Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13](=[O:17])[CH:14](Br)[CH3:15])([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:8]([O:12][C:13](=[O:17])[C@H:14]([CH3:15])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccccc1)C(=O)OC(C)(C)C
Yield: 81.3 %

Procedure:
A mixture of aniline (9.30 g, 0.10 mol), 2-bromopropionate t-butyl ester 20.9 g, 0.10 mol), Hunig's base (12.90 g, 0.10 mol) and toluene (200 mL) were stirred at reflux for 16 hours. The salt that formed was removed by filtration and the filtrate concentrated in vacuo to an oil (20 g). The oil was distilled. Pure N-phenylalanine t-butyl ester (18.0 g, 81% yield) was collected at 105-115 C (0.08 mm Hg).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:25])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:8][C:7]1[C:2]([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)=[CH:3][C:4]([F:26])=[C:5]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:25])[CH:6]=1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2cc(Cl)c(Br)cc2F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2cc(Cl)c(-c3ccc4cccnc4c3)cc2F)C1
Temperature: 100 °C
Yield: 32.8 %

Procedure:
To a microwave vial were added 4-(4-bromo-5-chloro-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.124 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.16 mmol), cesium carbonate (0.37 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.0062 mmol). The mixture was purged with nitrogen and suspended in 1,4-dioxane (1 mL) and water (0.5 mL). The mixture was heated for 15 h at 100° C. Analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜-6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4, and concentrated to afford the title product as an off-white solid (20 mg, 33%). MS(ES)+ m/e 492.2, 494.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:32]5[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]5)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:29])([F:31])[F:30])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: O=C(O)C1CNC1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CC(C(=O)O)C5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][CH2:23][OH:24])[C:9]([CH:11]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:1]([N:8]1[C:9](=[O:10])[CH:11]([OH:12])[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:24][CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C1OC1c1ccc(Cl)c(Cl)c1)N(CCO)Cc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: O=C1C(O)C(c2ccc(Cl)c(Cl)c2)OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
To a solution of (2RS,3SR)—N-benzyl-3-(3,4-dichlorophenyl)-N-(2-hydroxyethyl)oxirane-2-carboxamide (42.2 g) in acetonitrile (350 ml) was added scandium(III)trifluoromethanesulfonate (5.67 g), and the mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (31.0 g).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C1COCC1.Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>CCN(CC)CC>[CH:34]([O:33][C:31]([N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[S:15][CH:16]=[C:12]([CH2:11][O:10][C:9]3[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:24][CH:23]=3)[N:13]=2)[CH2:18][CH2:19]1)=[O:32])([CH3:36])[CH3:35]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the HCl salt (Intermediate 3, 43 mg, ˜0.12 mmol) of 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine was added 3 mL of THF, followed by isopropyl chloroformate (1.0 M solution in toluene, 0.15 mL, 0.15 mmol) and Et3N (0.05 mL). The resulting mixture was stirred at room temperature for 2 hours, and then partitioned between EtOAc and H2O. After concentration of the organic layer in vacuo, the residue was purified by silica gel column chromatography with EtOAc/hexanes (40-70%) to give the desired product. 1H NMR (CDCl3): δ 7.86 (2H, d, J=9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J=9.0 Hz), 5.22 (2H, s), 4.92 (1H, m), 4.24 (2H, m), 3.17 (1H, m), 3.03 (3H, s), 2.90 (2H, m), 2.10 (2H, m), 1.72 (2H, m), 1.23 (6H, d, J=6.4 Hz).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([Sn:11](Cl)([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>O1CCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
Under argon stream, 3.53 ml (25 mmol) of trimethylsilylacetylene was dissolved in 25 ml of tetrahydrofuran and cooled to -78° C. Into the solution was added dropwise 14.9 ml (24 mmol) of butyllithiumhexane solution, and the reaction was carried out with stirring for 30 minutes. Then, 6.5 ml (24 mmol) of tributyltin chloride was added dropwise, and the reaction was carried out with stirring for 22 hours, while elevating gradually the temperature of the reaction mixture to room temperature. After the reaction, the solvent was evaporated and the residue was distilled under reduced pressure (0.6 mm Hg, 100°-102° C.) to obtain 4.84 g of a transparent liquid (yield: 52.2%).
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#N>C(O)C.[Ni]>[CH2:10]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:7][CH2:8][NH:12][CH2:11]1
Reactant: N#CCc1ccccc1CC#N
Agent: [Ni]
Solvent: CCO
Product: c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.7 %

Procedure:
1,2-Phenylenediacetonitrile (7.5 g, 48 mmol) dissolved in ethanol (150 ml) was added to Raney Ni (2 g) which had been previously washed with ethanol (3×20 ml). The mixture was then hydrogenated at 50° C. at 50 psi pressure with shaking for 24 h. The reaction mixture was then cooled to room temperature and filtered through a pad of kieselguhr and washed through with ethanol (100 ml). The filtrate was evaporated in vacuo to give a brown oil which was chromatographed on silica gel (100 g), eluting with 2-10% methanol in CH2Cl2 to give the title compound as a brown oil (2.45 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5].[Cl-].[NH4+].CO.[H][H]>C1(C)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1Cl
Temperature: 70 °C
Reaction time: 10 h

Procedure:
8.00 g (0.023 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide and 70 mg (6 mol %) of ammonium chloride in 33 g of toluene and 8 g of methanol were admixed with 0.19 g (0.15 mol %) of 10% Pd/C and hydrogenated with 5 bar of hydrogen with stirring at 70° C. After 10 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 6.4 g (89%) of the title compound in the form of a solid (m.p.: 147-149° C.).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.Cl[CH2:21][C:22]1[NH:27][C:26](=[O:28])[NH:25][C:24](=[O:29])[CH:23]=1>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:21][C:22]2[NH:27][C:26](=[O:28])[NH:25][C:24](=[O:29])[CH:23]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=c1cc(CSc2ccc(F)cc2)[nH]c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
DBU (4.02 mL, 26.91 mmol) was added to 4-fluorobenzenethiol (3.45 g, 26.91 mmol), in DMF (90 mL) at RT. The resulting solution was stirred at 20° C. for 15 minutes. 6-(Chloromethyl)-1H-pyrimidine-2,4-dione (2.88 g, 17.94 mmol) was then added and the reaction stirred for 4 hours. The reaction mixture was concentrated and diluted with DCM (100 mL), and washed with water (100 mL). The aqueous layer was acidified with 2M hydrochloric acid to give a white solid which was filtered and washed with water then dried under vacuum to give desired product (2.5 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5](=O)[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:3]1
Reactant: CC1(C)CCC(=O)N(Cc2ccccc2)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCCN(Cc2ccccc2)C1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
A solution of 3,3-dimethyl-1-(phenylmethyl)-2,6-piperidinedione (200 g) in THF (400 ml) is added over 1-4 h (for example 1-2 h) at −5 to +5° C. to a solution of lithium aluminium hydride (68 g) in THF (2 L). The mixture is then heated to 20-35° C. for about 1-2 h, and then to reflux for 24-30 h. The mixture is then cooled to −5 to +5° C. and ethyl acetate (280 ml) is added slowly, followed by aqueous sodium sulphate (257 g in water 1.4 L) and further ethyl acetate (1 L). The mixture is stirred at 25-35° C. for about 1 h. The organic layer is filtered through a Hyflow bed, washing with ethyl acetate (2×2 L). The filtrate layers are combined, then washed with brine (1 L) and evaporated to give the product. The product may be further purified by column chromatography, eluting with petroleum ether and ethyl acetate mixtures or by fractional distillation (dry weight 105 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[O:33][C:34]=1[CH3:35].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl]-1H-pyrazol-4-yl]propionate (505 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 58.0 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. 4-Chloromethyl-5-methyl-2-(2-thienyl)oxazole (310 mg) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[3-methoxy-4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (500 mg, yield: 66%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.Cl>C(O)C.[Ru](=O)=O>[NH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cc1ccc(CCN)cc1
Agent: O=[Ru]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCC(CCN)CC1
Yield: 90 %

Procedure:
by hydrogenation of ethyl 4-(aminoethyl)-phenylacetate hydrochloride in the presence of ruthenium dioxide in ethanol. Yield 90% of theory; hydrochloride m.p. 108°-110° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH3:18].C(O)C(CC)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][C@@H:16]([CH2:17][CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCC(C)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)CO
Product: CC[C@H](C)CCCCCOc1ccc(C#N)cc1

Procedure:
Add 5.75 g of 4-cyanophenol 10 g of 1 brom-6-methyl octane synthesized of available active amyl alcohol, 6.67 g of anhydrous potassium carbonate, 30 ml of N,N-dimethyl formamide into 100 ml four-mouth flask under nitrogen atmosphere, allow to react for 8 hours at 110° C. After the reaction, filter the insoluble matter, then extract ether. The organic layer is then washed with 5% NaOH, water and saturated salt water, then dried and evaporated to remove the ether. Then when the obtained oily matter is refined, 11.4 g of optical (s)-4-(6-methyloctyloxy)benzonitrile is obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([O:25]CC)=[O:24].O.[OH-].[Li+].Cl>C1COCC1.O>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
To a suspension of ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate (10.5 g, 24.5 mmol) in THF (200 mL) and water (100 mL) was added lithium hydroxide monohydrate (3.98 g, 95.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and at ambient temperature for 17 h. The mixture was neutralized with of 4 M HCl (15.0 mL). The residue obtained upon removing the solvent was acidified by the addition of 4 M HCl (6.2 mL) to pH 3. The solid was filtered, washed with water and hexane, and dried under the reduced pressure to give the title compound (8.48 g, 87%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.32-7.06 (m, 4H), 6.79 (d, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 5.84 (m, 2H), 4.92 (m, 1H), 4.69-4.63 (m, 2H), 4.45 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8, 171.8, 155.8, 149.0, 142.4, 141.2, 132.0, 129.0, 124.1, 124.0, 119.2, 108.3, 103.4, 101.5, 93.5, 80.2, 58.2, 41.1; MS (ES−) m/z 338.2 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.Cl.[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28]([NH2:30])=[NH:29].C(N(CCCC)CCCC)CCC.Cl>>[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28]1[N:30]=[C:11]([OH:13])[C:10]([C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[C:16]([OH:18])[N:29]=1
Reactant: N=C(N)c1cnccn1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc(-c2cnccn2)nc(O)c1-c1c(F)cc(F)cc1F
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-(2,4,6-trifluorophenyl)malonate (U.S. Pat. No. 6,156,925)(870 mg, 3.0 mmol), 2-pyrazinecarboxamidine hydrochloride (500 mg, 3.15 mmol), and 600 mg of tributylamine is stirred under nitrogen atmosphere at 180° C. for 1 h and cooled to room temperature. The mixture is cooled to room temperature and treated with 1.0 N hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)pyrimidine-4,6-diol as a tan solid (401 mg), which is used directly in the next step.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13]O>O1CCOCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[ClH:12].[NH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][CH3:20]>C(O)(=O)C>[ClH:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH2:19][CH3:20])=[CH:5][CH:4]=1
Reactant: CCc1nccn1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCc1nccn1N=Cc1ccc(N(C)C)cc1
Reaction time: 24 h

Procedure:
2.24 g (15 mmol) of p-dimethylaminobenzaldehyde are added to a solution of 2.22 g (15 mmol) of 1-amino-2-ethylimidazole hydrochloride in 40 ml of glacial acetic acid. After leaving to stand at room temperature for 24 hours the product is crystallized out by the addition of ether and subsequently recrystallized from ethanol/ether. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazole hydrochloride of melting point 226°-228°.
Reaction SMILES: [C:1]1([C:7](O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:22].S(Cl)(Cl)=O.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]1([C:7]([Cl:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: ClC(c1ccccc1)(c1ccccc1)c1ccncc1
Temperature: 25 °C

Procedure:
92.1 g (0.353 mol) of diphenyl(4-pyridyl)methyl alcohol recrystallized from chloroform and 800 ml of simple-distillation benzene were charged in a 2-l three-necked flask provided with a stirrer and reflux condenser. The mixture was treated at 50° C. to form a suspension. 29.6 ml (0.407 mol) of thionyl chloride was poured in the suspension and the mixture was stirred under reflux for 1 h. The resulting solution was cooled to room temperature. 72.5 ml (0.522 mol) of triethylamine was added thereto and the mixture was stirred for 7 h. The reaction solution was filtered and the filtrate was concentrated to obtain crude diphenyl(4-pyridyl)methyl chloride.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:51]([C:56]([OH:58])=O)=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH2:65]>C1COCC1>[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:56]([C:51]1[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:58]
Reactant: O=C(O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Reactant: CN(C)CCCCN
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (4-dimethylamino-butyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (1.0 g, 2.74 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.45 g, 2.79 mmol, 1.02 eq.) and 4-dimethylaminobutylamine (0.35 g, 3.01 mmol, 1.1 eq.). When complete, the reaction was worked up as described leaving a brown oil.