Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:19]=[O:20])C.P(Cl)(Cl)(Cl)=O.O>ClCCCl>[CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:19]=[O:20])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc[nH]1
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Temperature: 50 °C

Procedure:
Next, To a stirred solution of 1H-pyrrole-2-carboxylic acid benzylester (2.0 g, 9.94 mmol) in 1,2-dichloroethane (15 mL) at 5° C. is sequentially added DMF (1.12 g, 15.31 mmol) and phosphoryl trichloride (2.35 g, 15.31 mmol). After the addition, the mixture is heated to 50° C. and stirred for an hour. Water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=3:1) to give 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester; HPLC Retention time 1.64 minutes (condition C): MS 230.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 54 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.22 g, 0.014 mole) and concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into three portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 2.6 g (54% yield) of an oily glass. The glass was dissolved in hot isopropyl ether (with a little isopropyl alcohol added), filtered while hot, and cooled to room temperature with stirring, causing a solid to precipitate. The mixture was cooled in the freezer, and the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature to give 1.60 g of title compound, mp. 110°-113° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.CI.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17]([CH3:27])[C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C(C)(C)C1=O
Temperature: 80 °C

Procedure:
A mixture of 204 mg (0.50 mmol) of 1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione, 0.0411 ml (0.66 mmol) of methyl iodide and 244 mg (0.750 mmol) of Cesium Carbonate in 5.0 ml of N,N-Dimethylformamide was heated at 80° C. for 2 hours. The mixture was filtered, the filtrate concentrated in high vacuum, the residue partitioned between ethyl acetate and water. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to give 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dione. Weight 0.205 (97%). MS (ESI+): 421.9
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1C2C(=CC(OC)=CC=2)N=CC=1C(OCC)=O>CCOC(C)=O.C(O)C.[Pd]>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: [Pd]
Agent: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Reaction time: 8 h
Yield: 89 %

Procedure:
Ethyl 7-methoxyquinoline-3-carboxylate. To a solution of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate (1.24 g, 4.67 mmol) in a mixture of EtOAc (30 mL) and ethanol (30 mL) was added 10% Pd/C (10 mg). The flask was evacuated and filled with nitrogen three times and evacuated and filled with hydrogen three times and stirred overnight. After filtration through a plug of silica the reaction mixture was concentrated onto silica. Purification by FCC (SiO2, 0-10% MeOH/DCM) afforded the title compound as a brown solid (955 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J=2.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H), 4.01-3.93 (m, 3H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=232.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]([CH3:17])=[CH2:16])[C:6]=2[N:18]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]=2[N:18]=1
Reactant: [H][H]
Reactant: C=C(C)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
2-Amino-9-(2-methylprop-2-en-1-yl)-9H-pyrido[2,3-b]indole-3-carboxamide (xii-a, 143 mg) was dissolved in ethanol (40 mL) and placed under an argon atmosphere. 10% Palladium on carbon (26 mg) was added and the reaction placed under an atmosphere of hydrogen by repeated evacuation followed by back-filling using a balloon filled with hydrogen gas. The reaction stirred for 16 h at room temperature then the catalyst was removed by filtration through Celite® and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (5% methanol in methylene chloride) to afford the title compound (44, 44 mg, 65%). NH4OAc standard conditions. DAD Retention time =7.45 min. M+H=283. 1H NMR (300 MHz, CDCl3): Δ 8.22 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.30-7.36 (m, 3H), 7.21 (br s, 1H), 6.66 (br s, 1H), 5.67 (br s, 1H), 4.07 (d, J=7.3 Hz, 1H), 2.28-2.42 (m, 1H), 0.94 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH:1]([C:3]([F:10])([F:9])[C:4]([F:8])([F:7])[CH:5]=[CH2:6])=[CH2:2].[Cl:11][SiH:12]([Cl:14])[Cl:13]>C(Cl)Cl.O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl>[Cl:11][Si:12]([Cl:14])([Cl:13])[CH2:2][CH2:1][C:3]([F:10])([F:9])[C:4]([F:8])([F:7])[CH2:5][CH2:6][Si:12]([Cl:14])([Cl:13])[Cl:11]
Reactant: C=CC(F)(F)C(F)(F)C=C
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: FC(F)(CC[Si](Cl)(Cl)Cl)C(F)(F)CC[Si](Cl)(Cl)Cl
Temperature: 40 °C
Yield: 96 %

Procedure:
1,2-Diethenyltetrafluoroethane (1 g, 6.5 mmol) and 4 mg of hydrogen hexachloroplatinate (IV) hydrate were dissolved in dried CH2Cl2 (15 mL). Trichlorosilane (10 mL, 9.9 mmol) was added dropwise to the stirred solution. The reaction mixture was heated at 40° C. overnight, followed by removal of excess HSiCl3 and solvent by vacuum evaporation. The crude product was recovered in a yield of greater than about 96% (2.6 g). 1H NMR (400 Mz, CDCl3): δ 2.4 (m, 4H), 1.4 (m, 4H). 29Si NMR (CDCl3): 14.1 (s). 19F NMR (CDCl3): −115.1 (t, J=12 Hz, 4F).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.B.CSC.[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][CH2:30][C:31]2=[O:36]>C(Cl)Cl>[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][CH2:30][C@@H:31]2[OH:36]
Reactant: O=C1CCc2c(Br)cccc21
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CSC
Solvent: ClCCl
Product: O[C@H]1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a 100 mL 3-neck flask equipped with an internal thermometer and an addition funnel was added (R)-(+)-2-methyl-CBS-oxazaborolidine (1.6 ml, 1M solution in toluene) and borane-dimethylsulfide (150 uL) under N2. The reaction was stirred at room temperature for 10 min then diluted with DCM (10 mL). Borane-dimethylsulfide (6.0 mL) was added and the reaction cooled to −20° C. A solution of 4-Bromo-2,3-dihydro-1H-inden-1-one (2.5 g, 11.8 mmol) in DCM (10 mL) was added dropwise over 20 min while maintaining the reaction temperature at −20±5° C. The reaction was stirred for 2 h after the addition was complete, then quenched by the dropwise addition of MeOH (10 mL). The reaction mixture was diluted with MeOH (20 mL) and the solvent distilled at atmospheric pressure. MeOH (30 mL) was added in two portions and the distillation was repeated twice. All the solvent was evaporated to give a solid which was purified by silica gel column chromatography (EA/hexanes) and recrystallization from 5:1 hexane/EA (30 mL) to provide 1.56 g (62%) of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol as a white powder IND INT-1. LCMS-ESI (m/z) calculated for C9H9BrO: 213.1; found 196.9 [M-OH]+, tR=3.06 min. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=7.9 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 5.29 (dd, J=12.6, 6.9 Hz, 1H), 3.05 (ddd, J=16.6, 8.7, 4.6 Hz, 1H), 2.87-2.71 (m, 1H), 2.50 (dddd, J=13.2, 8.4, 7.0, 4.6 Hz, 1H), 1.94 (dddd, J=13.5, 8.8, 6.6, 5.5 Hz, 1H), 1.80 (d, J=7.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 146.82, 143.50, 131.24, 128.58, 123.21, 120.25, 76.83, 34.69, 31.19. Chiral HPLC: (S)-4-bromo-2,3-dihydro-1H-inden-1-ol was eluted using 10% IPA in hexanes: >99.9% % ee, tR=6.27 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:12](OC(OCC)OCC)C.[N-:22]=[N+:23]=[N-:24].[Na+]>C(O)(=O)C>[CH3:11][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([N:1]2[CH:12]=[N:24][N:23]=[N:22]2)[CH:3]=1
Reactant: Cc1cc(N)cc2ccoc12
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-n2cnnn2)cc2ccoc12
Reaction time: 4 h

Procedure:
A mixture of 5-amino-7-methyl-benzofuran (350 mg) and triethylorthoformate (0.42 ml) in glacial acetic acid (10 ml) was heated at 80° for 1 hour. Sodium azide (470 mg) was added and stirring continued at 80° C. for 4 hours. The mixture was partitioned between ethyl acetate (25 ml) and 8% sodium bicarbonate solution (40 ml), the aqueous was further extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with hydrochloric acid (2M:25 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by FCC eluting (with ether-hexane (3:1) to give the title compound as a white solid (174 mg), m.p. 118°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:18]=O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=O
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCO
Product: N#CC(CN1CCCC1)c1ccc(Cl)c(Cl)c1

Procedure:
To 100 mL of ethanol is added (18.6 g (0.1 mol) 3,4-dichlorobenzeneacetonitrile, 12.6 g (0.12 mol) of pyrrolidine hydrochloride, 6.0 g (0.2 mol) of paraformaldehyde and 1 mL of concentrated hydrochloric acid. Stir the mixture at reflux. Monitor the progress of the reaction by thin-layer chromatography. Upon completion add 300 mL of 1N HCl and extract with 200 mL of Et2O. Add 4N NaOH to the aqueous solution until basic and extract the aqueous solution with two 100 mL portions of CH2Cl2. Dry the organic phase over anhydrous Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].O1CCC[CH2:11][CH:10]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].BrC(Br)C.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[O:25]1[CH2:29][CH2:28][CH:27]([C:15]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH2:26][CH2:1]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CC1CCCCO1
Reactant: C1CCOC1
Agent: CC(Br)Br
Agent: [Li+]
Product: CCOC(=O)C1(C2CCOCC2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
6.83 mmol of lithium diisopropylamide (2M in tetrahydrofuran) are added dropwise to a solution of 5.69 mmol of ethyl tetrahydropyranylacetate [103260-44-2] in 10 ml of tetrahydrofuran at −78° C. The mixture is stirred at −78° C. for 15 minutes and 7.39 mmol of dibromoethane are added. The reaction mixture is warmed to 0° C. over 15 minutes and then cooled again to −78° C. 6.83 mmol of lithium diisopropylamide (2M in tetrahydrofuran) are again added dropwise to the reaction mixture. It is warmed to room temperature over 2 hours and quenched with 1M HCl. The phases are separated and the aqueous phase is extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is identified by means of the Rf from the residue by flash chromatography (SiO2 60 F).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1>CN1C(=O)CCC1.C(Cl)Cl>[ClH:1].[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:2]3[C:7]([C:8]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=4)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:29]=2)[CH:25]=[N:26]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CC(C)c1ccc(NC(=O)c2cccnc2Cl)cc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1
Product: Cl

Procedure:
A mixture of (2-chloro(3-pyridyl))-N-(4-isopropylphenyl)carboxamide (1.5 g, Step A) and 6-aminoindazole (880 mg) was heated at 160° C. in NMP for 3 h. The reaction was cooled and diluted with CH2Cl2 and washed with water twice, followed by brine. The organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography with 35% EtOAc/Hexane and further mixed with MeOH and 1 N HCl/Et2O (3 ml). The solution was evaporated to furnish the titled compound. MS (ES+): 372 (M+H)+; (ES−): 371 (M−H). Calc'd. for C22H21N5O—371.2.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[C:16]([F:15])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc(F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(F)c3)nc2n(CC)c1=O
Yield: 39.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.77 g (16.7 mmol) of 3-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.96 g (yield 40%) of Compound 128 as a pale yellow powder.
Reaction SMILES: C(O[C:4](=O)[CH:5](N)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2N=C(C3C=CC(NC(OC(C)(C)C)=O)=CC=3)ON=2)=[C:9](F)[CH:8]=1)C.C([O:37][C:38](=[O:85])[CH:39]([NH:67][C:68](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:69])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[N:51]=[C:50]([C:52]3[CH:57]=[CH:56][C:55]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:54][CH:53]=3)[O:49][N:48]=2)=[C:43]([F:66])[CH:42]=1)C.N1CC[O:89][CH2:88]C1>CN(C=O)C>[C:62]([O:61][C:59]([NH:58][C:55]1[CH:56]=[CH:57][C:52]([C:50]2[O:49][N:48]=[C:47]([C:44]3[CH:45]=[CH:46][C:41]([CH2:40][CH:39]([NH:67][C:68]([C:88]4[O:89][C:6]([C:7]5[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=5)=[CH:5][CH:4]=4)=[O:69])[C:38]([OH:37])=[O:85])=[CH:42][C:43]=3[F:66])[N:51]=2)=[CH:53][CH:54]=1)=[O:60])([CH3:65])([CH3:64])[CH3:63]
Reactant: CCOC(=O)C(Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C(N)Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C(=O)NC(Cc3ccc(-c4noc(-c5ccc(NC(=O)OC(C)(C)C)cc5)n4)c(F)c3)C(=O)O)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
2-Amino-3-{4-[5-(4-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluorophenyl}propionic acid ethyl ester. To a stirring solution of 3-{4-[5-(4-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluorophenyl}-2-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid ethyl ester (8.25 g, 12 mol) in DMF (10 mL) was added morpholine (30 mL). The solution was stirred for 2 hrs at room temperature. The solution was then concentrated and extracted with EtOAc (3×100 mL). The combined organic layers were washed sequentially with brine and dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography (PE/EtOAc, 2/1) to give the title compound (4.1 g, 72.7% yield) as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.99 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 4.02-4.08 (m, 2H), 3.63 (t, J=6.8 Hz, 1H), 2.85-2.99 (m, 2H), 1.50 (s, 9H), 1.13 (t, J=6.8 Hz, 3H); EI-MS (m/z): 469 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:9]1[CH2:13][CH2:12][C@H:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][Mg+].[Br-].[NH4+].[Cl-].[CH2:36]1[CH2:40][O:39]CC1>>[CH2:24]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:13][CH2:12][C@H:11]([C:40]([OH:39])([CH3:36])[CH3:31])[CH2:10]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C1CCOC1
Reactant: C[Mg+]
Reactant: O=C(OCc1ccccc1)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 133 %

Procedure:
To a 0° C. solution of trans-benzyl 3-(dibenzylamino)cyclopentanecarboxylate (2.8 g, 7 mmol) in THF (250 mL) was added dropwise MeMgBr (23 mL, 70 mmol). After the addition, the reaction mixture was stirred at room temperature overnight. TLC (PE) showed the reaction was complete. The mixture was cooled and poured into sat. NH4Cl (300 mL) and extracted with EtOAc (100 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to give crude 2-(trans-3-(dibenzylamino)cyclopentyl)propan-2-ol (3 g, 133%) as a yellow liquid.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:33][C:1](=[O:11])[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH2:3])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: NC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: C=C(C(=O)NC1CCCCC1)c1ccccc1
Yield: 28.9 %

Procedure:
This compound was made from atropic acid (10.48 g, 70.8 mmol), N-methylmorpholine (7.8 ml, 70.9 mmol), iso-butyl chloroformate (9.2 ml, 70.9 mmol), and cyclohexylamine (8.1 ml, 70.7 mmol) using the procedure described in Example 3. The crude product was purified by recrystallisation from cyclohexane to give the product (4.69 g), as white crystals, m.p. 131°-133°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CC(C)=O>O>[CH2:34]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2[C:6]([NH:8][C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.3 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenol (56 mg, 0.15 mmol), prepared as described in Example 2, potassium carbonate (40 mg, 29 mmol), benzyl bromide (0.034 mL, 0.29 mmol) and acetone (3 mL) was stirred at room temperature under N2 for 48 h. The reaction mixture was diluted with water, and extracted (3×) with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the target compound (62 mg, 91%) as a white solid: mp 166–168° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.20 (br s, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.36–7.40 (m, 5H), 7.05 (d, J=8.8 Hz, 2H), 6.91 (s, 2H), 5.12 (s, 2H), 2.39 (s, 3H), 2.31 (s, 3H), 2.00 (s, 6H); ESI MS m/z 474 [(M+H)+, calcd for C27H28N3O3S, 474.2].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([O:24][CH3:25])[CH:16]=1>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=1[O:24][CH3:25]
Reactant: COC(=O)CNc1cnccc1I
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (73%). MS (ESI): m/z=291.113 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[C:27](=[O:29])=[O:28]>O1CCCC1>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:27]([OH:29])=[O:28])=[CH:3][CH:4]=3)[CH2:9]2)[CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=O
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a suspension of (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (3.46 g, 10.0 mmol) in tetrahydrofuran (80 ml) was added n-butyllithium (7.7 ml, 12.0 mmol, 1.56 M in hexane) at −78° C. After stirring the mixture for 10 minutes, excess of dry ice was added to the mixture and the reaction mixture was maintained at −78° C. for 1.5 hours and then partitioned between diethyl ether and 0.2 N aqueous sodium hydroxide. The aqueous layer was washed with diethyl ether and neutralized with 1N hydrochloric acid. The resulting aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Filtration of the precipitate gave 4-[(2S)-4-((1R)-1-phenyl-ethy)-morpholin-2-yl]-benzoic acid (3.05 g, 98%) as white crystals.