Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH:12]1[C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[CH:24]=1)=[O:19])=O)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[F:29][C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([CH:18]([CH:12]3[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][NH:11]3)[OH:19])=[CH:24][C:23]=2[CH:25]=1
Reactant: CN1CCN(C(=O)OCc2ccccc2)C(C(=O)c2cc3cc(F)ccc3o2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCNC(C(O)c2cc3cc(F)ccc3o2)C1
Yield: 90 %

Procedure:
(RS)-2-[1-(5-Fluoro-benzofuran-2-yl)methanoyl]-4-methyl-piperazine-1-carboxylic acid benzyl ester, D50 (0.65 g, 1.6 mmol) in ethyl acetate (20 ml) and methanol (20 ml) was hydrogenated at NTP over 10% Pd—C (0.47 g, 50% w/w paste in water) for 3.5 h. The reaction mixture was filtered through Kieselguhr, washing well with methanol and the filtrate evaporated to afford the title product (0.41 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12](=[O:20])[O:13][C:14]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10]=2[C:9]2[C@@H:8]([OH:21])[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]=2[N:3]=1.N1C(C)=CC=CC=1C.[C:32]([Si:36](OS(C(F)(F)F)(=O)=O)([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[Si:36]([O:21][C@H:8]1[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]2[N:3]=[C:2]([Cl:1])[C:11]3[C:12](=[O:20])[O:13][C:14]4([CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:10]=3[C:9]1=2)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O)C1)C1(CCOCC1)OC3=O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.69 g (S)-4-chloro-9-hydroxy-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one are dissolved in 60 ml tetrahydrofurane and cooled to 0° C., 2.05 ml 2,6-lutidine and 3.71 ml trifluoromethanesulfonic acid-tert.-butyldimethylsilylester are added dropwise and the mixture is stirred for further 18 hours while warming to room temperature. Then the reaction is quenched by addition of 0.5 ml methanol. The mixture is partitioned between 0.1 M hydrochloric acid and ethylacetate. The aqueous phase is twice extracted with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 70:30).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH3:11]>C(O)C>[CH3:11][C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: Nc1ccccn1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2ccccc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-aminopyridine (9.4 g), chloroacetone (9.5 ml), and ethanol (25 ml) was heated and stirred for 5 hours on an oil bath at 100° C. After that, the reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate-aqueous potassium carbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to a column chromatography using NH silica gel with 20 to 30% ethyl acetate/hexane to yield the title compound (5.5 g).
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:11][CH:10]1[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]2[O:13][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: Fc1cccc(Cl)c1Cl
Product: Cc1cc2c(o1)CN(C)CCC2Oc1cccc(Cl)c1Cl

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [N:1]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][CH2:26][C@H:2]1[C:3]([NH:5][C@H:6]([C:12]([NH:14][CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10])=[O:4].[H][H]>CO.[Pd]>[N:1]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][CH2:26][C@H:2]1[C:3]([NH:5][C@H:6]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10])=[O:4]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)O

Procedure:
Boc-Pro-Gln-Gly-OBzl (4.0g, 8.2 m mol) was dissolved in 90% methanol (60 ml), and hydrogen gas was passed through the solution in the presence of a spoonful of Pd-C for 6 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was solidified by the addition of ether and recrystallized from methanol-ether.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][C:9]=1[N:21]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:7])(C)(C)C.[ClH:39].O1CCOCC1>ClCCl>[ClH:39].[CH2:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([N:21]([C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])[C:9]2[CH:10]=[C:11]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:12]=[CH:13][C:8]=2[C:6]([OH:7])=[O:5])[CH2:23][CH2:24]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)N1CCC(N(C(=O)C(F)(F)F)c2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(N(C(=O)C(F)(F)F)c2cc(N3CCN(C)CC3)ccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
ethyl 4-{[2-(tert-butoxycarbonyl)-5-(4-methylpiperazin-1-yl)phenyl](trifluoroacetyl)amino}piperidine-1-carboxylate (2.15 g, 3.960 mmol) was dissolved in dry dichloromethane (8 mL) under nitrogen atmosphere. A 4 M solution of HCl in dioxane (9.9 mL, 39.6 mmol, 10 eq) was then added dropwise and the mixture was stirred at room temperature. After 5 hours 5 more equivalents of HCl were added and the reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and stripped twice with DCM. It was then taken up with DCM/dioxane 1:3 and slurried for 1 hour. The solid was filtered, washed with ether and dried under vacuum at 50° C. for 1 hour. 1.78 g of title compound were obtained as a beige powder (86% yield).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Si:20]([O:27][CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:29][CH:30]=[O:31])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C1COCC1>[Si:20]([O:27][CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:29][CH:30]([OH:31])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(CC=O)O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CC(CCCCCCC/C=C\C/C=C\CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: 45 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
A suspension of Mg (165 mg, 6.77 mmol) in THF (1 mL) was treated with a solution of linoleyl bromide (2.03 g, 6.15 mmol) in THF (1.5 mL) in one portion. The suspension was heated (45° C.) and stirred (4 h). The newly generated Grignard was then treated with a solution of (11Z,14Z)-3-((tert-butyldimethylsilyl)oxy)icosa-11,14-dienal (5) (2.0 g, 4.73 mmol) in THF (8 mL) and stirred (2 h). The reaction mixture was quenched by the addition of H2O, extracted with ether, washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was subjected to chromatography (2%→3% EtOAc-hexanes) to yield (6Z,9Z,29Z,32Z)-21-((tert-butyldimethylsilyl)oxy)octatriaconta-6,9,29,32-tetraen-19-ol (6)(2.44 g, 77%) as a pale yellow oil. Rf 0.59 (10% EtOAc-hexanes), FW 673.22, C44H84O2Si.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=C[C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].IC.[H-].[Na+].C(OCC)(=O)C.[CH3:34][N:35]([CH:37]=O)[CH3:36]>O>[CH3:34][N:35]([CH3:36])[C:37]1[CH:7]=[C:4]([CH:3]=[CH:2][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:21])[F:22])=[N:11]1)[C:5]#[N:6]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C)c1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(I)ccnc21
Reaction time: 1 h

Procedure:
Compound (158a) (0.100 g) and iodomethane (0.18 mL) were dissolved in DMF (6.0 mL), and sodium hydride (0.038 g, a 55% dispersion in paraffin liquid) was added to the resulting solution under ice cooling, followed by stirring for 1 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away to obtain 3-(dimethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. This 3-(dimethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (3.0 mL), and a hydrogen peroxide solution (30 wt %) (0.060 mL) and a 4 mol % aqueous sodium hydroxide solution (0.15 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and dried under reduced pressure to obtain 3-(dimethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide. Lastly, according to Example 99(2), compound (159) (0.025 g, the third stage yield: 17%) was prepared using 3-(dimethylamino)-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide instead of compound (99a).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:5]([O:7]C(C)(C)C)=[O:6])CO.[NH2:19][C:20]1[CH:21]=[C:22]([Cl:31])[C:23]([CH3:30])=[C:24]([S:26]([OH:29])(=[O:28])=[O:27])[CH:25]=1.ClC(Cl)(O[C:36](=[O:42])[O:37][C:38](Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:31][C:22]1[CH:21]=[C:20]([NH:19][C:36]([O:37][CH2:38][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])=[O:42])[CH:25]=[C:24]([S:26]([OH:29])(=[O:27])=[O:28])[C:23]=1[CH3:30]
Reactant: Cc1c(Cl)cc(N)cc1S(=O)(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(NC(=O)OC[C@H](N)C(=O)O)cc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Ser-OtBu, 100 mg (0.38 mmol), 86 mg (0.38 mmol) of 5-amino-3-chloro-2-methylbenzenesulfonic acid and 37 mg (0.0127 mmol) of triphosgene were suspended in 1 ml of methylene chloride, and 66 μl (0.76 mmol) of DIEA was added to the suspension. After stirring at room temperature overnight, the solvent was removed by distillation. The mixture was purified according to the purification step A to give the protected title compound. The protected product obtained was dissolved in 2 ml of trifluoroacetic acid and stirred for 2 hours. The solvent was then removed by distillation and the mixture was purified according to the purification step A to give the title compound.
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH2:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.CN(C1C=CC=CN=1)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([O:1][C:2]1([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH2:6][C:5](=[O:7])[CH:4]=[C:3]1[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)(=[O:32])[CH3:31]
Reactant: Cc1cccc(C2(O)CC(=O)C=C2c2ccncc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=O)OC1(c2cccc(C)c2)CC(=O)C=C1c1ccncc1
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-3-pyridine-4-yl-4-m-tolyl-cyclopent-2-en-1-one and it's regioisomer (265 mg, 1.0 mmole) in methylene chloride (5 mL) was added dimethylamino pyridine (183 mg, 1.5 mmole) and acetic anhydride (0.12 mL, 1.2 mmole) at r.t. The reaction mixture was stirred at that temperature for 1 hr before quenching the reaction with 1 mL of methanol. Concentration and purification (silica, hexane/ethyl acetate) gave the title compound as the faster eluting isomer. MS (m/z): Calcd. C19H17NO3(M+): 307, found (M+H)+: 308.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[C:16]([CH3:23])[NH:15][C:14]3=O)[CH2:3][CH2:2]1.S(Cl)([Cl:27])=O.N>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[C:16]([CH3:23])[N:15]=[C:14]3[Cl:27])[CH2:3][CH2:2]1
Reactant: COc1cc2nc(C)[nH]c(=O)c2cc1OCCCN1CCOCC1
Reactant: O=S(Cl)Cl
Agent: N
Solvent: CN(C)C=O
Product: COc1cc2nc(C)nc(Cl)c2cc1OCCCN1CCOCC1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A mixture of 6-(3-morpholinopropoxy)-7-methoxy-2-methylquinazolin-4(3H)-one (600 mg), thionyl chloride (20 mL) and DMF (0.5 mL) was refluxed for 3 h. The reaction mixture was attained to rt and poured into ice cold water and stirred for 10 min. The solution was basified with ammonia solution and extracted with chloroform (3×100 mL). The combined CHCl3 layer was washed water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as a yellow color solid (500 mg, 79%), mp 116-118° C. 1H NMR (400 MHz, CDCl3): δ 7.36 (1H, s), 7.25 (1H, s), 4.25 (2H, t, J=6.6 Hz), 4.03 (3H, s), 3.73 (4H, t, J=4.6 Hz), 2.79 (3H, s), 2.58 (2H, t, J=7.2 Hz), 2.49 (4H, t, J=4.4 Hz), 2.12 (2H, pentet, J=6.8 Hz); LC-MS (positive ion mode): m/z 352, 354 (M+H)±.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[CH3:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[F:21][C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]([F:23])=[CH:25][CH:26]=1)=[O:35])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4])([F:22])[CH3:20]
Reactant: CC(F)(F)c1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(F)(F)c1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol (0.40 g, 1.42 mmol) in acetonitrile (10 ml) were added 4-fluoronaphthalene-1-carboxylic acid (0.283 g, 1.49 mmol) and 1-hydroxybenzotriazole monohydrate (0.22 g, 1.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.49 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, 2:1) and recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide (0.52 g, 81%) as colorless crystals.
Reaction SMILES: [N:1]#[N:2].C([O:5][C:6](=[O:41])[CH2:7][N:8]([C:13](=[O:40])[C@H:14]([CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])[NH:15][S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[CH:25]=2)[CH:20]=1)(=[O:18])=[O:17])[CH2:9][CH2:10][O:11][CH3:12])C>C(O)C.[OH-].[Na+]>[N:1]#[N:2].[CH3:30][O:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:31][CH3:32])[CH:20]=[C:19]([S:16]([NH:15][C@H:14]([C:13]([N:8]([CH2:9][CH2:10][O:11][CH3:12])[CH2:7][C:6]([OH:41])=[O:5])=[O:40])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])(=[O:18])=[O:17])[CH:28]=[CH:27]2
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Yield: 55.4 %

Procedure:
A solution of 2.5 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 5 ml of ethanol and 7 ml of 1N sodium hydroxide solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml of Daiaion® SK 102 ion exchange resin (200 - 300 mesh, H+ form manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-ethyl ether to give 1.32 g (72 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine as an amorphous solid.
Reaction SMILES: [CH2:1]([N:8]([C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12]O)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O.C(O)C>C(Cl)(Cl)Cl>[ClH:18].[CH2:1]([N:8]([C:10]([CH3:15])([CH2:11][CH2:12][Cl:18])[CH3:14])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(C)(C)CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(Cc1ccccc1)C(C)(C)CCCl
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-(N-benzyl-N-methylamino)-3-methyl-butan-1-ol (6.9 g--Preparation 7), in chloroform (20 ml) was added dropwise over 30 minutes to a solution of thionyl chloride (4.9 ml) in chloroform (20 ml) at 0°. When the addition was complete, the mixture was stirred at room temperature for 18 hours. Ethanol (5 ml) was added and the mixture concentrated in vacuo to give an oil which was crystallized from ethyl acetate to give the title compound as a colourless powder, yield, 2.62 g, m.p. 164°-166°.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:16]=[CH:15][C:10]2[NH:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].CC(O)=O>C1COCC1.O>[O:14]1[C:9]2[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:17])=[O:3])[CH:16]=[CH:15][C:10]=2[NH:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)OCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)OCCN2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-propionic acid ethyl ester (258 mg) in THF (3 mL) and H2O (3 mL) was added NaOH (134 mg) at room temperature. After being stirred for 20 h at room temperature, the reaction mixture was acidified with AcOH (pH=4) and diluted with water. The resulting mixture extracted with dichloromethane and the combined organic layer was dried magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (CH2Cl2:MeOH=15:1) to afford the product as a brown oil. (150 mg, 65.8%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[C:13]([CH3:26])([CH3:25])[CH:14]([CH2:23][CH3:24])[NH:15][C:16](OC(C)(C)C)=[O:17])[CH2:8][CH2:7]1)[CH3:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.[N:44]1([C:50]([C:52]2[CH:60]=[CH:59][C:55](C(O)=O)=[CH:54][CH:53]=2)=[NH:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1C=CC2N(O)N=NC=2C=1>C(N(CC)CC)C>[N:44]1([C:50]([C:52]2[CH:53]=[CH:54][C:55]([C:16]([NH:15][CH:14]([CH2:23][CH3:24])[C:13]([CH3:25])([CH3:26])[C:12]([N:9]3[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH2:7][CH2:8]3)=[O:27])=[O:17])=[CH:59][CH:60]=2)=[NH:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)OC(C)(C)C)CC1
Reactant: N=C(c1ccc(C(=O)O)cc1)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCOCC3)cc2)CC1
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To the obtained N-(N-Boc-βethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid ethyl ester (0.38 g, 0.95 mmol) were added anisole (0.3 ml) and TFA (10 ml) and the mixture was stirred for 1 hour under cooling with ice. After the TFA was distilled off at room temperature, the residue was washed with hexane 3 times and dissolved in DMF (20 ml) under cooling with ice. After the resulting solution was neutralized with triethylamine, 4-(4-morpholinoimidoyl)benzoic acid (0.25 g, 1.05 mmol), HOBT (0.14 g, 1.05 mmol) and WSDC (0.22 g, 1.14 mmol) were added thereto and the mixture was stirred overnight. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed sequentially with a 5% aqueous solution of citric acid, a 5% aqueous solution of sodium hydrogencarbonate and saturated saline 3 times each, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was applied to a silica gel column (2.1 φ×20 cm) and eluted with a mixed solution (chloroform:ethanol=30:1). The desired fractions were collected and the solvents were distilled off to yield a powder of the titled compound (108 mg, 22%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH3:9][I:10]>CC(C)=O>[I-:10].[CH3:1][N+:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: CI
Solvent: CC(C)=O
Product: C[N+]1(C)CCC(=O)CC1
Product: [I-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To 45.0 g (398 mmol) of 1-methyl-piperid-4-one in 500 mL of acetone was added dropwise 60.0 g (423 mmol) of MeI over 1 h. The mixture was stirred for 3 h, cooled to 0° C., and filtered. The solids were washed with cold acetone, and dried to provide 1,1-dimethyl-4-oxo-piperidinium iodide as a pale yellow solid (95.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(O)c(Br)c1
Reaction time: 8 h
Yield: 77.1 %

Procedure:
Methyl 4-hydroxyphenylacetate (10.5 g, 63.0 mmol) was dissolved in acetic acid (200 mL) and the solution was stirred while bromine (150 mL, 0.463 M in acetic acid, 69.5 mmol) was added over 60 minutes. The mixture was stirred overnight and then concentrated by evaporation. Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1) to give methyl 3-bromo-4-hydroxyphenylacetate (11.9 g).