Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:12][B-](F)(F)F.N#[O+]>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([F:12])[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=1
Reactant: F[B-](F)(F)F
Reactant: NC(=O)c1ncc(Br)cc1N
Agent: N#[O+]
Solvent: ClCCl
Product: NC(=O)c1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 3-amino-5-bromopyridine-2-carboxamide (40.0 g, 185.2 mmol) in CH2Cl2 was added nitrosonium tetrafluoroborate (22.71 g, 191.4 mmol). The reaction was stirred at room temperature for 4.5 hours, then concentrated in vacuo and azeotroped with toluene. The residue was suspended in toluene (1100 mL) and heated to 100° C. for 2 hours. The reaction was concentrated in vacuo, and the residue suspended in CH2Cl2. The solid was collected to provide 5-bromo-3-fluoropyridine-2-carboxamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 219.1 for M+H+(79Br).
Reaction SMILES: O[CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[O:8]=[C:6]1[NH:7][C@H:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])[CH2:4][CH2:5]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1CC[C@@H](CO)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CC[C@@H](CN2C(=O)c3ccccc3C2=O)N1
Temperature: -30 °C
Reaction time: 16 h

Procedure:
To (S)-5-(hydroxymethyl)pyrrolidin-2-one (2.00 g, 17.39 mmol) dissolve in 25 mL THF was added phthalimide (2.81 g, 19.13 mmol), triphenylphosphine (5.01 g, 19.13 mmol) and diisopropylazodi-carboxylate (3.33 g, 19.13 mmol). This mixture was stirred for about 16 hr, and then diluted with 200 mL of hexanes and 2 mL of DCM, and then cool at −30° C. The product precipitated and was filtered and dried (4.11 g, 96%, white solid).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)=[N:5][N:4]=[N:3]1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1cccc(N)c1
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
1-Methyl-5-(3-nitrophenyl)-tetrazole (28.8 g, 140 mmol) was dissolved in ethyl acetate (430 mL) and methanol (1270 mL). Palladium on carbon (2.7 g, 10 wt %) was added and the mixture was shaken under a hydrogen atmosphere (60 psig) for 1.5 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to give a white solid (24.0 g, 98%). 1H NMR (300 MHz, CDCl3), δ7.21 (dd, J=8, 7 Hz, 1H) 6.99 (s, 1H), 6.90 (d, J=7 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 5.44 (bs, 2H), 4.10 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:6][CH2:7][C:8]([C:11]1[CH:12]=[C:13]([NH2:32])[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH:17]=2)[N:15]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:48]([O:50][CH2:51][C:52]([Cl:55])([Cl:54])[Cl:53])=[O:49]>CCOC(C)=O.O>[Cl:53][C:52]([Cl:55])([Cl:54])[CH2:51][O:50][C:48](=[O:49])[NH:32][C:13]1[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH:17]=2)[N:15]=[C:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Yield: 126.7 %

Procedure:
A solution of Intermediate 153e (0.41 g, 0.67 mmol) in EtOAc (3 6 mL) was treated with aqueous 1N NaOH (1.2 mL, 1.2 mmol) then 2,2,2-trichloroethyl chloroformate (0.10 mL, 0.74 mmol) and the mixture was stirred at RT for 4 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red oil (0.67 g). The oil was purified by FCC, using 0-25% EtOAc in cyclohexane to give the title compound as a pale golden gum (0.38 g, 72%). LCMS (Method 3): Rt 5.86 min, m/z 788.3, 790.3 [MH+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:20])=[O:19])[CH:14]=3)[CH:9]=2)[CH:2]=1.C(=O)(O)[O-].[Na+:25]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([O-:20])=[O:19])[CH:14]=3)[CH:9]=2)[CH:2]=1.[Na+:25]
Reactant: O=C(O)c1ccc2cc(Cc3cccnc3)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccc2cc(Cc3cccnc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-pyridylmethyl)naphthalene-6-carboxylic acid is dissolved in methanol and to this solution a stoichiometric amount of sodium bicarbonate dissolved in water is added. The mixture is stirred at room temperature for one hour, azeotroped with benzene twice and dried under high vacuum for 3 hours. The solid material is recrystallized from methanol and diethyl ether mixture and dried in vacuum at room temperature overnight to give sodium 2-(3-pyridylmethyl)naphthalene-6-carboxylate.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].O1CCCC1.C(OC(=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26]2[N:34]=[C:33]3[C:29]([N:30]=[CH:31][N:32]3[CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:28]([NH:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[N:27]=2)[CH2:21][CH2:20]1)(C)(C)C.Cl>O1CCOCC1>[CH3:1][NH:2][S:3]([N:44]1[CH2:45][CH2:46][CH:41]([NH:40][C:28]2[N:27]=[C:26]([NH:25][CH:22]3[CH2:23][CH2:24][CH:19]([NH2:18])[CH2:20][CH2:21]3)[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:42][CH2:43]1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4CCCC4)c3n2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNS(=O)(=O)N1CCC(Nc2nc(NC3CCC(N)CC3)nc3c2ncn3C2CCCC2)CC1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Treat a stirred, cooled (0° C.) solution of N-methyl sulfamoyl chloride (0.2 mmol) and anhydrous tetrahydrofuran (275 mL) with a solution of trans-{4-[9-cyclopentyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9a, 0.2 mmol) triethylamine (9a 0.2 mmol) and tetrahydrofuran (4 mL) overnight at room temperature. Warm to 55° C., cool to room temperature and add 1.0 ml of 4N HCl in dioxane. Allow to stand for 3 hours, concentrate and dissolve the residue in DCM using a small amount of methanol as co-solvent if necessary. Purify the product by chromatography on a 2 g silica gel SPE cartridge pre-equilibrated with heptane. Elute the column in three fractions; first fraction 5 ml DCM; fractions 2 and 3 with 10-15 ml of DCM/methanol (4:1). Concentrate the desired fractions, dissolve the residue in ethanol and adjust to pH 2.0 with 10% HCl. Concentrate to dryness to give 4-[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purin-6-ylamino]-piperidine-1-sulfonic acid methylamide. Using N,N-dimethyl sulfamoyl chloride under similar conditions provides the corresponding trans-4-[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purin-6-ylamino]-piperidine-1-sulfonic acid dimethylamide. The corresponding 9-isopropyl and 9-cyclopent-2-enyl compound I sulfonic acid amides are prepared in a similar manner from 9b and 9c.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:25]([C:29]1[N:30]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:31]([CH:35]=[O:36])=[C:32]([Cl:34])[N:33]=1)[CH2:26][CH2:27][CH3:28].C1CCN2C(=NCCC2)CC1>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([NH:47][S:44]([C:41]1[CH:42]=[CH:43][C:38]([CH2:37][N:30]2[C:31]([CH:35]=[O:36])=[C:32]([Cl:34])[N:33]=[C:29]2[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:39][CH:40]=1)(=[O:46])=[O:45])=[O:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
N-Boc-glycine (2.8 g, 16 mmol, 1.0 eq) was dissolved into 50 mL THF. CDI (2.6 g, 16 mmol, 1.0 eq) was added, and the mixture heated to 80° C. for 2 hours. The solution was cooled to room temperature and added to a solution of intermediate (2c) (5.7 g, 16 mmol, 1.0 eq) in 100 mL THF followed by DBU (2.4 mL, 16 mmol, 1.0 eq). The mixture was stirred at room temperature overnight. The mixture was then concentrated, redissolved into 100 mL EtOAc, washed with saturated bicarbonate, saturated aqueous NaCl, dried over MgSO4, and evaporated. The residue was chromatographed (10% MeOH:EtOAc with 0.7% NH3) to yield intermediate (2d) (5.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C1C(=O)N([Br:18])C(=O)C1.C(O)(C(F)(F)F)=O>C(#N)C>[Br:18][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc2nccn2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc2ncc(Br)n2n1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (5 g, 32.6 mmol) in acetonitrile (300 mL) was added NBS (6.37 g, 35.8 mmol) and TFA (0.75 mL). The resulting solution was allowed to stir at it overnight. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc, washed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo to afford 7.2 g (92%) of the title compound as a light yellow solid. 1H-NMR (400 MHz, CDCl3) ppm 7.91 (d, 1H), 7.79 (s, 1H), 7.12 (d, 1H). LCMS (method A): [MH]+=232/234, tR=4.48 min.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].O[CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.C(#N)C>CCOCC>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:27][CH2:28][NH:29][C:30]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:31])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: O=C(NCCO)c1cccnc1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc2c(c1)c(CC(=O)OCCNC(=O)c1cccnc1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A reaction of indomethacin (1.79 g, 5.00 mmol) and the product of Example 91 (0.830 g, 5.00 mmol) was carried out, using dicyclohexylcarbodiimide (1.10 g, 5.50 mmol) as the coupling agent and acetonitrile as the solvent. The first two reactants were dissolved completely and the solution was then cooled to 0° C. The dicyclohexylcarbodiimide was added and the mixture was stirred overnight. The reaction was allowed to continue for 48 hours. The precipitate (1.2 g) was removed by vacuum filtration. The solvent was removed from the filtrate under reduced pressure leaving an oily residue. The product was solidified by stirring with anhydrous ether. It was filtered, air-dried and recrystallized from ethanol/ether. The final product was vacuum filtered, washed with ether, and air dried. The product weighed 1.65 g, giving a 65.2% yield: mp 123°-125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.FC1C=CC(C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[OH:15])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Fc1ccc(Br)cc1
Agent: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Product: OC(c1ccc(F)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared starting from 6.00 g (34.29 mmol) of 4-bromofluorobenzene and 5.78 g (41.14 mmol) of 4-chlorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 7.14 g (88% of theory) of the title compound were obtained.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Br[CH2:18]Br>CN(C=O)C>[O:1]1[CH:2]2[CH2:3][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:6]2[O:7][CH2:18]1
Reactant: BrCBr
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2OCOC2C1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
tert-Butyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate (34.6 g; 0.17 mol) was dissolved in DMF (400 mL) under argon and cooled down to 0-5° C. Sodium hydride (15 g; 0.375 mol) was added portionwise. The reaction mixture formed a foam which was difficult to stir. After 1 hour at 5° C., dibromomethane (15.6 mL; 0.22 mol) was added. After an additional 30 minutes at the same temperature, the reaction mixture was left to rise to ambient temperature. The temperature rose to 35° C. and was stirred overnight. The DMF was evaporated off and the residue partitioned between ethyl acetate and water. The water phase was extracted with ethyl acetate, the organic phases were combined and washed with water, brine, dried over magnesium sulphate and evaporated. The residue was dissolved in a minimum of dichloromethane and purified by flash chromatography using ethyl acetate/petroleum ether (3/7). Evaporation of the solvent gave tert-butyl tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (19.77 g; 54%) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:22])[O:9][CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:21])[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:22])[O:9][CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:21][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:12]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(OCC1CCc2c(O)cccc2C1)N(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 74 %

Procedure:
A suspension of (1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl N,N-diphenylcarbamate (67 mg), ethyl bromoacetate (33 mg) and potassium carbonate (37 mg) in N,N-dimethylformamide (1.0 ml) was stirred at room temperature for 5.5 hours and then extracted with ethyl acetate. The extract was washed with water and brine (twice), dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel to afford [5-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydro-2-naphthyl]methyl N,N-diphenylcarbamate (61 mg) as an oil.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:10]=[C:11]([C:19]([F:22])([F:21])[F:20])[C:12]([CH:15]([CH3:18])[C:16]#[N:17])=[N:13][CH:14]=1)([O-])=O>CC(=O)OCC>[NH2:6][C:9]1[CH:10]=[C:11]([C:19]([F:22])([F:20])[F:21])[C:12]([CH:15]([CH3:18])[C:16]#[N:17])=[N:13][CH:14]=1
Reactant: CC(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C#N)c1ncc(N)cc1C(F)(F)F
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Tin(II) chloride dihydrate (135 mg, 0.600 mmol) was added to a solution of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (73.6 mg, 0.300 mmol) in EA (15 mL). The mixture was at 50° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (55 mg, 0.256 mmol, 85.0% yield) was used to next step without further purification. TLC (PE/EA=5:1, Rf=0.5): 1H NMR (400 MHz, CDCl3) δ: 8.25 (s, 1H), 7.17 (d, J=2.2 Hz, 1H), 4.15-4.28 (m, 1H), 1.66 (d, J=7.1 Hz, 3H); ES-LCMS m/z 216.0 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24].O>O1CCOCC1>[C:25]([C:23]1[CH2:24][O:16][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:15][C:12]=2[CH:13]=1)(=[O:26])[CH3:27]
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Reactant: C=CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)C1=Cc2cc(Oc3ccccc3)ccc2OC1

Procedure:
The starting material is prepared as follows: 5-Phenoxysalicylaldehyde (6.17 g, 28.8 mmol) is dissolved in 100 ml of 1,4-dioxane and treated with potassium carbonate (7.96 g, 57.6 mmol) and methyl vinyl ketone (3.03 g, 43.2 mmol) under nitrogen. The mixture is heated at reflux for 3 hours. Water is added and three extractions with dichloromethane are carried out. The organic extracts are combined, dried (MgSO4) and evaporated. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yields 3-acetyl-6-phenoxy-2H-1-benzopyran as a solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:4]([N:6]1[CH2:14][C@H:13]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH2:30])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH2:12][C@H:7]1[C:8]([O:10][CH3:11])=[O:9])=[O:5]>ClCCCl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:31]1([C@H:3]([NH:2][CH2:20][CH2:19][CH2:18][CH2:17][CH:22]=[CH2:21])[C:4]([N:6]2[CH2:14][C@H:13]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH2:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:7]2[C:8]([O:10][CH3:11])=[O:9])=[O:5])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: C=Cc1cccc(-c2cccc(CO[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](N)C4CCCCC4)C3)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCCCCN[C@H](C(=O)N1C[C@H](OCc2cccc(-c3cccc(C=C)c3)c2)C[C@H]1C(=O)OC)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Et3N (2.0 eq.), hex-5-enal (1.0 eq.) (obtained from hex-5-en-1-ol via a PCC oxidation and sodium triacetoxyborohydride (1.3 eq.) were sequentially added to a 0.07 M solution of methyl (4R)-1-[(2S)-2-amino-2-cyclohexylacetyl]-4-[(3′-vinylbiphenyl-3-yl)methoxy]-L-prolinate hydrochloride 108 in DCE. The reaction mixture was stirred at RT for 2 h then it was diluted with DCM, saturated aqueous NaHCO3 and extracted. The collected organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure to yield a residue that was purified by flash chromatography (SiO2, PE:EtOAc=7:3) to afford the title compound 109 (67%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([C:18]2[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=1)[CH2:14][CH:11]1[CH2:13][CH2:12]1)=[O:6]
Reactant: Cc1cnc(C(CN)CC2CC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1cnc(C(CNC(=O)c2ccccc2Cl)CC2CC2)cn1

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-(5-methylpyrazin-2-yl)propylamine. LCMS (MH+): m/z=330.0, tR (minutes, Method E)=0.61
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].N([O-])=O.[Na+].[BrH:20]>O>[Br:20][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Br
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Temperature: -5 °C

Procedure:
Hydrobromic acid (48% wt. in water, 120 ml) is added dropwise to a suspension of 3-amino-4′-chloro-4-methylbiphenyl (21 g, 0.09 mol) in water (80 ml), and the mixture stirred until the solid is dissolved. The mixture is cooled to −5° C. and a solution of sodium nitrite (10.12 g, 0.14 mol) in water (50 ml) is added dropwise, maintaining the temperature at 0-5° C. The reaction mixture is stirred for 1 hour, then added to a pre-cooled solution of cuprous bromide (17.9 g, 0.12 mol) in hydrobromic acid (48% wt. in water, 120 ml) at 0° C. The reaction mixture is stirred and allowed to warm to room temperature overnight. The mixture is extracted with ethyl acetate, and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 2% ethyl acetate in hexane to give 3-bromo-4′-chloro-4-methylbiphenyl (15.0 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>CN1C(=O)CCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:2]2[N:11]=[C:10]([O:12][CH3:13])[C:9]3[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=3)[N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1cc2nc(Cl)nc(OC)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(OC)c2cc1OC
Yield: 15 %

Procedure:
A mixture of 2-chloro-4,6,7-trimethoxy-quinazoline (0.8 g, 3.14 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 6.28 mmol, 2.0 equiv; commercially available) in anhydrous NMP (8 mL) and triethylamine (2 mL) was heated by microwave irradiation to 170° C. for 1 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with a gradient of toluene/ethyl acetate (4:1→2:1) providing 0.2 g (15%) of the title compound. MS (ISP): 419.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:21][C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:20][C:17]=1[CH:18]=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1C=O
Yield: 71.2 %

Procedure:
In a manner similar to the method described in Example 1a, (2-bromo-ethyl)-carbamic acid tert-butyl ester (10 g, 44.8 mmol) was reacted with 5-chloro-2-hydroxy-benzaldehyde (7 g, 44.8 mmol), K2CO3 (18.6 g, 134 mmol) and KI (1.48 g, 8.96 mmol) to give title compound as a oil (9.56 g)