Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)(=[O:15])=[O:14])=[CH:11][C:10]([CH2:23][OH:24])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[C:7]([N:8]2[C:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)(=[O:15])=[O:14])=[CH:11][C:10]([CH:23]=[O:24])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(S(=O)(=O)c2cc(CO)nn2-c2cccnc2F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1cccc(S(=O)(=O)c2cc(C=O)nn2-c2cccnc2F)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
{1-(2-Fluoropyridin-3-yl)-5-[(3-methylphenyl)sulfonyl]-1H-pyrazol-3-yl}methanol (320 mg) was dissolved in toluene (5 mL), manganese dioxide (802 mg) was added, and the mixture was stirred at 90° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield 266 mg, yield 83%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[CH2:35]([O:42][C:43]([NH:45][C@H:46]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:47](O)=[O:48])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[CH2:35]([O:42][C:43]([NH:45][C@H:46]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:47]([O:9][C@@H:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)=[O:48])=[O:44])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.4 %

Procedure:
(R)-quinuclidin-3-ol (214 mg, 1.68 mmol), N,N′-methanediylidenedicyclohexanamine (347 mg, 1.68 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (227 mg, 1.68 mmol) were added to a solution of (R)-2-(benzyloxycarbonylamino)-2-phenylacetic acid (400 mg, 1.40 mmol) in THF (15 ml). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. DCM was added, and the insoluble solid was removed by filtration. The organic phase was washed twice with Na2CO3 and brine, dried over Na2SO4 and evaporated. The crude was purified by silica gel flash chromatography (DCM/MeOH=9/1) to obtain (R)—((R)-quinuclidin-3-yl) 2-(benzyloxycarbonylamino)-2-phenylacetate (63 mg; 11.4% yield). ((R)-quinuclidin-3-yl 2-(benzyloxycarbonylamino)-2-phenylacetate is also collected (300 mg; 54.2% yield)).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:23]([C:34](O)=[O:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>C1COCC1.CO>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C@H:23]([CH2:34][OH:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1CO
Temperature: 0 °C
Reaction time: 27 h
Yield: 49 %

Procedure:
(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 53; 0.250 g, 0.511 mmol) was dissolved in THF (5.0 mL) and the mixture was cooled to 0° C. BH3—SMe2 (0.242 mL, 2.55 mmol) was added and the mixture was warmed to ambient temperature and stirred for 27 hours. The reaction was quenched with MeOH (2 mL) and concentrated. The residue was taken up in EtOAc (30 mL), water (5 mL) and a saturated aqueous Na2CO3 solution (5 mL). The layers were mixed and separated and the aqueous phase washed once with CH2Cl2 (10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. During concentration a precipitate formed which was slurried in MeOH, isolated by filtration and washed with Et2O to give 0.119 g (49%) of the desired product as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[C:6]([CH3:14])=[C:5]2[OH:15].[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17]>>[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH:8]=[C:7]([CH:12]=[O:13])[C:6]=2[CH3:14])=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: CCS(=O)(=O)c1ccc(F)cc1
Reactant: Cc1c(C=O)cc2ccc(F)cc2c1O
Product: CCS(=O)(=O)c1ccc(Oc2c(C)c(C=O)cc3ccc(F)cc23)cc1

Procedure:
Starting with 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carbaldehyde (115 mg, 0.6 mmol) and 1-ethanesulfonyl-4-fluoro-benzene (226 mg, 1.2 mmol), using a method analogous to the one described for the methyl ester of example 1-1,4-(4-ethanesulfonyl-phenoxy)-6-fluoro-3-methyl-naphthalene-2-carbaldehyde (120 mg, 57%) was obtained as a yellow solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 8.32 (s, 1H), 8.07 (dd, J=8.97, 5.68 Hz, 1H), 7.84 (d, J=9.09 Hz, 2H), 7.33-7.45 (m, 2H), 6.94 (d, J=8.84 Hz, 2H), 3.12 (q, J=7.41 Hz, 2H), 2.59 (s, 3H), 1.31 (t, J=7.45 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH:8]([CH3:10])[CH3:9].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:14]([O:13][C:12]([NH:11][C@@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])/[CH:5]=[CH:4]/[CH2:3][C:2]([OH:21])=[O:1])=[O:18])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)C[C@@H](/C=C/CCO)NC(=O)OC(C)(C)C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)C[C@@H](/C=C/CC(=O)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (5) (1.00 g, 3.89 mmol) in acetone (40 mL) at 0° C. was added a freshly prepared solution of Jones Reagent (2.5 M, 3.89 mL, 9.71 mmol) and the reaction was stirred at 0° C. for 1 h. The dark solution was extracted with Et2O (3×50 mL), the organic layers washed with water (2×75 mL), brine (1×50 mL), dried (Na2SO4), filtered and concentrated to yield 990 mg (94% crude) of acid (6) as a yellow oil that was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]4[C:17]([CH:18]=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1.[Br:35]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>II.C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]4[C:17]([C:18]([Br:35])=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1
Reactant: c1ccc2cc(-c3ccc4ccc(-c5c6ccccc6cc6ccccc56)cc4c3)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1c2ccccc2c(-c2ccc3ccc(-c4ccc5ccccc5c4)cc3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Under the nitrogen atmosphere, 9-([2,2′-binaphthalen]-7-yl) anthracene (10.0 g) as the ninth intermediate compound, N-bromosuccinimide (NBS) (4.6 g), iodine (0.1 g), and THF (60 ml) were added to a flask and stirred overnight at room temperature. By adding an aqueous solution of sodium thiosulfate, the reaction was terminated. Liquid separation was performed by adding water and toluene. Subsequently, the solid obtained by distillation of the organic layer under reduced pressure was purified by silica gel column chromatography (solvent: toluene). The solid obtained by distillation of the solvent under reduced pressure was washed with heptane to give 9-([2,2′-binaphthalen]-7-yl)-10-bromoanthracene (11.0 g) as a tenth intermediate compound. The scheme is shown in the following “Reaction 15”.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.B.C(N)(C)(C)C>CO>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: B
Solvent: CC(C)(C)N
Solvent: CO
Product: O=c1[nH]c2ccccc2n1C1CCN([C@H]2CC[C@H](O)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,3-dihydro-1-{1-[4-oxocyclohex-1-yl]piperidin-4-yl}-2H-benzimidazol-2-one (100 mg) in methanol (4 mL) at 0° C., under nitrogen, was added tert-butylamine-borane (28 mg). The reaction mixture was stirred at 0° C. for 1 h, then quenched with water (2 mL) and concentrated to remove the methanol. The resulting oil was dissolved in ethyl acetate (50 mL) and the organic solution was washed with saturated sodium carbonate (10 mL), then water (10 mL), then brine (10 mL) and then dried over sodium sulfate. Concentration under reduced pressure yielded trans-1,3-dihydro-1-{1-[4-hydroxycyclohex-1-yl]piperidin-4-yl}-2H-benzimidazol-2-one (75 mg) as a colorless solid: 1H NMR (400 MHz, CD3 OD) 7.42 (m, 1H), 7.04 (m, 3H), 4.28 (m, 1H), 3.50 (m, 1H), 3.09 (m, 2H), 2.45 (m, 5H), 2.03-1.94 (m, 4H), 1.78-1.75 (m, 2H), 1.44-1.26 (m, 4H). The hydrochloride salt was precipitated from diethyl ether/chloroform: analysis calculated for C18H25N3O2.HCl.0.50 H2O.0.70 CHCl3C: 50.54, H: 6.28, N: 9.45; found C: 50.54, H: 6.19, N: 9.64.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13]>C(N(CC)CC)C.O.[Cu]I.Cl[Pd]Cl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:13][C:12]#[C:11][OH:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: C#CCO
Reactant: CC(=O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc(CC#CO)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A suspension of 3 g (15.1 mmol) of 2-acetyl-6-bromopyridine, 0.89 g (15.9 mmol) of propargyl alcohol, 0.078 g of CuI, 300 mg of PdCl2 (P (Ph)3)2 in 60 ml of triethylamine was stirred under nitrogen at room temperature for 6 h. The mixture was diluted with water, extracted with ether, and the organic layer was washed with water (2×), brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was purified by MPLC (silica gel 60, hexane/ethyl acetate, 1:1) to afford 1.3 g (50%) of 2-acetyl-6-(3-hydroxy-2-propynyl)pyridine, as a solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2([CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=3)[O:16]2)[CH2:12][CH2:11]1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2([CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)=[O:29])[CH:21]=3)[O:16]2)[CH2:12][CH2:11]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3F)CC1)O2
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3F)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-[2-(2-Fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (165 mg, 0.370 mmol) was suspended in DCM (5 ml). TEA (0.075 ml, 0.54 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(2-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (163 mg) as a yellow solid. The compound was then dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving the hydroxamic acid as a light yellow solid (103 mg, hydrochloride salt).
Reaction SMILES: [Mg].II.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.CN(C)[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16]>O1CCCC1.COC(C)(C)C>[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16]
Reactant: Fc1ccccc1CCl
Reactant: CN(C)C(=O)C1CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(Cc1ccccc1F)C1CC1

Procedure:
A 1000 ml round-bottomed flask is filled with magnesium (10.7 g, 0.44 mol). Iodine (0.2 g) is sublimated to the magnesium, then tert-butyl methyl ether (240 ml) is added and under boiling, a solution of 2-fluorobenzyl chloride (47.8 ml, 0.4 mol) and tert-butyl methyl ether (80 ml) is added to the reaction mixture. The mixture is refluxed for 2 hours and at this temperature a solution of cyclopropanecarboxylic acid dimethylamide (36.2 g, 0.32 mol), prepared according to example 1, and tetrahydrofuran (200 ml) are added. The reaction mixture is stirred for half an hour and under cooling aqueous hydrogen chloride (160 ml, 1:1) is added dropwise to the mixture. The organic layer is dried and the residue is fractionated in vacuo.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].COCCN(S(F)(F)[F:29])CCOC.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:29][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCCO)COC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1[C@@H](CCCF)COC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (3.05 g) in chloroform (40 mL) was cooled in a dry ice-acetone bath, bis(2-methoxyethyl)aminosulfur trifluoride (2.77 mL) was added thereto, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the organic layer was washed with water and brine, followed by drying with anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=10:1-2:1) to afford tert-butyl (4S)-4-(3-fluoropropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (900 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]>OC(CCC=CC)CC(OC)=O>[O:1]=[C:2]([CH2:8][CH2:9][CH:10]=[CH:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCC(O)CC(=O)OC
Agent: CC=CCCC(O)CC(=O)OC
Product: CC=CCCC(=O)CC(=O)OC

Procedure:
The hydrogenation of methyl acetoacetate results in methyl 3-hydroxybutanoate; the hydrogenation of methyl 3-oxovalerate results in methyl 3-hydroxypentanoate; and the hydrogenation of methyl 3-oxo-6-octenoate results in a mixture of methyl 3-hydroxyoctanoate and methyl 3-hydroxy-6-octenoate.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(F)c3)c(=O)n12
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3cccc(F)c3)c(=O)n12
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.037 g, 0.11 mmol) in tetrahydrofuran (0.3 mL) and water (0.0811 mL) was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.13 mmol) at room temperature and stirred for 1 hour. To the mixture was added EtOAc and was extracted twice with 1N HCl. The combined extracts were neutralized with solid sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step (31 mg, 90.9%). LCMS calculated for C15H15FN3OS (M+H)+: m/z=304.1. Found: 304.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH2:26][CH3:27].CN(C=O)C>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:25][CH2:26][CH3:27])[CH:9]1[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 93 %

Procedure:
A solution of benzyl 3-[(tert-butoxycarbonyl)amino]azetidine-1-carboxylate obtained in Example (227a) (472 mg, 1.54 mmol) in THF (5 mL) was added to a suspension of sodium hydride (55%) (134 mg, 3.08 mmol) in THF (10 mL) at 0° C. Subsequently, propyl iodide (0.75 mL, 7.70 mmol) was added at 0° C., and the mixture was stirred at room temperature for 70 minutes. THF (4 mL) and DMF (5 mL) were added, followed by further stirring for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Thereafter, the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 499 mg of the title compound as a colorless oily substance (93%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].O.[BrH:19]>>[Br:19][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
To a mixture of 3-amino-5-nitro-benzoic acid (8.0 g) in 48% aqueous HBr (90 ml) at 0° C. was added sodium nitrite (4.0 g) over 15 minutes. The resulting solution of diazonium salt was added to CuBr (4.0 g) in 48% HBr (10 ml) at 60–70° C. at such a rate to maintain the temperature at 60–70° C. After completion of the addition, the mixture was warmed to 70° C. for 45 minutes. The mixture was cooled to room temperature, water (500 ml) was added and the product was extracted into ether (3×). The combined extracts were washed with water (2×), dried over sodium sulfate and evaporated to give a beige solid, 10.53 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:22]([C:15]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[CH3:13])(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)N2CCCC2c2ccc(F)cc2)c(C)c1

Procedure:
The title compound, white solid, m.p. 111° C. and MS: m/e=347 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2,4,6-trimethyl-benzenesulfonyl chloride.
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[CH3:25][C:26]1([CH3:37])[O:30][C:29]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[CH:34][C:28]=2[O:27]1.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH:48][CH2:35][C:33]2[CH:32]=[CH:31][C:29]3[O:30][C:26]([CH3:37])([CH3:25])[O:27][C:28]=3[CH:34]=2)[CH:42]=[CH:43][C:44]=1[Cl:45]
Reactant: CC1(C)Oc2ccc(C=O)cc2O1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)Oc2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2O1

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 83 mg of 2,2-dimethyl-benzo[1,3]dioxole-5-carbaldehyde (0.47 mmol) (described in example S119), 89 mg of 2-(3,4-dichloro-phenyl)-ethylamine (0.47 mmol) and 26 mg of sodium borohydride (0.70 mmol). The isolated colorless liquid (133 mg, 81%) was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.66 (s, 6H), 2.76 (m, 2H), 2.86 (m, 2H), 3.68 (s, 2H), 6.66 (s, 1H), 6.68 (d, J=7.4 Hz, 2H), 7.04 (dd, J=8.2 and 2.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([CH2:17][NH:18][C:19](=[O:34])[O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12]2)=[O:4].CO.COCCOC.Cl>[OH-].[Na+]>[C:3]([CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([CH2:17][NH:18][C:19](=[O:34])[O:20][CH:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12]2)([OH:4])=[O:2]
Reactant: COC(=O)COc1cccc2c1CCC(CNC(=O)OC(c1ccccc1)c1ccccc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: O=C(O)COc1cccc2c1CCC(CNC(=O)OC(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of benzhydryl N-[[1,2,3,4-tetrahydro-5-(methoxycarbonylmethoxy)-2-naphthyl]methyl]carbamate (60 mg) in a mixture of 1N sodium hydroxide aqueous solution (0.20 ml), methanol (1 ml), and 1,2-dimethoxyethane (1 ml) was stirred at room temperature for 30 minutes, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was powdered from diisopropyl ether to afford benzhydryl N-[[1,2,3,4-tetrahydro-5-(carboxymethoxy)-2-naphthyl]methyl]carbamate (51 mg) as a colorless powder. mp: 160°-161° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:26])([F:25])[C:5]1[CH:24]=[CH:23][C:8]2[NH:9][C:10]([S:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=3)=[O:13])=[N:11][C:7]=2[CH:6]=1.[Na].FC(F)(F)C1C=CC2NC(S(CC3C=C(OC)C=CN=3)=O)=NC=2C=1.[Cl-].[Ca+2:53].[Cl-]>O1CCOCC1.O>[Ca:53].[F:26][C:4]([F:3])([F:25])[C:5]1[CH:24]=[CH:23][C:8]2[NH:9][C:10]([S:12]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=3)=[O:13])=[N:11][C:7]=2[CH:6]=1
Reactant: [Ca+2]
Agent: COc1ccnc(CS(=O)c2nc3cc(C(F)(F)F)ccc3[nH]2)c1
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Product: [Ca]

Procedure:
0.09 g (0.003 mole) of 80% sodium hydride (in paraffin) are added to a solution of 1.1 g of 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)-sulfinyl]-(1H)-benzimidazole in 20 ml of dry dioxan under an inert gas atmosphere. After the evolution of gas has subsided, the solvent is stripped off in vacuo. The residue (5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)-sulfinyl]-(1H)-benzimidazole sodium salt) is dissolved in a little water, and a 1% strength aqueous calcium chloride solution is added. The precipitate which has separated out is filtered off with suction and dried in a high-vacuum for several hours. M.p. 176° C. (decomposition).