Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[NH2:12]>>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1
Product: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Acetic anhydride (14 ml) was added dropwise at 0° C. to 3-bromo-5-nitroaniline (14 g, 64.5 mmol). The mixture was stirred for 30 min at RT and then quenched by the addition of crushed ice. The precipitate formed was filtered and washed with cold water to obtain off-white solid. The solid was dried under vacuum to give the product in 78% yield (13 g). 1H NMR (300 MHz, DMSO-d6): δ 10.54 (br s, 1H), 8.45 (s, 1H), 8.2 (s, 1H), 8.03 (s, 1H), 2.11 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:24])[C@@H:14]3[C@H:17]([O:19][Si](C)(C)C)[CH3:18])[C:11]=2[C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])[CH:7]=[CH:8][CH:9]=1)=[O:3].Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C1COCC1>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:24])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cccc(C(N)=O)c3)C[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cccc(C(N)=O)c3)C[C@H]12
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
[(2,2-Dimethylpropanoyl)oxy]methyl (5R,6S)-3-[3-(aminocarbonyl)phenyl]-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (11 mg) obtained in Step b) was dissolved in ethyl acetate (2 ml) and THF (2 ml), and thereto was added 0.1N hydrochloric acid under ice-cooling to adjust the pH value thereof to the range of from pH 2 to pH 3. The mixture was vigorously stirred for 20 minutes, and the reaction solution was diluted with ethyl acetate, and poured into a cold aqueous sodium hydrogen carbonate solution. The mixture was extracted and separated, and the organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (ethyl acetate/acetone=4/1) to give [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-[3-(aminocarbonyl)phenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (9 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)CCC.Cl>CN(C=O)C.[Cu]Cl>[CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)c1csc(I)c1P(=O)(OCC)OCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1csc(-c2cccs2)c1P(=O)(OCC)OCC
Temperature: 80 °C
Reaction time: 9.75 h

Procedure:
3,4-bis(diethoxyphosphoryl)-2-iodothiophene and different equivalents of copper(I) chloride (commercially available product) indicated in Table 6 were dissolved in DMF, to which 2-tributylstannylthiophene (1.2 equivalents) was added at room temperature. Thereafter, the reaction mixture was heated to 80° C. and stirred for 8.5 to 11 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 0.6 M hydrochloric acid aqueous solution was added, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure and the resulting crude product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH2:35][CH:36]([NH2:42])[C:37]1[CH:41]=[CH:40][S:39][CH:38]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH2:35][CH:36]([NH:42][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:37]1[CH:41]=[CH:40][S:39][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccsc1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CCNC(=O)OC(C)(C)C)c5ccsc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and (3-amino-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester (from Example 69 supra) (412 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to afford crude (3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester. (Yield 400 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[NH2:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)=[O:28]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([C:27]([NH2:26])=[O:28])=[CH:30][CH:31]=3)=[C:4]([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Product: NC(=O)c1ccc(C(=O)NCc2c(-c3ncco3)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
N-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-terephthal-amide was prepared starting from intermediate A and 4-(aminocarbonyl)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (t, J=4.50 Hz, 1H) 8.31 (d, J=8.59 Hz, 1H) 8.02 (br. s, 1H) 7.97 (d, J=0.78 Hz, 1H) 7.83-7.87 (m, 2H) 7.73-7.78 (m, 2H) 7.37-7.54 (m, 7H) 7.16 (d, J=0.78 Hz, 1H) 6.72 (d, J=1.56 Hz, 1H) 4.25 (d, J=4.30 Hz, 2H). MS calcd. for C27H19ClN4O4 [(M+H)+] 499.1, obsd. 499.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OC(C)C)cn2)cc1

Procedure:
N-{3-[4-(5-Hydroxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide (50 mg, 166 μmol), 2-iodopropane (28 mg, 166 μmol) and cesium carbonate (135 mg, 416 μmol) were stirred in 3 ml of DMF at 50° C. for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 35 mg (61%), M+H+: 343.16.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([F:25])([F:37])[F:38])(=[O:35])=[O:34])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and 2-trifluoromethyl-benzenesulfonyl chloride (146 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 mL, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). Then, the organic compound was extracted into ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified by using an ISCO (40 g) column chromatography eluting with 5-30% ethyl acetate in hexanes to afford {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (132 mg, 82%) as a light yellow foam. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H), 8.16 (d, J=7.2 Hz, 1 H), 8.03 (dd, J=7.2, 1.7 Hz, 1 H), 7.82-7.96 (m, 4 H), 7.45 (dd, J=8.8, 1.6 Hz, 1 H), 7.25 (d, J=8.5 Hz, 2 H), 7.12 (d, J=8.5 Hz, 2 H), 6.95 (d, J=1.6 Hz, 1 H), 3.92 (s, 2 H), 3.63 (s, 3 H), 1.98 (s, 3H). HRMS calcd. for C27H20ClF3NO4S [(M−H)−] 546.0759, obsd. 546.0762.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NCCOc2ccccc2)=N3)CC1
Yield: 101.1 %

Procedure:
Prepared from the above described 2-chloro-N-[2-(2-phenoxy-ethylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (180 mg, 0.50 mmol; HPLC 1.096 min) and 1-methylpiperazine (1.1 ml, 10 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (214 mg, 100%; HPLC 0.494 min), MS (ISP) m/e=424.1 [(M+H)+].
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:26]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)c1ccccc1)c1ccc(OC)c(OC)c1
Yield: 100.2 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (0.689 grams, 2.50 mmol) and triethylamine (0.7 milliliters, 5 mmol) in 15 milliliters of tetrahydrofuran was added 0.3 milliliters of benzoyl chloride (2.6 mmol). The cooling bath was removed after 15 minutes and the mixture stirred for an additional 45 minutes. The reaction mixture was then diluted with 15 milliliters of brine and 15 milliliters of water and then partially concentrated in vacuo to remove the tetrahydrofuran. The reaction slurry was filtered, the solid air-dried, then dried in vacuo (60° C., <1 mm) to afford 0.86 g (100%) of the product as a white powder: 1H NMR (dmso-d6, 250 MHz) δ 8.84 (d, J=8.3 Hz, 1 H, NH), 7.83 (m, 2 H, Ar), 7.60-7.35 (m, 3 H, Ar), 7.06 (s, 1 H, Ar), 6.90 (m, 2 H, Ar), 5.50-5.30 (m, 1 H, CHN), 3.75 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.46 (s, 3 H, CO2CH3), 3.05-2.75 (m, 2 H, CH,); 13C NMR (dmso-d6) δ 17 165.6, 148.6, 147.9, 134.9, 134.5, 131.2, 128.3, 127.3, 118.5, 111.6, 110.6, 55.5, 55.5, 51.4, 49.7, 40.6. Anal. Calcd for C19H21,NO5. Theoretical C, 66.46; H, 6.16; N, 4.08. Found C, 66.22; H, 6.05; N, 3.98.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].ClS([N:18]=[C:19]=[O:20])(=O)=O.O>C(Cl)Cl>[NH:1]([C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])[C:19]([NH2:18])=[O:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NC(=O)c1c(N)sc2ccccc12
Solvent: ClCCl
Solvent: O
Product: NC(=O)Nc1sc2ccccc2c1C(N)=O
Yield: 40.9 %

Procedure:
To the mixture of 2a (20 mg, 0.104 mmol) in CH2Cl2 (10 mL) was added chlorosulfonyl isocyanate (15 μL, 0.15 mmol). The resultant mixture was stirred at room temperature for 1 h and mixed with water (0.5 mL). Separation via a reverse phase HPLC provided the title compound (10 mg, 40%) as a white solid: MS (ES) m/z 236 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ10.77 (s, 1H), 7.84 (m, 2H), 7.56 (brs, 3H), 7.20 (m, 1H), 7.08 (m, 1H), 6.98 (brs, 1H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:11][C:10]=1[C:24]([O:26][CH3:27])=[O:25])C1C=CC=CC=1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:27][O:26][C:24]([C:10]1[N:11]=[C:12]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:13]([CH3:16])[C:14](=[O:15])[C:9]=1[OH:8])=[O:25]
Reactant: COC(=O)c1nc(CC2CCCCC2)n(C)c(=O)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(CC2CCCCC2)n(C)c(=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of methyl 5-(benzyloxy)-2-(cyclohexylmethyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (60 mg, 162 μmol) and 20% palladium hydroxide on carbon (11.4 mg, 16.2 μmol) in EtOAc (10 ml) was placed under an atmosphere of hydrogen and stirred at room temperature overnight. The mixture was filtered and then evaporated to dryness. Chromatography (SiO2; 0 to 20% EtOAc in hexanes) gave the title product as a white solid (0.032 g; 70%). LCMS: m/z=281 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:19][C:20]#[CH:21])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:8][CH2:9][CH2:10][N:11]([CH2:19][C:20]#[CH:21])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CCN(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.9 %

Procedure:
To a solution of 950 mg of 10c in 5 ml of THF was added 5 ml of 1M tetra-n-butyl ammonium fluoride in THF. The mixture was stirred for 1 hr at RT and then poured into 50 ml of water and extracted with ethyl acetate. The crude product thus obtained was chromatographed on silica gel (using a gradient of heptane/ethyl acetateas eluent) and provided 700 mg of 10d, as a colorless oil; Rf 0.35 (heptane/ethyl acetate 1/1);
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=1)(=O)C.[OH-].[Na+].Cl>C(O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:7]=[C:6]([CH2:5][OH:4])[O:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(=O)OCc1cc(-c2ccc(F)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1cc(-c2ccc(F)cc2)no1

Procedure:
[3-(4-fluorophenyl)isoxazol-5-yl]methyl acetate was stirred in a mixture of aqueous 2N sodium hydroxide (1.60 g, 20 mL H2O) and ethanol (10 mL) at room temperature for 2 hours. The reaction mixture was then neutralized with 2N HCl aqueous solution (20 mL), and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over sodium sulfate and solvent removed under reduced pressure, to provide [3-(4-fluorophenyl)isoxazol-5-yl]methan-1-ol. C. Conversion of a Compound of Formula (30) in which X1 is 4-Fluorophenyl to a Mesylate
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH2:23]([O:25][P:26]([C:31]([C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)([F:33])[F:32])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:23]([O:25][P:26]([C:31]([F:33])([F:32])[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[CH:36][CH:35]=1)(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(N)cc1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Yield: 6 %

Procedure:
The title product was prepared according to the procedure for Example 102 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 40.0 mg, 0.12 mmol) and diethyl[(4-aminophenyl)(difluoro)methyl]-phosphonate (Compound 188A, 40.5 mg, 0.15 mmol). The crude product was purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white solid (4.1 mg, yield: 6%). 1H NMR (CD3OD, 400 MHz): δ=1.32 (t, J=7.2 Hz, 6H), 2.90 (s, 3H), 4.14-4.25 (m, 4H), 7.22 (t, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.51 (dt, J=1.2, 7.2 Hz, 1H), 7.66 (dd, J=1.2, 7.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 2), 8.39 (s, 1H), 8.47 (d, J=8.4 Hz, 1H). MS (ES+): m/z 574.12 [MH+]. HPLC: tR=4.13 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:15][N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C=C[N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-Fluoro-4-methoxy-benzaldehyde (1 equivalent) was dissolved in MeOH and chilled in an ice bath. Nitromethane (1 equivalent) was added. NaOH (1.05 equivalents) in water was added dropwise to the nitromethane/aldehyde solution, such that the temperature did not rise above 15° C. The reaction was then allowed to stir at 0° C. for 15 minutes. The reaction mixture was poured into concentrated HCl diluted with water. Product was extracted with EtOAc and washed with water, brine, and dried (Na2SO4). Solvent was removed to yield a yellow oil which was freeze-dried in 90% MeCN/H2O to give the product 2-fluoro-4-methoxy-1-(2-nitro-vinyl)-benzene, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]3[CH:11]([CH2:12][N:13](C(OC=C)=O)[CH2:14]3)[C:10](=[O:21])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:28]>O1CCOCC1>[ClH:28].[C:22]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10](=[O:21])[CH:9]=[CH:8]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=COC(=O)N1CC2C(=O)C=CC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C=CC(c2ccccc2)(c2ccccc2)C2CNCC12

Procedure:
7,7-Diphenyl-2-vinyloxycarbonyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-one (2.6 g) is stirred in a 3N solution (30 cc) of hydrogen chloride in dioxane at room temperature for 30 minutes; the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with ethanol (50 cc) and heated to reflux for 30 minutes; the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in ethyl ether (20 cc); the crystals obtained are drained and dried. 7,7-Diphenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-one hydrochloride (2 g), m.p. above 260° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1F)[C:6]#[N:7].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>CN(C)C(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17])[C:6]#[N:7]
Reactant: OCCNCCO
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(N(CCO)CCO)c(C(F)(F)F)c1

Procedure:
A solution of 3-trifluoromethyl 4-fluoro-benzonitrile (9.45 g, 50 mmol) and diethanolamine (15.8 g, 0.15 mol) in N,N-dimethylacetamide (200 ml) was stirred for 7 days at 50° C. The solvent was evaporated, the residue partitioned between CH2Cl2 (400 ml) and H2O (400 ml), the organic layer dried (MgSO4) and evaporated to dryness. The residue was chromatographed using CH2Cl2-EtOH as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][CH:6]=[CH:5]2.[C:13]1([CH3:23])[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:23])(=[O:21])=[O:20])=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(O)cccc2c1
Product: Cc1ccccc1S(=O)(=O)Oc1cccc2cc(N)ccc12

Procedure:
Additional substituents can be added to the naphthol ring by reacting a 6-aminonaphth-1-ol (SM11) with toluene sulfonyl chloride in the manner disclosed above to yield the 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN). The 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN) was then reacted with t-butyl nitrite in a solvent, for example at 0° C. followed by a copper (II) halide, for example, copper (II) chloride, to yield the appropriate 6-halo-1-(methylphenylsulfonyloxy)naphthalene (PP). The 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN) was also reacted with an excess of a copper (II) halide, for example, copper (II) chloride, in a solvent followed by t-butylnitrite in the manner disclosed above to form the appropriate 5,6-dihalo-1-(methylphenylsulfonyloxy)naphthalene (QQ). The appropriately substituted naphthalene (QQ) or (PP) can then reacted with a base, for example, potassium hydroxide, and an alcohol, for example, ethanol, in a mixture of a solvent, for example, THF, and water to yield the appropriately substituted. naphthol (RR), for example 5,6-dichloronaphthol. When the naphthol was a 5,6-dihalonaphthol (RR) it was reacted with either the appropriately substituted benzaldehyde (BB), alcohol (CC), toluene (DD), or hydrochloride (EE) and a borane-pyridine complex under acidic conditions, or a base, for example, sodium hydride or triethylamine, in a solvent, for example DMF, or a phosphine complex, for example n-butylphosphine, and DPAD in a solvent, for example, THF, to form the targeted 1-substitutedalkylthio or alkoxy-4-((5,6-substituted naphth-1-yl)oxyalkyl)benzene (Ia), for example, (2-(4-((5,6-dichloronaphthyloxy)methyl)phenoxy)ethyl)diethylamine.