Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:42])[C:26]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:29]=[CH:28][C:27]=1[N+:39]([O-])=O.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O.C(O)C>[NH2:39][C:27]1[CH:28]=[CH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:31][C:26]=1[C:25]([NH:24][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:2]=1[Cl:1])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([F:21])[CH:10]=1)=[O:7])=[O:42]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)Nc3cc(C(=O)Nc4cc(F)cc(N5CCOCC5)c4)ccc3Cl)c2)CC1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(C(=O)Nc3cc(C(=O)Nc4cc(F)cc(N5CCOCC5)c4)ccc3Cl)c2)CC1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
Iron powder (0.726 g) was added to a stirred suspension of 4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-[5-(4-methylpiperazin-1-yl)-2-nitrobenzamido]benzamide (0.76 g), water (2 ml), acetic acid (0.5 ml) and ethanol (15 ml) and the resultant mixture was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. Water (80 ml) was added and the mixture was basified by the addition of sodium carbonate. The resultant mixture was filtered through diatomaceous earth and the separated solids were washed in turn with methylene chloride and methanol. The combined filtrates were evaporated and the residue was triturated under ethyl acetate. The mixture was filtered and the filtrate was evaporated to give the title compound (0.385 g); Mass Spectrum: M+H+ 567.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>CN(C)C=O.CCOC(C)=O>[CH:14]1([CH2:13][O:1][CH:2]2[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]2)[CH2:16][CH2:15]1
Reactant: N#CC1=CCCC(O)C1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1=CCCC(OCC2CC2)C1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To the solution of (R or S)-5-Hydroxycyclohex-1-enecarbonitrile (Intermediate #40, 2.0 g, 16 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (850 mg, 21 mmol, 60% dispersion in oil) at 0° C. The resulting suspension was stirred at ambient temperature for 30 minutes before the addition of bromomethylcyclopropane (3.3 g, 24 mmol). The mixture was then stirred at 75° C. for 6 hours, and diluted with EtOAc (50 mL). The organic solution was washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 2-5% EtOAc/hexane) to afford the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.63-6.62 (m, 1H), 3.69-3.66 (m, 1H), 3.34-3.32 (m, 2H), 2.54-2.49 (m, 1H), 2.38-2.30 (m, 1H), 2.29-2.24 (m, 2H), 1.85-1.83 (m, 1H), 1.75-1.72 (m, 1H), 1.08-1.04 (m, 1H), 0.59-0.54 (m, 2H), 0.24-0.20 (1,2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccccc2)n1
Product: c1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)cc1
Yield: 89 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-phenyloxazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-phenyloxazole. The yield was 89%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 113-114° C.
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CS(C)=O>[C:6]([C:5]1[CH:8]=[C:9]([CH3:10])[C:2]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: Cc1cc(C#N)cnc1F
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)cnc1NCCCC(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 6-fluoro-5-methylnicotinonitrile (10.0 g, 73.4 mmol), tert-butyl 4-aminobutanoate (Bachem F-3755, 17.4 g, 88.1 mmol) and TEA (25.6 mL, 183.6 mmol) was prepared in DMSO (100 mL) under nitrogen, and the heated at 150° C. for 4 hours. The reaction mixture was cooled to 100° C., and then water was added (100 mL) drop wise. The resulting mixture was stirred at RT for 2 hours, and then the precipitate was filtered off, washed with water and dried under reduced pressure to afford the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (1H, s), 7.53 (1H, s), 6.95 (1H, m), 3.40 (2H, t), 2.23 (2H, t), 2.03 (3H, s), 1.75 (2H, m), 1.37 (9H, s).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH3:8])[S:5][CH3:6])#[N:2].ClC1C=CC=C(C(OO)=[O:17])C=1>CC(C)=O>[C:1]([NH:3][C:4]([S:5]([CH3:6])=[O:17])=[N:7][CH3:8])#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN=C(NC#N)SC
Solvent: CC(C)=O
Product: CN=C(NC#N)S(C)=O
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a stirred suspension of N-cyano-N',S-dimethylisothiourea (19.4 g) in acetone (700 ml) was added dropwise a solution of m-chloroperbenzoic acid (80% purity, 38.8 g) in acetone (120 ml) at 20°-25° C. After stirring for 1 hr. at the same temperature, the reaction mixture was cooled in an ice bath for 1 hr. and the precipitate was filtered and washed with acetone to give N-cyano-N'-methyl-methylsulfinylformamidine (13.65 g). Yield 62.8%, m.p. 115.5°-116° C.
Reaction SMILES: I[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH:7]=[N:6][C:5]=2[N:4]([CH3:17])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:17][N:4]1[C:5]2[N:6]=[CH:7][N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:9](=[O:11])[C:10]=2[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cn1cc(I)c2c(=O)n(CC(F)(F)F)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccccn2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 90 °C
Yield: 21.4 %

Procedure:
A mixture of 5-iodo-7-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (2 g, 5.60 mmol) and 2-(tributylstannyl)pyridine (2.2 ml, 6.79 mmol) in toluene (20 ml) was degassed. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.324 g, 0.280 mmol). The resulting mixture was heated at 90° C. for 18 h. The reaction mixture was cooled and placed directly onto a silica column and purified by flash chromatography (0-100% ethyl acetate/cyclohexane) to give the title compound (0.37 g, 21%). LCMS RT=0.63 min, M+H+=309.1
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](O)[CH3:22]>>[CH2:21]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([OH:9])[CH2:3][C:1]#[N:2])[CH3:22]
Reactant: N#CC[C@@H](O)CC(=O)O
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CC#N
Yield: 90 %

Procedure:
(R)-4-cyano-3-hydroxybutyric acid (1.0 mol) in ethanol (500 ml) and conc. sulfuric acid (5 g) were refluxed for 5 hours. The reaction mixture was neutralized with sodium carbonate ancd filtered. The filtrate was concentrated in vacuo to afford (R)-4-cyano-3-hydroxybutyric acid ethyl ester (141 g, 90%).
Reaction SMILES: N[C:2](N)=[O:3].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11].N>>[NH2:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][NH:11][C:2]1=[O:3]
Reactant: NC(N)=O
Reactant: NCCNCCN
Agent: N
Product: NCCN1CCNC1=O
Temperature: 140 °C

Procedure:
In a suitable reactor equipped with agitation and a reflux condenser, 465 parts by weight of urea and 798 parts by weight of diethylenetriamine were charged. The reaction mix was slowly heated to 140° C. Ammonia started to evolve at about 130° C. The temperature was slowly raised to 150° C. As the evolution of ammonia subsided, vacuum was applied and the remaining ammonia was removed. Product yield was approximately 1000 parts by weight. The product had a viscosity of 6000 cps at 25° C. and an MEQ/g of 6.5. (MEQ=milliequivalent weight). Gel phase analysis of the product showed approximately 95% purity. The product can be used as is or further purified by vacuum distillation. The major impurity is unreacted diethylenetriamine.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(O[C:18](=[O:28])[CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])(C)(C)C.[CH:29]([C:31]1[C:32]([NH:38]C(=O)C(C)(C)C)=[N:33][CH:34]=[CH:35][C:36]=1[CH3:37])=O.[NH4+].[Cl-]>C(OCC)C.C1COCC1>[CH3:37][C:36]1[CH:35]=[CH:34][N:33]=[C:32]2[C:31]=1[CH:29]=[C:19]([CH2:20][C:21]([OH:23])=[O:22])[C:18](=[O:28])[NH:38]2
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1C=O
Reactant: CC(C)(C)OC(=O)CCC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccnc2[nH]c(=O)c(CC(=O)O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a precooled solution of N,N-diisopropylamine (6.2 mL, 0.044 mol) in diethyl ether (125 mL, dried over molecular seives) was added BuLi (2.5 M in hexanes) (17.8 mL, 0,044 mol) and the resulting solution was stirred at rt. for 15 minutes whereafter di-tert-butylsuccinate (5.35 g, 23 mmol) dissolved in diethyl ether (10 mL, dried over molecular seives) was slowly added. After 30 min at −78° C., 3-formyl-4-methyl-2-(pivaloylamino)-pyridine (4.65 g, 21.0 mmol) dissolved in THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was slowly added, and stirring at this temperature was continued for 30 min. The solution was allowed to warm to rt. and poored into a solution of NH4Cl (sat., aqueous, 100 mL). The aqueous phase was extracted three times with diethylether (3×50 mL) and the organic extracts washed with water (50 mL) and brine (50 mL), dried over MgSO4 and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/hexane to yield the diastereomeric mixture which was used as such after drying in vacuo. The diastereomeric mixture was dissolved in HCl (3M, aqueous, 50 mL) the solution was stirred under reflux for 3.5 h, cooled to rt. and washed with diethyl ether (2×50 mL), neutralised with K2CO3 and again washed with chloroform (3×50 mL). After precipitation upon cooling 1.39 g (37%) of the title compound was obtained (mp >250° C.). 1H NMR (D2O/NaOD): δ 8.25 (d, 4.9 Hz, 1H), 7.71 (s, 1H), 6.84 (d, 4.9 Hz, 1H), 2.36 (s, 2H), 1.05 (s, 3H). 13C NMR (D2O/NaOD): δ 180.30, 171.68, 155.44, 148.84, 146.04, 132.61, 127.08, 117.60, 116.21, 27.22, 16.98. FAB+ MS (m/z): 219.10 (M+H+, calc. for C11H10N2O3+H+ 219.0770).
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]2[C:13](=[N:20]O)[CH2:14][C:15]3([O:19][C:11]=2[CH:10]=1)[CH2:18][CH2:17][CH2:16]3)C1C=CC=CC=1>CO.[Pd]>[NH2:20][CH:13]1[C:12]2[CH:22]=[CH:23][C:9]([OH:8])=[CH:10][C:11]=2[O:19][C:15]2([CH2:16][CH2:17][CH2:18]2)[CH2:14]1
Reactant: ON=C1CC2(CCC2)Oc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Product: NC1CC2(CCC2)Oc2cc(O)ccc21

Procedure:
This compound was prepared by hydrogenation of 7-Benzyloxy-3,4-Dihydro-4-hydroxyimino-spiro[2H-1-benzopyran-2,1′-cyclobutane] in presence of 10% Pd/C in methanol. The amine was isolated as hydrochloride salt.
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](N)=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1.ClC1C=CN=C(C#N)C=1>>[F:26][C:21]1[CH:20]=[C:19]([NH2:18])[CH:24]=[CH:23][C:22]=1[O:25][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[CH:7]=1
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: Nc1ccc(O)c(F)c1
Agent: N#Cc1cc(Cl)ccn1
Product: Cc1cc(Oc2ccc(N)cc2F)ccn1

Procedure:
{3-Fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amine (2J) was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-amino-2-fluorophenol and 4-chloro-2-cyanopyridine, MS ES: 219 (M+H)+, calcd 219, RT=1.07 min.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:19]([OH:22])(=[O:21])=[O:20]>ClCCl>[C:1]([O:9][C:10]1[CH:15]=[C:14]([S:19]([OH:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1OC(=O)c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)O)cc1OC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
A stirred solution of 2-methoxyphenyl benzoate (10 g) in dichloromethane (100 mL) from 0°-5° C. is treated dropwise with chlorosulfonic acid (2.9 mL) and the solution is then stirred for 3 hours from 0°-5° C. The precipitate which forms is filtered off, washed with cold dichloromethane, and dried in vacuo, to give 3-benzoyloxy-4-methoxybenzenesulfonic acid (11.45 g), in the form of a white solid, m.p. 139°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:17][S:18][CH2:19][C:20](O)=[O:21])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]1([C@H:44]2[CH2:48][O:47][C:46](=[O:49])[NH:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:17][S:18][CH2:19][C:20]([N:45]3[C@@H:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:48][O:47][C:46]3=[O:49])=[O:21])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(CSCC(=O)O)OCC(C)(C)CO2)cc1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2(CSCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)OCC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
({[2-(4-Methoxyphenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetic acid (5.4 g, 16.5 mmol) was dissolved in dry CH2Cl2 (80 ml) and cooled to 0° C. N,N′-dicyclohexylcarbodiimide (DCC, 3.76 g; 18.2 mmol) in 20 ml of CH2Cl2 and 4-(dimethylamino)pyridine (DMAP, 4.04 g, 33.1 mmol) were added and the mixture was stirred at 0° C. for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (2.69 g, 16.5 mmol) was added and the mixture was stirred at room temperature for 17 h. The mixture was filtered, concentrated under reduced pressure and purified by flash-chromatography (hexane:EtOAc 4:1 then 2:1). This afforded 5.69 g (73%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 2.8 (s, 2H), 3.4 (s, 4H), 3.8 (s, 2H), 3.8 (s, 3H), 4.3 (dd, 1H), 4.7 (t, 1H), 5.4 (dd, 1H), 6.9 (d, 2H), 7.3 (m, 7H).
Reaction SMILES: [C:1](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:28](=[O:41])[C:27]2=[O:42]>>[C:1]([O:42][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=2)[N:29]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28]1=[O:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: O=C(OC1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21)c1ccccc1

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 5-chloro-1-phenethylindoline-2,3-dione. 1H-NMR δ 8.11 (dd, 2H), 7.60 (dt, 1H), 7.47 (m, 2H), 7.41 (dd, 1H), 7.34-7.24 (m, 6H), 6.68 (d, 1H), 6.07 (s, 1H), 3.97 (dd, 2H), 3.02 (t, 2H).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[C:6]([N:34]([CH3:36])[CH3:35])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].O.[OH-].[Li+].O.C(O)(=O)C>O1CCCC1.CO>[CH3:36][N:34]([CH3:35])[C:6]1[C:5]([CH2:4][C:3]([OH:37])=[O:2])=[C:10]([N:11]([CH3:12])[CH3:13])[N:9]=[C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:33])[C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc(N(C)C)c1CC(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A stirred suspension of [4,6-bis-dimethylamino-2-[4-(4-trifluoromethylbenzoylamino)-benzyl]pyrimidin-5-yl]acetic acid methyl ester (50 g, obtained according to step B) and lithium hydroxide monohydrate (6.3 g) in a mixture of 100 mL of tetrahydrofurane and 50 mL of methanol in a 1500 mL double jacketed vessel is heated to 60±5° C. over a period of 1 hour. Deionized water (75 mL) is slowly added. The obtained solution is stirred for 2 hours at 60±5° C. A solution of acetic acid (11.6 g) in 50 mL of methanol is added at 60±5° C. The resulting suspension is gradually cooled to 5±5° C. over a period of 2 hours and stirred at this temperature for another 30 minutes. The solid is filtered off, washed with 200 mL of methanol and dried in vacuo at 50° C. to yield [4,6-bis-dimethylamino-2-[4-(4-trifluoromethyl-benzoyl-amino)benzyl]pyrimidin-5-yl]acetic acid (compound of formula (I)) in an amount of 43.65 g (yield: 90%; HPLC-purity: 99.6%).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[NH2:5].ClC(OCC(C)C)=O.[NH2:28][C@H:29]([C:34]([NH:36][C@H:37]([C:43]([NH:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C)C=O.O1CCCC1.CN1CCOCC1.O>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:28][C@H:29]([C:34]([NH:36][C@H:37]([C:43]([NH:45][NH:46][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:9])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
H-Leu-Gln-NHNHBoc obtained in the above-mentioned step 9(a) was dissolved in 30 ml of dimethylformamide, the solution was cooled under stirring condition. On the other hand, 1.61 g of Z-Asn-OH was dissolved in 30 ml of tetrahydrofuran, to this solution 0.62 ml of N-methylmorpholine was added and was cooled to -15° C., then 0.80 ml of isobutyl chloroformate was added dropwise thereto under stirring condition. 30 Seconds after the addition of isobutyl chloroformate, the dimethylformamide solution of H-Leu-Gln-NHNHBoc as prepared previously was added thereto, the whole mixture was stirred at 0° C. for 5 minutes, next at 40° C. for 1 minute in water bath, further at 15° C. for 30 minutes. From the reaction mixture tetrahydrofuran and dimethylformamide were removed by distillation under a reduced pressure, the residue thus obtained was extracted with ethyl acetate. The extract was washed with 1N-citric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in this order, then was dried with anhydrous sodium sulfate, and ethyl acetate was removed by distillation. The oily residue obtained was solidified by adding ethyl ehter, reprecipitated from methanol-ethyl acetate to obtain 2.55 g of the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCOCC2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Trifluoroacetic acid (3 mL) was added to the obtained tert-butyl 2-(2-hydroxy-5-(morpholin-4-yl)benzamido)-4-phenylbenzoate (0.036 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and water and 2-propanol were added to the obtained residue. After adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.027 g of 2-(2-hydroxy-5-(morpholin-4-yl)benzamido)-4-phenylbenzoic acid as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:13])=[CH:4][C:3]=1[O:32][CH3:33].CN1CC[O:38][CH2:37][CH2:36]1.CN(C)C=O.C(Cl)(=O)C>O>[C:37]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:13])=[CH:4][C:3]=1[O:32][CH3:33])(=[O:38])[CH3:36]
Reactant: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)ccc1O
Reactant: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)Cl
Product: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC(C)=O
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a mixture of 1-[2-{5-(4-hydroxy-3-methoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (0.89 g), dry N-methylmorpholine (1.0 g) and dry N,N-dimethylformamide (10 ml) was added slowly acetyl chloride (0.26 g) at 5° to 10° C. After stirring for 1 hours, the reaction mixture was poured into water (50 ml) and stirred for 1 hour. The resulting precipitate was collected, washed with water and then recrystallized from a mixture of ethanol and water (7:3 V/V) to give 1-[2-{5-(4-acetoxy-3-methoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (0.22 g).