Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:53][CH2:54][F:55]>O1CCCC1.O>[F:55][CH2:54][CH2:53][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FCCI
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(OCCF)c2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 71.2 %

Procedure:
128 mg (0.21 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(3-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 2.25 ml tetrahydrofurane. 134 mg (0.41 mmol) cesium carbonate and 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 70 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 48 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 70 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane, 2 ml tetrahydrofurane and 134 mg (0.41 mmol) cesium carbonate were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 70 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 100 mg (65%) tert-butyl 4-{3-[(3R)-3-{[1-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].[F:11][C:12]1[C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>>[NH2:9][C:4]1[C:3]([F:10])=[C:2]([C:13]2[C:14]([C:15]#[N:16])=[CH:17][CH:18]=[CH:19][C:12]=2[F:11])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: Nc1ccc(F)c(Br)c1F
Reactant: CC1(C)OB(c2c(F)cccc2C#N)OC1(C)C
Product: N#Cc1cccc(F)c1-c1c(F)ccc(N)c1F
Yield: 25 %

Procedure:
3-Bromo-2,4-difluorophenylamine and 3-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile were coupled together as described in Example 2 to give 3′-amino-6,2′,6′-trifluorobiphenyl-2-carbonitrile as an off-white solid (400 mg, 25%): δH (360 MHz, CDCl3) 6.88 (2H, s), 7.41-7.46 (1H, m), 7.50-7.56 (1H, m), 7.61 (1H, dd, J 7 and 1).
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CCO.C(OCC)C>[C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1(c2ccccc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)C1(c2ccccc2)CCOCC1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
Methyl 4-phenyl-tetrahydro-2H-pyran-4-carboxylate (15.4 g, 69.9 mmol) was dissolved in EtOH (100 mL). KOH (39.2 g, 699 mmol) was then added. The reaction mixture was then heated at reflux for 2 hours and then cooled to ambient temperature, diluted with 150 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, and separated. The aqueous layer was acidified to a pH of 2 with concentrated HCl and extracted with CHCl3 (3×100 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound (11.58 g) as a light yellow solid. MS m/e=229 (M+Na)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(Oc2ccccc2)cc1N
Product: COc1ccc(Oc2ccccc2)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-methoxy-5-phenoxyaniline (62 mg, 0.290 mmol) similar to Example 58 and isolated as a tan solid (46 mg, 54%). 1H NMR (CDCl3): 9.57 (dd, J=1.1, 2.3 Hz, 1H), 8.67 (dd, J=1.8, 4.8 Hz, 1H), 8.42–8.38 (m, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.38–7.31 (m, 2H), 7.25–7.21 (m, 1H), 7.11 (t, J=1.2 Hz, 1H), 7.09–7.03 (m, 2H), 6.91 (d, J=8.7 Hz, 2H), 6.82 (dd, J=2.7, 8.7 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18]([CH2:19][O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 1.47 g, 36.7 mmol) in anhydrous DMF (50 mL) at 0° C. was added solid 3′-hydroxyacetophenone (5.0 g, 36.7 mmol). The mixture was stirred under N2 for 10 min and a clear yellow solution was formed. Then, tert-butylbromoacetate (6.23 mL, 38.5 mmol) was added and the mixture stirred at 0° C. for 5 min and then at room temperature for 20 min. TLC showed no starting material remaining. The mixture was partitioned between EtOAc (250 mL) and water (100 mL). The organic layer was separated, washed with saturated brine, dried (MgSO4) and concentrated in vacuo. Chromatography on silica (20% EtOAc/hexanes) gave 7.6 g (83%) of a white crystal. 1H NMR (CDCl3, 300 MHz) 7.60-7.14 (m, 4H), 4.59 (s, 2H), 2.60 (s, 3H), 1.51 (s, 9H); 13C NMR (CDCl3, 75 MHz) 198.0, 168.0, 158.6, 138.9, 130.1, 122.3, 120.6, 113.5, 83.0, 66.1, 28.4, 27.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([OH:12])=[C:6]([CH2:13][CH3:14])[CH:5]=1.[OH-].[Na+].O.S(OC)(O[CH3:23])(=O)=O>CCOCC>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([O:12][CH3:23])=[C:6]([CH2:13][CH3:14])[CH:5]=1
Reactant: CCc1cc(C(=O)OC)cc(CC)c1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCc1cc(C(=O)OC)cc(CC)c1OC

Procedure:
To a cooled solution of 16.2 (0.078 mol.) of 3,5-diethyl-4-hydroxybenzoic acid methyl ester and 4.0 g. (0.1 mol.) of sodium hydroxide in 100 ml. of water is added 9.8 g. (7.3 ml., 0.079 mol.) of dimethyl sulfate. The reaction mixture is refluxed for two hours. After cooling, ether is added and the layers are separated. The organic phase is washed with water, dilute sulfuric acid and water, dried (Na2SO4) and concentrated to give 3,5-diethyl-4-methoxybenzoic acid methyl ester.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][OH:3])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1
Reactant: CCOC(=O)C=Cc1cc(OC)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCCO)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Synthesized from 3-(3,5-dimethoxyphenyl)acrylic acid ethyl ester according to an analogous synthetic method to Example 22,ethyl 3-(3,5-dimethoxyphenyl)propionate (38.4 g) was added dropwise to a solution of lithium aluminum hydride (12.3 g) in tetrahydrofuran (200 ml) on an ice bath, and the solution was stirred for 15 minutes at room temperature. To the reaction solution were sequentially added water (12 ml), an aqueous solution of 5N sodium hydroxide (12 ml) and water (28 ml), the suspension was filtered, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (24.3 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:27]=[CH:28][CH:29]=[C:17]([Cl:16])[CH:18]=1)[CH2:25][CH3:26]
Reactant: NCc1ccccn1
Reactant: CCC(Oc1cccc(Cl)c1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(Oc1cccc(Cl)c1)C(=O)NCc1ccccn1
Reaction time: 4 h
Yield: 62.9 %

Procedure:
In 50 ml of toluene were dissolved 1.6 g (0.012 mole) of 2-aminomethylpyridine and 1.2 g (0.012 mole) of triethylamine, and thereto was added dropwise a solution 2.8 g (0.012 mole) of 2-(3-chlorophenoxy)-butyroyl chloride in 20 ml of toluene at room temperature with stirring. After the reaction was carried out for 4 hours, the reaction mixture was washed with water, dilute aqueous sodium hydroxide and then water successively. After the toluene layer was dried, the toluene was removed by distillation. The thus obtained oil was subjected to column chromatography to give 2.3 g of N-(2-pyridylmethyl)-2-(3-chlorophenoxy)-butyramide showing nD26 1.5610 as pale yellow oily liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:40](=[O:42])[CH3:41])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(NC(C)=O)c(Cl)c1)CC2
Temperature: 25 °C

Procedure:
A solution of 3 gm (0.0063 mol) of 1-[7,8-dimethoxy-1,3,4,5,-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{4amino-3,5-dichloro-phenyl}ethyl)-amino]-propane in 50 ml of chloroform and 0.7 gm (0.007 mol) of triethylamine was mixed at the boiling point in portions with altogether about 0.8 ml of acetyl chloride. After boiling it for several hours, the reaction mixture was cooled to room temperature and washed with water. The aqueous phase was made strongly alkaline with 2N sodium hydroxide and extracted with methylene chloride. The separated organic phase was dried over sodium sulfate and evaporated. The crude product thus obtained was purified by chromatography on silica gel (particle size: 0.063 to 0.2 mm, eluant: methylene chloride/methanol=8:1).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH3:33])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH3:33])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCCc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: CCCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-propyl-pyrimidine following a procedure analogous to that described in Example 19. LC (method 9): tR=1.86 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C2OCCO2)ccc1F
Temperature: 70 °C

Procedure:
To a solution of 2-fluoro-5-formylbenzonitrile (450 mg, 3 mmol) in toluene (10 mL) was added ethylene glycol (2 mL) and p-toluene sulfonic acid (25 mg). The solution was heated to 70° C. overnight. The solution was cooled to room temperature. Ethyl acetate (100 mL) was added and the solution was washed with sat. sodium bicarbonated (10 mL), water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated to a clear oil (567 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd 1H, J=6.3, 2.3 Hz), 7.74-7.70 (m, 1H), 7.27-7.24 (m, 1H), 5.80 (s, 1H), 4.14-4.08 (m, 4H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[C:14](=[O:16])[NH:13][CH2:12]2)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:6]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[C:14](=[O:16])[NH:13][CH2:12]2)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc2c1C(=O)NC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc2c1C(=O)NC2
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
To a solution of 7-((trimethylsilyl)ethynyl)isoindolin-1-one (160) (0.172 g, 0.634 mmol) in dry THF (8 mL) under an atmosphere of nitrogen was added TBAF (1.0 M in THF, 0.697 mL, 0.697 mmol) dropwise at 0° C. The solution was stirred at this temperature for 1.5 hours and then quenched by the addition of water (2 mL). The reaction mixture was concentrated in vacuo and diluted with DCM (100 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the aqueous layer was extracted with DCM (70 mL), the combined organic layers were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a beige solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 12 g Si Cartridge, 0-80% EtOAc in DCM) to give the title compound (I61) (0.076 g, 76% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 8.59 (s, 1H), 7.61-7.50 (m, 3H), 4.39 (s, 1H), 4.33 (s, 2H). LCMS Method C: rt 4.56 min, m/z 158.1 [M+H]+
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11].Cl>[OH-].[Na+]>[CH2:1]([O:8][CH2:11][CH2:10][C:9]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
To a mixture of benzyl alcohol (108 g, 1 mol) and 40% aqueous solution of sodium hydroxide (10 mL) was added prop-2-enenitrile (58.3 g, 1.1 mol) and the mixture was stirred for 6 hours at room temperature. The mixture was neutralized with 1 N hydrochloric acid, and extracted with dichloromethane (300 mL). The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo to afford 150 g of the desired compound (yield was 93%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[Cl:20][CH:21]([Cl:25])[C:22]([OH:24])=[O:23]>>[Cl:20][C:21]([Cl:25])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:22]([OH:24])=[O:23]
Reactant: Clc1ccc(OCCCCCCCCCCBr)cc1
Reactant: O=C(O)C(Cl)Cl
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCOc1ccc(Cl)cc1
Yield: 50 %

Procedure:
Analogously to the preparation of 62, 13.6 g (65%) 63 was obtained from 7.7 g (60 mmol) 4-chlorophenol and 18 g (60 mmol) 1,10-dibromodecane. 13.3 g (38.0 mmol) 63 was reacted with dichloroacetic acid according to example 9. 5.9 g (50%) 11, melting point 63-64° C. was obtained.
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:14]([O-])=O)=[C:7]([B:11]([OH:13])[OH:12])[CH:8]=[CH:9][CH:10]=1)(=O)C.O[C:18]([C:21](O)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>Cl.O1CCOCC1.C(O)(=O)C.[Pd]>[NH2:14][C:6]1[C:7]([B:11]2[O:12][C:21]([CH3:23])([CH3:22])[C:18]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1cccc(B(O)O)c1[N+](=O)[O-]
Reactant: CC(C)(O)C(C)(C)O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC1(C)OB(c2cccc(N)c2N)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3-acetamido-2-nitrophenyl)boronic acid (300 mg) in 2M aqueous hydrochloric acid solution (4 mL) was heated at 80° C. for 20 min. After cooling to room temperature, the solvent was reduced in vacuo to give a brown solid which was redissolved in 1,4-dioxane (5 mL). Pinacol (316 mg) was added and the mixture heated at 100° C. for 30 min. After cooling to room temperature the solvent was reduced in vacuo to give a beige solid which was dissolved in acetic acid (5 mL). Palladium on carbon (100 mg) was added and the mixture stirred under an atmosphere of hydrogen at 40° C. for 1 h. The reaction mixture was then filtered through Celite and the filtrate reduced in vacuo. Purification by column chromatography gave 2-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9]([NH2:16])([CH2:10]3)[CH2:8]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]#[N:34])=[O:27]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:10][C:9]([NH:16][CH2:25][C:26]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[C:33]#[N:34])=[O:27])([CH2:8]1)[CH:13]([CH2:12]3)[CH2:14]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred mixture of 1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.03,7]nonan-3-amine prepared as in preparation 10 (0.17 g, 0.66 mmol), and K2CO3 (0.28 g, 2.0 mmol) in DMSO (2.6 mL) at ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.13 g, 0.66 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl) hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.1 g) in 40% yield. m/z (M+1) 393; 1H NMR (CDCl3) 300 MHz δ 4.80-4.75 (m, 1H), 3.70-3.37 (m, 4H), 3.36 (t, J=6.6 Hz, 2H), 3.16 (t, J=7.4 Hz, 2H), 2.43-2.37 (m, 1H), 2.35-2.13 (m, 9H), 2.05-1.99 (m, 1H), 1.95-1.75 (m, 5H), 1.70-1.63 (m, 1H), 1.54-1.47 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].C([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)(C)C.Cl.[Al+3].[Cl-].[Cl-].[Cl-]>CCCCCC>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[C:7]([C:12](=[O:13])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C(=O)O)c(C(=O)c2ccccc2)c1
Temperature: 70 °C
Yield: 54 %

Procedure:
4-t-Butyl-phthalic anhydride (36.0 g; 176 mmol) and t-butyl benzene were placed under nitrogen in a 3-neck round-bottom flask equipped with a condenser. The condenser was attached to a water-gas trap for HCl released during the reaction. AlCl3 (56.0 g; 420 mmol) was added in portions during which time the mixture turned dark brown. Stirring became difficult in the thick mixture. The reaction was heated at 70° C. for 1 h and then cooled to room temperature. Ice was added slowly to the flask followed by concentrated HCl solution. A large clump of solid stuck to the bottom of the flask. This was washed multiple times with water and then dissolved in CH2Cl2, washed with water, dried over Na2SO4 and concentrated to give an oily solid. Hexane was added and after sonication, a blue-white solid was collected by filtration. Drying gave product as white solid 32.0 g (54% yield). 1H NMR (CDCl3) δ (ppm): 1.33 (s, 18 H), 7.30 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.63-7.70 (m, 3H), 8.08 (s, 1H); 13C NMR (CDCl3): 30.98, 34.92, 125.36, 125.41, 127.78, 127.84, 128.02, 129.51, 129.60, 129.81, 134.56, 139.83, 152.94, 156.80, 170.80, 196.89.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=2[C:17](O)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=2[C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])[CH2:13][CH2:14]1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CCc1cccc(C2CC2)c1C(=O)O
Product: CCc1cccc(C2CC2)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=327.4 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclopropyl-6-ethyl-benzoic acid (intermediate T).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(Nc2ccccc2N)cc1
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-[(2-nitrophenyl)amino]benzoate from Step A (755 mg, 2.64 mmol) and 10% Pd—C (505 mg) in EtOH (25 mL) was stirred under an atmosphere of hydrogen (ca.1 atm) for 4 h. The mixture was filtered through a pad of celite, washing with EtOH, and the filtrate was concentrated to give the title compound. MS: m/z=257 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: ClCc1nc2ccccc2o1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2nc3ccccc3o2)c(=O)[nH]c1=O
Yield: 54.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (215 mg, yield: 54.9%).