Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@H:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(Cl)(Cl)Cl>C1CCCCC1>[CH3:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[NH:1][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@H:6]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:4])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)[C@H]1CS[C@@H](c2ccccc2)N1C(=O)CN
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](C(=O)OC(C)(C)C)CS[C@H]2c2ccccc2)c1

Procedure:
The operation is carried out in a fashion similar to that described in Example 34, but starting from 0.3 g of tert-butyl (2S,4S)-3-(2 aminoacetyl)-2-phenyl-4-thiazolidinecarboxylate and 0.12 cm3 of 3-methylphenyl isocyanate. After vigorous stirring in cyclohexane, 0.16 g of tert-butyl (2S,4S)-3-{2-[3-(3-methylphenyl)ureido]acetyl}-2-phenyl-4-thiazolidinecarboxylate is thus obtained in the form of an amorphous pale yellow powder ([α]D20 =-62.0°±1.1° (C=1.02%; CHCl3)). [Proton NMR (250 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., general description valid for the other products of the thiazolidine family (at 120° C.): 1.50 (bs, 9H, (CH3)3); 2.3 (s, 3H, CH3); 3.25 and 3.5 (ABX, 2H, CH2S); 3.7 and 4.05 (ABX, 2H, CH2N); 5.0 (bd, 1H, CHN); 6.2 (bds, 1H, NH); 6.4 (bs, 1H, SCHN); 6.7 (bd, 1H, N--C6H4 --C in position 4 or 6); 7.05 to 7.2 (m, 3H, N--C6H4 --C in position 2, 4 and 5); 7.35 (m, 3H, C6H5); (bd, 2H, C6H5); 8.35 (bs, 1H, NH). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2990, 2940, 2860, 1745, 1650, 1615, 1600, 1560, 1495, 1460, 1375, 1155, 785, 735, 700].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH:26]([NH:29][CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(Cc1nc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)no1)C(C)C
Reaction time: 20 h
Yield: 59.9 %

Procedure:
A suspension of 1.20 g (3.14 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 20 ml of N,N-dimethylformamide was treated with 1.59 g (0.0166 mol) of diisopropylamine. After stirring at 80° for 20 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 39:1 as the eluent. The product was recrystallized from ether/n-hexane. There was obtained 0.84 g (60%) of 7-chloro-3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as whitish crystals; m.p. 153°-156°.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8](I)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cu](C#N)[C:14]#[N:15]>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:14]#[N:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(=O)O)c1N
Temperature: 150 °C
Reaction time: 9 h
Yield: 62.9 %

Procedure:
A mixture of 1.0 g of 2-amino-5-iodo-3-methylbenzoic acid, 0.45 g of copper cyanide and 10 ml of N,N-dimethylformamide was stirred at 150° C. for 9 hours. The reaction mixture was concentrated under reduced pressure. Into the residue, 20 ml of water and 2 ml of ethylenediamine were poured, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was filtered, the filtrate was adjusted to around pH 5 by an addition of concentrated hydrochloric acid, and then extracted with ethyl acetate three times. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to obtain 0.40 g of 2-amino-5-cyano-3-methylbenzoic acid of the formula:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl.Cl[CH2:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:17][CH:16]=1>CN(C=O)C>[N:1]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]3)=[O:20])=[CH:29][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN(C)C1CCN(C(=O)c2ccc(CCl)cc2)C1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)c2ccc(Cn3ccc4ccccc43)cc2)C1
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
A solution of indole (29 mg, 0.25 mmol) in DMF (5 mL) at room temperature is treated with sodium hydride (30 mg), stirred for 10 minutes, treated with 1-(4-chloromethylbenzoyl)-3-(N,N-dimethylamino)pyrrolidine hydrochloride (113 mg, 0.37 mmol) stirred at room temperature overnight and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse-phase semi-preparative HPLC to give the title product as a white powder (63 mg), identified by HPLC and mass spectral analyses. MS [348.2 m/e (M+H)], retention time 2.58 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:3][C:2]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(-c2ccncc2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccncc2)cc1-c1ccccc1
Temperature: 80 °C

Procedure:
A stirred mixture of 4-(3-bromo-4-methoxyphenyl)pyridine (1.32 g, 5 mmol), phenylboronic acid (0.67 g 5.5 mmol), tri-o-tolylphosphine (0.152 g, 0.50 mmol), palladium (II) acetate (0.056 g, 0.25 mmol), sodium carbonate (1.06 g, 10 mmol) and water (10 mL) in dimethylformamide (20 mL) is heated at 80° C. for 3 h. The mixture is then treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed (saturated NaCl, dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 98% ethyl acetate/1.8% ethanol/0.2% aqueous NH3(25%)) to give 4-[4-methoxy-3-(phenyl)phenyl]pyridine base. The base is dissolved in diethylether (5 mL), treated with methanolic HCl (excess), evaporated to dryness under reduced pressure and recrystallised from isopropanol-diethylether to give 4-[2-methoxy-(1,1-biphenyl)-5-yl]pyridine, hydrochloride as a pale-yellow crystalline solid, m.p. 180-200° C., and having the following physical characteristics:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[CH:7]=[CH:8][C:9]=1[C:10](=[O:15])[CH2:11][C:12]([CH3:14])=[CH2:13].[Cl-].[NH4+]>CO>[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]([OH:15])[CH2:11][C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)CC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: C=C(C)CC(O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
88.8 mg of sodium borohydride was added to a methanol (5 ml) solution of 280 mg of N-(3-fluoro-4-(3-methyl-3-butenoyl)phenyl)pyridine-2-carboxamide. The reaction liquid was stirred at room temperature for 3 hours, and then poured into an aqueous saturated ammonium chloride solution, extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to obtain the entitled compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH2:11]1[O:14][CH:12]1[CH3:13]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:11][CH:12]([OH:14])[CH3:13]
Reactant: c1ccoc1
Reactant: CC1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)Cc1ccco1
Reaction time: 2 h

Procedure:
To a solution of furan (7.93 g) in tetrahydrofuran (100 ml) cooled to 5° C. was added dropwise n-butyl lithium (80.2 ml, 1.6M in hexanes). The mixture was stirred for 2 h. A solution of propylene oxide (12.2 ml) was added dropwise and the resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with saturated ammonium chloride and extracted with diethyl ether. The organics were dried (MgSO4) and concentrated. The crude oil was distilled to give 1-(2-furyl)-propan-2-ol (3.85 g, b.p. 68-70° C. at 6.0 mm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:24])[CH:11]([CH:16](O)[CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:12][C:13]=2[O:14]C)=[C:4]([CH3:25])[CH:3]=1>CC(C)=O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([CH:9]2[C:10](=[O:24])[C:11](=[CH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:12][C:13]2=[O:14])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)C2CCOCC2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(C)c1C1C(=O)CC(=CC2CCOCC2)C1=O
Temperature: 13 °C

Procedure:
A solution of 2-(4-bromo-2,6-dimethylphenyl)-5-[hydroxy(tetrahydropyran-4-yl)methyl]-3-methoxycyclopent-2-enone (16.0 g, 39.0 mmol) in a mixture of acetone (320 ml) and 2N hydrochloric acid (160 ml) is heated at 13°C. under microwave irradiation for 40 minutes. Volatile solvents are removed in vacuo, followed by the addition of distilled water (250 ml) and extraction with ethyl acetate (3×150 ml). The combined organic extracts are washed with water, brine, dried over sodium sulphate, then filtered and the filtrate concentrated in vacuo. The residue is finally purified by flash column chromatography to afford 2-(4-bromo-2,6-dimethylphenyl)-4-[1-(tetrahydropyran-4-yl)methylidene]cyclopentane-1,3-dione.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(Cl)C(C1C=CC=CC=1)(C)C.[Mg].[CH3:25][Si:26](Cl)([Cl:28])[Cl:27]>C1COCC1>[CH2:1]([CH2:25][SiH:26]([Cl:28])[Cl:27])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Reactant: C[Si](Cl)(Cl)Cl
Agent: CC(C)(CCl)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CC[SiH](Cl)Cl)c1ccccc1
Yield: 65 %

Procedure:
In accord with the procedure of Example 1, neophylmagnesium chloride was prepared from 674 g (4 mol) of neophyl chloride and 105 g (4.4 mol) of magnesium turnings in 1.5 liters of dry THF. The neophylmagnesium chloride was added to 598 g (4 mol) of methyltrichlorosilane and 2 g of cuprous cyanide in 500 ml of THF. 640 g (65% of theory) of neophylmethyldichlorosilane was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].Cl[O-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[N+:1]1([O-:3])[O:2][N:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=12
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: [O-][n+]1onc2ccccc21

Procedure:
18.4 kg (133 moles) of 2-nitroaniline and 0.42 kg (1.3 moles) of tetrabutylammonium bromide are dissolved in 70 kg of toluene. After the addition of 25.3 kg (226 moles) of 50% aqueous potassium hydroxide solution, there is added at 15° to 20° C., during one hour, 110 kg (185 moles) of an aqueous sodium hypochlorite solution. After the addition has been completed, the reaction mixture is allowed to react at 15° to 20° C. for 3 hours, and the aqueous phase is then separated. There is obtained in this manner a solution of benzofurazan-1-oxide in toluene, which solution is suitable for use directly for further reactions, for example for reaction with an acetoacetic acid derivative to the corresponding quinoxaline-1,4-dioxide.
Reaction SMILES: C[C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[H-].[Na+].ClC[CH:18]1C[CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19]1>CN(C)C=O>[C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][CH:3]([CH2:2][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])[CH2:21]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCC1CCN(Cc2ccccc2)C1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CC1CCN(Cc2ccccc2)C1
Temperature: 110 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirred mixture of 43.5 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one and 270 parts of N,N-dimethylformamide are added portionwise 10 parts of sodium hydride dispersion 60%. After stirring for 1 hour at about 40°-50° C., there are added 53 parts of 3-(chloromethyl)-1-(phenylmethyl)pyrrolidine and the whole is stirred and heated overnight at about 110° C. The reaction mixture is cooled and poured onto water. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is taken up in a diluted hydrochloric acid solution and the whole is stirred for 1 hour at room temperature. After cooling, the mixture is alkalized and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane with activated charcoal. The latter is filtered off and the filtrate is allowed to crystallize. The product is filtered off and dried, yielding 40 parts (53%) of 1,3-dihydro-1-[1-(phenylmethyl)-3-pyrrolidinylmethyl]-2H-benzimidazol-2-one.
Reaction SMILES: [O:1]=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12]C)=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.O.[OH-].[Li+]>>[O:1]=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([OH:12])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2=O

Procedure:
The title compound was synthesized from methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (11 mg, 0.06 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol) according to General Procedure 7 (6.8 mg, 67%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.89-2.93 (m, 2H), 2.98-3.02 (m, 2H), 6.89 (s, 1H); LCMS-MS (ESI+) 163.7 (M−H); HPLC (UV=100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][C:8]([CH3:15])([C:11]([O:13]C)=[O:12])[CH2:7][O:6]1.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]1[O:6][CH2:7][C:8]([CH3:15])([C:11]([OH:13])=[O:12])[CH2:9][O:10]1
Reactant: COCCC1OCC(C)(C(=O)OC)CO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCC1OCC(C)(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
478 mg of methyl 2-(2-methoxyethyl)-5-methyl-1,3-dioxane-5-carboxylate (Va-9) are dissolved in 8 ml of tetrahydrofuran, and 92 mg of lithium hydroxide in 2 ml of water are added. The mixture is stirred at room temperature for 16 hours, 92 mg of lithium hydroxide, dissolved in 2 ml of water, are added, and the mixture is stirred for 24 hours. The mixture is acidified with 1N hydrochloric acid and extracted with ethyl acetate, and the solvent of the organic phase is removed under reduced pressure. Water is added to the residue, and the mixture is made basic using 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The aqueous phase is acidified with 1N hydrochloric acid and extracted with ethyl acetate, the organic phase is separated off and dried over sodium sulphate and the solvent is removed under reduced pressure. This gives 261 mg of 2-(2-methoxyethyl)-5-methyl-1,3-dioxane-5-carboxylic acid as a mixture of two isomeric forms in a purity of about 78% (LCMS).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([NH:7][C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[H-].[Na+].[C:19](Cl)(=[O:23])[CH2:20][CH:21]=[CH2:22]>O1CCCC1>[C:10]([C:9](=[C:19]([OH:23])[CH2:20][CH:21]=[CH2:22])[C:8]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)=[O:12])#[N:11]
Reactant: N#CCC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: C=CCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(O)=C(C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
6.0 g (0.026 mole) of 4'-trifluoromethyl-cyanoacetanilide in 200 ml of dry tetrahydrofuran were stirred under nitrogen at room temperature and were treated with 1.95 g (0.065 mole) of sodium hydride 80% oil dispersion. The mixture was stirred for a further 30 minutes at room temperature and cooled to -50° C. before the dropwise addition of 3.3 g (0.033 mole) of 3-butenoyl chloride prepared as described in J. Chem. Soc. (1948), p. 661. The mixture was stirred at -50° C. for 2 hours, then was poured onto dilute hydrochloric acid/ice and filtered. The solid was chromatographed over silica gel eluting with dichloromethane to give 2.4 g (31%) of the title compound as colorless crystals and 3 g of starting material were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3F)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1F)Oc1ccc(Br)cc12
Yield: 69.1 %

Procedure:
A suspension of 6-bromo-2-(2-fluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (250 mg, 0.64 mmol) and Lawesson's Reagent (259 mg, 0.64 mmol) in dry 1,4-dioxane (20 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(2-fluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (180 mg, 67%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20](O)=[O:21])[C:13]=3[N:12]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:48][O:49][C:50](=[O:62])[CH:51]([NH2:61])[CH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=1>C(OCC)(=O)C>[CH3:48][O:49][C:50](=[O:62])[CH:51]([NH:61][C:20]([C:19]1[C:13]2[N:12]=[C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:15][C:14]=2[CH:16]=[CH:17][CH:18]=1)=[O:21])[CH2:52][C:53]1[CH:54]=[C:55]([F:60])[CH:56]=[C:57]([F:59])[CH:58]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Reactant: COC(=O)C(N)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cc(F)cc(F)c1)NC(=O)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Temperature: 25 °C
Yield: 49.3 %

Procedure:
145 mg (0.5 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid (synthesized in Example 1, Step 3)) was reacted with 280 mg (0.75 mmol) of HBTU and 2-amino-3-(3,5-difluoro-phenyl)-propionic acid methyl ester HCl salt (126 mg, 0.5 mmol) as described in general procedure A. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL). The organic phase was washed with 1% NaOH aq. solution, then dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography (DCM/EtOAc=1:1 then DCM/EtOAc/MeOH=15:15:1) to give 3-(3,5-difluoro-phenyl)-2-[(2-isoquinolin-3-yl-1H-benzoimidazole-4-carbonyl)-amino]-propionic acid methyl ester (120 mg, 50%). LCMS: 487 (M+1)+.
Reaction SMILES: CN(C)C1C=CC=CC=1.[NH2:10][C:11]1[C:12]([Cl:19])=[N:13][C:14]([CH3:18])=[CH:15][C:16]=1[Cl:17].O.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[Cl:19][C:12]1[C:11]([NH:10][C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])=[C:16]([Cl:17])[CH:15]=[C:14]([CH3:18])[N:13]=1
Reactant: Cc1cc(Cl)c(N)c(Cl)n1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)c1ccccc1
Product: CC(=O)OCC(=O)Nc1c(Cl)cc(C)nc1Cl
Temperature: 23 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
N,N-Dimethylaniline (142.4 g, 1,175 mmol) was added to a solution of 3-amino-2,4-dichloro-6-methylpyridine (130.0 g, 734 mmol) in chloroform (910 mL). Under cooling with water, a solution of acetyloxyacetyl chloride (150.4 g, 1,102 mmol) in chloroform (390 mL) was added dropwise thereto over 30 minutes while the temperature of the reaction mixture was maintained at 19 to 27° C., followed by stirring at room temperature overnight (18 hours). After HPLC was performed to confirm that starting materials had been completely consumed, water (650 mL) was added to the reaction mixture. The formed organic layer was collected, and the aqueous layer was extracted with chloroform (650 mL). The obtained organic layers were combined, followed by washing sequentially with water and saturated brine. The thus-washed organic layer was dried over sodium sulfate anhydrate, and the solvent was removed under reduced pressure. Subsequently, isopropyl alcohol (195 mL) and diisopropyl ether (390 mL) were added to the residue, and the resultant mixture was heated for dissolution. Diisopropyl ether (650 mL) was added dropwise thereto at an internal temperature of 62 to 66° C. The reaction mixture was cooled, followed by stirring for 3.5 hours under cooling with ice. The crystals that precipitated were collected through filtration, followed by washing with a cooled mixture of isopropyl alcohol (19.5 mL) and diisopropyl ether (104 mL). The obtained mixture was dried at room temperature under reduced pressure, to thereby yield N-[2,4-dichloro-6-methylpyrrolidin-3-yl]-2-acetyloxyacetamide as colorless crystals (171.7 g, 619.6 mmol, yield: 84.4%, HPLC: 99.20%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH2:2]([N:9]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Reactant: NOC1CCCCO1
Agent: Cl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2)NOC1CCCCO1

Procedure:
(−)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid hydrochloride salt (110 mg, 0.275 mmol) was treated with NH2OTHP following the procedure described in Example 1, Step C, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (80 mg) as a light yellow solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH2:6]1[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[CH:9][C:8]=2[O:7]1.C(O)(=O)C>O>[CH2:6]1[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH:16]=[CH:2][C:1]([OH:5])=[O:4])=[CH:9][C:8]=2[O:7]1
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccc2c(c1)OCO2
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C=CC(=O)c1ccc2c(c1)OCO2

Procedure:
44 g of glyoxylic acid, 50 wt.% in water, are heated under reduced pressure to eliminate the major part (80%) of the water present; there are then introduced into the reaction medium 49.2 g of 3',4'-methylenedioxy-acetophenone, and 100 cm3 of acetic acid.