Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1>>[Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C)nc1

Procedure:
C7d was prepared in an analogous fashion to C4d from (S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoic acid C7c and 5-methylpyridin-2-amine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:14])[C:9](=[O:10])[CH2:8][C:7](=[O:11])[C:6]([CH3:13])([CH3:12])[O:5]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=[C:47]([Pb+3])[CH:46]=2)=[CH:41][CH:40]=1>ClCCl.Cl>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=[C:47]([CH:8]3[C:7](=[O:11])[C:6]([CH3:13])([CH3:12])[O:5][C:4]([CH2:3][O:2][CH3:1])([CH3:14])[C:9]3=[O:10])[CH:46]=2)=[CH:43][CH:44]=1
Reactant: COCC1(C)OC(C)(C)C(=O)CC1=O
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(COC)C1=O
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
To a mixture of 2-methoxymethyl-2,6,6-trimethylpyran-3,5-dione (0.141 g, 0.705 mmol) and N,N-dimethylaminopyridine (0.43 g, 3.52 mmol) in a mixed solvent system of anhydrous chloroform (7.5 ml) and anhydrous toluene (1.75 ml), is added 4′-chloro-4-ethylbiphenyl-3-yllead triacetate (0.465 g, 0.775 mmol) in one portion and the mixture heated at 80° C. for 2 hours. The mixture is allowed to cool to room temperature, diluted with dichloromethane and dilute aqueous hydrochloric acid, and stirred for 5 minutes then filtered through diatomaceous earth to remove inorganic residues (additional washing with solvents). The organic fractions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate 4:1 ratio). Fractions containing the desired product are combined and evaporated in vacuo. Trituration with hexanes affords 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2-methoxymethyl-2,6,6-trimethylpyran-3,5-dione (0.070 g) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:23](=[O:24])[C:22]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[C:18]([O:25][CH3:26])[CH:19]=5)[N:14]([CH2:27][O:28][CH3:29])[C:13]=4[C:12]([CH:30]=O)=[CH:11][C:10]=3[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[CH3:33][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]1([N:7]2[C:23](=[O:24])[C:22]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[C:18]([O:25][CH3:26])[CH:19]=5)[N:14]([CH2:27][O:28][CH3:29])[C:13]=4[C:12]([CH:30]=[CH2:33])=[CH:11][C:10]=3[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCn1c2ccc(OC)cc2c2c3c(cc(C=O)c21)C(=O)N(c1ccccc1)C3=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cc2c(c3c4cc(OC)ccc4n(COC)c13)C(=O)N(c1ccccc1)C2=O
Yield: 87.1 %

Procedure:
150 mg of N-phenyl-1-formyl-6-methoxy-9-methoxymethylcarbazole-3,4-dicarboximide and 220 mg of methyltriphenylphosphonium iodide were dissolved in N,N-dimethylformamide. Thereto was added 20 mg of 60% sodium hydride with stirring under ice cooling. The resulting mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added 100 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with 50 ml of water and an aqueous saturated sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: benzene/ethyl acetate=50/1 to 20/1) to obtain 130 mg (yield: 87%) of N-phenyl-6-methoxy-9-methoxymethyl-1-vinylcarbazole-3,4-dicarboximide.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])=[C:2]=[O:3].[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH2:25])[CH2:19][CH2:18]1>C1C=CC=CC=1>[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:2]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=2[C:13]([F:14])([F:15])[F:16])=[O:3])[CH2:19][CH2:18]1
Reactant: NCCN1CCOCC1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Solvent: c1ccccc1
Product: O=C(NCCN1CCOCC1)Nc1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
To a solution of 1-isocyanato-4-nitro-2-(trifluoromethyl)benzene (339 μL, 2.21 mmol, 1.0 equiv) in benzene (3.0 mL), was added 2-morpholinoethanamine (316 mg, 2.43 mmol, 1.0 equiv). The resulting precipitant was filtered and washed with hexanes to provide 1-(2-morpholinoethyl)-3-(4-nitro-2-(trifluoromethyl)phenyl)urea, which was advanced without further purification. MS (MH+) 363; Calculated for C14H17F3N4O4: 362.1
Reaction SMILES: B.CSC.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][CH:17]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH2:18][CH:19]=[CH2:20])=[CH:14][CH:13]=1.O.CC[O:34]CC>C1COCC1>[OH:34][CH2:20][CH2:19][CH2:18][CH:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1)[O:16][C:15]1[CH:29]=[CH:30][C:12]([O:11][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][O:5]2)=[CH:13][CH:14]=1
Reactant: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Reactant: CCOCC
Agent: B
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(CCCO)Oc2ccc(OC3CCCCO3)cc2)cc1
Reaction time: 1.5 h
Yield: 58 %

Procedure:
Borane-dimethylsulfide complex (3.5 mL of 2 M in ether, 7 mmol) was added dropwise to a cooled (5° C.) solution of 4-{1-[4-(tetrahydro-2H-pyran-2-yloxy)phenoxy]-3-butenyl}benzonitrile (see step (i) above; 4.6 g, 13 mmol) in dry THF over a period of 15 min. The resulting mixture was stirred at between 0 and 5° C. for 1.5 h. Stirring was then continued for a further 4 h at rt. Water (14 mL) and NaBO3 (5 g) were added and the mixture stirred overnight. Ether was added and the resulting organic layer was separated, washed with water and brine, dried and then evaporated. The resulting residue was purified by chromatography on silica gel, eluting with IPA:EtOAc:heptane (5:20:70), to give 2.44 g (58%) of the sub-title compound.
Reaction SMILES: CO[N:3]=[C:4]([CH3:22])[CH2:5][C:6]1[C:7](=[O:21])[NH:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[H][H]>C(O)C.[Ni]>[NH2:3][CH:4]([CH3:22])[CH2:5][C:6]1[C:7](=[O:21])[NH:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CON=C(C)CC1=C(c2ccc(OC)cc2)CCCNC1=O
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(C2=C(CC(C)N)C(=O)NCCC2)cc1

Procedure:
The solution of 6.5 g of 3-(2-methoxyiminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone in 150 ml of ethanol is hydrogenated at room temperature and atmospheric pressure in the presence of 10 g of Raney nickel until the uptake of 2 mole equivalents of hydrogen is complete. The mixture is filtered, the filtrate evaporated and the residue dissolved in 100 ml of water and 10 ml of 6 N hydrochloric acid. The acidic solution is washed with diethyl ether, filtered, basified with 30 ml of 3 N aqueous sodium hydroxide and repeatedly extracted with chloroform. The extract is dried, evaporated and the residue is purified by suspension in diethyl ether, to give the 3-(2-aminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 131°-133°.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:23]2[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.[F-].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([C:9]2[N:8]([CH2:7][C:5]3[O:6][C:2]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=4)=[CH:3][CH:4]=3)[C:16]3[C:11]([CH:10]=2)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:25][CH2:24]1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(Br)o2)c1C(F)(F)F
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(-c3cccc(C(F)(F)F)c3)o2)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a solution of (1-[(5-bromo-2-furanyl)methyl]-2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 310C) (0.05 g, 0.12 mmol) in dry dioxane (3 mL) were added [3-(trifluoromethyl)phenyl]boronic acid (0.046 g, 0.24 mmol), potassium fluoride (0.021 g, 0.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol). The mixture was stirred at 100° C. in a sealed tube overnight. Solids were filtered and the filtrate was then concentrated in vacuo. The residue was purified by radial chromatography (0-40% EtOAc-hexanes gradient) and recrystallized by methanol to afford the title compound (0.0185 g, 32% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.69 (d, J=4.9 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 6.63 (d, J=3.4 Hz, 1H), 6.46 (s, 1H), 6.24 (d, J=3.4 Hz, 1H), 5.52 (s, 2H), 2.04 (m, 1H), 1.14 (m, 2H), 0.89 (m, 2H); MS (ES) m/z 475 (M+1).
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[O:15][P:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[C:1]1([C:11]([P:16]2(=[O:15])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]3[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=3[O:17]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: Cc1ccccc1
Product: O=C(c1cccc2ccccc12)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 125 °C

Procedure:
50 g (0.262 mol) of 1-naphthoyl chloride were warmed to 80° to 85° C. under a nitrogen atmosphere. 60.3 g (0.262 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. The reaction proceeded exothermically. The temperature was then increased in steps to 125° C. When the reaction was complete, 90 ml of toluene were added at 40° C. After crystallization 77 g (80% of theory) of the abovementioned compound of melting point 149° to 151° C. were obtained.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][C@H:11]([CH3:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[NH:3][C:4]([C@@H:8]2[CH2:12][C@H:11]([CH3:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:5][CH:6]=1
Reactant: C[C@H]1C[C@@H](c2nc(I)c(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1C[C@@H](c2ncc(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 46.2 %

Procedure:
A solution of (2S,4S)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (2.25 g, 4.4 mmol) in 18 mL ethanol and 18 mL water was treated with sodium sulfite (5.59 g, 44.4 mmol) and heated at 90° C. overnight. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with more ethyl acetate and the combined organic phase was washed with brine, dried over sodium sulphate, filtered, concentrated, and purified by silica gel chromatography to give 766 mg (2S,4S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].[CH2:18]([Mg]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:18]([CH:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1ccccn1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N1C=CC=CC1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 4 chloropyridine (2.50 g) in tetrahydrofuran is chilled to 40° . Phenyl chloroformate (2.8 ml) is then added dropwise, and the resulting thick slurry is warmed to -20° . A solution of 1M benzylmagnesium chloride in tetrahydrofuran (22 ml) is added dropwise, taking care to maintain the temperature below 0°. Upon completion of the addition, the cooling bath is removed and the reaction allowed to warm to room temperature. The reaction is then treated with 50% saturated aqueous ammonium chloride and diluted with diethyl ether (200 ml). The organic phase is washed with 1N hydrochloric acid (50 ml) and 1M disodium hydrogen phosphate (50 ml). Drying and concentration of the organic phase affords the intermediate 2-benzyl-1-carbophenoxy-1,2-dihydropyridine as an oil (7.2 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.Cl.[CH3:27][N:28]([CH2:30][C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>C1COCC1>[CH3:27][N:28]([CH3:29])[CH2:30][C:31]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1)=[O:32]
Reactant: CN(C)CC(=O)Cl
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CN(C)C)C3)s2)noc1C(F)(F)F
Reaction time: 16 h
Yield: 77.6 %

Procedure:
A solution of ((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 26, 79 mg, 0.20 mmol) in THF (3 mL) was treated with dimethylaminoacetyl chloride hydrochloride (40 mg, 0.24 mmol) followed by triethylamine (62 μL, 0.44 mmol). The resulting mixture was stirred for 16 hr, evaporated to an oil, and dissolved in water (3 mL). The solution was then basified with a saturated aqueous K2CO3 solution and the precipitated product filtered, washed with water, and air dried to afford product as a colorless solid (69 mg, 78%). 1H NMR (CDCl3) 1.62-1.72 (m, 2 H), 1.78-1.84 (m, 1 H), 1.94-2.04 (m, 1 H), 2.25 (s, 6 H), 2.32 (d, J=1.3, 3 H), 2.49 (s, 2 H), 3.24-3.40 (m, 2 H), 3.94-4.04 (m, 2 H), 4.12 (br d, J=13.2, 1 H), 7.23 (br d, J=7.5, 1 H), 7.44 (d, J=4.0, 1 H), 7.47 (br s, 1 H). 13C NMR 7.9, 23.5, 30.4, 45.6, 46.2, ˜51 (br), 63.2, 114.8, 118.8 (q, J=271), 128.3, 129.5, 131.6, 140.2, 155.1 (q, J=40), 157.9, 163.1, 170.7. 19F NMR −63.1. LC/MS 4.59 min, [M+1]+ 445.
Reaction SMILES: C1(=O)N[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.NN.Cl.N[CH2:16][C:17]1[CH:18]=[N:19]C(C#N)=N[CH:22]=1.Cl>>[NH2:19][CH2:18][C:17]1[CH:16]=[CH:22][C:17]([C:18]#[N:19])=[CH:16][C:22]=1[O:6][CH2:4][C:3]1[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ncc(CN)cn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: NN
Product: N#Cc1ccc(CN)c(OCc2ccccc2)c1

Procedure:
Synthesis took place via the stage of the corresponding phthalimide as in Example 3.(f). The hydrazine cleavage was carried out as in Example 3.(g). The free amine was generated at pH 9-10 from the initially produced hydrochloride and was extracted from the aqueous solution with ether.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].COC(N1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15])=O.S(=O)(=O)(O)O>C(=O)(O)[O-].[Na+]>[OH:2][CH2:1][CH2:3][N:4]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15]
Reactant: NCCO
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1C=CC(=O)N1CCO
Temperature: 0 °C
Yield: 96.1 %

Procedure:
As shown in FIG. 1, to a solution of ethanolamine (1.8 g, 29.5 mmol) in saturated sodium bicarbonate solution (100 ml) was added N-methoxycarbonylmaleimide (95 g, 32.3 mmol) in portions with vigorous stirring at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The pH of the mixture was adjusted to 6-7 by careful addition of concentrated sulfuric acid (5 ml). The resultant solution was freeze dried and the solid residue extracted with ethyl acetate (2×400 ml) by stirring for 30 min. with each extraction. The ethyl acetate extracts were collected by filtration and evaporated in vacuo to afford N-(2hydroxyethyl)maleimide (formula I) as a white solid (4.0 g, 96% yield); thin layer chromatography (TLC), Rf=0.27, ethyl acetate/petroleum ether 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][S@](C(C)(C)C)=O)[CH2:9][CH:10]=[CH2:11])[CH:3]=1.Cl.CCN(CC)CC.[O:27](C(OC(C)(C)C)=O)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=O>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][C:28](=[O:27])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:9][CH:10]=[CH2:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(Cl)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.8 %

Procedure:
1B (75 g, 261 mmol) was dissolved in methanol (1500 mL). Hydrochloric acid (6N) (750 ml, 4.5 mol) was added. The reaction was stirred at rt for 2-3 hrs and then was concentrated. The residue was diluted with water (2 L), washed with ethyl acetate (500 ml). The aqueous layer was basified with saturated sodium carbonate solution, extracted into ethyl acetate (3×1 L). The combined organic layers were washed with water (1×1 L) and brine (1×1 L), dried over sodium sulfate, filtered and conc. under vacuum at 50-55° C. to give crude product (43 g, 90%). MS (ESI) m/z: 183.2 (M+H)+. The crude product (42 g, 230 mmol) was dissolved in dichloromethane (420 mL), Et3N (32.1 mL, 230 mmol) was added followed by dropwise addition of BOC2O (53.4 mL, 230 mmol). The reaction was stirred at rt for 2-3 hrs. The reaction was diluted with excess DCM (1 L), washed with water (1×500 ml) and brine (1×500 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was then purified using silica gel chromatography to give 1C (61 g, 86%) as a pale yellow solid. MS (ESI) m/z: 283.2 (M+H)+.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)C=O.[C:29]([CH2:32][C:33]([NH:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([OH:40])=[O:39])=[O:34])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:29]=[CH:32]/[C:33]([NH:35][C:36]2[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=2[C:38]([OH:40])=[O:39])=[O:34])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1
Reactant: COc1cc(C=O)ccc1OCc1ccc2ccccc2c1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OCc1ccc2ccccc2c1

Procedure:
Piperidine (0.27 mL, 2.7 mmol) was added to a suspension of 3-methoxy-4-(naphth-2-ylmethoxy)benzaldehyde (0.80 g, 2.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.55 g, 2.5 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH providing (E)-2-[[3-(3-methoxy-4-(naphth-2-ylmethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic (0.74 g, 66%) as a yellow crystalline solid; mp 197-200° C.; δH (400 MHz, DMSO-d6) 3.86 (s, 3H, OCH3), 5.30 (s, 2H, OCH2), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.15 (1, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.37 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.50-7.63 (m, 5H, CH═CHCO, H5, Naphth-H), 7.91-8.01 (m, 5H, H3, Naphth-H), 8.63 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.7, 70.1, 110.8, 113.4, 116.6, 120.1, 120.3, 122.5, 122.7, 125.9, 126.2, 126.4, 126.6, 127.6, 127.7, 127.8, 128.1, 131.2, 132.6, 132.7, 134.0, 134.5, 141.1, 141.6, 149.3, 149.6, 164.2, 169.5; HRMS (ESI) calculated for C28H23NO5 [M−H]− 452.1493. found 452.1495; vmax 1135, 1260, 1511, 1584, 1668, 3055 cm−1.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CC[O:29]CC>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:29])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CCOCC
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of nBuLi (2.5 m in hexanes, 2.00 mL) at −50° C. was added 2-bromopyridine (780 mg) in dry ether (10 mL). After 10 minutes an ethereal solution of BOC-piperidone (1.16 g) was added and the reaction mixture was gradually warmed to room temperature. After 1 hour, the reaction mixture was quenched with ammonium chloride solution, extracted with ether, dried (MgSO4) and the solvent removed in vacuo to yield an oil which was purified using flash chromatography to yield 4′-Hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester. Cleavage of the BOC group with HCl yielded 2′,3′,5′,6′-tetrahydro-1′H-[2,4]bipyridinyl-4′-ol.
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8]OC)[C:4]#[N:5].C[Si]([I:26])(C)C>C(Cl)(Cl)Cl>[F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][I:26])[C:4]#[N:5]
Reactant: COCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reactant: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O

Procedure:
2-Fluoromethyl-2-phthalimido-5-methoxy-valeronitrile (1.20 g, 4.14 mmol), trimethylsilyl iodide (3.2 g, 16 mmol) and chloroform (15 mL) are heated to 60° C. under nitrogen for 48 hours. After removal of the solvent, the residue is dissolved in chloroform, washed with water, sodium thiosulfate solution and water again, dried and evaporated to give the crude product as an oil (1.2 g). This is purified by chromatography on silica (ethyl acetate/petroleum ether 1:3) to give pure 2-fluoromethyl-2-phthalimido-5-iodo-valeronitrile. NMR (CDCl3) δ: 2.0 (4H, m), 3.10 (2H, t), 4.90 (2H, ABX, JAB =9 Hz, JAX =JBX =JH-F =46 Hz), 7.70 (4H, s).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:14][CH:13]=2)[CH:8]=1)=O.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:14][CH:13]=2)[CH:8]=1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-n4ccc(CNC(=O)C(F)(F)F)c4)cc3)[nH]c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccn(-c2ccc(-c3nc4cccc(C(N)=O)c4[nH]3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.7 g (4 mmol) of the compound from Example 24 were dissolved in 70 ml of tetrahydrofuran and admixed with a solution of 0.38 g (15.9 mmol) of lithium hydroxide in 25 ml of water. The entire mixture was stirred at room temperature for 2 hours. The reaction mixture was then neutralized using dilute hydrochloric acid and the organic solvent was removed under reduced pressure. The resulting precipitate was filtered off with suction and dried. This gives 0.87 g of the product.