Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[C:19]([S:21]([CH3:23])=O)[N:18]=[C:17]([NH2:24])[N:16]=2)=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3.SC[CH2:27][CH2:28][OH:29].C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O.O>[NH2:24][C:17]1[N:18]=[C:19]([S:21][CH2:23][CH2:27][CH2:28][OH:29])[CH:20]=[C:15]([C:3]2[C:2]([Cl:1])=[CH:14][C:6]3[CH2:7][O:8][CH2:9][C:10]4[C:5]=3[C:4]=2[CH:13]=[CH:12][CH:11]=4)[N:16]=1
Reactant: OCCCS
Reactant: CS(=O)c1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(SCCCO)cc(-c2c(Cl)cc3c4c(cccc24)COC3)n1
Temperature: 80 °C
Yield: 42.7 %

Procedure:
Partially purified 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (29.1 mg) obtained in Step 5 of Example 314 was dissolved in N,N-dimethylformamide (1 mL), 3-mercapto-1-propanol (17 μL, 0.197 mmol) and N,N-diisopropylethylamine (55 μL, 0.316 mmol) were added, and this was stirred at 80° C. Four hours later, 3-mercapto-1-propanol (8 μL, 0.093 mmol) and N,N-diisopropylethylamine (23 μL, 0.132 mmol) were added, and this was stirred at 80° C. for another eleven hours. The reaction solution was cooled to room temperature, water (10 mL) and 1 N hydrochloric acid (1 mL) were added, and this was extracted with ethyl acetate (15 mL, 10 mL). The organic layers were combined, and then washed with 0.01 N hydrochloric acid (8 mL), water (8 mL), and brine (8 mL), then dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; methylene chloride:methanol=20:1), and thus, 3-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-propan-1-ol (compound 326) (13.4 mg) was obtained.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:43][CH3:44])=[C:21]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH:41]=[O:42])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[O:25][N:24]=2)[CH:22]=1>O.O1CCOCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:43][CH3:44])=[C:21]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([C:41]([OH:6])=[O:42])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[O:25][N:24]=2)[CH:22]=1
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C=O)c2)n1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A solution of sodium chlorite (59 mg; 0.65 mmol; 5.5 eq.) and sodium dihydrogenphosphate (51 mg; 0.43 mmol; 3.6 eq.) in water (1 mL) was added to a mixture of 2-methyl-2-butene (0.13 mL) and 4-[3-(5-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2′-methylbiphenyl-2-carbaldehyde (46.2 mg; 0.12 mmol; 1 eq.) in dioxane (1 mL) and the reaction was stirred at room temperature for 16 hours. The suspension was partitioned between water and ethyl acetate. The aqueous phase was acidified to pH 3-4 with acetic acid and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (43 mg; 89%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.Cl.[N:24]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30].C([N:39](CC)CC)C.Cl.N1CCCCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[N:24]1([CH:31]2[CH2:36][CH2:35][N:34]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])([NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])[C:9]([NH2:39])=[O:11])[CH2:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30]
Reactant: CCN(CC)CC
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Reactant: O=C1CCCCN1C1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: NC(=O)C(NC(=O)Nc1ccc(Cl)cc1)(c1ccccc1F)N1CCC(N2CCCCC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (45 mg, 0.14 mmol), 4-(2-piperidinon-1-yl)piperidine hydrochloride (40 mg, 0.18 mmol) and triethylamine (0.085 mL, 0.61 mmol) in DMF (1.0 mL, containing 0.050 mL of H2O to solubilize the piperidine hydrochloride), BOP (100 mg, 0.23 mmol) was added. After being stirred at room temperature for 30 min, the mixture was purified by HPLC to give the titled compound (20 mg). MS 487.3 and 489.3 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:23])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Product: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 55 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (55 mg, 0.16 mmol) obtained in Example 36 and morpholine (0.016 ml, 0.18 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (36 mg, 0.088 mmol, yield 55%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH2:11][CH2:12][Br:13])=[CH:7][C:6]=1[OH:16])=[O:4].[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br-:13].[F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH2:11][CH2:12][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:7][C:6]=1[OH:16])=[O:4]
Reactant: O=C(c1ccc(OCCCBr)cc1O)C(F)(F)F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccc(OCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1O)C(F)(F)F
Product: [Br-]

Procedure:
The title compound is prepared analogously to Example 1c) from 3-(4-trifluoroacetyl-3-hydroxyphenoxy)-propyl bromide and triphenylphosphine; m.p. 125°-130° C.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[CH2:3][C:4]#[N:5].[NH2:13][NH2:14].CCO.OP(O)(O)=O>O.CO>[Br:12][C:8]1[CH:7]=[C:6]([C:2]2[CH:3]=[C:4]([NH2:5])[NH:13][N:14]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: N#CCC(=O)c1cccc(Br)c1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Solvent: CO
Product: Nc1cc(-c2cccc(Br)c2)n[nH]1

Procedure:
Ten vials were each charged with 3-oxo-3-(3-bromophenyl)propionitrile (1.0 g, 4.5 mmol), hydrazine (0.2 mL) and EtOH (1 mL), and subject to microwave irradiation at 120° C. for 60 min. The contents of all vials was pooled and the solvent was evaporated in vacuo. The crude product was dissolved in ethanol (approx. 200 mL) and acidified by the addition of 4N HLC in dioxane, after 0.5 h the precipitate was collected, washed with additional ethanol and dried to yield 9.60 g. LC/MS (10% MeOH, 90% H2O, 0.2% H3PO4 to 90% MeOH, 10% H2O, 0.2% H3PO4, 2 minute gradient with an Exterra C18 S-5 column 4.6×30 mm): [M+H]+ m/z=239.0, 241.0; retention time=0.85 min.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][NH:18][CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.[CH3:36][N:37]=[C:38]=[O:39]>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:38]([NH:37][CH3:36])=[O:39])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CN=C=O
Reactant: C[C@@H](O[C@H]1CNC[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)N1C[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 25 mg of the product of Step D (0.06 mmol) in 3 mL dry methylene chloride was added 0.01 mL pyridine (0.12 mmol) and 0.007 mL methylisocyanate (0.12 mmol). The resulting reaction mixture was stirred at RT for 1 hr, then the volatiles were removed under vacuum. The residue was purified by prep TLC eluting with methylene chloride/methanol (9/1) to give 25 mg of yellow glass. Further purification was achieved by prep HPLC on Chiralpak AD column eluting with heptanes/ethanol (95/5) to obtain a minor isomer A and the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.43 (d, 3H, 6.5 Hz), 2.86 (2s, 3H), 3.32-3.5 (m, 3H), 3.75-3.90 (m, 3H), 4.20 (br. s, 1H), 4.53 (q, 1H, 6.5 Hz), 6.95 (t, 2H), 7.04 (m, 2H), 7.57 (s, 2H), 7.77 (s, 1H)ppm. MS: 479.1 (MH+) observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([NH:20][CH:30]4[CH2:32][CH2:31]4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2cc(NC3CCSCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccnc(Cl)c1)c1cnc2c(NC3CC3)cc(NC3CCSCC3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
A solution of N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-thiopyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (27 mg, 0.048 mmol) in DCM (0.5 mL) was treated with TFA (1.0 mL, 12.98 mmol) and stirred at room temperature for 1 hour and then concentrated to dryness. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 254 nm). The product (retention time=36.913 minutes) was isolated and lyophilized to dryness to afford N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-(tetrahydro-2H-thiopyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.9 mg, 8.33%). HPLC Rt=4.481 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=443.9.
Reaction SMILES: BrC1C=CC(C2C3C=CC(O)=CC=3OC=2)=CC=1.BrC/C=C/CBr.Br[CH2:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]1[CH:45]=[CH:44][C:33]2[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=3)=[CH:35][O:36][C:32]=2[CH:31]=1.[CH2:46]([NH:49][CH3:50])[CH:47]=[CH2:48]>>[CH2:46]([N:49]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]1[CH:45]=[CH:44][C:33]2[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=3)=[CH:35][O:36][C:32]=2[CH:31]=1)[CH3:50])[CH:47]=[CH2:48]
Reactant: C=CCNC
Reactant: BrC/C=C/COc1ccc2c(-c3ccc(Br)cc3)coc2c1
Agent: BrC/C=C/CBr
Agent: Oc1ccc2c(-c3ccc(Br)cc3)coc2c1
Product: C=CCN(C)C/C=C/COc1ccc2c(-c3ccc(Br)cc3)coc2c1

Procedure:
Analogously to Example 1, from 3-(4-bromo-phenyl)benzofuran-6-ol and (E)-1,4-dibromo-2-butene via (E)-6-(4-bromo-but-2-enyloxy)-3-(4-bromo-phenyl)-benzofuran and by reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 412 (M+H+, 1 Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:24]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: COc1cccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)c1
Yield: 58.6 %

Procedure:
Beginning with 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.8 μL (0.063 mMol) 3-methoxybenzoyl chloride, 9.8 mg (59%) of the title compound were recovered as a brown foam.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O1CCCC1>[OH:8][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([CH:9]=[O:10])=[CH:2][CH:1]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCCCCCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.2 %

Procedure:
Terephthaldicarboxaldehyde (2.00 g, 14.91 mmol) was dissolved in tetrahydrofuran (25 ml) and cooled to 0° C. Octylmagnesium chloride (7.5 ml, 2.0M in THF, 15 mmol) was added dropwise. After 15 minutes, the reaction was quenched with 2N aqueous hydrochloric acid (50 ml) and diluted with ethyl acetate (50 ml). The organic layer was separated, washed with sat'd NaCl (50 ml), dried over magnesium sulfate and concentrated. Silica gel chromatography eluting with 91:9 v/v hexane/EtOAc gave 0.19 g (0.77 mmol, 5.1%) of the title compound: 1H NMR (500 MHz) δ 10.0 (s, 1H), 7.87 (d, J=8.0, 2H), 7.52 (d, J=8.3, 2H), 4.75-4.80 (m, 1H), 1.68-1.82 (m, 2H), 1.22-1.45 (m, 12H), 0.91 (t, J=7.0, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[O:19][C:20]1[C:21](=[O:41])[C:22](=O)[C:23]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:26]=1.C[N:43](C)C(=O)C>CN(C)C=O.C(Cl)Cl>[NH2:43][C:22]1[C:21](=[O:41])[C:20](=[O:19])[C:23]=1[NH:24][C:25]1[CH:26]=[C:27]([N:31]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:14](=[O:16])[CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:17])[CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)N(C)C
Reactant: CC(C(=O)O)c1ccccc1
Reactant: COc1ccc(Nc2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)C(C)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.8 ml) and N,N-dimethylformamide (1 drop) were added to a solution of 2-phenylpropionic acid (900 mg) in methylene chloride (10 ml). This mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure to afford a yellow oil. A solution of 3-methoxy-4-[3-(4-methoxyphenylamino)phenyl]amino-3-cyclobutene-1,2-dione (576 mg) [prepared as described in step (a) above] in N,N-dimethylacetamide (4 ml) was added to a solution of the oil in N,N-dimethylacetamide (4 ml) in an ice bath. The mixture was stirred at ambient temperature for 3 hours. At the end of this time, the reaction mixture was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 2:1 by volume mixture of methylene chloride and ethyl acetate as the eluant, to afford the title compound (603 mg) as a purple foamy solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]#N)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[OH-:24].[K+]>C(O)CC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][OH:24])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C#N
Agent: [K+]
Solvent: CCCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Temperature: 0 °C
Reaction time: 36 h

Procedure:
To a solution of 1.08 g of 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (EXAMPLE 3) in 25 mL of n-PrOH, was added 0.97 g of KOH. The mixture was heated to reflux and stirred at this temperature for 36 h, then cooled and concentrated to a clear oil. This oil was partitioned between 15 mL of water and 10 mL of Et2O. The aqueous phase was extracted with 10 mL of Et2O. The combined organics were washed with brine (15 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon 40S column, eluting with 1 CV of 95% hexanes-5% of a mixture of 5% formic acid in acetone, followed by a linear gradient of the acetone mixture in hexanes from 5 to 100% over 10 CV. The resulting white solid was dissolved in 10 mL of 9:1 benzene-MeOH and excess TMSCH2N2 was added. The mixture was stirred for 10 min at room temperature, then quenched with trifluoroacetic acid and concentrated. The residue was dissolved in 15 mL of Et2O and cooled to 0° C. A 1-M solution of LiAlH4 in Et2O (5.4 mL) was added dropwise via addition funnel. The cooling bath was removed once the addition was complete, and the mixture was stirred 2 h at room temperature, then recooled to 0° C. and quenched by dropwise addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.5 mL of water. The cooling bath was removed once the addition was complete, and the mixture was stirred 30 min at room temperature, filtered (washing the solids liberally with Et2O), and concentrated. Flash chromatography on a Biotage Horizon, 40S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 4 to 100% over 10 CV provided the title compound. Mass spectrum (ESI) 307.2 (M−17). 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25 (dd, J=2 Hz, 9 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.49 (m, 2H), 3.74 (s, 3H), 2.90 (septet, J=7 Hz, 1H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.O>C(Cl)Cl>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccccc1CBr
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2[N+](=O)[O-])CC1
Reaction time: 16 h
Yield: 117.3 %

Procedure:
A solution of 1-(bromomethyl)-2-nitrobenzene (13.2 g, 61 mmol) in DCM (60 ml) was added dropwise to a solution of tert-butyl 4-aminopiperidine-1-carboxylate (14.6 g, 73 mmol) and TEA (13.4 ml, 91 mmol) in DCM (100 ml), followed by stirring the reaction mixture for a further 16 hours. The reaction mixture was then poured into water, and the layers separated. The aqueous layer was then extracted with DCM (2×). The organic layers were combined, washed with water (2×), brine, dried (MgSO4) and evaporated to dryness. The residue was taken up in EtOAc and filtered through a large plug of silica. The silica was washed with EtOAc until TLC analysis show no further material was eluting. Evaporation gave the product as an orange oil (24 g, 74%). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=336; tR=2.23.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O>[Cl:23][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cccc(Cl)c1N1CCNCC1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.87 g, 5.47 mmol) was dissolved in trifluoroacetic acid (5.0 mL) and CH2Cl2 (5.0 mL) and allowed to stir for 2 h. The reaction mixture was concentrated, diluted with EtOAc, and washed with saturated aq. NaHCO3. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 100% CH2Cl2) to afford 1-(2-chloro-6-nitro-phenyl)-piperazine (1.26 g, 95%). MS (electrospray): exact mass calculated for C10H12ClN3O2, 241.1; m/z found, 242.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.54 (dd, J=8.2, 1.6 Hz, 1H), 7.49 (dd, J=8.2, 1.6 Hz, 1H), 7.10 (t, J=8.2 Hz, 1H), 3.08 (br s, 4H), 2.99 (br s, 4H), 2.07-2.12 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH3:18][O:19][C:20](=[O:30])[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=1[NH2:29].CCCCCC>CCOC(C)=O>[CH3:18][O:19][C:20](=[O:30])[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=1[NH:29][C:10](=[O:12])[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:13]
Reactant: COc1ccc(C(C)C(=O)O)cc1
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)cc1
Yield: 84.8 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-methoxy-phenyl)-propionic acid (1.45 g, 8.0 mmol), SOCl2 (2.09 mL, 24.0 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (1.54 g, 7.0 mmol). After normal workup, the pure objective compound (2.27 g, 85%) was obtained as pale yellow syrup by a flash column chromatography (n-hexane:EtOAc=10:1): 1H NMR (200 MHz, CDCl3) δ 1.56 (d, J=7.0 Hz, 3H, CH3), 3.77 (s, 3H, CO2CH3), 3.81 (s, 3H, OCH3), 3.84-3.95 (m, 1H, CH), 6.83-6.97 (m, 2H, ArH), 7.12 (d, J=2.0 Hz, 1H, ArH), 7.21-7.27 (m, 2H, ArH), 8.41 (d, J=2.0 Hz, 1H, ArH), 8.98 (s, 1H, NH); HRMS(EI) calcd. for C18H17O4NCl2 m/e 381.0536 [M+], found 381.0539.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5](=O)[NH:6][CH:7]=1.P(Cl)(Cl)([Cl:12])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-:21].[Na+]>>[Cl:21][C:5]1[N:4]=[C:3]([Cl:12])[C:2]([F:1])=[CH:7][N:6]=1
Reactant: [Cl-]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Product: Fc1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dry reaction flask equipped with a stir bar and a reflux condenser was placed 5-fluorouracil (0.65 g, 5 mmol) followed by phosphorus oxychloride (POCl3) (1.53 g, 10 mmol). The resultant mixture was heated at 110° C. for 8 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, phosphorus pentachloride (PCl5) (3.12 g, 15 mmol) was added and heated to 110° C. for a period of 12 hours. After cooling to room temperature, the mixture was poured into ice-water, saturated with sodium chloride and left for 1 hour at 0° C. to complete the decomposition of POCl3 and PCl5. The solid of 2,4-dichloro-5-fluoropyrimidine was collected by rapid filtration, dried using blotting paper and stored at low temperature. 1H NMR (CDCl3): δ 8.47 (s, 1H); 13C NMR (CDCl3): δ 155.42, 151.87, 147.43 and 147.13; 19F NMR (CDCl3): −38149.