Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:31]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([C:36]1[CH:37]=[C:38]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH:37]=4)[CH:16]=3)([OH:14])[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:39]=[CH:40][CH:41]=1)=[O:35])[CH3:32]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: CCOC(=O)c1cccc(-c2ccc(C(C)C(O)(c3ccnc(-c4cccc(C(=O)OCC)c4)c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 49, trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester) (Example 26, step 1) was reacted with 3-ethoxycarbonylphenylboronic acid 4 h at 70° C. to give the title compound as a white solid. MS (m/e)=612.2 [M+H+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:12][C:11]([CH:13]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[N:5][CH:4]=1.Cl.C(N=C=NC[CH2:37][CH2:38][N:39]([CH3:41])C)C.ON1C2C=CC=CC=2N=N1.N1CCC1>CN(C)C=O.C(OCC)(=O)C>[N:39]1([C:25]([C:24]2[CH:28]=[CH:29][C:21]([CH:13]([C:11]3[NH:12][C:8]([C:6]4[S:7][C:3]([CH2:2][OH:1])=[CH:4][N:5]=4)=[CH:9][CH:10]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)=[O:27])[CH2:38][CH2:37][CH2:41]1
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: C1CNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1)N1CCC1
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
To a solution of 4-[1-{5-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-pyrrol-2-yl}-2-(tetrahydro-2H-pyran-4-yl)ethyl]benzoic acid (100 mg) in N,N-dimethylformamide (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (70.0 mg) and 1-hydroxybenzotriazole (50.0 mg), and the mixture was stirred for 30 min. To the reaction mixture was added azetidine (21.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (30.0 mg, yield 28%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). MS: 452 (MH+).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][N:13]=2)[C:5]1=[O:26])(=O)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[C:6]2[NH:7][C:8](=[O:10])[C:9](=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:4][C:5]2=[O:26])=[N:13][CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N1CC(=O)NC(=Cc2ccc(OCc3ccccc3)cn2)C1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=Cc1ccccc1
Temperature: 60 °C
Yield: 83 %

Procedure:
Compound A (3.51 g) was added to a 40 mL of dimethylformamide solution containing equal molar of benzaldehyde and 4 equivalents of triethylamine. The solution was refluxed at 60° C. for 16 hr and cooled at ice bath to produce a yellow precipitate. The precipitate was then collected and washed with ethyl acetate to give 3.3 g (83%) of the desired product 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-phenylmethylidenepiperazine-2,5-dione (Compound 1) as a mixture of isomers. The mixture was predominately the ZZ and EZ isomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:50]([CH2:52][NH2:53])[OH:51]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](=[O:16])[NH:53][CH2:52][CH2:50][OH:51])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NCCO)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
(S)-Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (500 mg, 2.2 mmol), HATU (833 mg, 2.2 mmol) and Di-isopropylethylamine (761 μL, 4.4 mmol) were stirred in dry DCM (10 ml) in an ice bath for 5 min, then at room temperature for 5 min. Ethanolamine (198 μL, 3.28 mmol) was added and the reaction stirred at room temperature for 3 hrs. The reaction was diluted with DCM (40 ml), washed with water (50 ml), the DCM layer separated and dried (MgSO4) and concentrated. The residue was columned on silica (20 g isolute). Eluting: MeOH/DCM 0-5% 5 CV, MeOH/DCM 5%-5% 10 CV, MeOH/DCM 5-10% 5 CV. TLC visualized with KMnO4. This yielded the product as a clear oil (327 mg).
Reaction SMILES: COC(C1C=CC(C(O)=O)=CC=1C)=O.Cl.CNC.[CH3:19][N:20]([CH3:34])[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([CH3:33])[CH:24]=1)=[O:22]>>[CH3:19][N:20]([CH3:34])[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([CH3:33])[CH:24]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(=O)N(C)C)cc1C
Agent: CNC
Agent: COC(=O)c1ccc(C(=O)O)cc1C
Agent: Cl
Product: Cc1cc(C(=O)N(C)C)ccc1C(=O)O

Procedure:
In a sealed tube, 1.94 g of dimethyl 2-bromoterephthalate was dissolved in 4 mL of HMPA and degassed with nitrogen prior to adding 1.1 mL of tetramethyl tin and 0.077 g of palladium tetrakistriphenylphosphene. After sealing the tube, the reaction was heated to 65° C. for 16 h. The reaction was then partitioned into ethylether and water and extracted. The organic layers were washed with 5% ammonium hydroxide, 1N HCl, again with 5% ammonium hydroxide, and finally with water. Filtration of the solvent through sodium sulfate and evaporation gave 1.44 g of crude dimethyl 2-methylterephthalate. 210 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M to give 4-(methoxycarbonyl)-3-methylbenzoic acid. Silica gel chromatography was performed (0% to 70% EtOAc gradient in Hexanes) to yield 115 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid. 4-(methoxycarbonyl)-3-methylbenzoic acid was then coupled to dimethylamine hydrochloride via Procedure G. The crude methyl 4-(dimethylcarbamoyl)-2-methylbenzoate was then hydrolyzed via Procedure M to give 110 mg of 4-(dimethylcarbamoyl)-2-methylbenzoic acid. 4-chloro-3-(pyridin-2-yl)aniline was coupled to 110 mg of 4-(dimethylcarbamoyl)-2-methylbenzoic acid via Procedure G to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4,2-trimethylterephthalamide. MS (Q1) 394 (M)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Cl:19])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCl)cc1

Procedure:
A mixture composed of 286 mg of 4-(tert-butyldimethylsilyloxy)benzyl alcohol and 1.75 ml of thionyl chloride was heated under reflux for 1 hour. After the thionyl chloride was distilled off from the reaction mixture under reduced pressure, its azeotropic distillation with toluene was carried out three times to remove any thionyl chloride. Thus, there was obtained 4-(tert-butyldimethylsilyloxy)benzyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.C([O:11][CH:12]=[C:13]([C:19]([O-])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH2:17]([O:16][C:14]([C:13]1[C:12](=[O:11])[N:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]2=[N:8][CH:19]=1)=[O:15])[CH3:18]
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Reactant: Nc1ccc(Cl)nn1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2ccc(Cl)nn2c1=O

Procedure:
A mixture of 3-chloro-6-aminopyridazine [J. Druey et al., Helv. Chim. Acta., 37, 121 (1954)] (8.20 g, 63.56 m mol) and ethyl ethoxymethylenemalonate (15.0 g, 69.4 m mol) in diphenyl ether (70 ml) was heated to distil out ethanol produced. After cooling, the mixture was diluted with n-hexane (300 ml) to precipitate the crude title product, which was dissolved in chloroform (200 ml), treated with a small amount of carbon and evaporated under reduced pressure to 50 ml. The residual solution was diluted with n-hexane (200 ml) to precipitate pure title product. Yield, 7.73 g (56%), M.p. 149°-152° C.
Reaction SMILES: O=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.[BH4-].[Na+]>CO.CS(C)=O>[OH:23][CH2:22][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][C:12]3[CH2:11][C@:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[N:10]=[CH:2]4)[CH2:24][C:13]=3[CH:14]=2)[N:19]=1
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: OCc1ccc2cc3c(cc2n1)C[C@@]1(C=Nc2ncccc21)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde (80 mg, 0.25 mmol, described in Intermediate 10) in a mixture of MeOH (5 mL) and DMSO (1 mL) was added sodium borohydride (19 mg, 0.51 mmol). The resulting mixture was stirred at ambient temperature for 1 h, then the MeOH was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=318 (M+1).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.[Cl-].[Li+].O>CN1CCN(C)C1=O>[CH2:14]([C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:1]=1[OH:8])[OH:7])[C:10]1[O:9][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccco1
Reactant: O=C1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: Oc1ccc(O)c(Cc2ccco2)c1
Temperature: 165 °C
Yield: 70.5 %

Procedure:
A mixture of 1,4-cyclohexanedione (5.6 g; 50 mmol), furan-2-carbaldehyde (4.8 g; 50 mmol) and anhydrous lithium chloride (2.1 g; 50 mmol) in 1,3-dimethyl-2-imidazolidinone (20 ml) was heated with stirring over an a oil bath at atmospheric pressure. The temperature of the bath was maintained at 165° C. for 1 h. The cooled reaction mixture was poured into water (300 ml) and extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with water (2×100 ml), dried over magnesium sulphate and filtered. The organic solvent was removed in vacuo. The residue (9.4 g) was purified by flash chromatography using a silica gel column and toluene/ethyl acetate (90:10) as eluent, to give 6.7 g (70%) of 3-furfurylhydroquinone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.I[CH2:16][CH2:17][CH2:18][CH3:19]>[Cu]I.O1CCCC1>[CH2:16]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: CC1(C)CCCCc2ccc(Br)cc21
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCCc1ccc2c(c1)C(C)(C)CCCC2
Temperature: -15 °C

Procedure:
The corresponding Grignard compound was prepared under argon from 304 mg of Mg shavings and 2.50 g of 2-bromo-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene in 25 ml of abs. tetrahydrofuran. After cooling to −15° C. 206 mg of CuI and 1.78 ml of 1-iodobutane were added in succession. The mixture was left to react at room temperature for 2 hours and then poured into ice/ammonium chloride solution. The solution was extracted with diethyl ether, washed with water, dried and evaporated. After filtration over SiO2 with hexane as the eluent there were obtained 2.27 g of 2-butyl-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo-cycloheptene (contaminated with 4% regioisomers and 6% 5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocyloheptene).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C@@:5]([OH:16])([C:10]1[S:14][C:13]([SH:15])=[N:12][CH:11]=1)[C:6]([F:9])([F:8])[F:7].[OH-].[K+]>C1COCC1.CO.CCOC(C)=O>[F:9][C:6]([F:7])([F:8])[C@:5]([OH:16])([C:10]1[S:14][C:13]([SH:15])=[N:12][CH:11]=1)[CH2:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)C[C@@](O)(c1cnc(S)s1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)C[C@@](O)(c1cnc(S)s1)C(F)(F)F
Temperature: 45 °C

Procedure:
To a solution of (3S)-methyl-4,4,4-trifluoro-3-hydroxy-3-(2-mercapto-1,3-thiazol-5-yl)butanoate (enantiomer #1, 7.54 g, 26.2 mmol) in THF (80 ml) and MeOH (40 ml) was added a solution of KOH (39 ml, 2.67 N, 105 mmol). The mixture was heated at 45° C. for 4 h then cooled to room temperature. The reaction mixture was diluted in EtOAc, washed with HCl 10%, brine and dried over MgSO4. The solvent was evaporated to give the title compound in quantitative yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: Clc1nc(Nc2ccc(Cl)c(Cl)c2)c2nc[nH]c2n1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(Cl)c(Cl)c3)c3nc[nH]c3n2)CC1

Procedure:
2850 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 2140 mg of the product obtained in stage 1 above are added. 50 mg of the expected product are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.C(N(C(C)C)C(C)C)C.Cl.[CH2:24]([O:26][C:27](=[O:32])[C:28]([NH2:31])([CH3:30])[CH3:29])[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[NH:31][C:11]([C:9]1[N:10]=[C:5]2[N:6]([N:7]=[C:2]([Cl:1])[CH:3]=[CH:4]2)[N:8]=1)=[O:13])[CH3:25]
Reactant: CCOC(=O)C(C)(C)N
Reactant: O=C(O)c1nc2ccc(Cl)nn2n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)NC(=O)c1nc2ccc(Cl)nn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
1.52 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 1.45 ml of N-ethyldiisopropylamine were suspended in 15 ml of N,N-dimethylformamide; 1.37 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 3 hours. To the reaction mixture, 1.41 g of 2-aminoisobutyric acid ethyl ester hydrochloride was added, followed by stirring at room temperature for 4 hour. Water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 1.48 g of the title compound. The filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 450 mg of the title compound.
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.CC(C)=[O:17]>O>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([OH:17])[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Reactant: CC(C)=O
Solvent: O
Product: CC1(C)c2cc(C#N)ccc2OC1O

Procedure:
The product of Example 45 (2 g) was boiled under reflux in water (5 ml) and acetone (15 ml) for 31/2 hours. The product was then extracted into diethyl ether, the extracted solution then being washed twice with water, dried over sodium sulphate and run down under vacuum to give 1.7 g of crude product. Recrystallisation from toluene gave pure title product (1.3 g), mp 127°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][C@@H:54]2[CH2:56][O:55]2)[CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:48]4[CH:49]=[CH:50][CH:51]=[C:46]([OH:45])[CH:47]=4)=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc(OC[C@@H]2CO2)c1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(O)c3)cc2)CC1

Procedure:
4-[4-(2-Amino-ethyl)-phenylamino]-piperidine-1-carboxylic acid 4-fluoro-benzylamide (0.66 g, 1.6 mmol) was reacted tert-butyl{3-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane according to Procedure G to yield the title compound (0.284 g, 0.4 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
A slurry of dichlorobis(triphenylphosphine)palladium(II) (119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00 g, 2.79 mmol). The reaction slurry was stirred at 25° C. for 10 min and then treated with a solution of pyridine-4-boronic acid (515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8 mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was heated under reflux for 8 h. The reaction mixture was allowed to cool to 25° C. where it was stirred for 3 d. The reaction mixture was partitioned between water (75 mL) and methylene chloride (75 mL), and the layers were separated. The aqueous layer was further extracted with methylene chloride (75 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester (240 mg, 28%) as a brown oil that was used without further purification and characterization.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C-:18]#[N:19].[Na+].S(=O)(=O)(O)O>O1CCOCC1>[C:18]([CH:12]([OH:13])[C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)#[N:19]
Reactant: [C-]#N
Reactant: O=Cc1cccc(C(=O)c2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CC(O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 1 h

Procedure:
3-Benzoylbenzaldehyde (1.0 g) in dioxan (5 ml) was treated with water (2.5 ml) and sodium cyanide (0.5 g). The whole was cooled below 15° C. and 40% sulphuric acid (1.4 ml) added dropwise (care being taken to ensure that this temperature was not exceeded). Stirring was continued for 1 hour when water (30 ml) was added and the product extracted with methylene chloride and washed with water, saturated NaCl, dried over Na2SO4 and evaporated.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:8]1[C:12]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[C:18]1[C:30]2[C:22](=[CH:23][C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]=3[CH:29]=2)[CH:21]=[C:20]([CH3:32])[O+]=1)[CH3:7].C(C1C2C(F)=CC=CC=2SC=1C=O)C.O.[NH2:48][NH2:49]>CC(O)C>[CH2:6]([C:8]1[C:12]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[C:18]1[C:30]2[CH:29]=[C:28]3[O:27][C:26](=[O:31])[NH:25][C:24]3=[CH:23][C:22]=2[CH2:21][C:20]([CH3:32])=[N:49][N:48]=1)[CH3:7]
Reactant: CCc1c(-c2[o+]c(C)cc3cc4[nH]c(=O)oc4cc23)sc2cccc(F)c12
Reactant: NN
Agent: CCc1c(C=O)sc2cccc(F)c12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(C2=NN=C(C)Cc3cc4[nH]c(=O)oc4cc32)sc2cccc(F)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-(3-ethyl-4-fluoro-1-benzothien-2-yl)-7-methyl-2-oxo-1H,2H-isochromeno[6,7-d][1,3]oxazol-6-ium perchlorate (51 mmol) (obtained according to Steps A and B described in Example 1 using 3-ethyl-4-fluoro-1-benzothiophene-2-carbaldehyde instead of 2-naphthaldehyde) in 2-propanol (468 mL) there is added hydrazine hydrate (6.68 mL; 133 mmol), with vigorous stirring, at ambient temperature. The reaction mixture is stirred for 20 hours at ambient temperature. The crystals obtained are then filtered off and then stirred in warm water (1900 mL) for 30 minutes. After filtration and drying, the solid is purified by chromatography over a silica gel column (eluant: dichloromethane/acetonitrile) to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].I[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[N:6]([CH3:22])[C:15](=[O:18])[N:8]([CH3:7])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]1
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C)c2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
5-Chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one (1.00 g, 4.7 mmol) was stirred in DMF (50 mL) then potassium carbonate (1.29 g, 9.4 mmol) and iodomethane (2.66 g, 18.7 mmol) were added. The reaction was stirred at 75° C. for 1.5 h. The reaction was allowed to cool and solvents were removed under reduced pressure. The residue was partitioned between water and ethyl acetate and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were through a phase separation cartridge and evaporated to afford a brown solid (1.07 g, 95%), which was taken through to the next step with no further purification.