Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]3[C:14](O[C:17](=[O:18])[C:10]=3[CH:9]=2)=[O:15])=[CH:5][C:4]2[C:19](O[C:22](=[O:23])[C:3]=2[CH:2]=1)=[O:20].[CH2:24]([NH2:27])[CH:25]=[CH2:26].O>C(O)(=O)C>[CH2:24]([N:27]1[C:19](=[O:20])[C:4]2=[CH:5][C:6]([O:7][C:8]3[CH:9]=[C:10]4[C:17](=[O:18])[N:27]([CH2:24][CH:25]=[CH2:26])[C:14](=[O:15])[C:11]4=[CH:12][CH:13]=3)=[CH:1][CH:2]=[C:3]2[C:22]1=[O:23])[CH:25]=[CH2:26]
Reactant: C=CCN
Reactant: O=C1OC(=O)c2cc(Oc3ccc4c(c3)C(=O)OC4=O)ccc21
Solvent: CC(=O)O
Solvent: O
Product: C=CCN1C(=O)c2ccc(Oc3ccc4c(c3)C(=O)N(CC=C)C4=O)cc2C1=O
Temperature: 115 °C

Procedure:
N,N′-Bis(2-Propenyl)-4,4′-Oxydiphthalimide [ODPA-Bis (N-Allyl)] was synthesized in the following manner. A reaction flask was charged with 4,4′-oxydiphthalic dianhydride (21.7 g, 70 mmoles) in glacial acetic acid solvent (120 ml). Allyl amine (7.98 g, 140 mmoles) was added slowly to the flask while the reaction mixture temperature was controlled at 18° to 22° C. with external cooling. After addition was complete, the reaction mixture was heated to reflux (ca. 115° C.) for 90 min and the solution gradually turned to clear from cloudy. After cooling, the product mixture was poured into water (450 to 500 ml), The resulting mixture was then brought to boiling briefly. After cooling, product precipitated out of solution and was collected by filtration, washed several times with water, and finally with methanol. Product was then dried in a vacuum oven (150 mm Hg, room temperature). The white solid product was obtained in 76%.
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1>CCO>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][N:18]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][N:21]=[C:17]2[CH:16]=1
Reactant: COCCOc1ccnc(N)c1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(OCCOC)ccn12
Yield: 57 %

Procedure:
Ethyl 2-chloro-3-oxopropanoate (5.1 g, 33.9 mmol, Heterocycles 1991, pg. 699) and 4-(2-methoxyethoxy)pyridin-2-amine (5.70 g, 33.9 mmol) was dissolved in EtOH (50 mL) and heated to reflux overnight. The crude reaction mixture was concentrated and purified by flash column chromatography (EtOAc/MeOH 10:0 to 10:1) provided the desired product (57%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[CH2:31][CH2:30]1)[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:35][CH2:36][C:37](=[O:40])[CH2:38][CH3:39].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:37]([CH2:38][CH3:39])([OH:40])[CH2:36][CH3:35])[CH2:30]1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCC(=O)CC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCC(O)(CC)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
1.43 ml (3.58 mmoles) of butyllithium (as a 2.5M hexane solution) was added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 0.50 ml (3.57 mmoles) of diisopropylamine in 10 ml of anhydrous tetrahydrofuran. The mixture was then stirred for 30 minutes, after which a solution of 500 mg (1.61 mmoles) of (5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]dihydrofuran-2(3H)-one (prepared as described in Preparation 5) in 5 ml of anhydrous tetrahydrofuran was added thereto. The mixture was then stirred for a further 1 hour, and then 0.38 ml (3.59 mmoles) of distilled 3-pentanone was added to the mixture and stirred for a further 2 hours. At the end of this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a 10% w/v aqueous solution of citric acid, with water and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (using a 1:1 by volume mixture of hexane and diethyl ethyl as eluent), followed by recrystallization from hexane, to give 425 mg (yield 67%) of the title compound as white crystals, melting at 118°-120° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.CO.C1COCC1.CO.[N+:37]([C:40]1[NH:41][CH:42]=[C:43]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][C:48](=[O:52])[CH2:47]2)[N:44]=1)([O-])=O>[Ni].C(Cl)Cl.CO>[O:52]=[C:48]1[NH:49][CH2:50][CH2:51][N:46]([CH2:45][C:43]2[N:44]=[C:40]([NH:37][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:5])[NH:41][CH:42]=2)[CH2:47]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: O=C1CN(Cc2c[nH]c([N+](=O)[O-])n2)CCN1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN4CCNC(=O)C4)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazin-2-one (Step 142.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 540.0 [M+H]+; tR=3.18 min (System 1); TLC: Rf=0.18 (DCM/MeOH, 9:1).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH3:19]I>C1COCC1.CCOC(C)=O>[CH3:19][N:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cccc(Nc2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cccnc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
NaH (61 mg, 2.5 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (6 mL) was added. The slurry was cooled to 0° C. and compound 15 (500 mg, 2.33 mmol, 1.00 eq) was added as a solution in THF (6 mL). After stirring at 0° C. for 30 minutes methyl iodide (159 μL, 2.54 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 340 mg (64%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J=2.7 Hz, 1H), 8.35 (dd, J=4.7, 1.4 Hz, 1H), 7.70-7.66 (m, 1H), 7.66-7.64 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.60 (t, J=2.3 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.42 (dd, J=8.3, 4.7 Hz, 1H), 7.32 (dd, J=8.3, 2.5 Hz, 1H), 3.37 (s, 3H); ES-MS [M+1]+: 230.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][CH:16]([C:29]([CH3:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[O:28]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[N:18]1[CH2:17][CH:16]([NH:15][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:14])[C:29]([CH3:30])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:37]
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Reactant: CC(C)(c1ccccc1)C(N)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1cc(C(=O)NC(CN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccc2)cs1
Reaction time: 16 h
Yield: 29.6 %

Procedure:
To a heterogeneous mixture of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (155 mg, 0.74 mmol), 2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione (200 mg, 0.65 mmol)[from Preparation 4] and PyBrOP (426 mg, 0.91 mmol) in CHCl3 (10 mL) at 25° C. was added diisopropylethyl amine (0.5 mL, 2.9 mmol) dropwise. After 16 h, the mixture was adsorbed onto silica and the mixture purified via column chromatography (silica, 35-50% EtOAc/Hex) affording the title compound (96 mg, 26%) as a white solid: LC-MS (ES) m/z=499 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7]2[CH2:9][O:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([I:21])[CH:15]=2)[C:4]=1[C:22]([O:24]C)=[O:23])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:5]2[C:6]3[C:12](=[O:13])[CH2:11][O:10][CH2:9][C:7]=3[NH:8][C:3]3[C@H:1]([CH3:2])[O:24][C:22](=[O:23])[C:4]2=3)=[CH:15][C:16]=1[I:21]
Reactant: CCC1=C(C(=O)OC)C(c2ccc(F)c(I)c2)C2=C(COCC2=O)N1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: C[C@@H]1OC(=O)C2=C1NC1=C(C(=O)COC1)[C@@H]2c1ccc(F)c(I)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Example 11B (2.8 g, 6.1 mmol) in chloroform (50 mL) was treated with N-bromosuccinimide (1.2 g, 6.7 mmol), stirred at ambient temperature for 20 minutes, concentrated to dryness, heated at 130° C. under nitrogen for 15 minutes and allowed to cool to ambient temperature. The residue was purified on silica gel eluting with ethyl acetate:formic acid:water:hexane (38:1:1:40, then 38:1:1:20 then 38:1:1:10) to provide the title compound as the less polar diastereomer.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])=[CH:8][C:9]=2[CH:11]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[NH:4][N:3]=1.[ClH:31]>O1CCOCC1>[ClH:31].[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])=[CH:8][C:9]=2[CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[NH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc3[nH]nc(N)c23)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1n[nH]c2nc(-c3ccccc3O)cc(C3CCCNC3)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a stirred solution tert-butyl 3-[3-amino-6-(2-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-1-piperidinecarboxylate (0.075 g, 0.183 mmol) in 1,4-dioxane (3 mL) was added 4N HCl in 1,4-dioxane (3 mL). The mixture was stirred at room temperature for 12 hrs. The resulting solid was collected with filtration to give 2-[3-amino-4-(3-piperidinyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]phenol hydrochloride. (0.062 g, yield; 98%)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:8]=[CH:9][CH:10]=1.[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]2[CH2:24][O:25]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(CCCCc2ccccc2O)c1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCOc1cccc(CCCCc2ccccc2OCC2CO2)c1
Yield: 59.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), 2.87 g of 2-[4-(3-methoxymethoxyphenyl)butyl]phenol (prepared as described in Preparation 5), 1.18 g of potassium t-butoxide and 1.67 g of epibromohydrin were reacted in 30 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 2.05 g (yield 60%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:18][C:19]1[C:20]([C:29]2[CH:34]=[CH:33][C:32](F)=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>CN(C)C=O>[Cl:18][C:19]1[C:20]([C:29]2[CH:34]=[CH:33][C:32]([CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.9 g of an 80% strength by weight suspension of sodium hydride in mineral oil was added to 10 ml of anhydrous dimethylformamide. A solution of 5.1 g of di-tert-butyl malonate in 20 ml of dimethylformamide was added dropwise to this mixture, after which it was stirred for 30 minutes. A solution of 7.5 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine in 20 ml of dimethylformamide was then added dropwise. The reaction mixture was stirred at 23° C. for 20 hours and at 80° C. for 5 hours. The cooled reaction mixture was then poured into 200 ml of ice water. The aqueous phase was extracted three times with 100 ml of tert-butyl methyl ether each time. The combined organic phases were washed with 100 ml of water, dried over sodium sulfate and concentrated. Yield: 10.8 g (79%) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][C@H:9]1[CH2:13][C:12]([CH2:17][CH:18]=[CH2:19])([CH2:14]C=C)[CH2:11][NH:10]1.CO>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]1[CH2:13][C:12]2([CH2:14][CH:19]=[CH:18][CH2:17]2)[CH2:11][NH:10]1
Reactant: C=CCC1(CC=C)CN[C@@H](Cc2c(Cl)cncc2Cl)C1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: CO
Solvent: ClCCl
Product: Clc1cncc(Cl)c1C[C@H]1CC2(CC=CC2)CN1
Temperature: 40 °C
Reaction time: 20 h
Yield: 35.4 %

Procedure:
A mixture (R)-3,5-dichloro-4((4,4-diallylpyrrolidin-2-yl)methyl)pyridine (3.1 g, 9.96 mmol) and grubbs catalyst 2nd generation (1.691 g, 1.992 mmol) in DCM (996 ml). The mixture was stirred at 40° C. for 20 h. The mixture was concentrated and absorbed onto a plug of silica gel and purified by chromatography through a Biotage column (100 g), eluting with a gradient of 1% to 50% 1 M NH3.MeOH in DCM, to provide (R)-3-((3,5-dichloropyridin-4-yl)methyl)-2-azaspiro[4.4]non-7-ene (1.0 g, 3.53 mmol, 35.5% yield) as dark-brown oil. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 2H), 5.61-5.72 (m, 2H), 3.69-3.82 (m, 1H), 3.25 (br. s., 2H), 3.05 (d, J=10.47 Hz, 1H), 2.89-2.97 (m, 1H), 2.47 (br. s., 2H), 2.23-2.37 (m, 2H), 1.93 (dd, J=6.84, 12.59 Hz, 1H), 1.69-1.82 (m, 1H); LCMS (ESI) m/z 283.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[CH:14]=1)=[O:7].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([NH:39][CH2:38][CH2:37][CH2:36][N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)=[CH:19][CH:18]=2)[CH:14]=1)=[O:7]
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(F)cc1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(NCCCN2CCOCC2)cc1
Yield: 3 %

Procedure:
Using an analogous procedure to that described in Example 20, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-fluorobenzamide was reacted with 3-morpholinopropylamine to give the title compound in 3% yield; NMR Spectrum: (DMSOd6) 1.77 (m, 2H), 2.24 (s, 3H), 2.46 (m, 6H), 3.02 (s, 6H), 3.16 (q, 2H), 3.65 (t, 4H), 6.33 (t, 1H), 6.67 (d, 2H), 6.97 (m, 1H), 7.28 (m, 2H), 7.36 (t, 1H), 7.62 (m, 1H), 7.83 (m, 3H), 9.45 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 516.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][C:3]1([CH3:7])[CH:5]=[CH2:6].C([O:11]CC)C>>[F:1][C:2]1([F:8])[CH2:4][C:3]1([CH2:5][CH2:6][OH:11])[CH3:7]
Reactant: CCOCC
Reactant: C=CC1(C)CC1(F)F
Product: CC1(CCO)CC1(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
0.23 mol of diborane is produced from 6.7 g (0.18 mol) of sodium borohydride and 33 g (0.23 mol) of boron trifluoride etherate in 130 ml of diglyme, and, with the aid of a stream of nitrogen, is passed into a stirred solution of 30 g (0.25 mol) of 2,2-di-fluoro-1-methyl-1-vinyl-cyclopropane in 300 ml of dry diethyl ether, at room temperature. The reaction mixture is stirred for one hour more at room temperature and concentrated by stripping off the solvent and the excess alkene under reduced pressure. The residue which remains is taken up in 50 ml of diethyl ether, and 130 ml of 10% strength aqueous sodium hydroxide solution are added. 134 ml of a 30% strength aqueous hydrogen peroxide solution are added dropwise to this mixture at room temperature and with stirring. Stirring is continued for an hour at room temperature, the mixture is extracted several times using diethyl ether, and the combined organic phases are dried and distilled under reduced pressure. In this manner, 13 g (55% of theory) of 2-(2,2-difluoro-1-methyl-cyclopropyl)-ethanol are obtained in form of a liquid of boiling point 65°-67° C./20 torr.
Reaction SMILES: [CH2:1]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[CH3:18].C1(C)C=CC=CC=1.N1C=CC=CC=1>O>[CH3:18][C:17](=[N:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:16][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCCCCCCCCc1ccc(N)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCc1ccc(N=C(C)c2ccccc2)cc1

Procedure:
Nonyl benzene was prepared by alkylating benzene with mixed propylene trimer using Friedel Crafts reaction. Nonyl benzene was nitrated and reduced to give p-nonyl aniline. A solution of p-nonyl aniline (30 g), acetophenone (60 g), toluene (200 ml) and pyridine (20 ml) was refluxed with continuous removal pf water. N-(α-methyl benzylidene)-p-nonyl aniline (III) was obtained by fractional distillation. III had a boiling point of 194° C. at 0.05 millimeter.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30](=[O:31])[C:29]3[CH:32]=[CH:33][CH:34]=[C:27]4[C:28]=3[C:23](=[CH:24][CH:25]=[CH:26]4)[C:22]2=[O:35])[CH2:15][CH2:14]1)(O)=[O:2].CS([O-])(=O)=O.ClC1C=CC=C[N+:43]=1C.N>CN1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30](=[O:31])[C:29]3[CH:32]=[CH:33][CH:34]=[C:27]4[C:28]=3[C:23](=[CH:24][CH:25]=[CH:26]4)[C:22]2=[O:35])[CH2:15][CH2:14]1)(=[O:2])[NH2:43]
Reactant: O=C(O)c1ccc2[nH]cc(C3CCN(CCN4C(=O)c5cccc6cccc(c56)C4=O)CC3)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: CN1CCCC1
Agent: CS(=O)(=O)[O-]
Agent: N
Product: NC(=O)c1ccc2[nH]cc(C3CCN(CCN4C(=O)c5cccc6cccc(c56)C4=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.1 g of 2-[2-(4-(5-carboxy-3-indolyl)piperidino)ethyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione are suspended in 100 ml of N-methylpyrrolidine. 3.2 g of 2-chloro-1-methylpyridinium methanesulfonate are then added and the mixture is stirred at room temperature for 12 hours. Dried NH3 gas is passed into the resulting solution until it is saturated and the mixture is stirred again for 10 hours. Customary working up gives 2-[2-(4-(5-carbamoyl-3-indolyl)piperidino)ethyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)C1)=O)(C)(C)C.[C:25]([O:29][C:30]([N:32]1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2C[CH:33]1[CH2:34][CH2:35]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH:10]([C:13]2[NH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:11]2[CH2:12][CH:33]1[CH2:34][CH2:35]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Following the procedure used to prepare compound 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, except that 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was used instead of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([CH:18]([CH3:40])[C:19](=[O:39])[NH:20][CH2:21][C:22]2[C:23]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:6][CH2:5][C:4]1[CH:14]=[CH:15][C:16]([CH:18]([CH3:40])[C:19]([NH:20][CH2:21][C:22]2[C:23]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[N:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)=[O:39])=[CH:17][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1CN
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.8 %

Procedure:
To a stirred solution of tert-butyl 2-methoxy-4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzylcarbamate (161 mg, 0.29 mmol) in dichloromethane (4 mL), cooled to 0° C., were added trifluoroacetic acid (2 mL). The resulting reaction mixture was stirred for 2 h at 0° C. and 2 h at room temperature, then basified to pH 8-9 with aq. NaHCO3. The mixture was filtered using celite pad. The filtrate dissolved in dichloromethane and extracted with NaHCO3. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-(Aminomethyl)-3-methoxyphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (151 mg) was obtained as 99% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.[OH:14][CH:15]1[CH2:18][N:17]([C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=2)[CH2:16]1.[H-].[Na+].O>CN(C=O)C>[N:8]1([C:4]2[N:3]=[C:2]([O:14][CH:15]3[CH2:16][N:17]([C:19]4[CH:20]=[CH:21][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:23][CH:24]=4)[CH2:18]3)[CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Reactant: Clc1ccnc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(N4CCOCC4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 30 mg (0.15 mmol) 4-(4-chloro-pyrimidin-2-yl)-morpholine in DMF (1.0 mL) is added 30 mg (0.13 mmol) (S)—N-{1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1) in DMF (1.0 mL). 20 mg (0.45 mmol, 55% in mineral oil) NaH is added and the mixture is stirred for 12 h at room temperature. Water is added, the mixture is concentrated in vacuo and the residue is purified by HPLC (XBridge, acetronitrile/H2O (+0.1% NH4OH)) to yield the desired product.