Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C1C=CC=CC=1.[F:10][C:11]([F:20])([F:19])[C:12]1[N:17]=[C:16](O)[CH:15]=[CH:14][N:13]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:11]([F:20])([F:19])[F:10])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc(C(F)(F)F)n1
Solvent: CN(C)c1ccccc1
Product: FC(F)(F)c1nccc(Cl)n1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylaniline (6.06 mmol. 2.3 eq.) was added dropwise to a stirring solution of 2-(trifluoromethyl)pyrimidin-4-ol (2.72 mmol, 1 eq.) in POCl3 (4 ml) and the reaction mixture was stirred at 110° C. for 2 h. The reaction mixture was concentrated and the brown liquid was diluted with cold water (50 ml) and rendered basic with saturated sodium carbonate solution (50 ml). The mixture was extracted with methylene chloride (3×100 ml) and the combined organic phases were washed with water (2×50 ml) and sat. NaCl solution (50 ml) and dried over sodium sulfate. After concentration on a rotary evaporator, a blue liquid remained, which was employed in the next step without purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2].[Li+].[OH-].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate (750 mg, 0.0015 mol) was treated with 1 M of LiOH/H2O (1.6 mL) in MeOH (10 mL). The reaction was allowed to stirred at room temperature for 2 hours. The mixture was acidified by 10% citric acid aqueous solution was until PH=5, extracted with EtOAc twice, dried with MgSO4, and concentrated in vacuo. The crude was purified by Prep HPLC to provide 251. LC/MS (ESI+): m/z 462 (M+H). 1H NMR (500 MHz, DMSO) δ 8.44 (s, 1H), 8.36 (d, J=8.4, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4, 1.7, 1H), 7.35 (d, J=1.7, 1H), 5.82 (dt, J=13.1, 6.6, 1H), 4.52 (s, 3H), 2.25 (s, 2H), 1.78 (s, 4H), 1.45 (t, J=13.9, 4H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:27][N:28]([C:30](=[O:33])[CH2:31][CH3:32])[NH2:29].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCCl>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][N:28]([CH3:27])[C:30](=[O:33])[CH2:31][CH3:32])=[O:5]
Reactant: CCC(=O)N(C)N
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(=O)N(C)NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br

Procedure:
Prophetically, (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid can be reacted with N-methylpropionohydrazide in the presence of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl) and DMAP in 1,2-dichloroethane (DCE) to furnish the title molecule (Org. Lett. 2004, 6, 929-931).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.00 g (3.74 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was dissolved in 19 ml of CH2Cl2 and treated with 3.253 g (10 eq.) of MnO2. After vigorous stirring for 4 h at ambient temperature, the reaction mixture was filtered over Celite and carefully rinsed with CH2Cl2. Evaporation of the solvent left 0.920 g of the title compound, pure according to NMR and used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:6]=[CH:7][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(CNc2ccc(Br)cn2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
(5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (11, 3.81 g, 13 mmol) was dissolved in 150 mL of tetrahydrofuran at −78° C. under an atmosphere of nitrogen and tert-butyllithium (7.6 mL, 1.7 M in hexane) was added dropwise. After 30 minutes additional tert-butyllithium (16 mL, 1.7 M in hexane) was added dropwise and the reaction was stirred for 1.5 hours at −78° C. N,N-Dimethylformamide (2.4 mL, 31 mmol) was added and the mixture was stirred for 1.5 hours at −78° C., then allowed to warm up to room temperature for 1 hour. The reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate and concentrated. The desired compound was crystallized from a mixture of ether in ethyl acetate. The remaining material was purified with silica gel chromatography eluting with ethyl acetate and hexane to provide additional compound (12, 2.7 g, 85%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9]>CN(C=O)C.ClCCl>[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1Cl

Procedure:
Thionyl chloride (2.48 ml, 10 eq) and DMF (2 drops) were added to a solution of 2-chloronicotinic acid (535 mg, 3.4 mmol) in dichloromethane (3 ml). The mixture was heated at reflux overnight then concentrated in vacuo and azeotroped with toluene (2×5 ml) to give 2-chloronicotinoyl chloride as a yellow oil. A solution of this acid chloride in dichloromethane (5 ml) was added dropwise to a solution of Intermediate 5 (750 mg, 2.69 mmol) and NMM (355 μl, 1.2 eq) in dichloromethane (15 ml) at 00. Dimethylaminopyridine (catalytic) was added and the mixture stirred at room temperature for 2 h. The mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with aqueous NaHCO3 (2×50 ml). The organic phase was dried (MgSO4) and concentrated in vacuo, to give the title compound. δH (CDCl3) 10.55 (1H, s), 8.51 (1H, m), 8.05 (1H, m), 7.67 (1H, m), 7.57 (3H, m), 7.2 (2H, m), 4.24 (1H, m), 3.62 (3H, s), 3.08 (2H, m), 1.03 (9H, s); m/z (ESI, 70V) 418 (M++H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccnc1Cl

Procedure:
2-chloronicotinic acid chloride was prepared by refluxing 90g (0.571 mole) of 2-chloronicotinic acid in 315ml of thionylchloride for 2 hours. The excess thionylchloride was distilled off. The residue was diluted with 200ml of 1,4-dioxane and used as is.
Reaction SMILES: [CH2:1]([C:8]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:30][OH:31])[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[C:14]([C:26]([O:28]C)=[O:27])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>O>[CH2:1]([C:8]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:30][OH:31])[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[C:14]([C:26]([OH:28])=[O:27])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(COCC(CO)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(-c2ccccc2C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)(COCc1cc(C(=O)O)cc(-c2ccccc2C#N)c1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
To a solution of crude methyl 5-({2-benzyl-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropoxy}methyl)-2′-cyano-1,1′-biphenyl-3-carboxylate from step A (442 mg, 0.83 mmol) in 4 mL THP was added 1 N LiOH (1.25 mL, 1.25 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. 1 N LiOH (1.25 mL, 1.25 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, extracted with CH2Cl2 (3×), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (90 g silica, 0→85% (0.5% HOAc in EtOAc)/hexanes) to provide 259 mg of 5-({2-benzyl-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropoxy}methyl)-2′-cyano-1,1′-biphenyl-3-carboxylic acid as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.3 Hz, 1H), 7.30-7.16 (m, 5H), 4.98 (s, 1H), 4.69 (A of AB, d, J=12.0 Hz, 1H), 4.65 (B of AB, d, J=12.0 Hz, 1H), 3.77 (A of AB, d, J=12.0 Hz, 1H), 3.69 (B of AB, d, J=12.0 Hz, 1H), 3.59 (A of AB, d, J=9.3 Hz, 1H), 3.69 (B of AB, d, J=9.3 Hz, 1H), 3.17 (A of AB, d, J=13.8 Hz, 1H), 2.93 (B of AB, d, J=13.8 Hz, 1H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:20]>>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([C:15]([OH:20])=[O:16])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: CC(C)=O
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (93.4 g, 401 mmol) in 2.6 L of acetone was added 400 mL of Jone's reagent (2.45 M) at 0° C. The reaction was warmed to room temperature, and the mixture was stirred overnight. The solid was removed by filtration, and the filtrate was concentrated. The concentrated residue was poured into water. The resulting white solid was collected and washed with water and dried to obtain 5-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. 1H NMR<5 (400 MHz, d6-DMSO): 8.34 (s, 1H), 7.42-7.33 (m, 5H), 6.91 (s, 1H), 4.95 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[Cl-].[Cl-].[Cl-].[Al+3].[Cl:16][C:17]1[CH:18]=[C:19]([OH:28])[CH:20]=[CH:21][C:22]=1[CH:23]=[CH:24][N+:25]([O-])=O.Cl>C1COCC1.O>[NH2:25][CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([OH:28])=[CH:18][C:17]=1[Cl:16]
Reactant: O=[N+]([O-])C=Cc1ccc(O)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To lithium aluminum hydride 1.0 M in ether (1.50 mL, 1.50 mmol) at 0° C. a solution of aluminum trichloride (201 mg, 1.51 mmol) in THF (2 mL) is added. After 5 min a solution of compound obtained in step 1 above (100 mg, 0.50 mmol) in THF (2 mL) is added and the reaction is allowed to stir at room temperature overnight. Add water and then 3 N HCl. Extract the aqueous layer with 3/1 n-butanol/toluene. The combined organic layers are dried over sodium sulfate and concentrated. SCX ion-exchange chromatography of the concentrate afforded 70 mg (81%) of the title compound. Electrospray MS M+1 ion=172. 1H-NMR (methanol-d4, 200 MHz): 7.06 (d, 1H, J=8.3 Hz), 6.79 (d, 1H, J=2.4 Hz), 6.65 (dd, 1H, J=2.4 and 8.3 Hz), 2.82 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](=[CH:13][C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:9][C:8]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)[C@H](CCSC)NC(=O)C1=C(c2ccccc2)CC(=Cc2cccnc2N)C=C1

Procedure:
A mixture of the resultant aldehyde from Example 16E (1.0 equivalent), 2-aminopyridine (1.0 equivalent) and NaCNBH3 (1.5 equivalents) in methanouacetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHCO3 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([C:29]([F:32])([F:31])[F:30])[CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([CH3:27])([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([C:29]([F:30])([F:31])[F:32])[CH:15]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (6 g, 25.7 mmol) in DCM (50 mL) was added ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (7.45 g, 25.7 mmol), HATU (12.73 g, 33.5 mmol) and Et3N (10.74 mL, 77 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was washed with brine and saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated to yield a yellow oil of ethyl 3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (12 g, 19.99 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ: 7.94 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.36-7.25 (m, 3H), 7.22 (d, J=8.4 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.73 (s, 2H), 3.07 (s, 2H), 1.22 (t, J=7.2 Hz, 3H), 1.15 (s, 6H); ES-LCMS m/z 504 (M).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[N+]([O-])([O-])=[O:18].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:18])[NH:5]2
Reactant: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 38.1 %

Procedure:
To a stirred solution of 6-bromo-7-chloro-5-nitroquinoxaline-2(1H)-one (0.025 g, 0.082 mmol) in conc. H2SO4 (0.5 mL) was added KNO3 (0.011 g, 0.11 mmol) and the resulting dark red solution was stirred at r.t. for 65 h. The solution was then cooled in an ice-bath and diluted with ice to a total volume of 5.0 mL. The precipitated solid was filtered, washed with water (2.0 mL) and dried under vacuum to give 0.019 g (72%) of crude product. It was purified as follows. Crude product (0.016 g) was taken up in 1N NaOH (1.1 mL). The mixture was centrifuged and the supernatant liquid was acidified with conc. HCl to pH ~2. The precipitated solid was filtered, washed with water (1.0 mL) and dried under vacuum to furnish 0.010 g (50%) of pure title compound as a cream colored powder; m.p. 338°-343° C. (decomposed); 1H NMR (DMSO-d6): 7.351 (s, 1H), 12.251 (s overlapped by a br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[NH3:10]>C(O)(C)C>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH2:10])[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: N
Solvent: CC(C)O
Product: Nc1ncnc(Cl)c1N
Temperature: 130 °C

Procedure:
To a cold solution of 5-amino-4,6-dichloropyrimidine (2.0 g, 12.2 mmol) in isopropanol (20 ml) was added liquid ammonia (5 ml), and the mixture was transferred into a sealed tube. The tube was heated at 130° C. for 3 hours and then cooled to room temperature. The product precipitated out was filtered and dried in vacuo. Yield 2.0 g (quantitative).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>C(#N)C>[NH2:14][CH2:13][CH2:12][NH:15][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCN
Solvent: CC#N
Product: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reaction time: 20 h

Procedure:
The starting material (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine is prepared in the following manner. A mixture of 2-amino-6-chloro-3-nitropyridine (65 g, 376 mmol), acetonitrile (400 ml), and ethylene diamine (500 ml) are stirred overnight (ca. 20 h) at 75–80° C. under argon. When the diamine is added, this reaction can become exothermic! The ethylene diamine is removed under reduced pressure, and then in vacuo (12 h). The completely dried material is suspended in 2M sodium hydroxide solution (500 ml) with vigorous stirring for 30 min. The solid is filtered. The yellow solid is suspended in water (500 ml) with vigorous stirring for 30 min., after which the solid is filtered. The water wash and filtration is repeated one more time to get rid of salts. The yellow solid is dried in vacuo. The crude yellow solid is triturated with ether (3×500 ml) and dried overnight in vacuo resulting in 59 g of 2-(2-aminoethyl)amino-6-amino-5-nitropyridine in >99% purity.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)[C:5]([NH:16][CH:17]=O)=[C:4]([Cl:19])[N:3]=1.Cl>CO.[OH-].[Na+]>[ClH:19].[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:16]=[CH:17][N:8]2[C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)=[C:4]([Cl:19])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reaction time: 4 h
Yield: 184.4 %

Procedure:
A mixture of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (Example 7, 1.00 g, 3.50 mmol) and trietbylorthoformate (Aldrich, Sure Seal, 18 mL) was stirred while concentrated hydrochloric acid (37%, 1.25 mL) was added in one portion. The resulting clear, colorless solution was stirred under nitrogen A white precipitate began to form after 15 minutes. After 4 hours, TLC of a drop of the reaction mixture dissolved in methanol and neutralized with sodium hydroxide (silica gel plates developed in 10% methanol-chloroform, visualized in UV light) showed almost complete conversion of VIa to a higher-Rf material. The precipitate was filtered, washed with t-butyl methyl ether (15 mL) and dried at 0.2 mm Hgt 25° C. for 18 hours to give the title compound as a white powder (975 mg, 92%), mp. >300° C. dec.; mass spectrum (CI/CH4): 266(M+1); 1H-NMR DMSO-d6)δ: 8.18 (s, 1, purine CH), 7.2-6.7 (br s, NH2, OH overlapped by water), 620 and 5.90 (both m, 1 each, CH=CH), 5.48 (m, 1, NCH), 3.47 (d, J=5.7 Hz, 2, CH2O), 2.90 (m, 1, CH), 2.75-2.55 and 1.75-1.60 (both m, 1 each, CH2).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>[Pd]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=2[CH:10]=[O:11])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CCC(Cl)=C(C=O)C1
Agent: [Pd]
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting the 2-chloro-5,5-dimethylcyclohex-1-enecarbaldehyde, 4-chlorophenylboronic acid, a first phase transfer catalyst, a fifth base, and a first palladium catalyst to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([Cl:1])[CH:7]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1Cl
Yield: 75.5 %

Procedure:
The product was prepared by the alkylation of 2-chloro-4-nitrophenol (17.35 g) in DMF (150 mL) with ethyl bromoacetate (16.7 g) in the presence of potassium carbonate (13.8 g) to afford 19.6 g (75.6%) of ethyl 4-nitro-2-chlorophenoxyacetate as a white solid, m.p. 73°-74° C.; hydrogenation of the latter (10.0 g, 38.5 mmol) in ethanol (200 mL) on a Parr hydrogenator in the presence of 5% platinum on carbon (sulfided) (200 mg) afforded 8.1 g (92%) of ethyl 4-amino-2-chlorophenoxyacetate, m.p. 59°-62° C., after recrystallization from tert-butylmethylether, and finally, treatment of the latter (7.3 g, 31.8 mmol) in CH2Cl2 (75 mL) at 5° C. with pyridine (3.0 mL, 38.7 mmol) and methanesulfonyl chloride (2.29 mL) to afford N-[4-(ethoxycarbonylmethoxy)-3-chlorophenyl]methanesulfonamide, m.p. 87°-88° C. after recrystallization from tert-butylmethylether.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=[NH:51])(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([NH2:51])[CH:21]=[CH:22][CH:23]=2)[CH2:13]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 3-{(R*)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-phenyl ester (1.039 g, 2.27 mmol), cesium carbonate (1.036 g, 3.18 mmol), palladium acetate (0.015, 0.068 mmol), (R)-(±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.064 g, 0.102 mmol) and benzophenone imine (0.457 ml, 2.73 mmol) in dry tetrahydrofuran (6 ml) was heated in a microwave reactor at 80° C. for 10 hours. The mixture was filtered and evaporated to dryness. The crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent. The residue on evaporation was dissolved in dry methanol, sodium acetate (0.54 g, 6.55 mmol) and hydroxylamine hydrochloride (0.36 g, 5.24 mmol) was added and the mixture was stirred at room temperature for 1.5 h. The mixture was evaporated to dryness, dissolved in EtOAc and washed with 1M Na2CO3. The organic layer was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash chromatography using gradient of heptane and EtOAc as eluent to give 151 mg of the title compound.