Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(NCC)C.C1COCC1>[CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:20][N:6]([CH2:7][CH3:8])[CH2:5][CH3:1])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(OC[C@@H](O)CN(CC)CC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (from intermediate A3) in 1 mL of diethylamine and 2 mL of THF was stirred at 76° C. for 1 h in a microwave reactor. Upon completion (determined by LC/MS), the reaction was evaporated in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 96% EtOAc/(2M NH3/MeOH) as an eluent to afford (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:5]=2[CH:6]=[O:7])[CH2:3][CH2:2]1.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[CH:1]1([C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[C:5]=2[C:6]([OH:21])=[O:7])[CH2:3][CH2:2]1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 2-cyclopropyl-4,6-bis-trifluoromethyl-benzaldehyde (intermediate AM, 1.01 g, 3.58 mmol) was dissolved in 8.5 mL tert-butylalcohol and 4.5 mL 2-methyl-2-butene. At 0° C. a solution of sodium chlorite (340 mg, 3.76 mmol) and sodium dihydrogenphosphat (451 mg, 3.76 mmol) in 3 mL water was added. The reaction mixture was stirred at room temperature overnight. The solvents were evaporated off. The residue was taken up in 1N NaOH and extracted twice with tert-butyl methyl ether. The aqueous phase was adjusted to pH 2 by addition of 25% HCl and extracted twice with tert-butyl methyl ether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude material, off-white solid (1.01 g, 54%) was used without further purification.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16])C1C=CC=CC=1.[H][H]>C1COCC1.CCO.[Pd]>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[N:12][C:11]=1[CH2:10][CH2:9][OH:8]
Reactant: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCO
Yield: 60.2 %

Procedure:
A solution of {4-[4-(2-benzyloxy-ethyl)-5-methyl-oxazol-2-yl]-phenyl}-methyl-phenyl-amine (195 mg, 0.490 mmol) in THF (2 mL) and EtOH (10 mL) was treated a slurry of Pd/C (200 mg) in EtOH (2 mL). The resulting mixture was treated with hydrogen under balloon pressure for 14 h and filtered through a pad of Celite. The filtrate was concentrated, and crude product was purified by silica gel chromatography column (50% EtOAc/hexanes) to yield the title compound (91 mg, 60%).
Reaction SMILES: C[Si](I)(C)C.C[O:7][CH2:8][C@H:9]([CH3:38])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[CH:36][O:35][N:34]=3)=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]>C(#N)C.C(OCC)(=O)C>[OH:7][CH2:8][C@H:9]([CH3:38])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[CH:36][O:35][N:34]=3)=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(-c3ncon3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2ccc(-c3ncon3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
Trimethylsilyl iodide (0.062 mL, 0.434 mmol) was added to a solution of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(1,2,4-oxadiazol-3-yl)phenoxy]benzamide (78 mg, 0.174 mmol) in acetonitrile (2 mL) and the reaction mixture allowed to stir at RT for 18 hours. The reaction was diluted with ethyl acetate (15 mL) and quenched by the addition of saturated aqueous sodium bicarbonate (20 mL). The organic phase was washed with saturated aqueous thiosulphate solution (20 mL) and dried (MgSO4). The volatiles were removed under reduced pressure and the resulting oil purified by chromatography on silica, eluting with 0-100% ethyl acetate in iso-hexane, to give the title compound as a colourless solid (64 mg).
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]#[N:8])=[CH:5][CH:6]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[CH3:9][C:10]1([CH3:24])[O:11][C:12](=[O:23])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:2]3[O:3][C:4]([C:7]#[N:8])=[CH:5][CH:6]=3)=[CH:16][C:15]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1ccc(Br)o1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)o3)cc21

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile was prepared, according to the procedure of Example 5 from 2-bromo-5-cyanofuran (1.0 g, 5.6 mmol) (J. Med. Chem. (1997), 40(23), 3804-3819) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.8 g, 8.18 mmol), as a white solid (0.39 g, 1.45 mmol, 17%): mp 257-260° C.; 1H-NMR (DMSO-d6) δ10.48 (s, 1H), 7.73-7.70 (m, 3H), 7.19 (d, 1H, J=3.8 Hz), 6.98 (d, 1H, J=8.9 Hz), 1.66 (s, 6H); MS ((+)−APCI) m/z=269 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2].[Cu][C:28]#[N:29]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]#[N:29])[C:9]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2cc(-c3cccc(C(F)(F)F)c3)sc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C#N)c2cc(-c3cccc(C(F)(F)F)c3)sc2c1O
Temperature: 135 °C
Yield: 51 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-(3-trifluoromethyl-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 25.a, 108 mg, 0.24 mmol) and copper(I) cyanide (45 mg, 0.5 mmol) suspended in 1 mL DMF was heated at 135° C. for 15 minutes in a CEM microwave reactor. The resultant mixture was partitioned between ethyl acetate and water, and the organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to a crude residue. The desired product was purified by column chromatography eluting from silica gel with a gradient of 10-60% ethyl acetate in hexanes to give 48 mg of a white solid; MS: (+) m/z 392.9 (M+1)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[N:12]=[C:13]([O:15][C:16]3[CH:27]=[CH:26][C:19]([O:20][CH:21]([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[S:14][C:10]=2[CH:9]=1.Cl[CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O>[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[N:12]=[C:13]([O:15][C:16]3[CH:27]=[CH:26][C:19]([O:20][CH:21]([CH3:25])[C:22]([O:24][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:23])=[CH:18][CH:17]=3)[S:14][C:10]=2[CH:9]=1
Reactant: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)O
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)OC[Si](C)(C)C
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
2.9 g of potassium carbonate are added to a solution of 6.2 g (0.179 mole) of the R-enantiomer of 2-{4-[(6-chloro-2-benzothiazolyl)-oxy]-phenoxy}-propionic acid in 20 ml of dimethylformamide. After the mixture has been stirred at 50° C. for 15 minutes, 2.7 g (0.021 mole) of chloromethyltrimethylsilane are added dropwise at this temperature. The mixture is then subsequently stirred at 80° C. for 2 hours. It is then worked up by stripping off the solvent under reduced pressure, adding water to the residue and extracting the resulting oily product with 100 ml of toluene. The organic phase is washed successively with aqueous sodium carbonate solution and with water, dried and concentrated under reduced pressure. 7 g (89% of theory) of the R-enantiomer of trimethylsilyl-methyl 2-{4-[(6-chloro-2-benzothiazolyl)-oxy]-phenoxy}-propionate are obtained in this manner in the form of a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[N:3]=1.ClC1C=CC=C(C(O)=O)N=1.S(Cl)(Cl)=O.[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])[CH:30]=[C:29]([C:43]([F:46])([F:45])[F:44])[C:27]=1[NH2:28]>>[Br:25][C:26]1[CH:32]=[C:31]([C:33]([F:42])([C:34]([F:36])([F:37])[F:35])[C:38]([F:39])([F:41])[F:40])[CH:30]=[C:29]([C:43]([F:44])([F:45])[F:46])[C:27]=1[NH:28][C:8](=[O:9])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)c1cccc(Cl)n1
Agent: O=C(O)c1cccc(Cl)n1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc(Cl)n1

Procedure:
According to the method of 1-3 of Example 1, a target compound was prepared from 2-chloropyridine-6-carboxylic acid chloride prepared from 2-chloropyridine-6-carboxylic acid and thionyl chloride, and 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline obtained in 1-2 of Example 1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:26])[CH:14]3[NH:18]C(OC(C)(C)C)=O)[C:11]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:26])[CH:14]3[NH2:18])[C:11]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Yield: 96.8 %

Procedure:
A solution of 3-(2-acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (6.06 g) in acetonitrile (100 cc) is stirred with methanesulphonic acid (6 cc) for 30 minutes at 20° C., then diluted with ethyl acetate (200 cc) and stirred with a saturated sodium bicarbonate solution (300 cc). The aqueous layer is extracted with ethyl acetate (100 cc) and the combined organic solutions are washed with a half-saturated sodium chloride solution (2×250 cc), then dried over magnesium sulphate, and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 3-(2-Acetamido-thiazol-5-yl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.9 g) is obtained in the form of a yellow froth. This product is redissolved in dry tetrahydrofuran (75 cc). The solution, cooled to about 0° C, is treated successively with phenylacetyl chloride (1.54 g) and triethylamine (1.4 cc) and then stirred for 1 hour at between 0° and 4° C. The reaction mixture is diluted with ethyl acetate (100 cc) and a half-saturated sodium bicarbonate solution (200 cc). The organic layer is decanted, washed with water (100 cc) and then with a half-saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up in methylene chloride (25 cc). The precipitate is filtered off and then taken up in boiling acetonitrile (80 cc). After the mixture has cooled, the precipitate is filtered off, washed with acetonitrile (10 cc) and dried under reduced pressure (2 mm Hg; 0.27 kPa) at 25° C. 3-(2-Acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-phenylacetamido-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.65 g) is thus obtained in the form of a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>CCOCC.CO>[CH3:23][C:20]1[N:19]=[CH:18][C:17]([O:16][C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(Oc2cccc([C@H](C)NC(=O)OC(C)(C)C)c2)cn1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(Oc2cccc([C@H](C)N)c2)cn1
Yield: 141.6 %

Procedure:
(S)-{1-[3-(6-Methyl-pyridin-3-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.45 g, 10.52 mmol), hydrogen chloride in ether (36.8 mL, 1.0M) and methanol (5 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo to provide the title compound (3.4 g, quantitative yield) as yellow solid.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([C:30](=[O:39])[CH2:31][C:32]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)=[O:33])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51]([OH:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1>CO>[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([C:30](=[O:39])[CH2:31][C:32]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)=[O:33])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCc1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A solution of 0.390 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-2′-[2-(1-imidazoyl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.143 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 1 hour and evaporated. The residue was triturated with diethyl ether, filtered and dried to give 0.320 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-2′-[2-(1-imidazoyl)acetyl]-2′-isobutyl-4-methylvalerohydrazide p-toluenesulphonate in the form of a pale pink solid.
Reaction SMILES: [CH:1]([OH:14])([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.[F:15][CH2:16][CH2:17]O.S(=O)(=O)(O)O>C(OCC)C>[C:2]1([CH:1]([O:14][CH2:17][CH2:16][F:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCF
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: FCCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a stirred solution of 2.0 grams (0.011 mole) of benzhydrol in 15 ml of diethyl ether was added 4.0 ml (0.068 mole) of 2-fluoroethanol followed by the dropwise addition of 0.5 ml of concentrated sulfuric acid. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with diethyl ether. The organic extract was washed with water followed by an aqueous, saturated sodium bicarbonate solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 2.0 grams of 2-fluoroethyl diphenylmethyl ether as a liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]=[C:13]1[NH:17][C:16](=[O:18])[NH:15][C:14]1=O)([O-])=O.CO.II>CN(C)C=O.[Pd]>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:1]=[C:14]3[NH:15][C:16](=[O:18])[NH:17][C:13]3=[CH:12][C:5]=2[CH:6]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Agent: [Pd]
Agent: II
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Yield: 44 %

Procedure:
A solution of 5-[(2-nitro-5-methoxyphenyl)methylene]-2,4-imidazolidinedione (4.5 g, 17 mmol) in dimethylformamide (120 mL) was hydrogenated over 10% palladium on charcoal (0.45 g) at 60 psi. After 42 hours the mixture was filtered through infusorial earth and the solvent evaporated to leave a brown solid. A mixture of this material and methanol (150 mL) was heated to reflux and iodine (3.65 g, 14 mmol) introduced portionwise over 15 minutes. The reaction mixture was refluxed 45 minutes, cooled and concentrated to 20 mL before adding a solution of sodium thiosulfte (10 g) and sodium carbonate (10 g) in water (200 mL). The precipitate was filtered off, suspended in hot (80° C.) water (200 mL) and filtered. Recrystallization from aqueous dimethylformamide afforded 7-methoxy-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (1.61 g, 43%), m.p.>360° C.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:29])[N:7]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17](CC3C=CC=CC=3)[C:16](=[O:28])[CH:15]=[CH:14]4)[C:8]2=[O:10])[CH2:4][CH2:3]1>CO.[H][H].[OH-].[OH-].[Pd+2]>[OH:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:29])[N:7]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16](=[O:28])[CH:15]=[CH:14]4)[C:8]2=[O:10])[CH2:4][CH2:3]1
Reactant: O=C1[C@@H]2[C@H](O)CCN2C(=O)N1c1ccc2c(ccc(=O)n2Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1[C@@H]2[C@H](O)CCN2C(=O)N1c1ccc2[nH]c(=O)ccc2c1
Yield: 26.7 %

Procedure:
Compound 46E (80 mg, 0.20 mmol) was dissolved in MeOH (5 mL) and hydrogenated at 1 atmosphere of hydrogen for 24 h in the presence of 20 mg Pd(OH)2. The reaction was then filtered, concentrated under reduced pressure, and subsequently purified by silica gel flash chromatography eluting with a gradient of 5%-10% MeOH in CH2Cl2 to give the title compound (16 mg) as a white solid. HPLC: 98% at 0.79 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O-10% MeCN-0.1% TFA and B=10% H2O-90% MeCN-0.1% TFA); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 300 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][C:32](C(OCC)=O)([C:38]([O:40]CC)=[O:39])[C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][CH:32]([C:33]([OH:35])=[O:34])[C:38]([OH:40])=[O:39])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1)(C(=O)OCC)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCC(C(=O)O)C(=O)O)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.3 %

Procedure:
To a solution of triethyl 3-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]-1,1,1-propanetricarboxylate (200 mg) in 1,4-dioxane (9 mL) and water (3 mL) was added lithium hydroxide (100 mg). After stirring the solution at room temperature for 7 hours, water was added thereto and it was concentrated under reduced pressure. Acetic acid (0.14 mL) was added to the residue, and the solution was further concentrated under reduced pressure and to dryness. The residue was purified by chromatography (DIAION HP20 manufactured by Mitubishi Chemical Corporation, methanol) to give the title compound (150 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C@@H:3]([N:11]1[C:20](=[O:21])[C:19]2=[CH:22][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[C:17]3[C:18]2=[C:13]([CH:14]=[CH:15][N:16]=3)[CH2:12]1)[C:4]([O:6]C(C)(C)C)=[O:5].CO.[OH-].[Na+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:34])[C@@H:3]([N:11]1[C:20](=[O:21])[C:19]2=[CH:22][NH:23][C:17]3[C:18]2=[C:13]([CH:14]=[CH:15][N:16]=3)[CH2:12]1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(ccnc42)CN([C@@H](C(=O)OC(C)(C)C)C(C)C)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
A mixture of (R)-tert-Butyl 3-methyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate (840 mg, 1.74 mmol), MeOH (4 mL), and aqueous NaOH (1N, 2 mL) was stirred for 40 min at room temperature. The material was diluted with DCM and washed with brine. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/DCM) gave a yellow oil (390 mg), which dissolved in TFA/DCM (50%) and stirred at room temperature for 1 h. The solution was concentrated and dried under vacuum to give the title compound as a tan solid (320 mg, 67%). 1H NMR (500 MHz, CD3OD) δ 0.88 (d, J=7.0 Hz, 3H), 1.10 (d, J=7.0 Hz, 3H), 2.35-2.44 (m, 1H), 4.95-5.33 (m, 3H), 7.34 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 8.33 (d, J=6.0 Hz, 1H). [M+H] calc'd for C14H15N3O3, 274; found, 274.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Product from Example 140, step 3 (100 mg, 0.26 mmol) was dissolved in 3 ml EtOH, and NaBH4 (7.5 mg, 0.196 mmol) in 1 ml H2O was added and the mixture stirred at rt for 2 h. The mixture was then quenched with 3N NaOH (5 mL) and ether was added to extract the compound, which was dried over anhy. MgSO4 and concentrated to give a yellow oil (90.1 mg, 90.1%)
Reaction SMILES: [F:1][C:2]1C=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:15][C:16]2[C:17]3[NH:13][CH2:8][C:7](=[O:12])[CH2:6][C:5]=3[CH2:4][CH2:9][C:10]=2[CH:11]=1
Reactant: O=C1CCc2cc(F)ccc2C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1CNC2=C(CCc3cc(F)ccc32)C1

Procedure:
16.7 g of 6-fluoro-3,4-dihydro-2(1H)-naphthalenone were boiled at reflux for 2.5 hours in 200 ml of benzene and 8.4 ml of pyrrolidine in the presence of 0.35 g of anhydrous p-toluenesulphonic acid. The crude 1-(6-fluoro-3,4-dihydro-2-naphthyl)pyrrolidine obtained was, without further purification, treated with 10.8 g of acrylamide and 0.5 g of p-toluenesulphonic acid. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. The reaction mixture was dissolved in 180 ml of chloroform and washed with water. The organic phase was filtered over 150 g of silica gel (particle size 0.2-0.5 mm) while eluting with chloroform. After recrystallization from ethyl acetate there was obtained 8-fluoro-1,4,5,6-tetrahydrobenzo[h]quinolin-3(2H)-one of melting point 223°-224°.