Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[N:25]=[C:24]([CH:26]=O)[CH:23]=[CH:22][CH:21]=1.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].[BH3-]C#N.[Na+].ClCCl>C(O)C>[C:28]([NH:32][CH2:26][C:24]1[N:25]=[C:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:21]=[CH:22][CH:23]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(CNC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.79 g (5.09 mmol) of 6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridine-2-carbaldehyde, 1.85 g (25.4 mmol) of tert-butylamine and 0.641 g (10.2 mmol) of NaBH3CN in 100 ml of dry ethanol was stirred overnight at room temperature. The resulting mixture was evaporated to dryness. The product was isolated from the residue by flash chromatography on neutral alumina (eluent: dichloromethane, then dichloromethane-ether=1:1, vol.). Yield 1.10 g (53%) of yellowish oil. Anal. calc. for C28H31N3: C, 82.11; H, 7.63; N, 10.26. Found: C, 82.34; H, 7.79; N, 10.11. 1H NMR (CDCl3): 7.90 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.88 (m, 1H, 8-H in naphthyl), 7.79 (m, 1H, 4-H in Py), 7.65 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.38-7.48 (m, 4H, 3-H in Py and 5,6,7-H in naphthyl), 7.32 (m, 1H, 5-H in Py), 7.01-7.04 (m, 2H, 3,5-H in ortho-tolyl), 6.63 (m, 1H, 4-H in ortho-tolyl), 6.52 (m, 1H, 6-H in ortho-tolyl), 4.22 (m, 2H, Naph-CH2N), 4.01 (m, 2H, Py-CH2N), 3.50 (br. s, 2H, NH), 2.11 (s, 3H, Me in ortho-tolyl), 1.18 (s, 9H, tBu).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=[N:20]OCC)[C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[S:9][CH:10]=1)[CH3:2].[H][H]>Cl.C(O)C.[Pd]>[ClH:17].[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH2:20])[C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:19])[Cl:18])=[O:13])[S:9][CH:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCON=C(C(=O)OCC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Yield: 144.1 %

Procedure:
A solution of 10.45 g of α-ethoxyimino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester in a mixture of 10% hydrochloric acid and ethanol is catalytic-hydrogenated over 8.0 g of 5% palladium on charcoal at room temperature under atomospheric pressure. After the absorption of two equivalents of hydrogen, the catalyst in the reaction mixture is filtered off and the filtrate is concentrated to dryness under reduced pressure. By the procedure, 7.43 g of α-amino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester hydrochloric acid salt is obtained (yield, 72%). This product is suspended in ethyl acetate and the obtained suspension is washed with saturated sodium bicarbonate aq. solution, washed with water and dried over anhydrous magnesium sulfate. The oily product obtained by the distillation of the solvent, is dissolved in 60 ml of N,N-dimethylformamide and, to the solution is added 4.2 g of tetramethylguanidine and then 3.94 g of t-butyloxycarbonylazide, followed by the stirring for 15 hours at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and then saturated NaCl aq. solution and dried over anhydrous magnesium sulfate. The oily product obtained by the distillation of the solvent is purified by a column chromatography packed with silica gel. The procedure gives 4.06 g of α-t-butyloxycarbonylamino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester (yield, 46.5%). Melting point: 94°-95° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](OC(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:43])[NH:40][CH2:41][CH3:42])[CH:34]=[CH:33]2)#[N:2].[Na].O>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:43])[NH:40][CH2:41][CH3:42])[CH:34]=[CH:33]2)#[N:2]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc4cc(OCC5CCN(OC(=O)OC(C)(C)C)CC5)c(C#N)cc34)ccc21
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc4cc(OCC5CCNCC5)c(C#N)cc34)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 373.3 %

Procedure:
After dissolving 6-cyano-4-(1-ethylcarbamoylindol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline (180 mg, 0.0753 mmol) in trifluoroacetic acid (1 ml), the solution was stirred at room temperature for 0.5 hour. Saturated sodium bicarnobate water was added, extraction was performed with ethyl acetate and tetrahydrofuran, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, after which ethanol was added to the obtained amorphous substance for crystallization. After dilution with hexane, the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (132 mg, 0.2811 mmol, 88.96%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br>CN(C)C=O.[Cl-].[NH4+]>[CH3:12][O:13][C:14](=[O:17])[CH2:15][O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(O)ccc1F
Reactant: COC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-4-fluorophenol (3.0 g) was added to a stirred suspension of sodium hydride (60% in oil, 0.94 g) in N,N-dimethylformamide (30 mL) at 0° C. The mixture was warmed to room temperature for 15 minutes and then cooled to 0° C. and this mixture was treated with bromoacetic acid methyl ester (3.3 g). The resulting mixture was warmed to room temperature and then stirred at this temperature for 2 hours. The mixture was diluted with dilute aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (2:1:0 to 0:1:0 to 0:20:1 by volume) gave title compound, 2.7 g.
Reaction SMILES: Cl.[CH:2]1([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:21](O)[CH3:22]>O>[NH2:10][C@H:9]([CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:11]([O:13][CH2:21][CH3:22])=[O:12]
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)[C@H](N)CC1CCCCC1
Temperature: 80 °C

Procedure:
The process is performed as in Example 2, starting with 10 g of β-cyclohexyl-(D)-alanine hydrochloride in 96 cm3 of absolute ethanol, by treating it with a stream of dry hydrogen chloride at a temperature in the region of 0° C. for 20 minutes. After heating to about 80° C. for 4 days, followed by cooling to 0° C., the mixture is again treated with a stream of hydrogen chloride for 20 minutes, followed by heating to a temperature in the region of 80° C. for 20 hours. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C., and the residue obtained is dissolved in 200 cm3 of water, made alkaline by addition of 19 g of solid potassium carbonate. After evaporation, the resulting solid is taken up in 200 cm3 of ethanol at a temperature in the region of 80° C. The insoluble material is filtered off and the filtrate is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 130 cm3 of ethanol at room temperature. The insoluble material is filtered off and the filtrate is again evaporated under the same conditions as above. 4.8 g of ethyl (2R)-2-amino-3-cyclohexylpropionate are obtained in the form of a whitish paste. (Rf=0.80 in a 90/10 by volume mixture of ethanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:41]=[CH:40][C:20]([C:21]([N:23]([CH3:39])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][C:34](OCC)=[O:35])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:39])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH:34]=[O:35])=[O:22])=[CH:40][CH:41]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCOc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCC=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-ethoxycarbonylprop-1-yloxy)phenyl]benzamide (1.10 g) in dichloromethane (20 ml) was added dropwise a solution of diisobutylaluminum hydride in toluene (1.5 M solution, 2 ml) at −78° C. and the mixture was stirred at the same temperature for 2 hours. The reaction was quenched with addition of water and the resulting mixture was warmed to ambient temperature. The mixture was extracted with dichloromethane and the organic phase was washed successively with 1N hydrochloric acid, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-formylprop-1-yloxy)phenyl]benzamide (987 mg) as a syrup. The unstable aldehyde was immediately used for next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:22][C:13]2=[N:14][CH:15]=[C:16]([C:18]([O:20]C)=[O:19])[CH:17]=[C:12]2[N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:22][C:13]2=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]2[N:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnc2[nH]c(CNC(=O)OC(C)(C)C)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc2cc(C(=O)O)cnc2[nH]1
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
To a MeOH—H2O (5:1) 72 mL solution of methyl 2-{[(tert-butoxycarbonyl)amino]methyl}-3H-imidazo[4,5-b]pyridine-6-carboxylate (11.0 g, 37.6 mmol) was added lithium hydroxide monohydrate (7.5 g, 179 mmol). After stirring at 60° C. for 4 hr, the reaction mixture was cooled to 0 acidified by 1N HCl to pH 5, concentrated and purified by Prep-HPLC (77×250 mm, JT BAKER C-18 RP column, 10μ particle size, linear gradient, 5% MeCN/H2O+0.1% TFA to 35% MeCN/H2O+0.1% TFA@200 mL/min) to give the title compound (7.5 g, 71%). MS (ESI): m/z 293(M+H). 1H-NMR (400 MHz, d6-DMSO): δ 13.04 (br. s, 1H), 8.84 (s, 1H), 8.31 (s, 1H), 7.56 (s, 1H), 4.39 (s, 2H), 1.35 (s, 9H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Cl-].C([Al+2])C.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cl-].[Cl-].CC1([Ti+2]C2(C)C=CC=C2)C=CC=C1.N12CCN(CC1)CC2>[CH2:3]([C:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:13])=[CH2:1])[CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCC
Reactant: Clc1ccccc1
Agent: CC1([Ti+2]C2(C)C=CC=C2)C=CC=C1
Agent: C1CN2CCN1CC2
Agent: CC[Al+2]
Product: C=C(CCCC)CCCCCC

Procedure:
To a 30 ml glass bottle, under an argon atmosphere, were added 8 milligrams (0.029 millimol) of bis(methylcyclopentadienyl)titanium dichloride, 11 milligrams (0.10 millimol) of 1,4-diazabicyclo(2.2.2)-octane, 5 ml (40 millimol) of 1-hexene, 7 ml of chlorobenzene and finally 0.045 ml (0.44 millimol) of ethylaluminum dichloride. After a reaction of 19.5 hours at 25° C., there had been formed 1.57 millimol of 2-butyl-1-octene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>ClCCl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirred solution of 3-chlorobenzoyl chloride (6.0 mL, 58 mmol) in dichloromethane (150 mL) were added ethyl glycinate hydrochloride (10 g, 72 mmol) and triethylamine (20 mL, 142 mmol). After stirring for 1 h, the mixture was diluted with saturated NaHCO3 and the aqueous layer extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4 and evaporated to dryness in vacuo to give the desired product (9.8 g) as a white solid which was taken on without purification.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:13]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1CCCCC1.N1C=CC=CC=1>[C:1]([N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1=[O:20])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2=[O:20])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCCCCCCCCCCN1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: O=C1CCCCCCCCCCCN1C(=O)c1ccc(C(=O)N2CCCCCCCCCCCC2=O)cc1
Temperature: 0 °C

Procedure:
Terephthaloyl chloride (203 g, i mol) is added in the course of 30 minutes to a solution of ω-laurolactam (403 g, 2 mol) in 1600 ml of cyclohexane and 475 ml of pyridine at room temperature. The mixture is then refluxed for 3 h. After cooling, the flask contents are poured into 3 1 of ice water and the resulting light yellow precipitate is filtered off by suction and dried. Yield 498 g (95%).
Reaction SMILES: OC(C(F)(F)F)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([C:20]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:21]([C:23]#[C:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[N:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.Br[CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([C:20]([CH:35]4[CH2:40][CH2:39][N:38]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:37][CH2:36]4)=[C:21]([C:23]#[C:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[N:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: C(#Cc1nc2c(N3CCOCC3)ccnn2c1C1CCNCC1)c1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CN1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 41f (0.15 g, 0.27 mmol) in DCM (3 mL), DIEA (54 mg, 0.42 mmol) was added. The resulting mixture was stirred for 15 min before the addition of tert-butyl 2-bromoacetate (65 mg, 0.33 mmol). The reaction mixture was stirred at rt for 2 h, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (ethyl acetate:petroleum ether (1:2)) to obtain compound 41g as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H36N6O3: 553.3 (M+H). found: 553.1.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].Cl.[CH3:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34].CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[CH3:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:10]=[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])[C:12]([F:14])=[CH:13][C:2]=1[Cl:1])[CH3:9]
Reactant: CC(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CCNC(=O)C(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-[2-Chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl)-4-fluorophenoxy]propionic acid (20 g) and β-alanine methyl ester hydrochloride (8.2 g) were dissolved in dichloromethane (200 mL). After slowly adding 4-methylmorpholine (14.8 g) dropwise to the reaction mixture, stirring was performed for 1 hour. After adding (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (18.5 g) for 30 minutes, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed with water, dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (24 g) including a trace amount of impurities, which was recrystallized twice using a mixture solvent of ethyl acetate and hexane to give the target compound (18.2 g).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1>CN(C=O)C>[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg (4.2 mmol) of sodium hydride (55%) is added at 0° C. to a solution of 0.54 g (3.83 mmol) of 1-fluoro-4-nitrobenzene and 0.6 g (4.2 mmol) of 2-(4-methylpiperidin-1-yl)ethanol in 10 mL of DMF under an argon atmosphere. The reaction mixture is stirred for 2 hours at 0° C. and then stirred for a further 1.5 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted between water and ethyl acetate. The organic phase is dried, the desiccant is filtered off and the filtrate is evaporated down. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/methanol (9:1)). Yield: 700 mg (69% of theory); C14H20N2O3 (M=264.32); calc.: molecular ion peak (M+H)+: 265; found: molecular ion peak (M+H)+: 265; Rf value: 0.7 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5]([C:6](=[O:14])[O:7][CH2:8]2)=[CH:4][C:3]=1[O:15]C(=O)C.Cl>CO>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5](=[CH:4][C:3]=1[OH:15])[C:6](=[O:14])[O:7][CH2:8]2
Reactant: CC(=O)Oc1cc2c(c([N+](=O)[O-])c1O)COC2=O
Agent: Cl
Solvent: CO
Product: O=C1OCc2c1cc(O)c(O)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Acetic acid 6-hydroxy-7-nitro-3-oxo-1,3-dihydro-isobenzofuran-5-yl ester (4.1 g) was suspended in methanol (150 ml) and 37% HCl (20 ml) followed by stirring at room temperature for 3 days. The precipitate was filtered and washed with methanol.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])=[S:4].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[OH:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]1([N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:3](=[S:4])[NH:2][CH3:1]
Reactant: CNC(=S)C1(n2cnc(C)c2)CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(=S)C1(n2cnc(C)c2)CCCCC1O
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
19.09 g of the N-methyl-1-(4-methylimidazol-1-yl) 2-oxocyclohexanecarbothioamide prepared in the Preparative Example 2 was suspended in 290 ml of methanol. The obtained suspension was stirred under cooling with ice, followed by the addition of 1.44 g of sodium borohydride. The reaction mixture was analyzed by silica gel thin-layer chromatography (developer: a 10:1 mixture of chloroform and methanol). The product was a mixture comprising a lower-polarity diastereomer (L-form) as the main product and a higher-polarity one (M-form). After 30 minutes, the reaction mixture was concentrated to about 70 ml, followed by the addition of about 200 ml of water. The precipitate formed was recovered by filtration and washed with water to give 11.85 g of the title compound as a white solid (yield: 62%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH3:22])=[C:14]2[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>Cl>[C:4]([C:6]1[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH3:22])=[C:14]2[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCCn2c(-c3cccnc3)c(C)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(-c2cccnc2)n(CCOc2ccc(C(=O)O)cc2)c2ccccc12

Procedure:
A mixture of 4.7 g of 1-[2-(4-ethoxycarbonylphenoxy)ethyl]-2-(3-pyridyl)-3-methylindole in 220 ml of 2N hydrochloric acid is heated under reflux for 6 hours. After cooling the solution is made basic with 3 N NaOH and extracted with ethyl acetate. The basic solution is filtered and acidified to pH 6-7 with 5 N HCl. The solid is collected, dried and recrystallized from acetone to give 1-[2-(4-carboxyphenoxy)ethyl]-2-(3-pyridyl)-3-methylindole, m.p. 190°-193°.
Reaction SMILES: C([C@H](NC(=O)[C@H](C1OC(C2C=CC(C3C=CC=CC=3)=CC=2)=CC=1)CC(O)=O)CO)C1C=CC=CC=1.C([O:40][C:41](=[O:73])[CH2:42][CH:43]([C:56]1[O:60][C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)=[CH:58][CH:57]=1)[C:44]([NH:46][C@H:47]([C:52](=[O:55])[NH:53][CH3:54])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:45])(C)(C)C.FC(F)(F)C(O)=O.CC(OC)(C)C>C(Cl)Cl>[CH3:49][C:48]([CH3:51])([CH3:50])[C@H:47]([NH:46][C:44](=[O:45])[CH:43]([C:56]1[O:60][C:59]([C:61]2[CH:62]=[CH:63][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:65][CH:66]=2)=[CH:58][CH:57]=1)[CH2:42][C:41]([OH:73])=[O:40])[C:52](=[O:55])[NH:53][CH3:54]
Reactant: CNC(=O)[C@@H](NC(=O)C(CC(=O)OC(C)(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Agent: O=C(O)C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)C(CC(=O)O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 48 %

Procedure:
According to the procedure described in Example 15(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(S)-(2-biphenyl-4-yl-furan-5-yl)succinamic acid, N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propy]-3-(2-(biphenyl-4-yl)-furan-5-yl)succinamic acid t-butyl ester was deprotected with trifluoroacetic acid in CH2Cl2 after 1 hour. Trituration of crude with MTBE/hex provided in 48% yield N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3-(2-(biphenyl-4-yl)-furan-5-yl)succinamic acid as a rust-colored amorphous solid.