Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])(=[O:4])[CH:2]=[CH2:3].C1(C=CC(O)=CC=1)O.[CH2:20]1[S:24](=[O:26])(=[O:25])[O:23][CH2:22][CH2:21]1>C(#N)C>[C:1]([NH:5][CH2:6][CH2:7][CH2:8][N+:9]([CH3:11])([CH3:10])[CH2:22][CH2:21][CH2:20][S:24]([O-:23])(=[O:26])=[O:25])(=[O:4])[CH:2]=[CH2:3]
Reactant: O=S1(=O)CCCO1
Reactant: C=CC(=O)NCCCN(C)C
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: C=CC(=O)NCCC[N+](C)(C)CCCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
The solution of 6.2 g 3-acrylamidopropyldimethylamine (M=156.23 g/mol-39.7 mmol) and of 88 mg hydroquinone (M=110.11 mol/l-0.02 eq.) in 17 ml anhydrous acetonitrile is magnetically stirred at ambient temperature in an argon stream. The solution of 3.5 ml distilled propanesultone (M=122.14 g/mol-d=1.392-1 eq.) in 5 ml anhydrous acetonitrile is added drop by drop. A white precipitate appears. The suspension is stirred in an argon stream for 24 hours at ambient temperature. The precipitate is then filtered, washed with anhydrous acetonitrile, then with anhydrous acetone, and dried. 10.3 g 3-[(3-acrylamidopropyl)dimethylammonio]propanesulfonate (M=278.36 g/mol) are thus obtained. Yield: 93%. The purity of the product is controlled by elemental analysis: C: 47.27%; H: 7.88%; N: 10.41%; S: 11.55%, the percentages calculated from the empirical formula (C11H22N2O4S) being as follows: C, 47.46%, H: 7.97%, N: 10.06%; S, 11.52%.
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:45][O:46][CH2:47][CH3:48].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:47]([O:46][N:45]=[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:43][C:6]=2[N:7]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:29][CH:30]=2)[C:8]1=[O:23])[CH3:48]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: CCON
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CCON=C(Cn1c(=O)c2cc(CC)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), (aminooxy)ethane hydrochloride (0.04 g), pyridine (10 mL) and ethanol (10 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.14 g, 63%).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][N:28]3[CH2:29][CH2:30][CH:25]([C:21]4[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=4)[CH2:26][CH2:27]3)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCCO2
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)OCCCO4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(#N)C1C=CC=CC=1>[C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNc1ccccc1
Solvent: N#Cc1ccccc1
Product: O=C=Nc1ccccc1

Procedure:
The experiment of Example X was repeated in such a way that a mixture of phenyl formamide and benzonitrile was evaporated at a rate of 5 ml/hour in a gas stream of 110 liters of nitrogen and 3 liters of air/hour. The gas mixture also comprised carbon disulphide, which was fed at a rate of 0.67% per hour, calculated on the added amount by weight of n-hexyl formamide. Use of the same catalyst bed as in Example XIX at a temperature of 375° C. resulted in a yield of phenyl isocyanate of 41% at a selectivity of 74%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:41]1([CH:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:48]3[CH2:49][CH2:50][CH2:51][CH:47]3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCC1c1ccccc1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 30 mg of 1-(4-chlorophenyl)cyclopropanecarboxylic acid and 81 mg BOP reagent in 0.5 mL methylene chloride wad added 27 mg of 2-phenylpyrrolidine, followed by the addition of 53 ul of Hunig base. The reaction mixture was stirred at r.t. for 2 hours and directly purified by flash column using ethyl/hexane as the eluting solvent to provide the desired 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-2-phenylpyrrolidine. LCMS (ESI): 326.1 (M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([S:15][CH:16]1[N:19]([CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C:18](=[O:34])[CH2:17]1)([CH3:14])([CH3:13])[CH3:12].[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C>C1COCC1.C1(C)C=CC=CC=1>[C:11]([S:15][CH:16]1[N:19]([CH:20]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[O:22])[C:18](=[O:34])[CH2:17]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)SC1CC(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
6 ml of a freshly prepared 1M solution of lithium bis-trimethysilylamide in THF are added dropwise to a solution of 1059 mg (3 mmol) of p-nitrobenzyl (4-tert-butylthio-2-oxo-1-azetidinyl)acetate in 7 ml of dry THF at -70° C., and a solution of 382 mg of pivaloyl chloride in 1 ml of THF is subsequently added dropwise at -70° C., and the reaction mixture is then stirred for 30 minutes at the same temperature. The mixture is diluted with 200 ml of toluene and a little aqueous acetic acid is added. The organic phase is washed with 100 ml of 2N aqueous hydrochloric acid and twice with saturated sodium chloride solution (100 ml), the organic phase is dried using MgSO4, and the solvent is evaporated in vacuo to give a dark red oil. Purification of the crude product over 40 g of silica gel using toluene: ethyl acetate (9:1) gives 795 mg of a non-crystalline solid. IR spectrum in methylene chloride: 2970, 1770, 1760, 1715, 1610, 1530, 1370, 1350, 1315, 1180, 995, 845 cm-1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[CH2:32][CH2:33]3)=[O:16])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: c1ccc(N2CCNCC2)nc1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ccccn2)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(2-pyridyl)piperazine to give the title compound as an off-white solid. MS: 498.3 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.OB(O)[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:28]5[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=5)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)cc1

Procedure:
A microwave vial was charged with 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.29 mmol), 4-(dihydroxyboranyl)benzoic acid (0.32 mmol), PdCl2(dppf) (0.015 mmol), a solution of K2CO3 (0.73 mmol) in water (1 mL), and 1,4-dioxane (3 mL). The vial was purged with nitrogen, sealed and irradiated in a microwave reactor for 30 min at 130° C. (pressure ˜3-4 bar). Analysis of the crude reaction by LCMS indicated ˜80% conversion to desired product. Re-subjection of the reaction to the microwave at 130° C. for 30 min did not progress the reaction any further as judged by LCMS. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (3 mL), filtered through a syringe filter, and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The appropriate product fractions were concentrated to remove a majority of the acetonitrile, leaving an aqueous suspension of product which was collected by filtration and dried to constant weight to provide the title product (38 mg, 0.084 mmol, 29% yield) as an off-white solid. MS(ES)+ m/e 451.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:55]=[CH:54][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][C:41]([NH:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[N+:51]([O-])=O)=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)([O-])=O.[H][H].CCCCCC>C(OCC)(=O)C.[C].[Pd]>[NH2:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[NH:44][C:41]1[CH:40]=[CH:39][C:38]([O:37][C:34]2[CH:33]=[CH:32][C:31]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][C:14]4[CH:54]=[CH:55][C:11]([NH:10][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[NH2:1])=[CH:12][CH:13]=4)=[CH:17][CH:18]=3)([C:27]([F:28])([F:29])[F:30])[C:23]([F:26])([F:25])[F:24])=[CH:36][CH:35]=2)=[CH:43][CH:42]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(Oc2ccc(C(c3ccc(Oc4ccc(Nc5ccccc5[N+](=O)[O-])cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccccc1Nc1ccc(Oc2ccc(C(c3ccc(Oc4ccc(Nc5ccccc5N)cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1
Yield: 89.8 %

Procedure:
15 g (19.7 mmol) of 2,2-bis[N-(2-nitrophenyl)-{4-(4-aminophenoxy)phenyl}]hexafluoropropane synthesized above were dissolved in 200 ml of ethyl acetate. Thereto was added 800 mg of 10% palladium carbon as a catalyst, and replacement with hydrogen was then carried out. After that, reaction was conducted at room temperature under a hydrogen pressure of 1.01 MPa (10 atm) for 18 hours with stirring vigorously. The obtained reaction solution was filtered with cerite to remove the catalyst, and ethyl acetate was removed under reduced pressure. The obtained crude product was refined by using silica gel chromatography (hexane: ethyl acetate=2:1), and recrystallized by using a chloroform-hexane mixed solution, and ethanol-water mixed solution to obtain 12.4 g of 2,2-bis[N-(2-aminophenyl)-{4-(4-aminophenoxy)phenyl}]hexafluoropropane (hereinafter EPNPN) in white solid (yeild: 90%).
Reaction SMILES: N([O-])=O.[Na+].[C:5]([OH:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[NH2:8].[N-:15]=[N+:16]=[N-].[Na+].O.O.O.C([O-])(=O)C.[Na+]>O.Cl>[N:8]([C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[C:5]([OH:14])=[O:13])=[N+:15]=[N-:16]
Reactant: Nc1ccccc1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1C(=O)O
Reaction time: 0.17 h
Yield: 490.4 %

Procedure:
A solution of sodium nitrite (4.75 g, 0.07 mol) in water (63 mL) was added dropwise to a stirred solution of anthranilic acid (10 g, 0.07 mol) in concentrated HCl (125 mL) and water (125 mL), maintaining the temperature below 5° C. After addition the mixture was stirred for 10 min then rapidly filtered. The solution was transferred to a dropping funnel and added dropwise to a solution of NaN3 (4.2 g, 0.065 mol) and sodium acetate trihydrate (105 g, 0.77 mol) in water (125 mL). After addition the mixture was stirred at 0° C. for 15 min then at room temperature for 35 min. The suspension was filtered and washed with water. The solid was then dissolved in EtOAc, dried (MgSO4) and the solvent evaporated. The title compound (52 g, 49%) was isolated as a cream solid. 1H NMR (360 MHz, CDCl3) δ 7.24–7.29 (2H, m), 7.62 (1H, d of t, J=8.1 and 1.5 Hz), 8.12 (1H, d of d, J=7.7, and 1.6 Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@:19]([CH3:25])([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][C@:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:25])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)[C@](C)(N)CO
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)[C@@](C)(CO)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (2S)-2-amino-2,3-dimethyl-1-butanol (CAN 956102-64-0) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2175 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:13]=[C:14]([C:23](=[O:25])[CH3:24])[CH:15]=[C:16]([N:20]([CH3:22])[CH3:21])[C:17]=1[O:18][CH3:19])([CH3:11])([CH3:10])[CH3:9].[Br:26]N1C(=O)CCC1=O.C(OCC)(=O)C>O1CCCC1>[Br:26][CH2:24][C:23]([C:14]1[CH:15]=[C:16]([N:20]([CH3:22])[CH3:21])[C:17]([O:18][CH3:19])=[C:12]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH:13]=1)=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(N(C)C)cc(C(C)=O)cc1C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N(C)C)cc(C(=O)CBr)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Triethylamine (3.2 ml, 22.9 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (3.02 g, 11.4 mmol) were added to a solution of 1-[3-(tert-butyl)-5-(dimethylamino)-4-methoxyphenyl]-1-ethanone (1.9 g, 7.63 mmol) in tetrahydrofuran (50 ml) while cooling on ice and the mixture was stirred at the same temperature for 30 minutes, after which N-bromosuccinimide (2.7 g, 15.2 mmol) was added and stirring was continued for 30 minutes. Ethyl acetate was added, the reaction mixture was washed with brine and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (2.2 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])=[N:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:33]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:34].B(F)(F)F.CCOCC.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])=[N:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:33]([N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)=[O:34]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(O)c(C(=O)N4CCOCC4)c3)cc12
Agent: FB(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(O)c(C(=O)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
A solution of {2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone (34 mg, 61 μmol) in dichloromethane (15 mL) was cooled to 0-5° C. and boron trifluoride diethyl etherate (100 μl, 0.8 mmol) was added. The mixture was then stirred at 0-5° C. for 40 min before 10 ml of a 10% (w/v) solution of potassium hydroxide was added. The mixture was further stirred at room temperature for 1 h. The pH was then adjusted to approximately 3-4 by addition of citric acid and the aqueous phase saturated with sodium sulfate. The resulting mixture was extracted dichloromethane (3×). The organic phases were combined, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and evaporated to afford {2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone (11.5 mg, 44% yield) as a colorless solid. 1H-NMR (500 MHz, d6-DMSO) δ 13.76 (s, 1H), 10.06 (s, 1H), 8.78 (d, 1H), 8.23 (d, 1H), 7.64 (dd, 1H), 7.62 (dd, 1H), 7.51 (d, 1H), 7.46 (ddd, 1H), 7.22 (d, 1H), 7.10 (t, 1H), 6.99 (d, 1H), 3.84 (s, 3H), 3.7-3.2 (m, 8H). MS: m/z 431 [MH+].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH2:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1)=[O:5])C>Cl>[CH2:18]([N:8]1[CH2:9][CH:10]([C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1cccc(C)c1
Agent: Cl
Product: Cc1cccc(C2CN(Cc3ccccc3)CC2C(=O)O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (4.6 g, 14.5 mmol) was suspended in aqueous HCl (73 mL, 18.0 M), and stirred overnight at 80° C. The reaction mixture was concentrated via rotary evaporation and placed on the vacuum line. MS calculated for CO9H21NO2+H: 296, observed: 296.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:13]
Reactant: O=C1CCCCC1c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 2-phenyl-cyclohexanone (10.0 g, 57 mmol) in CHCl3 (20 mL) at −10° C. a solution of bromine (9.6 g, 3.1 mL, 60 mmol) in CHCl3 (10 mL) was added and the reaction mixture was allowed to warm to 0° C. After for 2 hours the solvent was evaporated, methanol (30 mL) was added to the residue, cooled to 0° C., stirred for 30 minutes and the white solid was filtered off to give the title compound as a white solid (5.48 g, 38%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)(=O)C([Cl:20])=O>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([Cl:20])=[O:16])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1

Procedure:
1-Boc-piperidine-4-carboxylic acid (4.4 g, 19.2 mmol) in oxalyl chloride (50 mL) was heated at reflux for 3 h and then concentrated and dried in vacuo to give the acid chloride, 4-chlorocarbonyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:3]1([C:6](Cl)=[O:7])[CH2:5][CH2:4]1)[CH3:2].[C:9]([Cu])#[N:10]>C(#N)C.ClC=C(Cl)Cl>[CH2:1]([C:3]1([C:6]([C:9]#[N:10])=[O:7])[CH2:5][CH2:4]1)[CH3:2]
Reactant: N#C[Cu]
Reactant: CCC1(C(=O)Cl)CC1
Solvent: CC#N
Solvent: ClC=C(Cl)Cl
Product: CCC1(C(=O)C#N)CC1
Yield: 77.3 %

Procedure:
90.5 g of 1-ethylcyclopropanecarboxylic acid chloride is stirred in 100 ml of acetonitrile:trichloroethylene (1:1) with 79.3 g of CuCN for 12 hours at 80° C. The cooled suspension is filtered, the filtrate is evaporated to dryness and the residue is distilled to yield 65 g of colourless 1-ethylcyclopropylcarboxylic acid cyanide having a boiling point at 60 millibars of 88° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>C(OCC)C>[C:20]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: C/C=C/C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C/C=C/C(=O)Oc1cc(C)nc(C(Cl)(Cl)Cl)n1
Yield: 30.5 %

Procedure:
To a solution of 3.0 g (0.02 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine and 1.3 g (0.02 mole) triethylamine in 75 ml diethyl ether was added 1.4 g (0.02 mole) crotonyl chloride. The reaction mixture was refluxed for 15 hours and filtered, and the filtrate was concentrated in-vacuo to give a viscous oil as residue. Trituration with petroleum ether caused the oil to solidify. Recrystallization from isopropyl alcohol gave 1.8 g (45% yield) of pure product; m.p. 55° C.
Reaction SMILES: [ClH:1].Cl.NCCCC1N=C(N)NC=1.C(OC([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][C:28](=O)[NH:29]C2CCCC2)[N:22]=[C:21]1[NH2:36])=O)(C)(C)C>>[ClH:1].[ClH:1].[NH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:23]1[N:22]=[C:21]([NH2:36])[NH:20][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(CCCC(=O)NC2CCCC2)nc1N
Agent: Cl
Agent: NCCCc1c[nH]c(N)n1
Product: NCCCCc1c[nH]c(N)n1
Yield: 18 %

Procedure:
Using the same general procedure as used for the synthesis of 4-(3-amino-propyl)-1H-imidazol -2-ylamine dihydrochloride 16, 12.5 g of lysine methyl ester dihydrochloride 28 afforded 2.25 g (18%) of the target compound 29 as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 6.09 (s, 1H), 4.96 (s, 2H), 2.56 (t, 2H, J=6.3 Hz), 2.27 (t, 2H, J=6.9 Hz), 1.35-1.51 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 149.11, 132.29, 110.59, 40.75, 31.41, 26.62, 26.12; HRMS (ESI) calcd for C7H15N4 (MH+) 155.1291, found 155.1293.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC(C2CCC(=O)CC2)=CC=1)C1C=CC=CC=1.C1(N)C=CC(OCC)=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CCN[C@H]2CC[C@@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: CCOc1ccc(N)cc1
Agent: O=C1CCC(c2ccc(OCc3ccccc3)cc2)CC1
Product: c1ccc(CCN[C@H]2CC[C@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1

Procedure:
Following the general method of example 3, cis-[4-(4-benzyloxy-phenyl)-cyclohexyl]-phenethyl-amine, (260 mg; 11% light yellow oil, MS: m/e=386.2 (M+H+)) trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-phenethyl-amine (370 mg; 15 % white crystals, MS: m/e=386.3 (M+H+)) were prepared from 4-(4-benzyloxy-phenyl)-cyclohexanone (1.8 g; 6.4 mmol) and phenetylamine (0.78 g; 6.4 mmol).