Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10](=S(C)(C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[ClH:21]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH:10]([Cl:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)=S(C)(C)=O
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.5 grams (0.05 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-(dimethyloxosulfuranylidene)-3-oxopropanoate prepared in Example XLVII (Compound 205) in 25 milliliters of chloroform was stirred at room temperature for two hours while passing in a flow of anhydrous hydrogen chloride. After ceasing the gas feed the solution was stirred at ambient temperature for about 64 hours after which the solvent was removed under reduced pressure. Flash chromatography of the residue, eluting with hexane-ethyl acetate (7:3), gave a white solid which was recrystallized from ethyl acetate-hexane to give 0.20 gram (0.001 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-chloro-3-oxopropanoate having a melting point of 104° C.-105° C. Elemental analysis of the product indicated the following:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>CC(O)C.CCN(C(C)C)C(C)C>[F:8][C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:9])[CH2:15]2)=[N:7][CH:6]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: C[C@@H]1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@@H]1CN(c2ncc(F)cn2)CCN1
Yield: 117.8 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (239 mg, 1.80 mmol) and (R)-2-methylpiperazine (271 mg, 2.71 mmol) in iPrOH (1 mL) and DIEA (617 μL) was heated in MW at 130° C. for 30 min. Solvent was removed under reduced pressure and the crude (600 mg) was purified by chromatography on silica using DCM/methanol (9/1) as eluent to afford The title compound as a white solid (416 mg, quantitative). TLC—DCM/MeOH (8/2); Rf: 0.3. 1H NMR (DMSO-d6) δ 8.14 (s, 2H), 4.48 (d, J=13.2 Hz, 2H), 4.33 (brs, 1H), 2.98-3.13 (m, 2H), 2.83 (m, 2H), 2.67 (t, J=12.7 Hz, 1H), 1.20 (m, 3H).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[C:5]([CH3:15])[C:4]=1[CH:16]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>C(#N)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:16]([C:4]2[C:3](=[O:2])[C:12]3[C:7]([C:6](=[O:13])[C:5]=2[CH3:15])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(CCCCC(=O)O)c2c(C)c(OC)c3ccccc3c2OC)cc1
Solvent: CC#N
Product: COc1ccc(C(CCCCC(=O)O)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a solution of 14.7 g of 6-(1,4-Dimethoxy-3-methylnaphthalen-2-yl)-6-(4-methoxyphenyl)hexanoic acid in 300 ml of acetonitrile at 0C was added an aqueous 147 ml solution of 57.2 g of ceric ammonium nitrate portionwisely over 5 min. After stirring for 16 hours at room temperature, the solution was extracted with ethyl acetate. The organic layer was washed, dried, evaporated, and the residue was purified with column chromatography over silica gel using ethyl acetate as an eluent. Recrystallization from isopropyl ether/ethyl acetate gave 10.8 g of the title compound.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([F:34])=[C:10]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29]C)=[O:28])[CH:25]=4)[C:20]([CH:31]([OH:33])[CH3:32])=[CH:19]3)=[N:16][CH:17]=2)[CH:11]=1)[CH3:5]>C1COCC1.O>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([F:34])=[C:10]([C:12]2[CH:17]=[N:16][C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=4)[C:20]([CH:31]([OH:33])[CH3:32])=[CH:19]3)=[N:14][CH:13]=2)[CH:11]=1)[CH3:5]
Reactant: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)OC)cc43)nc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)O)cc43)nc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Lithium hydroxide monohydrate (33 mg, 0.786 mmol) was added to an ice-cooled suspension of 331d) (0.22 g, 0.524 mmol) in THF/water (1:1, 10 mL) and the resulting mixture was stirred at room temperature for 48 h. The THF was distilled off and the residue was diluted with water (5 mL) and acidified with saturated sodium hydrogen sulfate solution. A precipitating solid was filtered off and washed with water. Remaining humidity was removed by repeated azeotropic distillation of toluene. White solid. Yield: 0.17 g (80% of theory)
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53]([NH2:57])[CH2:54][CH2:55][CH3:56].Br[C:59]1[CH:60]=[C:61]([CH:66]=[C:67]([Br:71])[C:68]=1[O:69][CH3:70])[C:62]([O:64][CH3:65])=[O:63]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:71][C:67]1[CH:66]=[C:61]([CH:60]=[C:59]([NH:57][CH2:53][CH2:54][CH2:55][CH3:56])[C:68]=1[O:69][CH3:70])[C:62]([O:64][CH3:65])=[O:63]
Reactant: COC(=O)c1cc(Br)c(OC)c(Br)c1
Reactant: CCCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCNc1cc(C(=O)OC)cc(Br)c1OC
Temperature: 80 °C

Procedure:
To a stirred solution of Pd(OAc)2 (144 mg), BINAP (1.2 g), and cesium carbonate (8.4 g) in toluene (100 mL) was added butylamine (1.6 mL), and the mixture was heated at 80° C. for 15 min. A solution methyl 3,5-dibromo-4-methoxybenzoate (4.2 g) in toluene (30 mL) was added dropwise over 20 min. The mixture was refluxed overnight. The mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 ethyl acetate/hexanes) provided 3.5 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.52, 7.19, 3.90, 3.88, 3.18, 1.66, 1.46, 0.97.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:40]>C(OCC)(=O)C>[ClH:40].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:19]=[CH:18][N:17]=2)[CH2:21][C:22]([C:33]([F:39])([F:38])[C:34]([F:35])([F:36])[F:37])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(N3CCNCC3)ccn2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[4-(4-BOC-piperazin-1-yl)-pyridin-2-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (350.0 mg, 0.6 mmol) prepared in Example 181 was added to a saturated solution of hydrochloric acid in ethyl acetate (3.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 325.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:12])=[CH:9]/[CH2:10][O:11][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C/C(=C\CO)c1ccc(Br)cc1
Agent: c1c[nH]cn1
Product: C/C(=C\CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1

Procedure:
The colourless oil, (E)-[3-(4-bromophenyl)-but-2-enyloxy]-tert-butyl-dimethylsilane was prepared from (E)-3-(4-bromophenyl)-but-2-en-1-ol (example 50b), imidazole and tert-butyl chlorodimethylsilane by a procedure analogous to that described in example 129b.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[N:28]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([S:34]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:36])=[O:35])[CH2:17][CH2:18]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: O=C(Nc1ccc(CC2CCNCC2)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
A solution of 2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (0.5 g, 1.75 mmol) (prepared as previously described in Example 19, steps 1 to 3) and triethylamine in dichloromethane (10 mL) was cooled in an ice bath under a nitrogen atmosphere. The mixture was then treated with a solution of 1-piperidinesulfonyl chloride (0.39 g, 2.09 mmol) in dichloromethane (1 mL). The reaction mixture was stirred for 1.5 hours at 0-5° C. and quenched with water. The organic layer was separated, and the aqueous layer extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried, and solvents removed in vacuo. The residue was chromatographed on silica gel, eluting with 30% ethyl acetate/hexanes, to give 2,2,2-trifluoro-N-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide (0.48 g) as a white solid, m.p. 156-157° C.; Analysis for C19H26N3O3SF3: Calc.: C, 52.64; H, 6.05; N, 9.69; Found: C, 52.84; H, 6.00; N, 9.79.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3](=[O:31])[O:4][C:5]1[CH:10]=[CH:9][C:8](/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=C(OC)C=2)=[CH:7][C:6]=1[O:29][CH3:30].BrCCO.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:32][N:2]([CH3:1])[C:3](=[O:31])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:29][CH3:30]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(OC(=O)N(C)C)c(OC)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1OC(=O)N(C)C
Yield: 89.6 %

Procedure:
The mixture of 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (88 mg, 0.2 mmol, 1.0 eq), 2-bromoethanol (37.5 mg, 0.3 mmol, 1.5 eq) and K2CO3 (110 mg, 0.8 mmol, 4.0 eq) in acetone (10 ml) was stirred under reflux for 5 h. Then the mixture was concentrated and The resulting residue was separated by Prep-HPLC to provide 4-41E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (35 mg, 36.1%). LRMS (M+H+) m/z calculated 484.2. found 484.2. 1H NMR (CDCl3, 400 MHz) δ 7.58-7.62 (dd, 2H), 7.07-7.13 (m, 5H), 6.91 (d, 1H), 6.48-6.56 (m, 2H), 5.83 (s, 1H), 4.14-4.17 (t, 2H), 3.96-3.99 (t, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.13 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH3:37][N:38]1[CH:42]=[C:41]([C:43](Cl)=[O:44])[CH:40]=[N:39]1.N1C=CC=CC=1>C(#N)C.CO>[CH3:37][N:38]1[CH:42]=[C:41]([C:43]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[CH:12]=[C:11]([C:13]4[CH:36]=[CH:35][C:16]5[N:17]([C:20]6[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=6)[CH:18]=[N:19][C:15]=5[CH:14]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)=[O:44])[CH:40]=[N:39]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Reactant: Cn1cc(C(=O)Cl)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CO
Product: Cn1cc(C(=O)N2CCC(n3cc(-c4ccc5c(c4)ncn5-c4cccc(NC(=O)NCC(F)(F)F)c4)cn3)CC2)cn1

Procedure:
To a solution of N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt (20.0 mg, 0.0385 mmol) in acetonitrile (1 mL) was added 1-methyl-1H-pyrazole-4-carbonyl chloride (8.3 mg, 0.058 mmol, Matrix Sci., Cat. No. 019861) and pyridine (60 μL, 0.8 mmol), the solution was stirred at r.t. overnight. The reaction solution was diluted with MeOH and then purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=592.3.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=2[S:24]1(=[O:37])=[O:36].Cl>>[O:37]=[S:24]1(=[O:36])[C:25]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:13]1[CH2:12][CH2:11][CH:10]([N:6]2[C:5]3[CH:16]=[CH:17][C:2]([CH3:1])=[CH:3][C:4]=3[O:8][C:7]2=[O:9])[CH2:15][CH2:14]1
Reactant: Cc1ccc2c(c1)oc(=O)n2C1CCNCC1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2S(=O)(=O)N1CCCCBr
Agent: Cl
Product: Cc1ccc2c(c1)oc(=O)n2C1CCN(CCCCN2C(=O)c3cc([N+](=O)[O-])ccc3S2(=O)=O)CC1

Procedure:
From 4-(6-methyl-2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-bromobutyl)-1,1-dioxido-5-nitro-1,2-benzisothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid:1H NMR, HCl salt, (400 MHz, CDCl3): 8.87 (d, J=2.0 Hz, 1H), 8.74 (d, J=2.18 Hz, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.11 (d, J=6.54 Hz, 1H), 7.03 (s, 1H), 6.94 (d, J=8.06 Hz, 1H), 4.18 (m, 1H), 3.89 (t, J=7.39 Hz, 2H), 3.06 (d, J=10.07 Hz, 2H), 2.46 (m, 2H), 2.38 (s, 3H), 2.34 (m, 2H), 2.14 (t, J=11.5 Hz, 2H), 1.94 (m, 2H), 1.85 (d, J=11.4 Hz, 2H), 1.65 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]([CH3:22])[C:10]=1[CH3:23])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][N:11]([CH3:22])[C:10]=1[CH3:23]
Reactant: Cc1c(OCc2ccccc2)c(=O)c(C(O)C(F)(F)F)cn1C
Agent: [Pd]
Solvent: CO
Product: Cc1c(O)c(=O)c(C(O)C(F)(F)F)cn1C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
3-Benzyloxy-1,2-dimethyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.97 g, 2.96 mmol) in methanol (30 mL) was debenzylated with Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 0.15 g) as catalyst under a hydrogen atmosphere at 50 psi pressure. The reaction was completed in 10 min. The reaction mixture was diluted with methanol (30 mL), sonicated for 10 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was collected and concentrated in vacuo to give 3-hydroxy-1,2-dimethyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid product (0.43 g, 61% yield, HPLC Method 1 (Example 24), RT=9.4 min, HPLC purity (peak percent area): 99.8% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 7.72 (s, 1H), 5.34 (q, J=7.3 Hz, 1H), 3.71 (s, 3H), 2.27 (s, 3H); MS (m/z) 238.1 [M+1]+, 220.2 (100%), 192.3, 172.1.
Reaction SMILES: S([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH:18]([C:22]3[N:27]=[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[N:25]=[C:24]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:23]=3)[CH2:17]2)=[CH:8][C:7]=1[CH3:38])(=O)(=O)C>[OH-].[Na+].CO>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH:18]([C:22]3[N:27]=[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[N:25]=[C:24]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:23]=3)[CH2:17]2)[CH:8]=[C:7]([CH3:38])[C:6]=1[OH:5]
Reactant: Cc1cc(CCCN2CCNC(c3cc(N4CCCC4)nc(N4CCCC4)n3)C2)cc(C)c1OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCCN2CCNC(c3cc(N4CCCC4)nc(N4CCCC4)n3)C2)cc(C)c1O

Procedure:
2,6-Dimethyl-4-[3-(2,4-bis(1-pyrrolidinyl)-6-pyrimidinyl)piperazinyl)propyl phenol O-mesylate (Part I, 1.0 g) in aqueous sodium hydroxide (25%, 10 ml) and methanol (20 ml) are stirred at 50° under nitrogen for 20 hr. The mixture is cooled and the methanol removed under reduced pressure. The aqueous layer is acidified with aqueous hydrochloric acid (10%) and then the pH adjusted to 8 with aqueous saturated sodium bicarbonate. The product is extracted with methylene chloride (2×). The extracts are washed with water, dried over sodium sulfate and concentrated. The concentrate is crystallized from ether/hexane to give the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7]1>C(O)(=O)C>[CH3:5][C:6]1([CH3:15])[O:7][C:8]2[CH:14]=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:9]=2[O:10]1
Reactant: CC1(C)Oc2ccccc2O1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
24 ml of nitric acid (d=1.4) in 60 ml of glacial acetic acid were added dropwise at 15°-20° C. to 39.0 g of 2,2-dimethyl-1,3-benzodioxole in 200 ml of glacial acetic acid. After stirring at room temperature for 3 hours, the mixture was poured into ice/water and extracted twice with 1 l of methylene chloride. The organic phase was washed neutral with water, dried over sodium sulfate and evaporated in vacuo. The residue, recrystallized from methanol, gave 17.0 g (33.5% of theory) of 2,2-dimethyl-5-nitro-1,3-benzodioxole of melting point 88°-90° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH3:13])=[C:2]([NH:1][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reaction time: 20 h
Yield: 68.4 %

Procedure:
To a solution of methyl 3-amino-5-chloro-2-methylbenzoate (100 mg, 0.50 mmol) in 1,2-dichloroethane (2.5 ml) at room temperature and under nitrogen was added tert-butyl 4-oxopiperidine-1-carboxylate (200 mg, 1.0 mmol) followed by acetic acid (0.17 ml, 3.0 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.32 g, 1.5 mmol) at room temperature. The resulting mixture was stirred for 20 hours under nitrogen. Deionized water (5 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 131 mg (68%) of the title compound as a white solid. LC-MS 98%, m/z=405.4/406.9 (M+Na), 1H NMR (500 MHz, Chloroform-d) δ ppm 7.10 (1H, d, J=2.05 Hz), 6.70 (1H, d, J=1.89 Hz), 3.98-4.16 (2H, m), 3.88 (3H, s), 3.58-3.72 (1H, m), 3.37-3.52 (1H, m), 2.97 (2H, br. t, J=11.50, 11.50 Hz), 2.24 (3H, s), 2.06 (2H, br. d, J=10.60 Hz), 1.44-1.51 (9H, m), 1.32-1.44 (2H, m).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3](OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)(=[O:5])=[O:4].[Br:28][C:29]1[C:38]([OH:39])=[C:37]([CH3:40])[CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33]([CH3:41])=[N:34]2>>[F:1][C:2]([F:27])([F:26])[S:3]([O:39][C:38]1[C:29]([Br:28])=[C:30]2[C:35](=[CH:36][C:37]=1[CH3:40])[N:34]=[C:33]([CH3:41])[CH:32]=[CH:31]2)(=[O:5])=[O:4]
Reactant: Cc1ccc2c(Br)c(O)c(C)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Product: Cc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1

Procedure:
Compound 5A was prepared following the procedure used to prepare compound 1F of Example 1, except that 5-bromo-2,7-dimethylquinolin-6-ol (2C) was used instead of compound 1E. LCMS-ESI+ (m/z): 383.9, 385.9 (M+14)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:18].C(O)C.C(OCC)(=O)C.O>CCCCCC>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:18])[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Yield: 33 %

Procedure:
4-Chloro-6-(4-nitrophenoxy)pyrimidine (1.04 g, 4.00 mmol) was heated and stirred in an ammonia-ethanol solution (14%, 10 ml) at 110° C. for 15 minutes using an autoclave. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=1:1), and the fraction containing the target substance was concentrated to obtain the title compound (306 mg, 1.32 mmol, 33%) as colorless crystals.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]1([OH:11])[CH2:10][CH2:9][CH2:8]1.F[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1.COCCOC>ClCCl>[CH:7]1([O:11][C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[C:15]([NH2:28])[N:14]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: OC1CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1nc(OC2CCC2)nc2c1ncn2C1CCCCO1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Sodium t-butoxide (3.31 g, 34.2 mmol) was added portionwise to cyclobutanol (10 ml) at room temperature. The mixture became very thick and was heated to 50° C. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added followed by 1,2-dimethoxyethane (3 ml) and the mixture stirred at 50° C. for 90 mins. and then cooled and partitioned between ethyl acetate (50 ml) and water (50 ml). A precipitate that failed to dissolve in either phase was removed by filtration. The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated to give a cream foam. This material was dissolved in dichloromethane and purified on an aminopropyl (NH2) cartridge (110 g) using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white solid (0.655 g).