Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:49]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:48]=1)[C:38]([O:40][C@H:41]([CH3:45])[C@H:42](O)[CH3:43])=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:49]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:48]=1)[C:38]([O:40][C@H:41]([CH3:45])[C@H:42]([O:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[CH3:43])=[O:39])=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: C[C@@H](O)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of benzoic acid (0.57 g, 4.8 mmol) in anhydrous dichloromethane was added triethylamine (1.7 mL, 12 mmol), and 2,4,6-trichlorobenzoyl chloride (0.9 mL, 5.76 mmol) were added. The resulting mixture was stirred for 30 min and a solution of (1R,2R)-2-hydroxy-1-methylpropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (2.4 g, 4.4 mmol) in dichloromethane was slowly added to the reaction mixture, followed by the addition of a catalytic amount of 4-(dimethylamino)pyridine. The resulting mixture was stirred at room temperature for 16 hrs, washed with 10% citric acid, dried over Na2SO4, and concentrated. Chromatography (silica gel, 20% ethyl acetate in hexane) of the residue afforded 2.6 g (90%) of (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate. 1H NMR (400 MHz, CDCl3): δ 1.26 (d, J=6.4 Hz, 6H), 1.39 (s, 9H), 2.78 (m, 1H), 2.96 (m, 1H), 4.51 (m, 1H), 4.89 (d, 1H), 5.10 (s, 4H), 5.15 (m, 1H), 6.57 (d, J=8 Hz, 1H), 6.71 (s, 1H), 6.77 (d, J=8 Hz, 1H), 7.25-7.43 (m, 12H), 7.52 (t, J=7.6 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([N:24](COCC[Si](C)(C)C)[S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]#[C:10][C:11]#[N:12])=[CH:4][CH:3]=1.Cl>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]#[C:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: CCC(C#CC#N)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: Cl
Solvent: CCO
Product: CCC(C#CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step D (15 mg, 0.028 mmol, enantiomer A) in EtOH (2 mL) was added 2N HCl (0.5 mL). The mixture was stirred at 50° C. overnight. The volatile was removed under reduced pressure and the residue was purified by Combiflash (Mobile phase: MeOH/H2O (0.08% of NH4HCO3) to obtain the title compound. LC/MS m/z=412.1 [M+H]+. 1H NMR (400 MHz, CDC13) δ• •7.53 (d, J=3.6 Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.01 (t, J=8.0 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.70 (d, J=3.6 Hz, 1H), 6.62 (br, 1H), 3.04 (s, 3H), 2.80-2.76 (m, 1H), 2.52-2.48 (m, 1H), 1.05 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12)C1C=CC=CC=1.[CH2:37]([N:44]([CH2:75][CH2:76]O)[C:45]([C:47]1[C:52]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:51]([OH:61])[N:50]=[C:49]([CH2:62][C:63]2([C:68]3[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=3)[CH2:67][CH2:66][CH2:65][CH2:64]2)[N:48]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([N:44]1[CH2:75][CH2:76][N:48]2[C:49]([CH2:62][C:63]3([C:68]4[CH:69]=[CH:70][C:71]([Cl:74])=[CH:72][CH:73]=4)[CH2:64][CH2:65][CH2:66][CH2:67]3)=[N:50][C:51](=[O:61])[C:52]([O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[C:47]2[C:45]1=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)Cc1ccccc1
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c21
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1Cc1ccccc1

Procedure:
This compound was prepared following the same method as described for pure 9-Benzyloxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (348) from N-benzyl-5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)pyrimidine-4-carboxamide (507).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1.[Sn:28](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27]([Sn:28]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:25]=[N:24]2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(-n2cccn2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 38.9 %

Procedure:
2,2,6,6-Tetramethylpiperidine (TMP, 0.25 g, 1.78 mmol) was dissolved in dry THF (10 ml) in a flask with a magnetic stirrer bar. The flask was flushed with argon and kept under an inert atmosphere. The mixture was cooled to −78° C., and n-BuLi (1.1 ml, 1.6M, 1.78 mmol) was added dropwise during 1 minute. The mixture was stirred for 5 minutes at this temperature, before adding a solution of 1-(4-chloro-phenyl)-1H-pyrazole (0.21 g, 1.1 mmol) in dry THF (2 ml). The solution was added dropwise over 2 minutes, and the obtained solution was stirred at this temperature for 20 minutes, before adding Bu3SnCl (0.36 g, 1.1 mmol) over 1 minute. The solution was allowed to slowly warm to RT and was then quenched with MeOH (1 ml). The residual mixture was partitioned between EtOAc and water, and the organic phase was dried and concentrated. Purification on silica afforded 0.2 g (40%) of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[N:8][CH:7]=2>CC(O)=O.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][N:4]=1)[CH2:7][NH:8][CH2:9][CH2:10]2
Reactant: COc1cc2ccncc2cn1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COc1cc2c(cn1)CNCC2

Procedure:
Crude 3-methoxy-2,7-naphthyridine (prepared from 4.4 mmol of 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde) was hydrogenated (30 psi pressure) at RT over PtO2 (approx. 0.1 g) in HOAc (25 mL) for 2.5 h. The solution was filtered through a Celite pad and the clear filtrate was concentrated by freeze-drying to give crude 6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine as the acetate salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:26](=[O:27])[O:28][CH3:29])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCNc1cccc(Br)c1)c1ccccc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)N(CCC(=O)c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 280.7 %

Procedure:
To the solution of 3-(3-bromophenylamino)-1-phenylpropan-1-one (0.03 mol) in anhydrous THF (30 mL) was added K2CO3 (0.06 mol) and methyl chloroformate (0.033 mol) at 0° C. under N2 atmosphere. Then the reaction mixture was stirred at rt for 2 h. The resulting mixture was filtered and the filtrate was concentrated. The residue was washed with H2O, 1N HCl and brine and then extracted with EtOAc. The combined organic layers were concentrated to give crude product, which was purified by column chromatography to afford methyl 3-bromophenyl(3-oxo-3-phenylpropyl)carbamate (30.5 g, 95%). 1H NMR (400 MHz, CDCl3): δ=3.22 (m, 2H), 3.62 (s, 3H), 4.02 (m, 2H), 7.05-7.20 (m, 2H), 7.3-7.5 (m, 4H), 7.8 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)nn3)CC2)c(C)c1
Yield: 34.7 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and 1-methylimidazolidin-2-one (68 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (62 mg) was obtained.
Reaction SMILES: FC(F)(F)CC(O[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])=O.[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:64])[C:38]([CH3:63])([C:40]([NH:42][C@H:43]([C:47]([N:49]([C@@H:51]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:52]([O:57][CH3:58])[CH2:53][C:54]([OH:56])=[O:55])[CH3:50])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[CH:29]1[C:30]2[CH:31]([CH2:33][O:34][C:35]([N:37]([CH3:64])[C:38]([CH3:63])([C:40]([NH:42][C@H:43]([C:47]([N:49]([C@@H:51]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:52]([O:57][CH3:58])[CH2:53][C:54](=[O:56])[O:55][C:7]3[C:8]([F:17])=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=3[F:13])[CH3:50])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:41])[CH3:39])=[O:36])[C:32]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: O=C(CC(F)(F)F)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Yield: 98.3 %

Procedure:
Pentafluorophenyl 3,3,3-trifluoropropanoate (2.44 mL, 13.4 mmol, 2.0 eq.) was added to a solution of #128 (4.18 g, 6.70 mmol, 1.0 eq.) in 50 mL of dichloromethane followed by pyridine (1.61 mL, 20.1 mmol, 3.0 eq.). Reaction was allowed to stir at room temperature for -12 hours. Reaction was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-70% acetone in heptanes) producing #135 (5.2 g, 98%) as a white foam. LC-MS (Protocol Q1): m/z 812.1 [M+Na+] retention time=1.24 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[C:20]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>>[NH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([OH:24])=[O:23])=[C:20]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1

Procedure:
Trifluoroacetic acid 3.0 mL solution of the obtained tert-butyl 4-(4-(aminosulfonyl)phenyl)-2-(4-fluoroanilino)benzoate was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-(4-(aminosulfonyl)phenyl)-2-(4-fluoroanilino)benzoic acid 20 mg of a pale yellow solid.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27].Cl.[Cl-].[Na+]>C1COCC1>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27]
Reactant: COCCOCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Temperature: 65 °C

Procedure:
6-(4-(2-Methoxy-ethoxymethoxy)-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (7.5 g) was added to a mixed solvent of THF (300 ml) and 1M HCl (aq). The mixture was heated to 65° C. until the full disappearance of all starting material. After adding saturated sodium chloride solution (200 ml), the mixture was extracted with ethyl acetate (300 ml×3), and the combined organic layers were then dried over sodium sulphate, solvent was removed under reduces pressure, and the residue was triturated in ether. Product, 6-(4-hydroxy-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (5.9 g) was collected by filtration.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:12][OH:13].C([O-])(O)=O.[Na+]>>[OH:13][NH:12][C:1](=[NH:2])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1
Reactant: NO
Reactant: C=Cc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=Cc1ccc(C(=N)NO)cc1

Procedure:
4-Cyanostyrene is transformed to the corresponding hydroxyamidine according to literature procedures using hydroxylamine hydrochloride and NaHCO3 as base (e.g. E. Meyer, A. C. Joussef, H. Gallardo, Synthesis 2003, 899-905); LC-MS: tR=0.55 min; [M+H]+=163.04; 1H NMR (D4-methanol): δ 4.86 (s br, 3H), 5.30 (d, J=11.0 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 6.77 (dd, J=17.6, 10.8 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].Cl.[C:21]([O:25][C:26](=[O:39])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:39])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:17](=[O:19])[C@H:15]([CH3:16])[NH:14][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Reactant: CCCCCSC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: Cl
Product: CCCCCSC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OCC

Procedure:
Following the general procedure of Example 27, the title compound was prepared as a colorless oil from 700 mg of the β-isomer of N-[(R)-1-ethoxycarbonyl-2-pentylthioethyl]-alanine prepared in Reference Example 30 and 730 mg of the hydrochloride of (S)-prolyl-(S)-proline t-butyl ester prepared in Reference Example 28. Yield 930 mg.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:10]1[CH2:14][CH:13]=[CH:12][C:11]1=[O:15]>C(Cl)Cl>[CH2:3]([N:2]([CH:13]1[CH2:14][O:10][C:11](=[O:15])[CH2:12]1)[CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CCO1
Reactant: CNCc1ccccc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
23.20 ml of N-methylbenzylamine are added to 15.00 g of 5H-furan-2-one in 150 ml methylene chloride. The reaction mixture is stirred for about 48 hours at ambient temperature. For working up the reaction mixture is concentrated by evaporation and chromatographed in batches over a silica gel column with ethyl acetate/petroleum ether (3:1) as eluant. The desired product is obtained as a yellowish oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[NH:14]1[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]1>>[CH2:1]([O:5][C:6]1[N:7]=[CH:8][N:9]=[C:10]([N:14]2[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]2)[C:11]=1[F:12])[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: C1=CCNCC1
Product: CC#CCOc1ncnc(N2CC=CCC2)c1F
Reaction time: 3 h
Yield: 101.4 %

Procedure:
0.2 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine and 0.25 g of 1,2,3,6-tetrahydropyridine were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.25 g of 1-(6-(2-butynyloxy)-5-fluoropyrimidin-4-yl)-1,2,3,6-tetrahydropyridine (hereinafter, referred to as Compound (53)).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:40]=[CH:39][C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:24][CH2:25][C:26]4[CH:38]=[CH:37][C:29]5[C:30]([O:33][CH2:34][O:35][CH3:36])=[N:31][O:32][C:28]=5[CH:27]=4)=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:18]=3)=[O:12])=[C:9]([OH:41])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:48]([O:54][CH2:55]Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50].O>CN(C)C=O.C(OCC)(=O)C>[C:48]([O:54][CH2:55][O:22][C:21](=[O:23])[CH2:20][CH2:19][C:17]1[CH:18]=[C:13]([C:11](=[O:12])[C:10]2[CH:39]=[CH:40][C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:8][C:9]=2[OH:41])[CH:14]=[CH:15][C:16]=1[O:24][CH2:25][C:26]1[CH:38]=[CH:37][C:29]2[C:30]([O:33][CH2:34][O:35][CH3:36])=[N:31][O:32][C:28]=2[CH:27]=1)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COCOc1noc2cc(COc3ccc(C(=O)c4ccc(OC5CCCC5)cc4O)cc3CCC(=O)O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1noc2cc(COc3ccc(C(=O)c4ccc(OC5CCCC5)cc4O)cc3CCC(=O)OCOC(=O)C(C)(C)C)ccc12
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.04 g of 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoic acid and 512 mg of potassium carbonate were suspended in 10 mL of N,N-dimethylformamide, to which 0.29 mL of chloromethyl pivalate was added, and this mixture was stirred for 2 hours at 40° C. Then, water and ethyl acetate were added to the reaction mixture, and the organic phase was separated therefrom. The remaining aqueous phase was extracted with ethyl acetate, and organic phases were combined together. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:1] to yield 1.02 g of {[3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoyl]oxy}methyl pivalate as light yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[C:10]2/[C:11](=O)[CH2:12][CH2:13][C:14]3[C:19]/2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:24][OH:25].N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:24]\[OH:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(/C=C2/C(=O)CCc3ccccc32)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one (50 mg, 0.16 mmol) and hydroxylamine hydrochloride salt (22 mg, 0.32 mmol) was added into pyridine (2.0 ml) and then stirred overnight at reflux condition. Cooled to room temperature, dichloromethane (40 ml) was added, washed twice using 2 N hydrochloric acid (40 ml) and again washed twice using the saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was made to solid by adding diisopropylether and n-hexane, filtrated and dried. As a result, 36.7 mg of the present compound (productive yield 70%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:1][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 4-hydroxy-2-nitroaniline (3.08 g, 20.0 mmol) in DMF (30 mL) was added NaH (60% oily, 880 mg, 22.0 mmol) followed by 1-fluoro-4-nitrobenzene (2.33 mL, 22.0 mmol). The mixture was stirred at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (4.56 g, 83%): MS m/e 274 (M−1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH:20]([CH3:28])[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:28])[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)C=CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 6 h
Yield: 7.3 %

Procedure:
In a reactor, 100 ml of ethanol was charged and 95.3 g (0.375 mole) of 4-(4-trifluoromethylphenoxy)phenol, 85.4 g (0.412 mole) of ethyl 4-bromo-2-pentenoate and 39.0 g (0.281 mole) of potassium carbonate were added. The mixture was refluxed with stirring for 6 hours to react them. Ethanol was distilled off and 100 ml of chlorobenzene and 100 ml of water were added and the mixture was stirred at the room temperature for 30 minutes. The water phase was separated and the organic phase was washed with 5% hydrochloric acid and with water and then, chlorobenzene, ethyl 4-bromo-2-pentenoate and low boiling by-products were distilled off under a reduced pressure to obtain 10.47 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoate. The yield was 73.5%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14](=S)[NH:13][C:12]3=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCO.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14](=[N:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:13][C:12]3=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1NC(=NCc2ccccc2)SC1=Cc1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
5-Benzo[1,3]dioxol-5-ylmethylene-2-thioxo-thiazolidin-4-one (100 mg, 0.37 mmol) were dissolved in EtOH/water, followed by 60 mg of Na2CO3. The reaction was stirred for 30 min and benzylamine (122 μl, 3 eq.) was added. The reaction mixture was refluxed for 2 h. and the solvents were evaporated. The crude was purified by Parallel Flex chromatography.