Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]\[C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(/C=C/C2N=C(NC(=O)C)SC=2)=CC=1)#N.CO.[H][H]>[Pd].C(O)(=O)C.O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)Nc1nc(/C=C\c2ccc(C#N)cc2)cs1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)Nc1nc(/C=C/c2ccc(C#N)cc2)cs1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(C#N)cc2)cs1

Procedure:
A mixture of N-{4-[(Z)-2-(4-cyanophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide and N-{4-[(E)-2-(4-cyanophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (Z:E=3:1) (1.5 g), 10% palladium on carbon (323 mg), methanol (20 ml), tetrahydrofuran (10 ml) and acetic acid (5 ml) were combined. The reaction mixture was stirred under 4 atm hydrogen at ambient temperature for 9 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (1:1)→chloroform/methanol (30:1) as an eluent, and triturated with ethyl ether to give N-{4-[2-(4-cyanophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (1.18 g) as a colorless solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22](=[O:61])[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH2:35][C:36]6[CH2:41][CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][C:37]=6[C:44]6[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=6)[CH2:31][CH2:30]5)=[CH:25][C:24]=4[O:51][C:52]4[CH:53]=[C:54]5[CH:60]=[CH:59][NH:58][C:55]5=[N:56][CH:57]=4)(=[O:20])=[O:19])=[CH:14][C:13]=3[N+:62]([O-:64])=[O:63])[CH2:7][CH2:6]2)[O:4]CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O.ClCCl>[NH:58]1[C:55]2=[N:56][CH:57]=[C:52]([O:51][C:24]3[CH:25]=[C:26]([N:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]5[CH2:41][CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][C:37]=5[C:44]5[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=5)[CH2:33][CH2:34]4)[CH:27]=[CH:28][C:23]=3[C:22]([NH:21][S:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)=[C:13]([N+:62]([O-:64])=[O:63])[CH:14]=3)(=[O:20])=[O:19])=[O:61])[CH:53]=[C:54]2[CH:60]=[CH:59]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCC6(CC5)OCCO6)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCC(=O)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 340B (386 mg) in acetone (10 mL) and water (5 mL) was added para-toluenesulfonic acid monohydrate (50 mg). The mixture was stirred at 120° C. in a Biotage Initiator microwave reactor for 30 minutes. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:4].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:6]([O:5][CH2:3][CH3:4])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CCONS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCON(c1ccc([N+](=O)[O-])cc1Cl)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.18 g (4.50 mmol)) in 6.0 ml of DMF, N-ethoxy-p-toluenesulfonamide (0.90 g (4.18 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3-chloro-4-fluoronitrobenzene (0.70 g (3.99 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 18 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give crude crystals. These crystals were filtered while washing with diisopropyl ether to give 1.06 g (72%) of the title compound as pale yellow crystals.
Reaction SMILES: C(N1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])C1)C.C[C@H](OC1N=[C:42]2[C:38](N=[C:40](OC)[N:41]2[CH2:44]CCC2CCCNC2)=C(N)N=1)CCC.ICC>>[CH2:42]([N:41]1[CH2:44][CH2:8][CH2:7][CH:6]([CH2:5][CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:40]1)[CH3:38]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Reaction time: 0.25 h
Yield: 192.2 %

Procedure:
Bis(4-bromophenyl)amine (4.0 g, 12.3 mmol) and phenylboronic acid (4.0 g, 32.7 mmol) were mixed in 250 mL of toluene and 60 mL of ethanol. The solution was bubbled with nitrogen while stirring for 15 minutes. Pd(PPh3)4 (1.4 g, 1.23 mmol) and K3PO4 (13.5 g, 64 mmol) were added in sequence. The mixture was heated to reflux overnight under nitrogen. After cooling, the reaction mixture was filtered through filter paper and the solvent was then evaporated. The solid was redissolved in nitrogen-purged hot toluene and was filtered through a Celite®/silica pad when the solution was still hot. The solvent was then evaporated. The white crystalline solid was washed by hexane and air dried to obtain 3.8 g of product.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-:3])=[O:2].[O:12]1[CH2:14][CH:13]1[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CCOC(C)=O>[Si:17]([O:16][CH2:15][CH:13]([OH:12])[CH2:14][N:5]1[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=[C:4]1[N+:1]([O-:3])=[O:2])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCC1CO1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(O)Cn1cc([N+](=O)[O-])nc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
A mixture of 2,4-dinitroimidazole (86) (2.02 g, 12.8 mmol) and tert-butyl(dimethyl)silyl 2-oxiranylmethyl ether (87) (3.84 g, 20.4 mmol) was stirred at 70° C. for 16 h. The resulting cooled mixture was diluted with EtOAc (300 mL) and washed with aqueous NaHCO3 (3×50 mL), water (2×50 mL) and brine (50 mL), and then the solvent was removed. Chromatography of the residue on silica gel, eluting with 10-20% EtOAc/petroleum ether, gave 1-{[tert-butyl(dimethyl)silyl]oxy}-3-(2,4-dinitro-1H-imidazol-1-yl)-2-propanol (88) (reported by Otera et al., US 2006063929A1, starting from 2,4-dinitroimidazole and glycidol) (2.63 g, 60%) as a yellow oil; 1H NMR (CDCl3) δ 8.01 (s, 1H), 4.78 (dd, J=13.9, 2.9 Hz, 1H), 4.46 (dd, J=14.0, 8.3 Hz, 1H), 4.08 (m, 1H), 3.76 (dd, J=10.4, 4.6 Hz, 1H), 3.67 (dd, J=10.5, 5.0 Hz, 1H), 2.60 (br s, 1H), 0.92 (s, 9H), 0.11 (s, 6H); APCI MS m/z 300 [M+H—HNO2]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[CH3:20][CH:21]([CH2:30][CH3:31])[C:22](=O)[CH2:23][C:24](OCC)=[O:25].[O-]CC.[Na+].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CN(C)C=O.O1CCCC1.C(=O)=O.ClCCl.CO.C(OCC)(=O)C.CCOCC>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]1[C:23]([CH2:24][OH:25])=[C:22]([C@@H:21]([CH3:20])[CH2:30][CH3:31])[O:6][N:5]=1
Reactant: ON=Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CC(=O)C(C)CC
Agent: CC(C)C[Al+]CC(C)C
Agent: CC[O-]
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Temperature: 25 °C
Yield: 3.7 %

Procedure:
To a solution of 2,6-dichlorobenzaldehyde oxime (26.4 g, 139 mmol) in N,N-dimethylformamide (70 mL) at 5° C. was added solid N-chlorosuccinimide (18.6 g, 139 mmol) in portions. The mixture was allowed to stir and warm to ambient temperature (with occasional cooling when warming was noted) over approximately 1.5 hour and then poured into ether. The ether layer containing the crude imidoyl chloride was washed twice with water followed by brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 4-methyl-3-oxohexanoate (28.8 g, 167 mmol) in tetrahydrofuran (50 mL) at 0° C. was added sodium ethoxide (21 wt % in ethanol, 62.3 mL, 167 mmol) quickly. Then the above imidoyl chloride was added dropwise in tetrahydrofuran (100 mL). The solution was allowed to stir while warming to ambient temperature overnight. The mixture was then poured into ether, washed twice with water followed by brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which was dissolved in tetrahydrofuran (75 mL) at 0° C. Then a 1.5 M solution of diisobutylaluminum hydride in toluene (100 mL, 150 mmol) was added slowly. The solution was allowed to warm slightly while stirring for approximately 2.5 hours and then was re-cooled to 0° C. and stirred for 1.5 hours. Then aqueous Rochelle's salt (20 mL) was added carefully followed by ethyl acetate and the mixture was stirred overnight. Then the layers were separated and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid. The enantiomers were resolved by supercritical fluid chromatography (Chiralpak AD, 10% methanol in supercritical carbon dioxide) and the resulting solid was taken up with dichloromethane, dried over magnesium sulfate and concentrated to afford {3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methanol (1.53 g, 7%) 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.85 (t, J=5 Hz, 1H), 4.20-4.06 (m, 2H), 3.15-3.10 (m, 1H), 1.69-1.62 (m, 2H), 1.29 (d, J=7 Hz, 3H), 0.79 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C@:11]1([C:23]([O:25][CH3:26])=[O:24])[CH2:21][C@@H:20]([OH:22])[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@@H:13]2[CH2:12]1.N1C=CC=CC=1>ClCCl>[C:1]([O:22][C@H:20]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@@H:13]2[CH2:12][C@@:11]([OH:10])([C:23]([O:25][CH3:26])=[O:24])[CH2:21]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@]1(O)C[C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@]1(O)C[C@@H](OC(=O)c2ccccc2)[C@@H]2OC(C)(C)O[C@@H]2C1
Reaction time: 12 h
Yield: 86.1 %

Procedure:
Benzoyl chloride (0.78 mL, 6.7 mmol) was added dropwise to 0° C. a solution of Example 13B (1.65 g, 6.7 mmol) and pyridine (0.82 mL, 10.1 mmol) in dichloromethane (40 mL). After stirring for 12 hours, the reaction mixture was washed with aqueous HCl (2N), saturated NaHCO3 solution, and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography using hexanes/ethyl acetate (3/2) to afford 2.02 g (86%) of the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12]([OH:15])(=O)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.S(Cl)(Cl)(=O)=O.[CH3:25][NH:26][CH3:27]>C(Cl)Cl>[CH3:25][N:26]([CH3:27])[S:12]([CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:15])=[O:13]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A flask was charged with 4.60 g (19.9 mmol) of solid 2-(4-nitro-phenyl)-ethanesulfonic acid (as prepared in Example 26, step (b)), which was treated with 29.0 mL (398 mmol) of thionyl chloride and heated to 80° C. for 6 h. Solvents were evaporated in vacuo, and the resulting solid was dried overnight under high vacuum. A solution of 2.12 g (8.49 mmol) of this solid sulfonyl chloride in 40 mL CH2Cl2 was treated with 15.0 mL (127 mmol) of 40% w/v aqueous dimethylamine and stirred at RT for 16 h then warmed to 40° C. for 3 h. The mixture was diluted with CH2Cl2 (100 mL) and washed with water (2×50 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 912 mg (41%) of the title compound as an off-white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.20 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.8 Hz), 3.29-3.14 (m, 4H), 2.89 (s, 6H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([O:26]CC1C=CC=CC=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2>CO.C(OCC)(=O)C.[Pd]>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([OH:26])[C:12]1[CH:24]=[CH:23][C:15]([C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2
Reactant: CS(=O)(=O)NC(=O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)NC(=O)c1ccc(C(O)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Reaction time: 2 h
Yield: 27.7 %

Procedure:
To a mixture of 4-(adamantan-2-yl(benzyloxy)methyl)-3-chloro-N-(methylsulfonyl)benzamide (0.290 g, 0.59 mmol) in methanol (10 mL) and ethyl acetate (10 mL) was added palladium on carbon (10%, 50 mg) and the reaction mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered over diatomaceous earth, and the filtrate was concentrated in vacuo. The obtained residue was purified by reverse-phase preparative HPLC to afford the title compound as a colorless solid (0.065 g, 28%): 1H NMR (300 MHz, DMSO-d6) δ 12.20 (br s, 1H), 7.94 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.64 (d, J=7.1 Hz, 1H), 5.45 (br s, 1H), 5.23-5.14 (m, 1H), 3.31 (s, 3H), 2.37-2.27 (m, 1H), 2.11-1.35 (m, 13H), 1.11-1.01 (m, 1H); MS (ES−) m/z 396.2, 398.2 (M−1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]3[CH2:15][CH:12]([CH2:13][CH:14]=2)[CH2:11][N:10](C(OCC)=O)[CH2:9]3)[CH:2]=1.Cl.[OH-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]3[CH2:15][CH:12]([CH2:13][CH:14]=2)[CH2:11][NH:10][CH2:9]3)[CH:2]=1
Reactant: CCOC(=O)N1CC2CC=C(c3cccnc3)C(C2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C1=C(c2cccnc2)C2CNCC(C1)C2
Yield: 14.8 %

Procedure:
A mixture of ethyl 6-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene-3-carboxylate (100 mg, 0.370 mmol) and 1.5 mL of concentrated HCl was heated under reflux for 16 h. The mixture was cooled in an ice bath and made basic by adding 5 M aqueous sodium hydroxide. The suspension was extracted with chloroform (3×5 mL), and the extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was filtered though a plug of silica gel, eluting with 90:10:1 dichloromethane/methanol/concentrated ammonium hydroxide, to give the product as an oil (11 mg, 15%).
Reaction SMILES: O1C2C=CC=CC=2N=C1.NC1C=CC=CC=1.C(OC(=O)[NH:23][CH:24]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[C:41]3[O:40]C(C(C)(C)C)=[N:38][C:37]=3[CH:36]=[CH:35][C:34]=2[Cl:46])(=[O:32])=[O:31])[CH2:26][CH2:25]1)(C)(C)C.OS(O)(=O)=O>O1CCOCC1.O>[NH2:38][C:37]1[C:41]([OH:40])=[C:33]([S:30]([N:27]2[CH2:26][CH2:25][CH:24]([NH2:23])[CH2:29][CH2:28]2)(=[O:32])=[O:31])[C:34]([Cl:46])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Solvent: Nc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCC(N)CC2)c1O
Yield: 74.9 %

Procedure:
Following the general procedure for the hydrolysis of the benzooxazole to the desired aniline outlined in example 51, [1-(2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl)-piperidin4-yl]-carbamic acid tert-butyl ester (4.18 g, 8.86 mmol), water (5.5 mL), and H2SO4 (5.5 mL) in 1,4-dioxane (55mL) were reacted to afford the title compound (2.03 g, 75%). LCMS m/z 306(M−H)+.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1.[CH3:22][S:23]([Cl:26])(=[O:25])=[O:24]>N1C=CC=CC=1>[ClH:26].[CH3:22][S:23]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Reaction time: 0.5 h

Procedure:
To a mixture containing 6.57 g of 5-(3-aminophenyl)-1,6-naphthyridin-2(1H)-one dihydrochloride monohydrate and 64 ml of pyridine was added dropwise with stirring 2.9 ml of methanesulfonyl chloride and the reaction mixture was stirred for about 30 minutes. The reaction mixture was concentrated on a rotary evaporator and to the residual oily material was added water whereupon a solid separated and then dissolved. To the solution was added about 10 ml of acetic acid and the mixture allowed to stand overnight. The solution was concentrated on a rotary evaporator and to the residue was added ethanol whereupon on standing crystallization resulted. The crystalline material was collected, washed with ethanol and dried in a vacuum oven at 90° C. to yield 6.0 g of 5-(3-methanesulfonylaminophenyl)-1,6-naphthyridin-2(1H)-one monohydrochloride, m.p. 258° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[O:28][CH3:29])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:32])=[CH:12][C:13]([CH3:31])([CH3:30])[NH:14]2.[OH-].[Na+].C(OCC)(=O)C>C(O)C.[Zn]>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([O:28][CH3:29])=[C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:33]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:34])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:31])([CH3:30])[CH:12]=[C:11]3[CH3:32])[CH:24]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 110 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-5-nitrophenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 14-48, 100.4 mg, 0.217 mmol) was dissolved in 4N aqueous NaOH solution (405 μL, 1.62 mmol)—ethanol (5 mL), and zinc (292.9 mg, 4.48 mmol) was added thereto, and then the reaction mixture was stirred at 110° C. overnight. Ethyl acetate (20 mL) was added to the reaction mixture and the unsoluble materials were filtered. After ethyl acetate (50 mL) was added to the filtrate, the whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (12.1 mg) as a yellow amorphous product. (Yield 13%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.I[C:17]1[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a vial containing ethyl 5-chloroindole-2-carboxylate (1.50 g, 6.70 mmol), were added 3-iodobenzotrifluoride (1.16 mL, 8.10 mmol), potassium phosphate (2.98 g, 14.1 mmol), copper iodide (64.0 mg, 0.34 mmol), and 1,2-trans-N,N′-dimethylcyclohexane diamine (0.211 mL, 1.33 mmol), and the mixture was purged with N2. Anhydrous toluene (degassed via N2-sparge, 6.7 mL) was added, and the reaction vial was capped and placed in a pre-heated (110° C.) oil bath. The mixture was stirred vigorously for 18 h, then was allowed to cool to room temperature. The reaction mixture was filtered, rinsing with ethyl acetate, and the filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30%, then 30 to 100% hexanes in ethyl acetate) afforded the title compound: LCMS C, tr=2.86 min, m/z 368.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.25 (dd, J=9.0, 2.0 Hz, 1H), 6.97 (d, J=9.0 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H), 1.22 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH:15]=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH:17]=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>C(#N)C>[CH:8]1[C:7]2[C:12](=[C:13]([CH:15]=[O:16])[C:14]3[C:5]([C:6]=2[CH:17]=[O:18])=[CH:4][CH:3]=[CH:2][CH:1]=3)[CH:11]=[CH:10][CH:9]=1
Reactant: O=CC1c2ccccc2C(C=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1c2ccccc2c(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 240 mg. of the product of Example 2 (prepared as described) in 15 ml. of acetonitrile is added a solution of 0.30 ml. of triethylamine in 5 ml. of acetonitrile. The reaction mixture is stirred at room temperature for 4 hours then is cooled in an ice bath. The precipitate is collected by filtration to give 136 mg. of the desired crude product as orange crystals, mp. 224°-228° C.