Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)OCCO2

Procedure:
To a well-stirred and ice-cooled solution of 1,4-dioxa-8-azaspiro[4.5]decane (34.9 mmol, 5 g) in dichloromethane (200 mL) under an argon atmosphere, was added triethylamine (52.4 mmol, 7.3 mL) and then benzyloxycarbonyl chloride (42 mmol, 5.93 mL) dropwise. The suspension was stirred at room temperature for 24 hours and the precipitated solid was filtered. The organic solution was evaporated under vacuum to give an oily residue which was chromatographed on silica gel eluting with a mixture of ethyl ether and petroleum ether to afford 8-benzyloxycarbonyl 1,4-dioxa-8-azaspiro [4,5] decane in quantitative yield. 1H-NMR (CDCl3): 1.63 (m, 4H); 3.56 (m,4H); 3.89 (s, 4H); 5.09 (s, 2H); 7.28 (s, 5H).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.N[CH:24]([CH2:28][CH3:29])[C:25]([OH:27])=[O:26].[Cl:30][C:31]1[CH:32]=[C:33]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:34][N:35]([CH3:46])[C:36]([C:38]1[CH2:39][N:40](C)[C:41](=[O:44])[C:42]=1[OH:43])=[O:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:34][N:35]([CH3:46])[C:36]([C:38]1[CH2:39][N:40]([CH2:29][CH2:28][CH2:24][C:25]([OH:27])=[O:26])[C:41](=[O:44])[C:42]=1[OH:43])=[O:37]
Reactant: CCC(N)C(=O)O
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Yield: 21 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and -aminobutyric acid as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (42.1 mg, 21% yield). 1H NMR (300 MHz, CDCl3) δ: 7.42 (d, 1H, J=8.05), 7.36 (s, 1H), 7.11 (dd, 1H, J=8.05, J=1.10), 4.60 (s, 2H), 4.21 (s, 2H), 3.58 (t, 2H, J=6.22), 3.03 (s, 3H), 2.40 (t, 2H, J=6.95), 1.96 (t, 2H, J=6.59). HRMS (M−H) calcd for C17H17N2Cl2O5: 399.0514. found: 399.0509.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][C@@H:6]([CH3:17])[CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.CCOC(C)=O>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:17][C@@H:6]1[O:5][S:1](=[O:2])[N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:8][CH2:7]1
Reactant: C[C@H](O)CCNC(=O)OC(C)(C)C
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To a solution of thionyl chloride (192 mL, 2.6 mol) in acetonitrile (1.0 L) at −40° C. is added dropwise a solution of tert-butyl [(3S)-3-hydroxybutyl]carbamate (200 g, 1.1 mol) in acetonitrile (2.5 L). The mixture is stirred for 10 min and 4-dimethylaminopyridine (12.9 g, 105.66 mmol) is added. After stirring for another 10 min, pyridine (427 mL, 5.3 mol) is added over 90 min, keeping the temperature below −40° C. EtOAc is added at −40° C. and the suspension is filtered to remove the solid. To the filtrate is added saturated Na2HPO4 solution and the mixture is stirred vigorously for 30 minutes at room temperature. The organic layer is separated, washed with 1M NaHSO4 solution, dried (Na2SO4) and concentrated to afford the title crude compound (250 g) as an oil which is used in the next step without purification.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:18]=2)[C:13]1=[O:40])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:18]=2)[C:13]1=[O:40]
Reactant: COC(=O)CCCC(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCC(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 20 (0.150 g, 0.274 mmol) was treated with trifluoroacetic acid (1.0 mL) in chloroform (10 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 9.0:1.0, to afford the product 25 (0.092 g, 75%) as a brown solid: mp 215-217° C. IR (KBr) 3075, 1729, 1687, 1673, 1572, 1532, 1433, 1202, 760, 722, 455 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ 10.2 (s, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 7.89 (dd, J=1.8, J=8.7 Hz, 1H), 7.74 (m, 3H), 7.54 (m, 2H), 7.47 (m, 1H), 4.53 (t, J=3.2 Hz, 2H), 3.59 (s, 3H), 2.96 (m, 2H), 2.38 (m, 4H), 2.13 (m, 2H), 1.87 (m, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 190.1, 173.0, 171.0, 162.6, 154.4, 138.3, 136.6, 134.2, 134.0, 131.0, 127.1, 125.8, 123.5, 123.4, 122.6, 116.6, 107.4, 79.1, 51.3, 41.2, 38.6, 36.6, 35.2, 32.6, 27.3, 20.2; ESIMS m/z (relative intensity) 448 (MH+, 100); HRESIMS calcd for C25H25N3O5 448.1867 (MH+). found 448.1877 (MH+); HPLC purity: 100% (1% TFA in MeOH—H2O, 70:30).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Product: OCc1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cc1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 4-(hydroxymethyl)phenylboronic acid was prepared the title compound as a yellow foam, MS (ESI+): m/z=409.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH2:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[OH-].[K+].O>CS(C)=O>[CH2:34]([O:41][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCc6ccccc6)ccn45)cccc32)n1
Temperature: 90 °C
Yield: 94.6 %

Procedure:
A mixture of 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (1.0 g, 2.2 mmol; prepared as in Example 65, step C), benzyl alcohol (1.2 g, 11 mmol) and potassium hydroxide (0.61 g, 11 mmol) was dissolved in DMSO (7 mL). The reaction mixture was heated at 90° C. for 20 hours. The mixture was cooled to ambient temperature, transferred into water (100 mL) with stirring, and the resulting solid was collected by vacuum filtration and dried under vacuum to give the product (1.1 g). MS (ES+APCI) m/z=529.7 (M+H).
Reaction SMILES: N[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[OH:22]>[OH-].[Na+]>[OH:14][C:10]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:22])[C:11]1([CH3:13])[CH3:12]
Reactant: CO
Reactant: CC1(C)C(N)=Nc2ccccc2C1(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C(=O)Nc2ccccc2C1(O)c1ccccc1

Procedure:
A solution of 2-amino-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (5.32 g., 0.02 mole) in methanol (40 ml.) and 2N aqueous sodium hydroxide (20 ml. ) was heated under reflux for 6 hours. The mixture was poured onto water, extracted with chloroform and the combined extracts washed and dried (MgSO4). After removal of the solvent the residue was crystallised from toluene to give the title compound (4.73g., m.p. 185° - 187° C). [Found: C, 76.25, H, 6.6, N, 5.3% C17H17NO2 requires, 76.4, H, 6.4, N, 5.25%].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O1[C:10]2([CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[O:27][CH3:28])[N:23]=[CH:22][NH:21][C:20]4=O)[CH2:12][CH2:11]2)[O:9]CC1.C(N(CC)CC)C.[Cl:37][C:38]1[C:39]([F:45])=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41]>C(#N)C>[Cl:37][C:38]1[C:39]([F:45])=[C:40]([NH:41][C:20]2[C:19]3[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH:13]4[CH2:12][CH2:11][C:10](=[O:9])[CH2:15][CH2:14]4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCC(=O)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
3.25 ml phosphorus oxychloride are added dropwise to 6.50 g 6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-7-methoxy-3H-quinazolin-4-one in 65 ml acetonitrile under an argon atmosphere. Then the reaction mixture is heated to 40° C., combined dropwise with 5.00 ml triethylamine and refluxed for 2 h. After cooling to ambient temperature 1.40 ml triethylamine and 2.60 ml 3-chloro-2-fluoro-aniline, dissolved in 5 ml acetonitrile, are added and the reaction mixture is stirred overnight at 40° C. Then a further 0.70 ml of 3-chloro-2-fluoro-aniline dissolved in 2 ml acetonitrile are added dropwise and the reaction mixture is stirred for a further 10 h. After cooling to ambient temperature the precipitate formed is suction filtered, taken up in 1 N hydrochloric acid, combined with 6 N isopropanolic hydrochloric acid and stirred at ambient temperature until the ketal cleaving is complete. The precipitate formed is suction filtered and combined with methylene chloride and 1 N sodium hydroxide solution. The aqueous phase is separated off and extracted with methylene chloride, the combined extracts are evaporated down and the flask residue is brought to crystallisation with diisopropylether.
Reaction SMILES: [C:1]([C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[C:13]=1[OH:31])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:32]1[CH2:38][C:36](=[O:37])[NH:35][C:33]1=[S:34].C(=O)C1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[C:38]3[S:32][C:33](=[S:34])[NH:35][C:36]3=[O:37])=[CH:20][CH:19]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[C:13]=1[OH:31])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CSC(=S)N1
Reactant: CCCCCCCCCC(=O)c1ccc(OCc2ccc(C=O)cc2)c(CCC)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1
Product: CCCCCCCCCC(=O)c1ccc(OCc2ccc(C=C3SC(=S)NC3=O)cc2)c(CCC)c1O
Yield: 84 %

Procedure:
The 4-[(4-decanoyl-3-hydroxy-2-propylphenoxy)methyl]benzaldehyde thus obtained was coupled with the rhodanine by reacting equimolar amounts of the benzaldehyde and the rhodanine in the presence of sodium acetate and acetic acid as previously described to yield 1.6 g (84%) of the title product. mp 187.5°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Br:26][C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]Br)=[CH:29][CH:28]=1>C(#N)C>[Br-:26].[Br:26][C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33][N+:8]2[CH:9]=[CH:10][N:6]([CH2:5][CH:4]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[C:3]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=3[Cl:1])[CH:7]=2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: BrCCOc1ccc(Br)cc1
Solvent: CC#N
Product: Clc1ccc(COC(Cn2cc[n+](CCOc3ccc(Br)cc3)c2)c2ccc(Cl)cc2Cl)c(Cl)c1
Product: [Br-]

Procedure:
4.2 parts of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazole, 3.1 parts of 2-(p-bromophenoxy)ethyl bromide and 24 parts of acetonitrile are stirred together overnight at reflux temperature to obtain the desired 1-[2-(p-bromophenoxy)ethyl]-3-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazolium bromide product. The product is recovered from the reaction mixture by (a) diluting the latter with diisopropyl ether (b) adding three drops of water to precipitate the product as a crystalline solid, and (c) filtering off the precipitated solid. After purification by recrystallization from a mixture of 4-methyl-2-pentanone and diisopropyl ether, the product has a melting point of 131.5°-132.5° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH:12]1([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[N:22]2[C:26]([CH3:27])=[C:25]([C:28]([OH:30])=O)[N:24]=[N:23]2)[CH2:14][CH2:13]1.[NH2:31][C:32]1[C:33](=[O:45])[N:34]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[N:35]([CH3:38])[C:36]=1[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[CH:39]1([N:34]2[C:33](=[O:45])[C:32]([NH:31][C:28]([C:25]3[N:24]=[N:23][N:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[CH:12]4[CH2:13][CH2:14]4)[C:26]=3[CH3:27])=[O:30])=[C:36]([CH3:37])[N:35]2[CH3:38])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(F)cc1C1CC1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)nnn1-c1ccc(F)cc1C1CC1
Reaction time: 1 h

Procedure:
To a solution of oxalyl chloride (0.055 ml, 0.632 mmol) in DCM (5 ml) was added DMF (0.065 ml, 0.842 mmol) dropwise and the mixture was stirred for 1 hr. The resulting mixture was treated with 1-(2-cyclopropyl-4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (110 mg, 0.421 mmol) and stirring continued at RT for 30 mins. To the reaction mixture was added 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A) (97 mg, 0.463 mmol) followed by triethylamine (0.176 ml, 1.263 mmol) and stirring continued at RT for 30 mins. The resulting mixture was diluted with DCM, washed with water and eluted though a phase separating cartridge. The organic eluent was collected and concentrated under reduced pressure to give a brown oil. The was absorbed onto silica and purified by chromatography eluting with 0-10% MeOH in TBME. The product fractions were combined, concentrated and dried under reduced pressure to give a pale brown glassy solid. The solid was dissolved in DCM, washed with water, brine and eluted through a phase separating cartridge. The organic eluent was concentrated under reduced pressure to give the title compound as a glassy solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C(C1SCCCS1)(OCC)=O.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(Cl)Cl>[C:27]([O:1][CH2:2][CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1)(=[O:31])[C:28]([CH3:30])=[CH2:29]
Reactant: OCC1SCCCS1
Reactant: C=C(C)C(=O)Cl
Agent: CCOC(=O)C1SCCCS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCC1SCCCS1
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a 100-mL three-necked flask, 3.41 g of 2-hydroxymethyl-1,3-dithiane, which had been synthesized in accordance with the method known in the art (see Tetrahedron Letters, 41, 5653-5657 (2000)) using 2-carboethoxy-1,3-dithiane as a starting material, and 2.3 g of triethyl amine were added, and to this mixture 40 mL of dried methylene chloride were added and the resulting mixture was stirred with a stirrer bar coated with Teflon™ at 0° C. under nitrogen atmosphere. To the mixture, 2.3 g of methacryloyl chloride was slowly added through a dropping funnel, and the resulting mixture was reacted at 0° C. for 2 hours, and the temperature of the mixture was allowed to return to room temperature, followed by reacting for another 2 hours. After confirming consumption of the starting material by a thin layer chromatography (TLC), the reaction solution was poured into a 300-mL separatory funnel, washed with 100 mL of water, followed with 100 mL of saturated NaCl solution (brine), and dried with anhydrous sodium sulfate. From the obtained solution, the solvent was removed by an evaporator, to obtain an oily crude product. The crude product was purified by silica gel chromatography using a mixed solution of n-hexane and ethyl acetate to yield 3.64 g of 1,3-dithianylmethyl methacrylate (a dithiane derivative of the following formula 2) (yield: 79.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.ClC1C=CC(S(O[N:31]2[C:35]3[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=3[N:33]=[N:32]2)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][N:31]2[C:35]3[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=3[N:33]=[N:32]2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(On1nnc2ccc(Cl)cc21)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
p-Nitrobenzoic acid (1.67 g) is dissolved in chloroform (20 ml) and thereto are added triethylamine (1.40 ml) under ice-cooling and further 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (3.44 g) at room temperature. When the mixture is stirred at room temperature for 20 minutes, white crystals precipitate, and the mixture is further stirred for 7 hours. The precipitated crystals are separated by filtration to give white crystals of 1-(p-nitrobenzoyloxy)-6-chloro-1,2,3-benzotriazole (2.4 g), melting point: 198°-199° C. (decomp).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([OH:18])=[O:17].O[CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C1C=CN=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:23]([O:22][CH2:21][CH2:20][O:17][C:16]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1)=[O:18])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=C(O)c1ccc2sc3ccccc3c(=O)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(=O)c1ccc2sc3ccccc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 6.9 %

Procedure:
A mixture of thioxanthen-9-one-2-carboxylic acid (3.8 g, 19.8 mmol), 2-hydroxyethylmethacrylate (7.7 g, 59.3mmol), 4-dimethylamino-pyridine p-toluenesulfonic acid salt (2.3 g, 7.9mmol), and anhydrous dichloromethane (31 mL) is cooled to 0° C. under nitrogen and treated with 1,3-dicyclohexyl-carbodiimide (2.1 g, 10.1 mmol). After 15 min, the reaction mixture was warmed to ambient and stirred for 12 h. The precipitated urea by product was filtered, and the filtrate was washed successively with 10% aqueous HCl, 10% aqueous NaHCO3, water, and brine. The solution was dried (Na2SO4)and concentrated to deposit yellow oil. The product was purified by column chromatography to provide 500 mg of a pale yellow solid (17% of theory). 1H (CDCl3): δ 1.99 (s, 3H), 4.60 (dd, 4H), 5.60 (s, 1H), 6.20 (s, 1H), 7.60 (m, 4H), 8.20 (d, 1H), 8.70 (d, 1H), 9.30 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:49]=[CH:48][C:28]([C:29]([NH:31][C@H:32]5[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46]C)=[O:45])[CH2:33]5)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1.CCOC(C)=O>[C:40]([O:39][C:37]([N:35]1[CH2:36][C@@H:32]([NH:31][C:29](=[O:30])[C:28]2[CH:48]=[CH:49][C:25]([NH:24][C:14]3[N:13]=[C:12]([NH:11][C:8]4([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[CH2:9][CH2:10]4)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=3)=[CH:26][CH:27]=2)[CH2:33][C@@H:34]1[C:44]([OH:46])=[O:45])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)C[C@@H]1C(=O)O
Reaction time: 2 h
Yield: 100 %

Procedure:
(2S,4R)-1-tert-butyl 2-methyl 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-1,2-dicarboxylate (500 mg, 0.708 mmol), was dissolved in THF (Ratio: 1.000, Volume: 4 mL) followed by the addition of LiOH (85 mg, 3.54 mmol) and Water (Ratio: 1.000, Volume: 4). The reaction was headed to 65° C. for 2 h. The reaction was diluted with EtOAc and acidified with 1N HCl. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated under vacuum to give (2R,4S)-1-(tert-butoxycarbonyl)-4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-2-carboxylic acid (490 mg) which was used in the next step without further purification. 1H NMR (400 MHz, MeOD) δ ppm 1.33-1.41 (m, 4H), 1.45 (s, 9H), 2.28-2.49 (m, 2H), 3.40-3.47 (m, 1H), 3.85 (dd, J=10.7, 6.9 Hz, 1H), 4.33-4.47 (m, 1H), 4.60-4.72 (m, 1H), 4.86-4.93 (m, 2H), 7.20-7.32 (m, 4H), 7.59-7.71 (m, 3H), 7.77-7.89 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 692.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:25])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(Br)cc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(-c3ccc(F)cc3)cc2)cs1
Yield: 43 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(4-bromobenzyl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid ethyl ester (0.9 g) synthesized in Example 155-2 and 4-fluorophenylboric acid (425 mg) were dissolved in dioxane (10 mL) and aqueous sodium carbonate solution (2 mol/L, 5 mL), tetrakis(triphenylphosphine)palladium (117 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (400 mg) as a colorless oil.