Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=3)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[F:56][C:57]1[CH:86]=[CH:85][C:60]([CH2:61][O:62][C:63]2([OH:84])[C:73](OCC3C=CC(F)=CC=3)([OH:74])[CH:72]=[CH:71][C:65](/[CH:66]=[CH:67]/[C:68]([OH:70])=[O:69])=[CH:64]2)=[CH:59][CH:58]=1>>[F:56][C:57]1[CH:86]=[CH:85][C:60]([CH2:61][O:62][C:63]2([OH:84])[C:68]([O:69][CH2:61][C:60]3[CH:85]=[CH:86][C:57]([F:56])=[CH:58][CH:59]=3)([OH:70])[CH:67]=[CH:66][C:65](/[CH:71]=[CH:72]/[C:73]([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=3)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:74])=[CH:64]2)=[CH:59][CH:58]=1
Reactant: O=C(O)/C=C/C1=CC(O)(OCc2ccc(F)cc2)C(O)(OCc2ccc(F)cc2)C=C1
Reactant: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1O
Product: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)/C=C/C2=CC(O)(OCc3ccc(F)cc3)C(O)(OCc3ccc(F)cc3)C=C2)cc1O

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-3-hydroxy-4-methoxyaniline (565 mg, 0.8 mmol, example 109, step A) as described for example 109 (step B) using 3,4-di-(4-fluorobenzyloxy)caffeic acid (459 mg, 1.2 mmol) instead of N-(4-fluorobenzyl)indole-2-carboxylic acid. The crude material was purified by flash chromatography using successively 15%, 20% and 30% EtOAc/CH2Cl2 as the eluent. The title compound was obtained as white crystals (250 mg, 37%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:19])[O:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][O:9]1.O.[OH-].[Na+]>CCOCC>[CH3:7][C:8]1([CH3:19])[O:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][O:9]1
Reactant: CCOC(=O)C1COC(C)(C)OC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)OCC(CO)CO1
Reaction time: 16 h
Yield: 86.8 %

Procedure:
Lithium aluminum hydride (80 g) is stirred in ether (2000 ml) while the product of Example 3 (230 g) in ether (250 ml) is added dropwise. When the addition is complete the mixture is stirred an additional 16 hours. The reaction mixture is decomposed by careful addition of water (80 ml) followed by 15% aqueous sodium hydroxide (80 ml) and additional water (240 ml). The resulting suspension is filtered, the filter cake washed with ethanol and ether and the combined filtrates evaporated to give a residue. Distillation of the residue gives the title product (155 g) (81%) B.P. 75° C. (0.05 mm).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([NH:13][CH2:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[NH2:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([CH2:14][NH:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(CNc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Next, to a solution of lithium aluminum hydride (0.91 g, 24 mmol) in tetrahydrofuran (60 mL) was added a solution of the resulting 4-phenylaminomethyl-benzonitrile (2.0 g, 9.61 mmol) in tetrahydrofuran (5 mL), and the solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (1.98 g, 97%) as a yellow oil. This compound was used in the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[CH2:16][C:17]3([CH3:22])[O:21][CH2:20][CH2:19][O:18]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([O:26]CC)=[O:25].[OH-].[Li+]>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[CH2:16][C:17]3([CH3:22])[O:21][CH2:20][CH2:19][O:18]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1cc2cc(NC(=O)CC3(C)OCCO3)ccc2n1Cc1ccccc1F
Agent: [Li+]
Agent: [OH-]
Product: CC1(CC(=O)Nc2ccc3c(c2)cc(C(=O)O)n3Cc2ccccc2F)OCCO1

Procedure:
Preparation analogously to Example XXII using 234 mg (0.63 mmol) of ethyl 1-(2-fluorobenzyl)-5-{[(2-methyl-1,3-dioxolan-2-yl)acetyl]amino}-1H-indole-2-carboxylate from Example XXXVIII and 0.53 ml (1.06 mmol) of lithium hydroxide solution.
Reaction SMILES: [CH2:1]([N:8]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:44]([NH2:56])[CH:43]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH2:32])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:63][S:64](Cl)(=[O:66])=[O:65]>O>[CH2:1]([N:8]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[C:44]([NH:56][S:64]([CH3:63])(=[O:66])=[O:65])[CH:43]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:32][S:64]([CH3:63])(=[O:66])=[O:65])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(CCN(CCCCCCN(CCc2ccc(OCc3ccccc3)c(N)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(CCN(CCCCCCN(CCc2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 7.5 g. (0.01 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylene-diamine in 30 ml. of pyridine is added 2.5 g. of methanesulfonyl chloride. The reaction mixture is allowed to stand at room temperature overnight and is then added to excess water to yield N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-methanesulfonamidophenyl)-ethyl]-hexamethylenediamine.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[CH:11]=2)=[CH:4][C:3]=1[CH3:19].C[OH:21]>>[OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[CH:11]=2)=[O:21])=[CH:4][C:3]=1[CH3:19]
Reactant: CO
Reactant: Cc1cc(Cc2cc(C)c(O)c(C)c2)cc(C)c1O
Product: Cc1cc(C(=O)c2cc(C)c(O)c(C)c2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 20 ml methanol was dissolved 500 mg/2.0 mmol of bis(4-hydroxy-3,5-dimethylphenyl)methane, and 886 mg/4.0 mmol of dicyanodichloroquinone was added to the solution at once in a stream of argon. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and the insoluble matter was separated by filtration and re-concentrated. The resulting crude product was purified by silica gel column chromatography using methylene chloride for the eluting solution to obtain 230 mg of the desired 4,4'-dihydroxy-3,3',5,5'-tetramethylbenzophenone. MS: 270 (M+), 1H-NMR (CDCl3 /DMSO-d6): δ2.29 (12H, s), 7.41 (4H, s), 7.96 (2H, s).
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)#[N:13]>CC(C)=O>[CH2:21]([O:20][C:18]([C:17]1[CH:23]=[CH:24][C:14]([C:12]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:13]=2)=[CH:15][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Reactant: CCOC(=O)c1nsc(=O)o1
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2nc(C(=O)OCC)ns2)cc1
Yield: 23.5 %

Procedure:
A solution of 1.75 g (0.010 mol) of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate and 17.5 g (0.10 mol) of ethyl p-cyanobenzoate was stirred at 190° C for 72 hours, cooled, and dissolved in acetone. Gc analysis of the solution revealed that the product had formed in 53% yield. Concentration of the solution to 90° C (0.1 torr) and two crystallizations of the residue from ethanol (charcoal) at -20° C gave 0.72 g (23.5%) of beige solid, mp 66°-67.5° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: C1CCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCCCC1
Yield: 89 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and piperidine gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a white solid (232 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 3.74 (s, 3H), 3.18-3.12 (m, 4H), 1.74-1.63 (m, 6H)
Reaction SMILES: [C:1]([C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])#[CH:2].Br[C:12]1[CH:13]=[C:14]([CH:18]([OH:22])[CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=1>>[OH:22][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:2]#[C:1][C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])[CH:13]=1)[CH2:19][C:20]#[N:21]
Reactant: N#CCC(O)c1cccc(Br)c1
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(C(O)CC#N)c1)CCC

Procedure:
Coupling of 4-ethynylheptan-4-ol with 3-(3-bromophenyl)-3-hydroxypropanenitrile following the method described in Example 12 gives 3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propanenitrile as a light yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](I)[CH:20]=[C:19]([Cl:24])[N:18]=1.[C@@H]1(N)CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:21]3[CH:20]=[C:19]([Cl:24])[N:18]=[C:17]([Cl:16])[CH:22]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc(Cl)nc(Cl)c2)CCN1c1cnccc1C1CC1
Yield: 93 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 500 mg, 2.4630 mmol) was reacted with 2,6-dichloro-4-iodopyridine (810 mg, 2.9556 mmol), copper iodide (47 mg, 0.2463 mmol), trans-cyclohexane-1,2-diamine (0.089 mL, 0.7389 mmol), potassium phosphate (1.56 g, 7.3891 mmol) and 1,4-dioxane (10 mL) to afford crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 800 mg of pure product (93.02% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[N:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: Brc1cnc(I)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2ncc(Br)cn2)CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 41.9 %

Procedure:
5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was aged for 15 minutes prior to dropwise addition of tetrahydro-4H-pyran-4-one (0.77 g, 7.72 mmol). The reaction was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over magnesium sulphate and filtered, then the solvent was removed under reduced pressure. The resulting crude orange oil (1.91 g) was absorbed onto a 50 g KP-Sil column, and eluted with 10-100% ethyl acetate in heptanes on a Biotage Isolera 4, to afford the title compound (762 mg, 42%) as a yellow oil. δH (500 MHz, CDCl3) 8.79 (s, 2H), 4.24 (s, 1H), 3.99-3.89 (m, 4H), 2.37 (td, J 12.3, 11.6, 6.3 Hz, 2H), 1.54 (dd, J 13.6, 2.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[C:33]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[C:33]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][NH:41][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:21][CH:20]=2)=[O:18])=[CH:37][CH:38]=1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(-c5ccccc5)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (50 mg, 0.133 mmol) in dichloromethane (1 ml) and a drop of DMF was added oxalyl chloride (2M in dichloromethane) (72.985 μL, 0.145 mmol) at ambient temperature. Gas evolution was observed. The mixture was stirred at ambient temperature for 30 minutes. 2-(Biphenyl-4-yl)ethanamine (27.488 mg, 0.139 mmol) and triethylamine (36.992 μL, 0.265 mmol) were added and the mixture was stirred for 1 hour at ambient temperature. The crude mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 62.5 mg of the title compound as a solid (85%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>N1C=CC=CC=1>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: COC(=O)c1c(N)ccc2c1CCCC2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])ccc2c1CCCC2
Reaction time: 24 h
Yield: 65.8 %

Procedure:
A solution of Example 418A (4.74 g, 23.09 mmol) in pyridine (46 mL) was treated with 2-nitrobenzenesulfonyl chloride (5.37 g, 24.25 mmol), stirred 24 hours, concentrated, diluted with ethyl acetate (150 mL), washed with 1N HCl (2×100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography (3:1 hexanes/ethyl acetate) to provide the desired product (5.93 g, 66%). MS (ESI(+)) m/e 408 (M+NH4)+; MS (ESI(−)) m/e 389 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.98 (d, 1H), 7.87 (m, 1H), 7.81 (m, 2H), 7.12 (d, 1H), 6.92 (d, 1H), 3.60 (s, 3H), 2.70 (m, 2H), 2.53 (m, 2H), 1.67 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][N:10]=[C:11]2[CH3:12]
Reactant: CC(=O)NCCc1ccccc1Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2c(Br)cccc21

Procedure:
In close analogy to the procedure described above, N-[2-(2-bromo-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.O.C([O:13][C:14](=[O:46])[CH2:15][CH:16]([C:29](=[O:45])[N:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[CH2:31][CH3:32])[CH:17]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([OH:20])=[O:19])(C)(C)C>C(Cl)Cl>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:35]=[CH:34][C:33]([N:30]([CH2:31][CH3:32])[C:29]([CH:16]([CH2:15][C:14]([OH:46])=[O:13])[CH:17]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]([OH:20])=[O:19])=[O:45])=[CH:38][CH:37]=1
Reactant: CCN(C(=O)C(CC(=O)OC(C)(C)C)C(CCc1ccccc1)C(=O)O)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCN(C(=O)C(CC(=O)O)C(CCc1ccccc1)C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of TFA (30%) in DCM (5 mL) containing water (5%) was added the compound of Example 55. The reaction mixture was stirred for 2 h at room temperature, after which time, the solvent was removed. The residue was triturated with ether and evaporated. The residue was partitioned between sodium hydroxide (1N) and ether. Following separation, the alkaline phase was acidified to pH 1 using HCl (1N) and extracted with ethyl acetate. The recombined organic layer was dried over sodium sulfate, filtered and evaporated. FAB: 460.1(MH+), FAB(M−H+): 458.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1F)[N:15]=[CH:14][C:13]([C:20]#[N:21])=[C:12]2[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:27][CH2:26][CH2:25][O:24][CH3:23])[N:15]=[CH:14][C:13]([C:20]#[N:21])=[C:12]2[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnc2cc(F)c(OCc3ccccc3)cc2c1O
Reactant: COCCO
Product: COCCOc1cc2ncc(C#N)c(O)c2cc1OCc1ccccc1
Yield: 86 %

Procedure:
Following the procedure used to prepare Reference Example 6, reaction of 6-benzyloxy-4-hydroxy-7-fluoro-3-quinolinecarbonitrile and 2-methoxyethanol provides 6-benzyloxy-4-hydroxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile in 86% yield, mp>250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.[N:40]1([C:44](=O)[CH2:45]Cl)[CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:44][CH2:45][O:39][C:38]2[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[CH:16]3[CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=4[CH2:17]3)=[CH:3][C:2]=2[F:1])[CH2:43][CH2:42][CH2:41]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCC3)c(F)c2)C(C)C)c1
Yield: 45.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azetidin-1-yl-2-chloroethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([OH:29])=O)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH2:44])[CH3:40].C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH:44][C:27](=[O:29])[C@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:17][C:15](=[O:16])[C@H:12]([CH2:13][OH:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:40]
Reactant: CCOC(=O)CN
Reactant: O=C(N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1

Procedure:
To a stirred mixture consisting of 4.82 g. of N-benzyloxycarbonyl-L-seryl-L-tyrosine, 1.519 g. of N-hydroxysuccinimide, 1.675 g. of glycine ethyl ester hydrochloride, and 60 ml. of N,N-dimethylformamide, cooled to -15° C., is added first 1.68 ml. of triethylamine and then 2.48 g. of dicyclohexylcarbodiimide, and the resulting mixture is stirred at -15° C. for 2 hours and at room temperature for 25 hours. The mixture is then concentrated to remove solvent, and the residue is partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer is separated, washed with saturated aqueous sodium chloride, with saturated aqueous sodium bicarbonate, and with saturated aqueous sodium chloride again, dried, and evaporated to give a solid residue of N-benzyloxycarbonyl-L-seryl-L-tyrosylglycine ethyl ester; m.p. 166°-169° C., following crystallization from ethyl acetate; [α]D25 -23.2° (2% in methanol).
Reaction SMILES: CN1CCOCC1.[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH2:23][C:24](O)=[O:25])[C:13](=[O:27])[CH:12]1[CH:28]([CH3:30])[CH3:29])(=[O:10])[CH3:9].ClC(OCC(C)C)=O.Cl.[NH2:40][C@@H:41]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:42]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[OH:43]>O1CCCC1.CS(C)=O.O>[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH2:23][C:24]([NH:40][C@@H:41]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:42]([C:44]2[S:45][CH:46]=[CH:47][N:48]=2)[OH:43])=[O:25])[C:13](=[O:27])[CH:12]1[CH:28]([CH3:30])[CH3:29])(=[O:10])[CH3:9]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)O)C(=O)C1C(C)C
Reactant: N[C@@H](Cc1ccccc1)C(O)c1nccs1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)c2nccs2)C(=O)C1C(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
N-Methylmorpholine (66.4 μl) is added to a solution of {(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetic acid (162 mg, Reference compound No. 51-1) in tetrahydrofuran (2.5 ml). The mixture is cooled to −10° C., isobutyl chloroformate (65.4 μl) is added to the mixture, and the whole is stirred for 15 minutes. A mixed solution of (1RS,2S)-2-amino-3-phenyl-1-(1,3-thiazol-2-yl)-1-propanol hydrochloride (150 mg, Reference compound No. 10-2) and N-methylmorpholine (132.6 μl) in tetrahydrofuran (2.5 ml) and dimethyl sulfoxide (1 ml) is added thereto, and the whole is stirred overnight. Water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with an aqueous sodium hydrogencarbonate solution, water and saturated brine successively and dried over magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to give the titled compound (162.9 mg).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.Br[CH2:27][CH2:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:30].O>C1C=CC=CC=1>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH:32]2[CH2:33][C:34](=[O:37])[CH2:35][CH:36]3[N:31]2[C:29](=[O:30])[CH2:28][CH2:27]3)=[CH:39][CH:40]=1
Reactant: O=C1C=CN(C(=O)CCBr)C(c2ccc(F)cc2)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Solvent: O
Product: O=C1CC2CCC(=O)N2C(c2ccc(F)cc2)C1
Reaction time: 3 h

Procedure:
A solution of tributyltin hydride (3.88 mL) and 2,2′-azobis(isobutyronitrile) (0.56 g) in benzene (25 mL) was added dropwise to a solution of 1-(3-bromopropionyl)-2-(4-fluorophenyl)-2,3-dihydro-1H-pyridin-4-one obtained above (2.9 g) in benzene (60 mL) at 90° C. over four hours. The reaction solution was stirred at the same temperature for three hours. The reaction solution was returned to room temperature and poured into water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 600 mg of the title compound. The property values of the compound are as follows.