Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[CH3:21][N:22]1[C@@H:39]2[CH2:40][C:27]3[CH:28]=[CH:29][C:30]([O:41][CH3:42])=[C:31]4[O:32][C@H:33]5[C:34]([CH2:36][CH2:37][C@@H:38]2[C@:25]5([C:26]=34)[CH2:24][CH2:23]1)=[O:35].Cl>O1CCOCC1>[NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[CH3:21][N:22]1[C@@H:39]2[CH2:40][C:27]3[CH:28]=[CH:29][C:30]([O:41][CH3:42])=[C:31]4[O:32][C@H:33]5[C:34]([CH2:36][CH2:37][C@@H:38]2[C@:25]5([C:26]=34)[CH2:24][CH2:23]1)=[O:35]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
To the Boc-Ala-Pro-Hydrocodone (0.100 g) was added 10 ml of 4N HCl in dioxane. The resulting mixture was stirred at ambient temperatures for 18 hours. Solvent was removed and final product dried under vacuum. Solid was collected as a slightly yellow solid (0.56 g, 71% yield): 1H NMR (DMSO-d6) δ 1.38 (s, 3H), 1.48 (t, 1H), 1.80-2.29 (m, 8H), 2.65 (m, 1H), 2.80 (s, 3H), 2.96 (m, 3H), 3.23 (m, 2H), 3.76 (s, 3H), 3.92 (s, 1H), 4.22 (s, 1H), 4.53 (s, 1H), 5.00 (s, 1H), 5.84 (d, 1H), 6.77 (d, 1H), 6.86 (d, 1H), 8.25 (br s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12](F)[C:11]=3[F:21])[CH:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12]([NH:31][C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH3:30])[C:11]=3[F:21])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1c(F)cc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of 5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method 103, 0.300 g, 1.01 mmol), (S)-1-(4-fluorophenyl)ethylamine (0.154 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in n-BuOH (2 ml) was heated in a sealed tube placed in an oil bath set at 135° C. for 8 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=3:1) to give the title compound as an orange solid (0.30 g, 71%). 1H NMR (400 MHz) 11.89 (s, 1H), 8.57 (s, 1H), 7.69 (d, 1H, J=13.6 Hz), 7.35 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 6.81 (d, 1H, 7.6 Hz), 5.39 (s, 1H), 5.00 (m, 1H), 1.80 (m, 1H), 1.49 (d, J=6.8 Hz, 3H), 0.90 (m, 2H), 0.62 (m, 2H). MS: Calcd.: 417; Found: [M+H]+ 418.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:35]([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)(=[O:37])=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, light yellow solid (109 mg, 89%), MS (ISP) m/z=489.4 [(M+H)+], mp 221° C., was prepared in accordance with the general method of example 48 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-fluoro-benzene-1-sulfonyl chloride.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:26])[O:11][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH:13]=2)=[CH:5][C:4]=1[CH3:27].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K].[I-].[Na+].CCCCCC>CN(C)C=O.O>[Cl:25][C:20]1[CH:19]=[C:18]([C:12]2([C:14]([F:15])([F:17])[F:16])[O:11][N:10]([CH3:26])[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:32]4[C:28](=[O:38])[C:29]5[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:31]4=[O:33])=[C:4]([CH3:27])[CH:5]=3)=[CH:13]2)[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CN1C(=O)c2ccccc2C1=O
Yield: 98 %

Procedure:
524 mg of 3-(4-Chloromethyl-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole, 216 mg of potassium phthalimide and 10 mg sodium iodide in 7 ml N,N-dimethylformamide were stirred at ambient temperature overnight. The mixture was diluted with water (100 ml) and extracted with 200 ml of ether. The organic phase was washed with water and dried. Evaporation of the solvent afforded a foam. Trituration with hexane gave 2-{4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzyl}-isoindole-1,3-dione as a white solid in 98% yield. 1H-NMR (CDCl3, δ in ppm): 7.88 (m, 2H), 7.75 (m, 2H), 7.22-7.43 (m, 6H), 5.30 (s, 1H), 4.86 (s, 2H), 2.96 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:16]([NH:17][C:18](=[O:32])[CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])C.C(O)C.C(=O)(O)[O-].[Na+].Cl>O>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH:20]=[CH:19][C:18]([NH:17][C:16]2[C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][C:10](=[O:12])[C:9]=3[CH:13]=[CH:14][CH:15]=2)=[O:32])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c(=O)cc(C(=O)OCC)oc23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c(=O)cc(C(=O)O)oc23)cc1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester (132 mg; synthesized in example 3) was dissolved into ethanol (10 ml). To the solution, an aqueous solution (1 ml) of sodium bicarbonate (126 mg) was added. The mixture was refluxed for 15 min. To the reaction solution mixture cooled to room temperature, water (20 ml) and 1N hydrochloric acid (2 ml) were added. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried, and concentrated under reduced pressure. The residue was washed with a mixture of ethyl acetate and hexane (1:1), and dried to give the title compound (62 mg) having the following physical data:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH:23]=O)[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[N+:26]([C:29]1[CH:54]=[CH:53][CH:52]=[CH:51][C:30]=1[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][C@@H:13](/[CH:23]=[CH:31]/[C:30]2[CH:51]=[CH:52][CH:53]=[CH:54][C:29]=2[N+:26]([O-:28])=[O:27])[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1C[C@@H](/C=C/c2ccccc2[N+](=O)[O-])OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-formylmorpholine-4-carboxylate (1 eq.) in DME (0.2 M) at rt were added (2-nitrobenzyl)(triphenyl)phosphonium bromide (1.1 eq.), potassium carbonate (2 eq.) and 18-C-6 (0.1 eq.). The reaction mixture was stirred at rt for 12 hrs, filtered on celite and the filtrate was concentrated under reduced pressure. The crude product was purified by automated SiO2 flash chromatography system using solvent gradient of 10% to 60% EtOAc/Hex to afford the desired compound
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:9][NH:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.O1CCCC1.C(N(CC)CC)C>O>[CH3:9][N:10]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:8]
Reactant: CCCCCN=C=O
Reactant: CNc1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
236 μL (1.84 mmol, 2 eq) of pentyl isocyanate are added to a solution of 250 mg (0.92 mmol, 1 eq) of methyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (obtained as in 4c) in 5 mL of a 9/1 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 12 h at room temperature. The reaction is stopped by addition of 10 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 245 mg of methyl 3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained. Yield=70%
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[Cl:25][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:15][CH:16]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCCl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 6, 2.2 g, 7.4 mmol) in toluene (40 mL) was added thionyl chloride (2.0 mL, 23.6 mmol), and the resulting mixture was stirred at 80° C. for 3 h. The volatile components were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 1:1) to afford 2.1 g (90%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.78 (2H, t, J=7.4 Hz), 3.15 (2H, t, J=7.4 Hz), 2.83 (2H, q, J=7.6 Hz), 2.71 (3H, s), 2.54 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH3:39])[CH2:37][OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH:36]([CH3:39])[CH2:37][OH:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-2-amino-1-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.1 (1H, br), 10.16 (1H, d, J=7 Hz), 8.56 (1H, s), 7.16 (2H, dd, J=8.5, 6 Hz), 7.03 (2H, t, J=8.5 Hz), 6.93 (1H, s), 4.96 (1H, d, J=7 Hz), 4.89 (1H, d, J=7 Hz), 4.27 (1H, m), 4.11 (2H, s), 3.74 (1H, m), 3.66 (1H, m), 3.50 (2H, t, J=5.5 Hz), 3.43 (2H, t, J=5.5 Hz), 2.23 (1H, m), 1.69 (2H, m), 1.52 (4H, m), 1.29 (3H, d, J=7 Hz); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2186.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([O:13]C)=[O:12].O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([OH:13])=[O:12]
Reactant: C=C(Oc1ccccc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(Oc1ccccc1OC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(2-methoxyphenyloxy)propenoate (0.30 g, 1.4 mmol) in tetrahydrofuran (30 mL) and water (30 mL) was added lithium hydroxide monohydrate 0.17 g, 4.0 mmol). After stirring at room temperature overnight, the reaction was quenched by addition of concentrated hydrochloric acid (final pH=2), and the product was extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.42 (ddd, 1H), 7.22 (dd, 1H), 7.10 (dd, 1H), 6.97 (ddd, 1H), 5.48 (d, 1H), 4.51 (d, 1H), 3.64 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][S:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19](Cl)=[O:20])[CH3:17].C(N(CC)CC)C>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][C:19]([O:18][CH2:16][CH3:17])=[O:20])=[O:14])[CH2:10][S:11][CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC(=O)[C@H](CSC)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)-S-methylcysteine (23.5 g, 0.100 mol) in THF (400 mL) was added dropwise ethylchloroformate (9.6 mL, 0.10 mol) and triethylamine (10.1 g, 0.100 mol) slowly at −10° C. The reaction mixture was stirred at −10° C. for 30 minutes, and then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethoxycarbonyl N-(tert-butoxycarbonyl)-S-methylcysteinate which was used without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1.[I:27]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=[N:11][C:12]=1[C:13]1[CH:18]=[C:17]([I:27])[C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(OC)c(F)c2)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2cc(F)c(OC)c(I)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
Sulfuric acid (2.5 mL) was added into a cold (ice bath) mixture of ethyl 5-chloro-6-(3-fluoro-4-methoxyphenyl)pyridine-3-carboxylate (500 mg, 1.614 mmol) and 1-iodopyrrolidine-2,5-dione (400 mg, 1.776 mmol) in acetic acid (7.5 mL). The reaction mixture was stirred in an ice bath and warmed up to room temperature in one hour before placed in a 55° C. oil bath overnight. The crude was combined with the crude from an identical probe reaction (33 mg scale). The combined crude was poured into an ice/water mixture and neutralized by NaHCO3. The resulting mixture was extracted with EtOAc. The separated organic phase was dried over Na2SO4, filtered and evaporated to afford a dark mixture. This dark crude mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 30%). Related fractions were pooled and evaporated to afford a white solid as the titled compound. LCMS calc.=434.95. found=435.77 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 9.13 (d, J=2.0 Hz, 1H), 8.38 (d, J=1.5 Hz, 1H), 8.02 (s, 1H), 7.60 (dd, J=12.5, 2.0 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H), 4.03 (s, 3H), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[N:9][C:4]2=[CH:3][CH:2]=1>N.CO.[Ni]>[N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[N:9][C:4]2=[CH:3][CH:2]=1
Reactant: N#Cc1ccn2nccc2n1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccn2nccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidine-5-carbonitrile (2-2) (620 mg, 4.31 mmol) in NH3 in MeOH (5 mL) was added Raney Ni (100 mg). The reaction mixture was stirred at room temperature for 3 h under H2. The mixture was filtered, and the filtrate was concentrated to afford the title compound (600 mg). MS (m/z): 149 (M+1)+.
Reaction SMILES: [OH:1][C:2]([CH:7]([F:9])[F:8])([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:14]1([S:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+].C>CC(N(C)C)=O>[C:14]1([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:27][C:3](=[O:4])[C:2]([OH:1])([CH3:6])[CH:7]([F:9])[F:8])=[CH:28][CH:29]=2)(=[O:21])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)(C(=O)O)C(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-difluoromethylpropionic acid (0.9 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.3 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured into ammonium chloride solution and extracted with ethyl acetate. The combined ethyl acetate fractions were washed with water and brine. After drying (Na2SO4) and decolorization (Charcoal) the solution was evaporated in vacuo. A foam was obtained which was triturated with toluene and crystallized from ethyl acetate/hexane to give the title tertiary carbinol (0.72 g, 47%) as white crystals; mp=168°-169° C. 1H-NMR (300 MHz, d6 -DMSO): 1.41 (s, 3H, CH3), 6.13 (t, J=54.9 Hz, 1H, CHF2), 6.76 (s, 1H, OH), 7.58-7.68 (m, 3H, ArH), 7.89-8.01 (m, 6H, ArH), 10.27 (s, 1H, NH). MS (CI, CH4): 356(M+1, 100). Analysis for C16H15F2NO4S: Calculated: C, 54.08; H, 4.25; N, 3.94 Found: C, 53.75; H, 4.40; N, 3.78
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32](=[O:34])[CH3:33].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[C:32]([CH2:33][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([C:13]([O:12][CH2:11][CH:2]2[CH2:3][CH2:4][N:5]3[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:1]2)=[O:14])=[CH:16]1)(=[O:34])[CH3:31]
Reactant: CC(=O)CBr
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)Cn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21
Reaction time: 72 h
Yield: 4 %

Procedure:
A stirred solution of eq-quinolizidin-2-ylmethylindole-3-carboxylate (E9b) (300 mg, 0.96 mmol) in acetone (10 ml) was treated with anhydrous potassium carbonate (270 mg, 2 mmole) and bromoacetone (150 mg, 1.1 mmole) and kept at room temperature for 3 days. The mixture was treated with 10% Na2CO3 solution (10 ml) and extracted with ethyl acetate (2×25 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with ethyl acetate/methanol (95:5). The pale yellow oil obtained was crystallised from ether to afford the title compound (E31) as a beige solid (14 mg) mp 139°-1420C.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][N:23]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26](=O)[C:24]2=[O:25])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].[CH3:35][O:36][NH2:37].Cl>CO>[ClH:34].[ClH:34].[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][N:23]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26](=[N:37][O:36][CH3:35])[C:24]2=[O:25])[CH2:18][CH2:19]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C(=O)N(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C1C(=O)N(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Yield: 121.2 %

Procedure:
A mixture of 1-[3-(4-benzhydryl-1-piperazinyl)propyl]isatin (1.81 g) and O-methylhydroxylamine hydrochloride (420 mg) in methanol (36 ml) was stirred for an hour at ambient temperature. After addition of 29% ethanolic hydrogen chloride (2 ml), the reaction mixture was evaporated to dryness. The residue was triturated with ethanol and then recrystallized from 90% ethanol to give pale yellow crystals of 1-[3-(4-benzhydryl-1-piperazinyl)propyl]-3-methoxyimino-2-indolinone dihydrochloride (1.65 g), mp. 191° to 196° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=2[F:22])[C:15](=[O:25])[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:13]1.C(O)(=O)C.ClC(Cl)C>CO.[Pd]>[NH2:9][C:5]1[CH:4]=[C:3]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=3[F:22])[C:15](=[O:25])[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:13]2)[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Ethyl 1-(2,4-difluoro-5-nitrophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.2 g) was dissolved in 20 ml of methanol, 50 ml of acetic acid, and 10 ml of dichloroethane, to which was added 200 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred overnight at room temperature. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Ethanol was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 1.12 g of the title compound.