Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].[C:3]([CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25]/[C:26](/[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:27]\[O:28][CH3:29])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])#[N:4]>>[C:3]([CH:5]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25]/[C:26](/[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[N:27]\[O:28][CH3:29])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)[CH2:6][C:7]([O-:9])=[O:8])#[N:4].[Na+:2]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)[O-])cc2)cc1)c1ccc(F)cc1
Yield: 73.84 %

Procedure:
Compound 54 was synthesized from sodium hydroxide (0.067 g, 1.6 mmol) and 3-cyano-3-{4-[(4-{[(2Z)-2-(4-fluorophenyl)-2-(methoxyimino)ethyl]oxy}benzyl)oxy]phenyl}propanoic acid (0.4 g, 0.8 mmol) by following the procedure described in scheme 12 (0.3 g, yield: 73.84%); Purity: 96.50%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7]2.[CH3:16][N:17]([CH3:23])[C@@H:18]([C:20](O)=[O:21])[CH3:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:16][N:17]([CH3:23])[C@H:18]([CH3:19])[C:20]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:7][CH2:8]1)=[O:21]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: C[C@H](C(=O)O)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@@H](C)N(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride (2 g, 8.67 mmol) in N,N-dimethylformamide (100 mL) was added N,N-dimethyl-D-alanine (1.524 g, 13.01 mmol), PyBOP (13.54 g, 26.0 mmol), and DIPEA (15.14 mL, 87 mmol). After stirring overnight at rt, the solvent was removed and the residue was suspended in dichloromethane (150 mL), washed with water (100 mL), concentrated on the rotovap, and purified by column chromatography (DCM to 5% MeOH/DCM) to provide 1-[(2R)-N,N-dimethyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanamine (2.2 g, 86%). ESIMS (M+H)+=294.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.CO.COCC(O)C.Cl>O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: COCC(C)O
Product: C=Cc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
In a reaction vessel, 40.00 g of the obtained 4-acetoxystyrene polymer (with main chain terminal (M-30)), 40 ml of methanol, 100 ml of 1-methoxy-2-propanol and 1.5 ml of concentrated hydrochloric acid were added, and the mixture was stirred for 5 hours under heating at 80° C. The reaction solution was allowed to cool to room temperature and then added dropwise to 3 L of distilled water. After dissolving the solid collected by filtration in 200 ml of acetone, the solution was again added dropwise to 3 L of distilled water, and the solid was collected by filtration and then dried under reduced pressure to obtain 29.31 g of a 4-hydroxystyrene polymer (with main chain terminal (M-14)). The weight average molecular weight by GPC was 15,000, and the molecular weight dispersity (Mw/Mn) was 1.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[H-].[Na+].[CH2:17](I)[CH:18]([CH3:20])[CH3:19].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1
Reactant: Oc1ccc(Oc2nccs2)c(Cl)c1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(Oc2nccs2)c(Cl)c1
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
To a solution of Example 9B (3.4 g, 0.015 mol) in N,N-dimethyl formamide was added sodium hydride (0.7 g, 0.018 mol) in portions at room temperature. After stirring for 15 minutes, isobutyl iodide (4.2 g, 0.023 mol) was added rapidly and the mixture was stirred at room temperature for 24 hours. More sodium hydride and isobutyl iodide were added later to complete the reaction. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (5˜35% ethyl acetate in hexane) to give 1.92 g of product as clear oil (45% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.02 (d, J=6.62 Hz, 6H) 1.98-2.18 (m, 1H) 3.71 (d, J=6.62 Hz, 1H) 6.79 (d, J=4.04 Hz, 1H) 6.83 (d, J=2.94 Hz, 1H) 6.86 (d, J=2.94 Hz, 1H) 7.00 (d, J=2.94 Hz, 1H) 7.19 (d, J=4.04 Hz, 1H) 7.24 (s, 1H). MS (ESI) m/z 284.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:10][CH2:11][CH2:12][N:13]=[C:14]=[O:15]>O1CCOCC1>[Cl:10][CH2:11][CH2:12][NH:13][C:14]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)=[O:15]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C=NCCCl
Solvent: C1COCCO1
Product: N#Cc1cccc(NC(=O)NCCCl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
65.00 g (550 mmol) 3-amino-benzonitrile are dissolved in 450 ml dioxane, 56 ml (660 mmol) 1-chloro-2-isocyanato-ethane dissolved in 60 ml dioxane are added dropwise. The reaction mixture is stirred for 3 hours at 60° C. and for 16 hours at ambient temperature. Then the precipitate is suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:14][C@@H:15]([C:24](OC)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>O1CCCC1>[OH:25][CH2:24][C@H:15]([NH:14][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccc(O)cc1
Temperature: 70 °C
Yield: 55.5 %

Procedure:
A solution of 29.6 cm3 of lithium aluminum hydride at 1M in tetrahydrofuran is added, with stirring and under an inert atmosphere, at a temperature in the region of 20° C., to a solution of 4.38 g of methyl BOC-D-tyrosinate in 25 cm3 of tetrahydrofuran. After addition of 60 cm3 of tetrahydrofuran, the reaction mixture is heated at a temperature in the region of 70° C. for 3 hours. The reaction mixture is cooled and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 60° C. The evaporation residue is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. and is then chromatographed under an argon pressure of 60 kPa on a column of silica gel (particle size 40-63μ; diameter 7 cm; height 24 cm), eluting with 10 dm3 of a dichloromethane/methanol mixture (98/2 by volume), 2 dm3 of a dichloromethane/methanol mixture (95/5 by volume) and 2 dm3 of a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 2.2 g of tert-butyl N-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]-carbamate are obtained in the form of a white foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.35 (s: 9H); 2.46 (dd, J=14 and 8 Hz: 1H); 2.68 (dd, J=14 and 6 Hz: 1H); from 3.15 to 3.40 (mt: 2H); 3.50 (mt: 1H); 4.61 (mt: 1H); 6.48 (d, J=8.5 Hz: 1H); 6.65 (d, J=8 Hz: 2H); 6.97 (d, J=8 Hz: 2H); 9.11 (broad s: 1H)].
Reaction SMILES: FC(F)(F)S(O[C:7]1[C@:8]2([CH2:25][CH2:24][C@H:23]3[C@@H:13]([CH2:14][CH:15]=[C:16]4[C@:21]3([CH3:22])[CH2:20][CH2:19][C@H:18]([O:26][C:27](=[O:29])[CH3:28])[CH2:17]4)[C@@H:10]2[CH2:11][CH:12]=1)[CH3:9])(=O)=O.C(B(CC)[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)C>>[CH3:28][C:27]([O:26][C@@H:18]1[CH2:17][C:16]2[C@@:21]([CH3:22])([C@@H:23]3[C@@H:13]([CH2:14][CH:15]=2)[C@@H:10]2[CH2:11][CH:12]=[C:7]([C:39]4[CH:40]=[CH:35][CH:36]=[N:37][CH:38]=4)[C@@:8]2([CH3:9])[CH2:25][CH2:24]3)[CH2:20][CH2:19]1)=[O:29]
Reactant: CCB(CC)c1cccnc1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1

Procedure:
The Suzuki reaction between 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (II) and diethyl(3-pyridyl)borane affords crude abiraterone acetate which is purified by silica gel chromatography, eluting with a mixture of ethyl ether and petroleum ether, and finally crystallised from hexane.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:24]1([CH2:23][C:22]2[CH:17]=[CH:18][N:19]=[CH:20][C:21]=2[N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Reactant: Brc1cnccc1CN1CCCC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cnccc1CN1CCCC1
Yield: 4 %

Procedure:
Using analogous conditions as described for the preparation of Example 1A above, 7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-4-d: 100 mg, 0.465 mmol) was reacted with 3-bromo-4-(pyrrolidin-1-ylmethyl)pyridine (I-52a: 140 mg, 0.558 mmol), 1,4-dioxane (10 mL), copper iodide (8.8 mg, 0.0465 mmol), trans-N,N′-dimethyl-cyclohexyl-1, 2-diamine (19.8 mg, 0.139 mmol) and potassium phosphate (295 mg, 1.395 mmol) to afford the crude product. Purification by column chromatography on silica gel (12% methanol in CHCl3), followed by preparative HPLC afforded 7 mg of the product (4.02% yield).
Reaction SMILES: O1CCC(C(O)=O)CC1.[CH2:10]([O:13][CH2:14][CH2:15]Cl)[CH2:11]Cl.[Na].[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[O:13]1[CH2:14][CH2:15][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:18]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][CH2:10]1
Reactant: ClCCOCCCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)C1CCOCC1
Agent: [Na]
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1

Procedure:
According to the statements in J. Chem. Soc., 2525-30 (1930) esters of tetrahydropyran-4-carboxylic acid can be prepared by treating 2,2'-dichlorodiethyl ether with the sodium salt of diethyl malonate to form diethyl tetrahydropyran-4,4-dicarboxylate, hydrolyzing to obtain tetrahydropyran-4,4-dicarboxylic acid, decarboxylating to tetrahydropyran-4-carboxylic acid, and finally esterifying.
Reaction SMILES: [Br:1][C@@H:2]([P:6](=[O:11])([O:9]C)[O:7]C)[C@@H:3]([OH:5])[CH3:4].Br>>[Br:1][C@@H:2]([P:6](=[O:7])([OH:11])[OH:9])[C@@H:3]([OH:5])[CH3:4]
Reactant: COP(=O)(OC)[C@H](Br)[C@H](C)O
Agent: Br
Product: C[C@H](O)[C@@H](Br)P(=O)(O)O
Temperature: 95 °C
Reaction time: 14 h

Procedure:
Following the method of Giordano, C, et al. [J. Org. Chem., 54, 1470(1989)], 100 mg of dimethyl (1R,2S)-1-bromo-2-hydroxypropylphosphonate were added to 1 ml of a 49% aqueous solution of hydrobromic acid, and the resulting mixture was stirred for 14 hours at 95° C. The solvent was distilled out of the reaction mixture to obtain (1R,2S)-1-bromo-2-hydroxypropylphosphonic acid in the form of a colorless oil. The result of analysis of the thus-obtained compound by 1H-NMP is described below.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce].C[O:8][C:9]1[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]2[C:10]=1[CH:11]=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[N:14]2>CC#N.O>[O:8]=[C:9]1[CH:18]=[CH:17][C:16](=[O:19])[C:15]2[N:14]=[CH:13][C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][C:10]1=2
Reactant: CCOC(=O)c1cnc2c(OC)ccc(OC)c2c1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc2c(c1)C(=O)C=CC2=O
Reaction time: 1 h
Yield: 90.3 %

Procedure:
7.4 g of cerium ammonium nitrate are added at ambient temperature to a solution of 1 g (3.83 mmol) of ethyl 5,8-dimethoxyquinoline-3-carboxylate in a CH3CN/H2O mixture (45 mL/23 mL). The reaction medium is stirred for 1 hour and the acetonitrile is then evaporated off. The medium is basified by adding 17 mL of saturated NaHCO3 solution. 60 mL of H2O are added and this mixture is then extracted with CH2Cl2 (3 times 100 mL). After drying over MgSO4 and evaporating off the solvent, 0.8 g of ethyl 5,8-dioxoquinoline-3-carboxylate is obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[O:43][CH3:44])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][C:35]=2[O:43][CH3:44])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)Nc1ccccc1

Procedure:
trans-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (266 mg, 0.604 mmol), 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (180 mg, 0.664 mmol), palladium tetrakistriphenyphosphine (42 mg, 0.036 mmol) and sodium carbonate (154 mg, 1.449 mmol) were mixed with ethylene glycol dimethyl ether (8 mL) and water (4 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give trans-N1-phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (226 mg, 69%). 1H NMR (CDCl3) δ 1.58 (m, 4H), 2.17 (m, 7H), 2.32 (s, 3H), 2.52 (m, 2H), 2.69 (2.69, 3H), 4.16 (s, 3H), 4.78 (m, 1H), 5.49 (bs, 2H), 7.14 (m, 1H), 7.43 (m, 4H), 7.69 (m, 2H), 8.44 (m, 2H), 9.77 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =541.2, Rt=2.61 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[C:25]1(O[Si](C)(C)C)[CH2:27][CH2:26]1)C.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:25]1([N:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: O=C(c1ccc(CN2CCOCC2)cc1)N1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 60 °C

Procedure:
A solution of (4-morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone (0.128 g) in methanol (7.5 mL) was treated with (1-ethoxy-cyclopropoxy)-trimethyl-silane (1.5 mL), acetic acid (0.2 mL), and NaBH3CN (˜400 mg). The mixture was heated at 60° C. for 18 h, and then was cooled to room temperature and concentrated. The residue was diluted with 1 N NaOH and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to yield the title compound.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]([NH:9][C@H:10]([C:15]([O:17]C(C)(C)C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]([S:4][CH2:5][CH:6]([CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)O
Yield: 73 %

Procedure:
The higher RfTLC fraction product of N-(2-acetylthiomethyl-4-phenylbutanoyl)-(L)-leucine, t-butyl ester (1.90 g, 4.5 mmole) was dissolved in 5 mL of trifluoroacetic acid (TFA) and 420 mg anisole at 0° C. for 18 h. No starting material was observed by TLC. The TFA was azeotroped off under reduced pressure with benzene. The product was suspended in hexane and filtered to remove the anisole. Recovered 1.2 g of N-(2-acetylthiomethyl-4-phenylbutanoyl)-(L)-leucine (73% yield).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:38]2[C:42](=[O:43])[NH:41][N:40]=[CH:39]2)[S:26][C:27]=1[C:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29]>>[CH3:22][C:23]1[N:24]=[C:25]([N:38]2[C:42](=[O:43])[N:41]([CH2:15][C:16]3[N:17]=[C:18]([CH3:21])[S:19][CH:20]=3)[N:40]=[CH:39]2)[S:26][C:27]=1[C:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29]
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(Cn2ncn(-c3nc(C)c(C(=O)NCc4cccnc4)s3)c2=O)cs1
Yield: 34 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(chloromethyl)-2-methylthiazole hydrochloride to react with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 34% yield: 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H), 8.46 (br s, 1H), 8.26 (s, 1H), 7.72-7.63 (m, 1H), 7.30-7.17 (m, 1H), 7.05 (s, 1H), 6.83 (t, J=5.8 Hz, 1H), 5.06 (s, 2H), 4.58 (d, J=5.8 Hz, 2H), 2.64 (s, 3H), 2.61 (s, 3H); MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
151 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(2-fluorophenyl)piperazine (74 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: Cl.[CH:2]([O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[O:19]=[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37](O)=[O:38])[CH:32]=2)=[N:22][NH:21]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:3][CH:2]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:37]([C:33]2[CH:32]=[C:31]([CH2:30][C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20](=[O:19])[NH:21][N:22]=3)[CH:36]=[CH:35][N:34]=2)=[O:38])[CH2:8][CH2:7]1)[CH3:4]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1
Reactant: CC(C)OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
A solution of 4-isopropoxypiperidine hydrochloride (192 mg, 1.07 mmol) and triethylamine (0.327 mL, 2.35 mmol) in N,N-dimethylformamide (3 mL) was added in one portion to a stirred solution of 4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)picolinic acid (5)(300 mg, 1.07 mmol), triethylamine (0.327 mL, 2.35 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (607 mg, 1.60 mmol) in DMF (3 mL) at 25° C. The resulting solution was stirred at 25° C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired compound as a solid (257 mg, 59.3%); 1H NMR (400.132 MHz, DMSO) δ 1.08 (6H, dd), 1.28-1.46 (2H, m), 1.65-1.74 (1H, m), 1.78-1.87 (1H, m), 3.12 (1H, ddd), 3.23-3.31 (1H, m), 3.42-3.51 (1H, m), 3.62 (1H, m), 3.69 (1H, quintet), 3.91-4.00 (1H, m), 4.40 (2H, s), 7.39 (1H, dd), 7.49 (1H, d), 7.83-7.97 (3H, m), 8.28 (1H, dd), 8.46-8.49 (1H, m), 12.60 (1H, s); m/z (LC-MS, ESI+), RT=1.54 (M+H 407).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:11])=[C:5]([O:39][CH3:40])[CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:11])=[C:5]([O:39][CH3:40])[CH:4]=1)(=[O:41])[NH2:2]
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To the solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.16 g, 0.28 mmol) in DMSO (3 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.47 g, 4.2 mmol) aqueous solution (1N) of NaOH (1.4 mL, 1.4 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield, 0.12 g, 73%)
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[C:5]([CH3:11])[C:3]=1[NH2:4].[F:12][B-:13]([F:16])([F:15])[F:14].[H+].[N:18]([O-])=O.[Na+]>O>[F:12][B-:13]([F:16])([F:15])[F:14].[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[C:5]([CH3:11])[C:3]=1[N+:4]#[N:18]
Reactant: Cc1cc(F)c(C)c(F)c1N
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(C)c(F)c1[N+]#N

Procedure:
To 2,4-difluoro-3,6-dimethylaniline (3.1 g) are added 42% tetrafluoroboric acid (9 ml) and water (4.5 ml) with stirring and under ice-cooling, followed by dropwise addition of a solution of sodium nitrite (1.6 g) in water (3.2 ml) below 10° C. After stirring the mixture at 0° C. for 15 minutes, the resulting crystals are filtered, washed with a mixture of ethanol-diethyl ether (1:2) and then with diethyl ether, followed by drying under reduced pressure to give 2,4-difluoro-3,6-dimethylbenzene diazonium tetrafluoroborate (1.78 g).