cooled to 0° C. (S)-epichlorohydrin (4.1 ml) dissolved in THF (40 ml) was added dropwise to the resulting mixture slowly over 30 min, heated to room temperature, and stirred for 2 hours. Satuated NH4Cl (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with 50 ml of satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[N:34](OCCCC)=O.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C(F)(F)F)=O>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[CH:23]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:25]=[CH:26][C:2]=3[N:1]=[N:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Reactant: CCCCON=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2nnc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Reaction time: 0.02 h

Procedure:
A solution of the free base of this amine (58 mg, 0.13 mmol) in dichloromethane (2 ml) was acidified with 5 drops of TFA then treated with butyl nitrite (100 ul). A deep orange colour formed immediately. After 1 minute, DBU was introduced dropwise until basic. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with methanol-dichloromethane-aqueous ammonia) to give the title compound which crystallised as a pale yellow HCl salt on treatment with 1M HCl in ether;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[C:5]([N+:23]([O-:25])=[O:24])=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1.Cl.C(OCC)C>CC(O)C>[ClH:1].[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([N+:23]([O-:25])=[O:24])=[CH:4][N:3]=[C:2]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][CH:32]=2)[N:7]=1)(=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(=O)Nc1ccc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3C(=O)c3ccccc3)n2)cc1
Temperature: 90 °C
Yield: 13.4 %

Procedure:
To a mixture of {2-[(2-chloro-5-nitropyrimidin-4-yl)amino]phenyl}(phenyl)-methanone (63 mg, 0.178 mmol) and N-(4-aminophenyl)acetamide (28 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for approx. 18 hours. After the reaction was cooled to room temperature cold diethyl ether was added to precipitate out the product. The precipitate was filtered and washed with cold diethyl ether, then dried under vacuum to give N-[4-({4-[(2-benzoylphenyl)amino]-5-nitropyrimidin-2-yl}amino)phenyl]acetamide hydrochloride (12 mg, 13%) as a tan solid. 1H NMR (DMSO-d6/D2O): δ 8.98 (s, 1H), 8.12 (m, 1H), 7.69-7.43 (m, 12 H), 2.05 (s, 3 H). MS m/z 468 (M+1).