Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH2:25](Br)[CH:26]=[CH2:27].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:27]([O:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:10]2)[CH:5]=[CH:4][CH:3]=1)[CH:26]=[CH2:25]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cccc(O)n2)CN1C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCOc1cccc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)n1
Temperature: 60 °C
Yield: 82 %

Procedure:
A 500 mL round bottom flask under nitrogen was charged with the product of Step 4 (4.95 g, 14.63 mmol), tetrahydrofuran (200 ml), allyl bromide (2.53 ml, 29.3 mmol), and cesium carbonate (4.77 g, 14.63 mmol). Heated in a 60° C. oil bath for 18 hours. HPLC/MS o.k. Cooled. Evaporated. Added 2.5% potassium bisulfate. Extracted three times with ethyl acetate, washed combined organic portions with brine, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate. Subjected to flash column chromatography eluting with 70 hexane/30 ethyl acetate. Evaporation of fractions containing product gave the title compound as a pale oil. (4.56 g, 12.05 mmol, 82% yield). LCMS (ES+) m/z 379.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]2[O:16][CH:6]1[CH2:7][C:8]([C:18]1[N:26](C3CCCCO3)[C:25]3[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22](=[O:37])[N:21]([CH2:38][CH2:39][CH3:40])[C:20]=3[N:19]=1)([OH:17])[CH2:9]2)=[O:4]>Cl.C1COCC1.CO>[CH3:1][O:2][C:3]([CH:5]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]2[O:16][CH:6]1[CH2:7][C:8]([C:18]1[NH:26][C:25]3[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22](=[O:37])[N:21]([CH2:38][CH2:39][CH3:40])[C:20]=3[N:19]=1)([OH:17])[CH2:9]2)=[O:4]
Reactant: CCCn1c(=O)c2c(nc(C3(O)CC4OC(C3)C(C(=O)OC)C4C(=O)OC)n2C2CCCCO2)n(CCC)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3(O)CC4OC(C3)C(C(=O)OC)C4C(=O)OC)nc2n(CCC)c1=O
Yield: 56.4 %

Procedure:
To a solution of 3-[2,6-dioxo-1,3-dipropyl-7-(tetrahydropyran-2-yl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-3-hydroxy-8-oxa-bicyclo[3.2.1]octane-6,7-dicarboxylic acid dimethyl ester (0.060 mmol, 0.030 g) in 1:1 THF/MeOH (6 ml) was added 1N HCl (3 drops). The reaction was stirred at room temperature 3d and then concentrated to dryness. The residue was purified by PLC on a 1 mm layer, eluting with 20% THF/CH2Cl2, providing the title compound (0.0162 g, 56%). 13C NMR (100 MHz, CDCl3): 11.53 (q), 11.50 (q), 21.72 (t), 21.75 (t), 41.74 (t), 43.82 (t), 45.85 (t), 51.02 (d), 52.64 (q), 70.37 (s), 77.12 (d), 107.53 (s), 149.12 (s), 151.17 (s), 156.32 (s), 159.98 (s), 173.36 (s).
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([CH:8]([CH2:9][OH:10])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl benzylmalonate (100g.) was added dropwise to a stirred suspension of lithium aluminium hydride (12g.) in anhydrous diethyl ether (300ml.) at 0° C. under argon. The reaction mixture was then stirred overnight at room temperature and worked up by the conventional procedure, described in J. Org. Chem. 1953, 18, 1190. Evaporation of the ether solution gave 2-benzylpropane-1,3-diol. Phosphorus tribromide (26ml.) was added dropwise to this diol (44g.), whilst stirring at 75° C. After the vigorous reaction had ceased, the temperature was raised to 100° C. and maintained at this temperature overnight. The cooled mixture was poured into ice water (500ml.) and extracted with diethyl ether (2 × 500ml.). The combined ether extracts were washed with aqueous sodium bicarbonate, then brine, dried over sodium sulphate and the ether was evaporated. Distillation of the crude product in vacuo gave 2-benzyl-1,3-dibromopropane b.p. 116°-121° C./1.0 mm. Hg.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+].C1COCC1>CO>[F:1][C:2]([F:16])([F:17])[CH2:3][O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(COCC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Methyl 4-[(2,2,2-trifluoroethoxy)methyl]benzoate (Intermediate 249, 1.05 g, 4.23 mmol) was dissolved in MeOH (10 mL), 2M aq. sodium hydroxide (6.4 mL, 12.69 mmol) was added and the mixture was stirred at room temperature for 3 h. THF (2 mL) was then added and the mixture stirred at room temperature over the weekend. The mixture was then concentrated under vacuum and the residue acidified by adding 2M hydrochloric acid. The mixture was diluted with a little water and extracted with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a white solid (0.974 g, 98%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.14 (2H, d), 7.49 (2H, d), 4.79 (2H, s) and 3.91 (2H, q).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[CH:17][C:15]=2[N:16]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][C:15]=2[N:16]=1
Reactant: CCOC(=O)CCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of ethyl 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionate (5.8 g) in ether (100 ml)-tetrahydrofuran (100 ml) was added lithium aluminum hydride (0.73 g), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added water (4 ml). Insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1, v/v), 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propanol (2.1 g, 41%) was obtained. Recrystallization from dichloromethane-isopropylether gave colorless prisms. Melting point: 102-103° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Cl[C:18]1[N:26]=[C:25]2[C:21]([N:22]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:23]=[N:24]2)=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][C:18]2[N:26]=[C:25]3[C:21]([N:22]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[CH:23]=[N:24]3)=[CH:20][N:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: Clc1ncc2c(ncn2C2CCCCO2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(Oc3ncc4c(ncn4C4CCCCO4)n3)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A 100-mL, round-bottom flask was charged with (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.170 g, 0.60 mmol), 2-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine (0.200 g, 0.84 mmol), potassium carbonate (0.247 g, 1.79 mmol) and N,N-dimethylformamide (6 mL). The resulting mixture stirred overnight at 110° C. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1:1, ethyl acetate/petroleum ether) to afford 1-((S)-6-bromo-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.200 g, 69%) as yellow oil. MS (ESI, pos. ion) m/z 486, 488 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].O[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CSc1ccc(O)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Yield: 64.9 %

Procedure:
A solution of 1.01 g 2-fluoro-4-methylsulfanyl phenol (compound in Production Example D088), 1.28 g t-butyl 4-hydroxy-1-piperidinecarboxylate, 2.5 g triphenylphosphine and 4.2 g diethyl azodicarboxylate (40% toluene solution) in anhydrous tetrahydrofuran (30 mL) was heated for 8 hours under reflux in a stream of nitrogen. Water was added thereto, the reaction mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate and purified by silica gel chromatography (hexane/ethyl acetate) to give 1.41 g t-butyl 4-(2-fluoro-4-methylsulfanylphenoxy)piperidine-1-carboxylate. 5 mL of 4 N hydrogen chloride in ethyl acetate was added to this product and left for 1 hour. The solvent was removed, and the precipitated crystals were washed with ethyl acetate-ether to give 780 mg of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[Si:18]([CH3:21])([CH3:20])[CH3:19].[NH2:22][C:23]1[C:28]([F:29])=[C:27](Cl)[N:26]=[C:25]([C:31]([O:33][CH3:34])=[O:32])[C:24]=1[O:35][CH3:36].C([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-]>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.O.CC#N>[NH2:22][C:23]1[C:28]([F:29])=[C:27]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][C:5]=2[F:17])[N:26]=[C:25]([C:31]([O:33][CH3:34])=[O:32])[C:24]=1[O:35][CH3:36]
Reactant: CC1(C)OB(c2cc(F)c([Si](C)(C)C)cc2F)OC1(C)C
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)c(F)c(N)c1OC
Yield: 59.7 %

Procedure:
(2,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (1.785 g, 4.69 mmol, 82% purity), methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (1 g, 4.26 mmol), Na2CO3 (0.542 g, 5.11 mmol), and PdCl2(PPh3)2 (0.299 g, 0.426 mmol) were suspended in a 3:1 mixture of CH3CN (7.99 mL) and H2O (2.66 mL) in a microwave vial. The reaction mixture was irradiated at 90° C. for 20 min. The reaction was monitored by TLC and ultra performance liquid chromatography (HPLC). The mixture was poured into a half satd aq NaCl solution and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, ISCO, 120 g column, hexanes/EtOAc gradient) to afford the title compound as a yellow solid (0.977 g, 60%): mp 137-139° C.; 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J=7.9, 5.1 Hz, 1H), 7.12 (dd, J=9.3, 4.0 Hz, 1H), 4.60 (s, 2H), 3.97 (s, 3H), 3.97 (s, 3H), 0.33 (d, J=0.8 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −107.12, −121.88, −137.27; ESIMS m/z 384 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.N1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.OC1C=CC=CC=1C=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[C:11](=[O:12])[O:13][C:14]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:15]=3)=[O:16])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: O=Cc1ccccc1O
Product: COc1ccc(C(=O)c2cc3ccccc3oc2=O)cc1
Reaction time: 8 h
Yield: 87.6 %

Procedure:
3.64 g (16.38 mmol) of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate and 1.39 g of piperidine (16.38 mmol) are added to a solution of 2 g (16.38 mmol) of 2-hydroxybenzaldehyde in 15 ml of ethanol. The reaction mixture is stirred for 8 hours at reflux. The solution is cooled, and then the white solid formed is filtered and rinsed with a minimum of ethanol to yield 4.02 g (88%) of 3-(4-methoxybenzoyl)-2H-chromen-2-one.
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=O)[CH2:3]1.[CH3:13][CH:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:15]([C:17]1[CH:18]=C(O)C=[C:21]([CH:23]=1)[OH:22])[CH3:16]>C(O)C>[OH:22][C:21]1[C:11]2[C:4]3[CH2:3][CH:2]([CH3:1])[S:6][C:5]=3[C:7](=[O:8])[O:9][C:10]=2[CH:18]=[C:17]([CH:15]([CH:14]([CH3:13])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:16])[CH:23]=1
Reactant: CCOC(=O)C1SC(C)CC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SC(C)C3
Reaction time: 72 h

Procedure:
To 45 ml. of ethanol was added 8.8 g. of crude ethyl 5-methyl-3-oxo-tetrahydrothiophene-2-carboxylate and 5 g. of 5-(3-methyl-2-octyl) resorcinol. The mixture was cooled in ice and hydrogen chloride was bubbled in for onehalf hour. The mixture was stoppered and let stand at room temperature for 3 days. The reaction mixture was concentrated and dissolved in ether. The ether solution was extracted twice with water and once with aqueous sodium bicarbonate solution. The solution was dried over magnesium sulfate and concentrated. The product was crystallized from acetonitrile to give 4.65 g., m.p. 146°-149°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][C:27](=[O:29])[CH:26]=[CH:25][C:24]=3[CH:30]=2)[C:11](=[O:31])[CH:10]([N:32]2C(=O)C3=CC=CC=C3C2=O)[N:9]=1.O.NN.C(Cl)(Cl)Cl>C1COCC1>[NH2:32][CH:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][C:27](=[O:29])[CH:26]=[CH:25][C:24]=3[CH:30]=2)[C:11]1=[O:31]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1ccc2oc(=O)ccc2c1
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2ccc3oc(=O)ccc3c2)C1=O
Temperature: 25 °C
Yield: 30.1 %

Procedure:
To a suspension of (3RS)-2,3-dihydro-5-(2-flurophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.30 g) in THF (50 ml) was added dropwise hydrazine monohydrate (0.12 g) under stirring at ambient temperature. The mixture was stirred for 2 hours at the same temperature and refluxed under stirring for 2 hours. The reaction mixture was cooled in an ice-bath. The resultant precipitates were filtered off and washed with THF. The filtrate and washing were combined and concentrated in vacuo to afford a residue. The residue was dissolved into chloroform (100 ml) and extracted with 1N-HCl aqueous solution (2×25 ml). The aqueous layer was alkalined with sodium bicarbonate, extracted with chloroform (2×100 ml), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate to afford (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-1H-1,4-benzodiazepin-2-one as a colorless crystalline solid (0.30 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNC(=O)c2ccncc2Nc2ccc(I)cc2F)cc1

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[2-(4-methylphenyl)ethyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.54 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.62 mmol of 2-(4-methylphenyl)ethylamine. LC/MS [10.25 min; 476 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:17]=1)[C:5]2([CH3:25])[CH3:24].[C:26](Cl)(=[O:28])[CH3:27].O>C(Cl)Cl>[C:26]([N:21]1[CH2:22][CH2:23][N:18]([C:16]2[CH:17]=[C:12]([N:6]3[C:5]([CH3:25])([CH3:24])[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:11])[CH:13]=[N:14][CH:15]=2)[CH2:19][CH2:20]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(N2CCNCC2)c1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 5-chloro-3,3-dimethyl-2-(5-piperazin-1-yl-pyridin-3-yl)-2,3-dihydro-isoindol-1-one (52 mg, 0.146 mmol) and TEA (29.5 mg, 0.292 mmol) in DCM (5 mL) was added acetyl chloride (17.2 mg, 0.219 mmol) dropwise at 0° C. After stirring for 1 hour at room temperature, the mixture was treated with water and extracted with DCM. The organic layer was dried over anhy. Na2SO4. After removal of solvent, the residue was purified by preparative HPLC to afford the title compound as a white solid (23 mg, 40%). MS: 399.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(O)CCC.CN1C(=O)N(C)CCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCO
Product: Clc1cccc(Nc2ncnc3[nH]c(-c4ccccc4)cc23)c1
Reaction time: 2 h

Procedure:
A suspension of 1.251 g (5.45 mmol) of 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine and 1.15 ml (10.9 mmol) of 3-chloro-aniline in 20 ml of n-butanol and 0.5 ml of DMPU is heated at boiling for 2 hours. The reaction mixture is cooled and filtered. Stirring of the residue in hot THF/methanol yields the title compound; m.p. 285-286° C.; FAB-MS: (M+H)+ =321.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16](CC#N)[CH:17]=[CH:18][CH:19]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2].[OH-].[Na+].Cl.[C:26]([O:29]CC)(=[O:28])[CH3:27]>C(O)C.O>[CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16]([CH2:27][C:26]([OH:29])=[O:28])[CH:17]=[CH:18][CH:19]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CC#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CC(=O)O)c1

Procedure:
195 mg of the resulting nitrile compound was dissolved in 6 ml of ethanol, and a 3N aqueous solution (2ml) of sodium hydroxide was added. The mixture was refluxed for 3 hours, and then acidified with 1N hydrochloric acid. Ethyl acetate and water were added, and the organic layer separated was worked up in a customary manner. The product was purified by silica gel column chromatography [ethyl acetate / methanol=20/1] to give 176 mg of the captioned compound as a colorless oil.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([C:8]1[CH:36]=[CH:35][C:11]([CH2:12][C:13]23[CH2:20][CH2:19][CH2:18][N:17]2[C:16](=[O:21])[N:15]([C:22]2[CH:27]=[C:26]([N:28]4[CH:32]=[CH:31][CH:30]=[CH:29]4)[CH:25]=[C:24]([Cl:33])[CH:23]=2)[C:14]3=[O:34])=[CH:10][CH:9]=1)#[N:7].[C:37]([O-])(O)=[O:38].[Na+]>CN(C=O)C.O.C(Cl)Cl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]23[CH2:20][CH2:19][CH2:18][N:17]2[C:16](=[O:21])[N:15]([C:22]2[CH:27]=[C:26]([N:28]4[CH:32]=[CH:31][CH:30]=[C:29]4[CH:37]=[O:38])[CH:25]=[C:24]([Cl:33])[CH:23]=2)[C:14]3=[O:34])=[CH:35][CH:36]=1)#[N:7]
Reactant: N#Cc1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(-n4cccc4)c2)C3=O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(-n4cccc4C=O)c2)C3=O)cc1
Reaction time: 1 h

Procedure:
To a solution of POCl3 (0.1 mL) and DMF (0.3 mL) was added after 45 minutes a solution of 5-(4-cyanobenzyl)-3-[3-chloro-5-(1-pyrrolyl)-phenyl]-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.22 g) in DMF (0.5 mL). After 1 hour at room temperature, the reaction mixture was diluted with water (2 mL) and stirred. After 30 minutes, the mixture was diluted with CH2Cl2 and satd. NaHCO3. The organic layer was collected, washed with brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel: EtOAc/hexane: 1/3, Chromatotron) afforded 0.091 g of the titled compound. MS (m/z) 459 (MH+). mp 109.7° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([O:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH:27][C@@H:28]1[CH2:33][CH2:32][NH:31][C@@H:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29]1)[CH3:14]>C(Cl)Cl>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:31]1[CH2:32][CH2:33][C@@H:28]([NH:27][C:19]2[N:18]([CH2:17][CH2:16][O:15][CH2:13][CH3:14])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)[CH2:29][C@@H:30]1[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:4]
Reactant: CCOCCn1c(N[C@@H]2CCN[C@@H](Cc3ccccc3)C2)nc2ccccc21
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: ClCCl
Product: CCOCCn1c(N[C@@H]2CCN(C(=O)c3ccccc3N)[C@@H](Cc3ccccc3)C2)nc2ccccc21
Reaction time: 3 h
Yield: 33.5 %

Procedure:
Isatoic anhydride (0.49 g) was added to a mixture of (±)-trans-1-(2-ethoxyethyl)-N-[2-(phenylmethyl)-4-piperidinyl]-1H-benzimidazol-2-amine (1.14 g) in CH2Cl2 (150 ml), the mixture was stirred for 3 hours and then refluxed for 3 hours. The solvent was evaporated, 2-propanol (100 ml) was added to the residue and the mixture was refluxed for 18 hours. Isatoic anhydride (0.2 g) was added again and the mixture was refluxed for 4 hours. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and evaporated. The residue was crystallized from DIPE, yielding 0.5 g (33.4%) of (±)-trans-1-[2-aminobenzoyl]-4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]amino]-2-(phenylmethyl)piperidine (comp 123; mp. 197.4° C.).
Reaction SMILES: [S-:1][S-:2].[Na+].[Na+].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[S].Br[CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23]>C(O)C>[F:23][C:22]([F:24])=[CH:21][CH2:20][CH2:19][S:1][S:2][CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23]
Reactant: [S-][S-]
Reactant: FC(F)=CCCBr
Agent: [Na+]
Agent: [S-2]
Agent: [S]
Solvent: CCO
Solvent: O
Product: FC(F)=CCCSSCCC=C(F)F

Procedure:
A solution of sodium disulfide (previously prepared from sodium sulfide nonahydrate (53 g) and sulfur (7.0 g) in ethanol (250 cm3)) was added to 1-bromo-4,4-difluorobut-3-ene (50 g) in ethanol (100 cm3). The mixture was gradually heated and stirred under reflux for 2 hours, then cooled and evaporated under reduced pressure. The residue was extracted with diethyl ether, the organic phase filtered to remove sodium bromide and the ether evaporated under reduced pressure to give a liquid which was distilled at 16 mm Hg, bp 120° C. to give the bis-(4,4-difluorobut-3-enyl)disulfide (24 g) as a colourless liquid.