Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[NH:15][C@@H:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[C@H:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])[CH2:4][CH2:3]1.C=O.[C:41]([BH3-])#N.[Na+].C(OCC)(=O)C>C(#N)C.O>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C@@H:11]2[N:15]([CH3:41])[C@@H:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[C@H:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])[CH2:4][CH2:3]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N[C@H]2CC[C@H](O)CC2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@@H](c2cccc(Cl)c2F)[C@@H]1C(=O)NC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a suspension of 0.50 g (0.89 mmol) of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexyl)-amide in 18.0 mL of acetonitrile under argon, were added 0.89 mL (0.97 mmol) of a 36.5% solution of formaldehyde in water, followed by 65 mg (0.98 mmol) of sodium cyanoborohydride. The resulting solution was stirred at room temperature for 2 hours, upon which it was poured into 50 mL of ethyl acetate. The aqueous phase was separated and the organic phase was washed with a saturated solution of sodium hydrogencarbonate. The latter aqueous phase was reextracted with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue (0.52 g) was purified by chiral HPLC chromatography on a Kromasil C18 column (1100 g batch 4680, 10 μm, 7.65×35 cm), eluting solvent: acetonitrile/water 40/60 v/v+0.1% trifluoroacetic acid; flow: 250 mL/min. The collected solution was treated with sodium hydrogencarbonate up to pH 8 and then extracted 3 times with 200 mL of ethyl acetate. The combined organic extracts were washed twice with 100 mL of water, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was then dried in a dessicator under reduced pressure for 16 hours. 0.17 g of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-1′-methyl-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-hydroxy-cyclohexyl)-amide was obtained as a white solid. mp: 188° C. (Kofler); LC-MS:
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: O=C1NCc2ccccc21
Reactant: Fc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-fluoro-benzene (0.227 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-fluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.198 g, 82%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.26 (s, 2H), 4.68 (s, 2H), 7.04 (t, 2H), 7.35-7.54 (m, 5H), 7.90 (d, 1H). GC-MS: m/z 241 (M)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[C:14]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:15]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:16][C:17]=1[CH2:18][CH3:19])=O)C.[OH-].[K+].C(OCC)C>O1CCCC1>[CH:20]1([C:15]2[C:14]([CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[C:13]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:12]([CH2:10][OH:9])=[C:17]([CH2:18][CH3:19])[N:16]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1c(CC)nc(C2CCCC2)c(COCc2cccc(C(F)(F)F)c2)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1nc(C2CCCC2)c(COCc2cccc(C(F)(F)F)c2)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C

Procedure:
A suspension of 30 mg (0.8 mmol) of lithium aluminum hydride in 10 ml of absol. tetrahydrofuran is heated under argon. After this, 212 mg (0.4 mmol) of 2-cyclopentyl-6-ethyl-4-(4-fluorophenyl)-3-(3trifluoromethylbenzyloxymethyl)-pyridine-5-carboxylic acid ethylester dissolved in 10 ml of absolute tetrahydrofuran is added. Next, the mixture is refluxed for 1 h. After cooling to room temperature, 10 ml of a 10% potassium hydroxide solution is added. The resulting sediment is drawn off by suction and boiled off several times with 10 ml of diethyl ether. The combined mother liquors are dried with sodium sulfate, concentrated in a vacuum, and chromatographed over silica gel (mobile solvent ethyl acetate/petroleum ether 2:8).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([O:19][CH3:20])[CH:8]=1.O>CO>[CH:14]1([O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:21])=[O:4])=[CH:8][C:9]=2[O:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)Cc1ccc(OC2CCCC2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.6 %

Procedure:
Sodium hydroxide (4.75 g, 119 mmol) was added to a solution of (4-cyclopentyloxy-3-methoxy-phenyl)-acetic acid methyl ester (12.4, 46.9 mmol) in methanol) 100 ml)/water (100 ml) and the reaction was stirred at room temperature for 3.5 hours. The methanol was removed under reduced pressure and the aqueous phase was washed with diethylether (100 ml) then acidified to pH 2 using concentrated hydrochloric acid. This was then extracted with ethyl acetate (2×200 ml) and the combined organic extracts were washed with brine (100 ml), dried over Na2SO4 and concentrated under reduced pressure to give (4-cyclopentyloxy-3-methoxy-phenyl)-acetic acid (11.1 g) as a white solid. 1H NMR (400 MHz, CD3OD): δ=6.87 (1H, s), 6.81-6.86 (1H, d), 6.76-6.80 (1H, d), 4.75-4.79 (1H, brs), 3.78 (3H, s), 3.49 (2H, s), 1.71-1.89 (6H, m), 1.56-1.64 (2H, m) ppm. LRMS (electrospray): m/z [M−H]+ 249, [2M−H]+ 499. Anal. Found C, 67.15; H, 7.25. C14H18O4 requires C, 67.18; H, 7.25%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].P(Cl)(Cl)(Cl)=O.[C:18]1(C)C=CC=CC=1.C(N(CC)CC)C>CO>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:12][CH3:18]
Reactant: Cc1ccccc1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: COc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 20 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 2.00 g (7.35 mmol) of 6-iodoquinazolin-4-one, 1.24 g (8.09 mmol) of phosphorus oxychloride, and 10 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 0.82 g (8.09 mmol) of triethylamine was slowly added. The resulting mixture was heated to 75° C., and the reaction was carried out for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 100 mL of methanol was added. The mixture was stirred for 15 minutes at the same temperature, to give 6-iodo-4-methoxyquinazoline. Analysis of the reaction mixture by high performance liquid chromatography indicated that 2.11 g (reaction yield: 99%) of 6-iodo-4-chloroquinazoline was produced.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH2:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
A mixture of (R)-3-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester (1.65 g, 4.79 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (1.14 g, 4.79 mmol), and DIPEA (2.5 mL, 14.4 mmol) in IMS (10 mL) was stirred in a sealed vial for 48 h at 90° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc). The product containing fractions were concentrated in vacuo affording (R)-3-(2-{(S)-1-[9-(Tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}benzoimidazol-1-yl)piperidine-1-carboxylic acid tertbutyl ester as a white foam (2.27 g, 87%). LCMS: RT 2.88 min [M+H]+ 547.1.
Reaction SMILES: [N+:1]([CH:4]([C:8]([OH:10])=O)[C:5]([OH:7])=O)([O-:3])=[O:2].[NH2:11][C:12]([NH2:14])=[O:13]>>[CH:4]1([N+:1]([O-:3])=[O:2])[C:5](=[O:7])[NH:14][C:12](=[O:13])[NH:11][C:8]1=[O:10]
Reactant: O=C(O)C(C(=O)O)[N+](=O)[O-]
Reactant: NC(N)=O
Product: O=C1NC(=O)C([N+](=O)[O-])C(=O)N1

Procedure:
Nitration of malonic acid with acetyl nitrate in acetic acid/acetic anhydride was conducted to obtain nitromalonic acid. To the nitromalonic acid is added urea to obtain a condensation reaction mixture which is refluxed to form dilituric acid in situ. Various salts are separately prepared from the dilituric acid in situ using as cation sources potassium chloride, ammonia, and guanidinium chloride. The potassium diliturate salt, ammonium diliturate, guanidinium diliturate salts are each recovered and isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1O[C:20](=[S:28])OC1C=CC=CN=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:20]=[S:28])[C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1cccc(Cl)c1C(F)(F)F
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: C1CCOC1
Product: FC(F)(F)c1c(Cl)cccc1N=C=S

Procedure:
Prepared analogously to example 192a from 3-chloro-2-trifluoromethyl-phenylamine, thiocarbonic acid O,O-dipyridin-2-yl ester and TEA in THF.
Reaction SMILES: C1(C2[O:12][CH2:11][CH:10]([O:13][C:14]([NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:9][O:8]2)C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH:10]([O:13][C:14]([NH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)=[O:15])[CH2:11][OH:12]
Reactant: CCOC(=O)c1ccc(NC(=O)OC2COC(c3ccccc3)OC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=O)OC(CO)CO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 4-((2-phenyl-1,3-dioxan-5-yloxy)carbonylamino)benzoate (4.70 g, 12.7 mmol) was dissolved in ethanol (500 ml) under argon and Pd/C (2.48 g, 2.3 mmol) was added. The flask was flushed with hydrogen and allowed to stir under 1 atm H2 at room temperature for 16 h. The crude reaction mixture was passed through a plug of celite and the solvent was removed under reduced pressure yielding (3.14 g, 11.2 mmol, 88%). The product was used without any further purification.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:15]=[C:16](C(C)(C)C)[C:17]=1[OH:18])C=C1CCNC1=O)(C)(C)C.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25].[H-].[Na+]>C(OCC)(=O)C>[CH3:23][N:24]([C:26]([O:18][C:17]1[CH:5]=[CH:6][CH:7]=[CH:15][CH:16]=1)=[O:27])[CH3:25]
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 301 mg of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidine-2-one (1.0 mmole) dissolved into 5 ml of DMF, NaH (60% in mineral oil, 85 mg, 2.1 mmole) was added under ice-cooling. The resulting mixture was stirred at room temperature for 30 min, then the solution was cooled again. N,N-Dimethylphenylcarbamate (282 mg, 1.71 mmole) which was prepared according to the method described in J. Org. Chem., p660, 21, 1956was added thereto, then the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was poured into ethyl acetate, which was washed with 1N-HCl, water, and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (toluene:ethyl acetate=2:1) and recrystallized from ether-n-hexane, whereby 190 mg of the objective compound was obtained in 51% yield. The physical constants are described on Table 1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[O:25][CH3:26].C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[O:25][CH3:26]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1I
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A stirred mixture of tert-butyl 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetate (3.93 g, 8.16 mmol) and TFA (5 ml) in CH2Cl2 (5 ml) was refluxed for 3 h. After cooling to rt, the mixture was concentrated in vacuo and H2O (50 ml) was added to this residue. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel with CHCl3—MeOH (9:1) as eluent to give 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetic acid (2.89 g, 83%) as a pale yellow crystalline powder. 1H-NMR (DMSO-d6) δ3.62 (s, 2 H), 3.88 (s, 3 H), 6.78 (d, J=8.3 Hz, 1 H), 6.83-6.87 (m, 1 H), 6.94 (s, 1 H), 7.32-7.36 (m, 1 H), 7.69 (dd, J=8.3, 1.5 Hz, 1 H), 7.84 (dd, J=8.3, 1.5 Hz, 1 H), 7.97-8.00 (m, 1 H), 8.55 (m, 1H), 8.82 (m, 1 H), 12.26 (br s, 1 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>O>[C:16]([NH2:20])(=[O:26])[C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19]([NH2:1])=[O:21].[NH2:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:6][CH2:7]1
Reactant: O=C1NC(=O)c2ccccc21
Agent: NC1CCC(CC2CCC(N)CC2)CC1
Solvent: O
Product: NC(=O)c1ccccc1C(N)=O
Reaction time: 0.67 h

Procedure:
Bis(p-aminocyclohexyl)methane phthalamide was prepared by the aqueous reaction of bis(p-aminocyclohexyl)methane with phthalimide, according to a procedure similar to that published by Spring and Woods noted hereinabove. Thus, an emulsion of the amine in water was made using vigorous stirring. Phthalimide (1.0 mole per 2.4 moles of amine) was finely grounded and added to the emulsion at room temperature within a 10-minute period. The mixture was stirred for an additional 40 minutes and poured into a separatory funnel and extracted with chloroform. The chloroform solution was dried over magnesium sulfate, filtered and stripped. The product was washed with hexane and with anhydrous ethyl ether and then stripped in a vacuum oven.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25](O)=[O:26].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.C(O)(=O)/C=C/C(O)=O.[NH2:51][CH2:52][CH2:53][C:54]#[N:55].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:52]([CH2:53][CH2:54][NH:55][C:25]([C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:8][CH:7]=1)=[O:26])#[N:51]
Reactant: N#CCCN
Reactant: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)c2ncc(C(=O)NCCC#N)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (170 mg, 0.46 mmol) in dry, N,N-dimethylformamide (5 mL) was chilled in an ice bath under argon. With stirring, triethylamine (97 uL, 0.69 mmol) and isobutylchloroformate (72 uL, 0.56 uL) were added. The solution was stirred for 30 min and then 3-aminopropionitrile fumarate (118 mg, 0.92 mmol) and triethylamine (250 uL, 1.79 mmol) were added. The solution was allowed to warmed to room temperature with stirring overnight. The reaction mixture was poured into a 2% aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 107 mg (55%) of an off white solid and used without further purification: APCI-MS m/e calcd for C23H21N3O5(M−H+) 420.4, found 420.0; 1H NMR (300 MHz) compatible.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:6]=1[C:7](OCC)=[O:8].[CH:17]([NH2:19])=O>>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:5]1[C:6]2[C:7]([OH:8])=[N:19][CH:17]=[N:1][C:2]=2[S:3][CH:4]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(-c2ccco2)csc1N
Product: Oc1ncnc2scc(-c3ccco3)c12

Procedure:
Ethyl 2-amino-4-(2-furyl)thiophene-3-carboxylate (500 mg, 2.1 mmol) in formamide (4 ml) was stirred at 180° C. for 3 hours. The precipitate obtained by cooling the reaction mixture was filtered to obtain 5-(2-furyl)-4-hydroxythieno[2,3-d]pyrimidine (330 mg, 1.5 mmol) having the following physical properties:
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=1[CH3:45])[CH3:33].[F:47][C:48]1[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[CH:50][C:49]=1[C:58]1[S:62][C:61]([CH2:63]O)=[C:60]([CH3:65])[CH:59]=1>>[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:63][C:61]2[S:62][C:58]([C:49]3[CH:50]=[CH:51][C:52]([C:54]([F:56])([F:55])[F:57])=[CH:53][C:48]=3[F:47])=[CH:59][C:60]=2[CH3:65])=[CH:40][C:39]=1[CH3:45])[CH3:33]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2F)sc1CO
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3F)cc2C)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate 7) and {5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol (intermediate 124).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[O:15][C:16](/[CH:18]=C/C4C=CC=CC=4)=[N:17][C:11]=3[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:32]CC1.I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>C1COCC1.O.[NH4+].[Cl-].[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[O:15][C:16]([CH2:18][OH:32])=[N:17][C:11]=3[CH2:10][CH2:9]2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(F)cc1)N1CCc2nc(/C=C/c3ccccc3)oc2CC1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(F)cc1)N1CCc2nc(CO)oc2CC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 68.9 %

Procedure:
A 2.5% solution of osmium tetraoxide in tert-BuOH (0.064 mL, 0.005 mmol) was added to a stirred solution of 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-2-[(E)-2-phenylethenyl]-4H-oxazolo[4,5-d]azepine (0.037 g, 0.10 mmol) and N-methylmorpholine-N-oxide (0.024 g, 0.20 mmol) in a mixture of THF (0.5 mL) and H2O (0.10 mL). The mixture was stirred at 100° C. for 5 minutes under microwave irradiation. The solvent was evaporated in vacuo and the crude product dissolved in a mixture of MeOH (0.5 mL) and THF (0.5 mL). Then sodium periodate (0.087 g, 0.41 mmol) was added and the mixture stirred at 120° C. for 15 minutes. The mixture was cooled down to 0° C. and sodium borohydride (0.0.15 g, 0.41 mmol) was added portionwise. The mixture was stirred at room temperature for 15 minutes, diluted with a saturated solution of NH4Cl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepine-2-methanol (0.02 g, 67% yield) as a yellow oil that was used in the next step without further purification. C15H15FN2O3 LCMS: Rt 1.74, m/z 291 [M+H]+ (using method, LC-MS Method 2).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([NH2:12])=[O:11].C(O)=O>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC=O
Solvent: O
Solvent: O=CO
Product: O=CNCc1ccc(O)cc1
Temperature: 189 °C
Yield: 77.4 %

Procedure:
4-hydroxybenzaldehyde (1.22 g or 10 mmol), formamide (22.72 g or 20.03 mL) and formic acid (2.43 g or 2 mL) were placed into a 50 mL round bottom flask equipped with a thermometer, a reflux condenser, a magnetic stirrer and a heating mantle. The reaction mixture was heated to 189° C. The heating was immediately turned off; the reaction flask was quickly raised from the heating mantle and allowed to cool to room temperature. The TLC conducted on the cold reaction mixture confirmed that the reaction was complete. The reaction mixture was diluted with 50 ml of water and extracted with ethyl acetate. The extract was dried with sodium sulfate and the solvent was evaporated to produce 1.17 g (77.1%) of 4-hydroxybenzylformamide (IV).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:16](=[O:27])[CH2:17][NH:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:7]2[CH:13]([CH3:15])[CH3:14].CCO.C(N(CC)CC)C.[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>[Pd].C(OCC)C>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[CH:13]([CH:7]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][C:9]=2[CH3:12])[CH2:4][CH2:5][N:6]1[C:16](=[O:27])[CH2:17][NH:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:15])[CH3:14]
Reactant: Cc1ccc(Br)c2c1C(C(C)C)N(C(=O)CNCC1(O)CCCCC1)CC2
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCO
Product: Cc1cccc2c1C(C(C)C)N(C(=O)CNCC1(O)CCCCC1)CC2
Reaction time: 6 h
Yield: 57.6 %

Procedure:
A mixture of 1-({[2-(5-bromo-1-isopropyl-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol (0.14 g), EtOH (10 mL), triethylamine (0.05 mL), and 10% palladium-supported carbon (10 mg) was stirred under a hydrogen atmosphere for 6 hours. The reaction liquid was filtered and the solvent was evaporated. A 1 M NaOH aqueous solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-MeOH). The resulting residue was dissolved in 2-propanol (0.8 mL). To the reaction liquid were added oxalic acid (23 mg) and diethyl ether (5 mL) and the precipitated solid was collected by filtration and dried to obtain 1-({[2-(1-isopropyl-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol oxalate (0.066 g).