Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][N:7]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:6]=1.O.Cl>CCO>[CH3:3][O:4][C:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:6]=1
Reactant: CCOC(=O)c1cn(-c2ncccn2)nc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1nn(-c2ncccn2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 N aqueous sodium hydroxide solution (10 mL) is added to a slurry of ethyl 3-methoxy-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (1.1 mg, 4.43 mmol) in 30 mL of EtOH. The reaction mixture becomes homogeneous and is stirred for 2 h at RT. Water (2-3 mL) is added, and the solution is cooled to 0° C. and acidified to pH=2-3 with cone. HCl. Most of the EtOH is removed in vacuo, and the resultant mixture is filtered. The collected solid is dried in vacuo to give the title compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:11]1[C:16](=O)[CH:15]=[C:14]([O:18]CC)[CH2:13][CH2:12]1)[CH2:8][CH:9]=[CH2:10]>CCOCC>[CH2:7]([CH:11]1[CH2:16][CH2:15][C:14](=[O:18])[CH:13]=[CH:12]1)[CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCC1CCC(OCC)=CC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCCC1C=CC(=O)CC1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a 0° C. slurry of 1.06 g. (26 mmoles) of lithium aluminum hydride in 75 ml. of ether was added a solution of 10 g. (51 mmoles) of 6-(3-butenyl)-3-ethoxy-2-cyclohexen-one in 25 ml. of ether. After stirring for one hour, the reaction was quenched by addition of 100 ml. of 2N hydrochloric acid. The quenched mixture was stirred for 30 minutes and then extracted with 300 ml. of ether. The ether extract was washed with 250 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated on a rotovapor. Distillation of the crude oil gave 5.98 g. (78%) of the title product.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33]Br.[CH3:35][C:36]([CH3:39])([O-:38])[CH3:37].[Na+]>O>[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33][O:38][C:36]([CH3:39])([CH3:37])[CH3:35]
Reactant: CC(C)(C)[O-]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reaction time: 3 h
Yield: 24.5 %

Procedure:
To 50 ml of N,N-dimethylformamide solution containing 2.52 g (4.44 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added 0.43 g (4.44 mmol) of sodium tert-butoxide at −10° C., and the mixture was stirred at the same temperature for 3 hours. The mixture was further stirred at 0° C. for 10 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=98:2→65:35 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.61 g of the title compound as a pale yellowish solid. (Yield: 25%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([I:11])=[CH:4][C:3]=1[OH:12].Br[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:3]([O:12][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][C:5]([I:11])=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCC(Br)CC
Reactant: CCOc1cc(I)cc(O)c1Cl
Product: CCOc1cc(I)cc(OC(CC)CC)c1Cl
Yield: 79 %

Procedure:
2-Chloro-1-ethoxy-5-iodo-3-(pentan-3-yloxy)benzene (8) (1.2 g, 79%) was prepared from 2-chloro-3-ethoxy-5-iodophenol (7) (1.1 g, 3.7 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that 3-bromopentane was used instead of cyclopentyl bromide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:39](=[O:41])=[O:40]>C(OCC)C>[CH3:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]1[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=[C:2]([C:39]([OH:41])=[O:40])[CH:7]=1
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2.00 g (0.0046 mol) of 2-bromo-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 100 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 2.2 ml of a 1.6M-hexane solution of BuLi (0.0023×1.5 mol) was added thereto, followed by stirring the suspension for about 10 minutes. After an interior of reactor was replaced with carbon dioxide gas, the reaction solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-HCl aqueous solution, and then distributed in ethyl acetate-water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to remove a main fraction therefrom. The fraction was concentrated, thereby obtaining an aimed product.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[CH2:13][CH2:12]1>[Ru]>[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([OH:21])[CH2:13][CH2:12]1
Reactant: O=C1CCOc2ccccc21
Agent: [Ru]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O[C@@H]1CCOc2ccccc21
Temperature: 30 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Argon was introduced into a 20 mL Schlenk-type reaction tube and bathed in an ice bath, then triethyl amine (3.6 mL, 26 mmol), formic acid (1.2 mL, 31 mmol), 4-chromanone (1.48 g, 10 mmol, substrate/catalyst ratio=500) and ruthenium complex RuCl[(R,R)-Tsdpen] (p-cymene) (12.7 mg, 0.02 mmol) were set therein, stirred at 30° C. for 24 hours. On its course, samples were collected after 3 hours for 1HNMR and HPLC analyses of the product. The conversion rate after 3 hours was 66%, and the optical purity was 99% ee. The reaction was allowed to further continue, and after 24 hours, (R)-4-chromanol was produced at 100% yield of and 99% ee optical purity.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[C:5]2=[N:6][C:7]([CH3:11])=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Cc1ncc2c(I)n[nH]c2n1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc2c(I)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
7.950 g (13.76 mmol) of 3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 4.930 g (15.13 mmol) of caesium carbonate were put in 20 ml DMF and 2.860 g (15.13 mmol) of 2-fluorobenzyl bromide dissolved in 5 ml DMF was added. The reaction mixture was stirred overnight at RT, diluted with 100 ml water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated in a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). 1.030 g of the target compound was obtained (20% of theor.).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2N(O)N=[N:7][C:5]=2C=1.C(N)CCCC.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[S:37]2(=[O:52])=[O:51])=[CH:32][CH:31]=1)[C:26]([OH:28])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:28])[NH:7][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[S:37]2(=[O:52])=[O:51])=[CH:34][CH:35]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc3)S2(=O)=O)cc1
Solvent: CCCCCN
Solvent: ClCCl
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HOBt (27 mg, 0.175 mmol), pentyl amine (0.020 mL, 0.175 mmol) and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (37 mg, 0.192 mmol) are added to a solution of the title A compound in Example 47, (S)-2-t-butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (91 mg, 0.175 mmol) in CH2Cl2 (4 mL) and the reaction is stirred at RT for 2 h. The mixture is concentrated and the product is taken up in EtOAc, washed with 1N aqueous HCl, saturated aqueous NaHCO3 and brine. The organic solution is dried over anhydrous MgSO4, filtered and concentrated to give a white solid. Chromatography on a 10 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of 30:70 (EtOAc:hexane) to 60:40 over 10 min yields ((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamic acid t-butyl ester as a white solid: [M+1]+=589.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]2[N:12]([CH2:13][CH2:14][CH2:15]2)[C:11](=O)[CH2:10][CH2:9]1>C1COCC1>[C:18]1([C:8]2([NH2:7])[CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10][CH2:9]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1(c2ccccc2)CCC(=O)N2CCCC21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1(c2ccccc2)CCCN2CCCC21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a slurry of 14 mg (0.33 mmol) LiAlH4 in 0.4 ml THF was added drop-wise a solution of 38 mg (0.165 mmol) (8R,S; 8aS,R)-8-amino-8-phenyl-hexahydro-indolizin-5-one in 0.4 ml THF at room temperature. The mixture was stirred at room temperature for 15 minutes and then refluxed for 30 minutes, cooled in an ice bath and quenched carefully with 15 ul water, 15 ul 5N NaOH and finally with 45 ul water. Ethyl acetate was added. The mixture was filtered and the filtrate was concentrated in vacuo to provide 30 mg (y: 84%) of the title compound as a colorless oil. (M+H+: 217.4).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)=O.CC(C)=O.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32](Cl)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.C(NCC)C.C>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C:32]([C:27]2[C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:35])[F:36])=[CH:21][CH:22]=3)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C=O)c(N)c1
Agent: C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCNCC
Product: Nc1cc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a nitrogen purged 12 liter 3-neck flask fitted with a mechanical stirrer and temperature probe was added THF (4.3 L) and 2,4-diaminobenzaldehyde (50 g, 0.37 mol, 1 equiv). After cooling the solution to -70° C. (dry ice/acetone bath), poly(4-vinylpyridine), which can be obtained from Aldrich, Milwaukee, Wis., 25% cross-linked, (210 g) was added. A solution of 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (105 g, 0.37 mol, 1 equiv) in THF (1 L) was added at such a rate as to maintain the temperature below −60° C. The light orange reaction mixture was allowed to warm to room temperature over 4 hours to give a dark red reaction mixture. (HPLC analysis showed an 18:1 mixture of mono- (retention time (rt)=4.8 min) to di- (rt=3.1 min) acylated products along with 5% residual starting material (rt=18.8 min), (Zorbax SlL (150 mm) from Agilent Technologies, Palo Alto, Calif. 2 mL/min 90:10 hexanes/isopropanol, 0.1% diethylamine, 250 nm, 40° C.). The reaction was quenched with 1 N NaOH (450 mL) and allowed to stir overnight at 25° C. The reaction mixture was filtered and the solids were washed with ethyl acetate (5×200 mL) and the combined organic layers were concentrated in vacuo to give a brown oil. The oil was dissolved in CH2Cl2 (1.5 L) and silica gel (EM Science, Gibbstown, N.J., 230-400 mesh or 0.04-0.06 mm particle size) (410 g) and Darco G-60® (10 g, BNL Fine Chemicals and Reagents) were added. The slurry was stirred for 15 minutes and filtered. The silica was washed with CH2Cl2 (5×200 mL). The combined organic layers were concentrated in vacuo and the methylene chloride was displaced with 1:1 hexanes/diisopropylether. The precipitated product was collected by suction filtration and dried in air to give 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-amino-4-formyl-phenyl)-amide (40 g, 30%, 43:1 mono:bis acylated by HPLC) as a light yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:41]([CH3:43])[CH3:42])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCCC1.O>[OH:8][CH2:9][CH2:10][N:11]([CH:41]([CH3:43])[CH3:42])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacid[2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (438) (150 mg, 0.248 mmol) of in tetrahydrofuran (4 mL), was added 1N HCl (1 mL), then this reaction mixture was stirred for 1 h, at room temperature, After completion of the reaction, volatile substances were removed the from the reaction, then dilute with water (10 mL) and adjust with NaHCO3 to pH8, then extract with ethyl acetate (2×30 mL), then organic part was dried over sodium sulfate, then concentrated, resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 50-60% ethyl acetate in hexane as gradient polarity mobile phase to get 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacid (2-hydroxyethyl)-isopropylamide (439) (100 mg, 82%) as white sticky liquid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1.[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19].[BH3-]C#N.[Na+].CC(O)=O>CO>[F:34][C:21]1[CH:22]=[C:23]([CH2:24][N:25]2[C:29]([CH2:30][NH:2][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)=[CH:28][N:27]=[CH:26]2)[CH:32]=[CH:33][C:20]=1[C:18]#[N:19]
Reactant: NCCc1ccccc1-c1cccc(O)c1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(Cn2cncc2CNCCc2ccccc2-c2cccc(O)c2)cc1F
Reaction time: 18 h

Procedure:
1-amino-2-(3′-hydroxybiphenyl-2-yl)ethane hydrochloride from Step C (0.47 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde from Example 3, Step G (112 mg, 0.49 mmol) were stirred in MeOH (1 mL) for 20 min, then NaCNBH3 (38 mg, 0.60 mmol) was added. The reaction mixture was adjusted to pH 5 with AcOH, as judged from wetted pH paper, and stirring was continued at ambient temperature for 18 hours. The reaction was quenched with 10% aq. citric acid and stirred for 20 min. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (3×20 mL).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:16])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:16]
Reactant: CCCCCCCCCCCCC(=O)N1CCCC[C@H]1C(=O)NCCCCCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCC(=O)N1CCCC[C@H]1C(=O)NCCCCCCN
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of (S)-(6-{[1-(1-tridecanoyl-piperidin-2-yl)-methanoyl]-amino}-hexyl)-carbamic acid tert-butyl ester (3.9 g, 7.45 mmol) in DCM (40 mL) was treated with TFA (8 mL) at −20° C. for two days until disappearance of the starting material. The reaction mixture was allowed to warm up to rt and was washed with an aqueous saturated solution of K2CO3. Extraction, drying over MgSO4 and evaporation in vacuo gave a yellow oil. Purification via flash chromatography (SiO2, 5×13 cm2 column) using a mixture (90:10:2) of DCM:MeOH(5% aqueous solution of NH3) gave the title compound (1.35 g) as a pale yellow oil. The residue was taken in anhydrous DCM (25 mL) and treated with TFA (246 μL, 365 mg) at —10° C. Evaporation of the solvents gave the title compound (1.67 g, 3.11 mmol) as a yellow oil in a 42% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([O:7]C(=O)C2C=CC=CC=2)[CH2:3]1.[CH:16]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([N:27]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:28]2[N:33]=[CH:32][C:31](Br)=[CH:30][N:29]=2)[CH2:24][C@H:23]1[CH2:50][CH3:51])=[O:21])([CH3:18])[CH3:17].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1.CO>[CH:16]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([N:27]([CH2:35][C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[C:28]2[N:33]=[CH:32][C:31]([N:2]3[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3]3)=[CH:30][N:29]=2)[CH2:24][C@H:23]1[CH2:50][CH3:51])=[O:21])([CH3:18])[CH3:17]
Reactant: O=C(O[C@H]1CCNC1)c1ccccc1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)C
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CC[C@H](O)C3)cn2)CN1C(=O)OC(C)C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
The resulting benzoic acid (S)-pyrrolidin-3-yl ester hydrochloride (0.45 mmol), (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (0.196 mmol; 114 mg), tris(dibenzylideneacetone)dipalladium(0) (0.0098 mmol; 9.0 mg), 2-(di-tert-butylphosphino)biphenyl (0.0196 mmol; 5.8 mg) and sodium tert-butoxide (0.784 mmol; 75.3 mg) are dissolved in toluene (1 mL). The mixture is stirred for 2.5 hours at 100° C. To the mixture are added aqueous 1 M NaOH (5 mL), MeOH (10 mL) and THF (3 mL) at room temperature. After stirring for 5 hours, the reaction mixture is quenched with saturated aqueous ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (82 mg, 71%); ESI-MS m/z: 590 [M+1]+, Retention time 2.15 min (condition A).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:18](O)[CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26].C(O)C(O)CCl.C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[C:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH2:13][CH2:12]1
Reactant: OCCOCCOCCO
Reactant: CC1(C)Cc2ccccc2C1=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: OCC(O)CCl
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC1(C)Cc2ccccc2C1=C1CCN(CCOCCOCCO)CC1
Reaction time: 12 h

Procedure:
2.5 g 4-(2,2-dimethyl-indane-1-ylidene)-piperidine, 1.95 g triethyleneglycol-monochlorhydrin and 2 g sodium carbonate in 50 ml methylisobutylketone are refluxed with stirring for 12 hours. After cooling, the reaction mixture is filtered and the filtrate evaporated. The residue is dissolved in ether, the solution washed two times with a little cold water, dried over sodium sulfate, filtered and evaporated, to give the title compound as a viscous oil. The neutral oxalate melts at 82°-85°.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C@H:5]([OH:25])[CH2:6][NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=2)[NH:11][C:10]([CH3:24])([CH3:23])[CH2:9]1.C(N(C(C)C)C(C)C)C.C(Cl)Cl.N1([C:51](=[O:53])[CH3:52])C=CN=C1>>[CH3:23][C:10]1([CH3:24])[CH2:9][C@H:8]([NH:7][CH2:6][C@@H:5]([OH:25])[C@@H:4]([NH:3][C:51](=[O:53])[CH3:52])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=2)[NH:11]1
Reactant: CC(=O)n1ccnc1
Reactant: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@@H](N)Cc1cccc(F)c1)CC(C)(C)N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cccc(F)c1)[C@H](O)CN[C@H]1CC(C)(C)Nc2ccc(CC(C)(C)C)cc21

Procedure:
To a solution of (2R,3S)-3-amino-1-((S)-2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-4-(3-fluorophenyl)butan-2-ol dihydrochloride (0.104 g, 0.379 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.396 ml, 2.27 mmol) in DCM (1.52 ml, 0.379 mmol) was added 1-(1H-imidazol-1-yl)ethanone (0.0396 g, 0.360 mmol) in one portion. The resulting solution was stirred over the weekend. The crude mixture was concentrated and purified with the HPLC. Due to insufficient purity, the title compound was free based and purified with the ISCO MPLC. MS m/z: 470 (M+1).