Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[O-][Mn](=O)(=O)=O.[K+].[OH:9][CH2:10][CH2:11][CH2:12][C:13]1[C:18]2[O:19][C@@H:20]([CH2:23][O:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:21][O:22][C:17]=2[CH:16]=[CH:15][C:14]=1[N+:35]([O-:37])=[O:36].S(=O)(O)[O-:39].[Na+].Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[N+:35]([C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][CH:20]([CH2:23][O:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[O:19][C:18]=2[C:13]=1[CH2:12][CH2:11][C:10]([OH:39])=[O:9])([O-:37])=[O:36]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(CCCO)c3O2)cc1
Reactant: O=S([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(CCC(=O)O)c3O2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a 50 ml 3-neck flask equipped with magnetic stirrer, thermometer, N2 line and dropping funnel, was added KMnO4 (1.24 g, 9.25 mmole), H2O (15 ml) and tetra-n-butylammonium chloride (0.17 g). The purple solution was cooled to 0° C. and to it was added dropwise the (R)-toluene-4-sulfonic acid 8-(3-hydroxy-propyl)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (1.20 g, 2.84 mmole) prepared above in 10.3 ml of benzene. The reaction was stirred at room temperature overnight and then 4.40 g of sodium bisulfite was added. The color of the mixture was discharged after five minutes' stirring. After an addtional 10 minutes' stirring, 4 N isopropanolic HCl was added to bring the pH to about 1. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed four times with 50 ml of brine, dried over MgSO4, filtered and concentrated to yield a clear yellow oil (0.95 g, 77%) of 3-[6-nitro-3-(toluene-4-sulfonyloxymethyl)-2,3-dihydro-benzo[1,4]dioxin-5-yl]-propionic acid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[C:15]([F:32])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C.C(O)(=O)C>[F:32][C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:18]=[CH:17][C:16]=1[NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc(C3CCN(Cc4ccccc4)C3)cc2F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(C3CCNC3)cc2F)cc1

Procedure:
A mixture of N-[4-(1-benzyl-pyrrolidin-3-yl)-2-fluoro-phenyl]-4-isopropyl-benzenesulfonamide (170 mg, 0.31 mmol) and 10% palladium on carbon (20 mg) in ethyl acetate (25 ml) and acetic acid (10 ml) was hydrogenated over night (20% conversion). The reaction mixture was irradiated with an infra-red lamp for 3 h (complete conversion). The catalyst was filtered, and the solvent was removed under vacuum to yield an oil (45 mg, 64% purity, 26%).
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[C:20]#[CH:21].[CH3:26][O:27][CH2:28][O:29][C:30]1[C:31]([CH3:41])=[CH:32][C:33]([N+:38]([O-:40])=[O:39])=[C:34]([CH:37]=1)[CH:35]=[O:36].C(O)(=O)C>O1CCCC1.O>[OH:36][CH:35]([C:34]1[CH:37]=[C:30]([O:29][CH2:28][O:27][CH3:26])[C:31]([CH3:41])=[CH:32][C:33]=1[N+:38]([O-:40])=[O:39])[C:21]#[C:20][C:19]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: C#CC(=O)OCC
Reactant: COCOc1cc(C=O)c([N+](=O)[O-])cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#CC(O)c1cc(OCOC)c(C)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (6.1 ml, 43.5 mmol) in tetrahydrofuran (60 ml) was added, at -78° C. under an argon atmosphere, a 1.5 N butyllithium hexane solution (27.4 ml, 41.1 mmol). The mixture was stirred for 30 min. A solution of ethyl propiolate (3.4 ml, 33.5 mmol) in tetrahydrofuran (10 ml) and a solution of 5-methoxymethoxy-4-methyl-2-nitrobenzaldehyde (5.45 g, 24.2 mmol) in tetrahydrofuran (50 ml) were added to the reaction mixture in that order, and the mixture was stirred at -78° C. for additional 1.5 hr. A solution of acetic acid (4.2 ml, 73.3 mmol) in tetrahydrofuran (10 ml) was then added to the reaction mixture, water was then added thereto, and the organic solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order. It was then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(5-methoxymethoxy-4-methyl-2-nitrophenyl)-2-butynoate as a brown oil. Ethyl 4-hydroxy-4-(5-methoxymethoxy-4-methyl-2-nitrophenyl)-2-butynoate was dissolved in toluene (30 ml), 4-methoxybenzylazide (11.8 g, 72.3 mmol) was added to the solution, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2) to give a 1:1 mixture of ethyl 4-(hydroxy-(5-methoxymethoxy-4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and ethyl 5-(hydroxy-(5-methoxymethoxy-4-methyl-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2: high polar product (MP)) as a brown crystal (7.57 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCC(CC(=O)c1ccc(OC)nc1)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-1-(6-methoxy-pyridin-3-yl)-hexan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless solid, MS (ESI+): m/z=350.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.Cl.[NH2:13][C:14]1([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: NC(=O)C1(N)CCCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cc(F)c(NC2(C(N)=O)CCCC2)nc1Cl
Yield: 49 %

Procedure:
A solution of 2,6-dichloro-3-cyano-5-fluoropyridine (250 mg, 1.30 mmol), 1-aminocyclopentanecarboxamide hydrochloride (214 mg, 1.30 mmol) and DIEA (0.650 mL, 3.73 mmol) in DMSO (3 mL) was stirred at 95 C for 4 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 50-100% EtOAc in hexane to give 1-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclopentanecarboxamide (180 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1I.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>>[F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[CH:20]=[CH2:21]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1I
Product: C=Cc1c(Oc2ccc([N+](=O)[O-])cc2F)ccnc1N

Procedure:
The title compound was prepared from 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine and tributylvinyltin via a Stille coupling reaction in the same manner as described in Step B of Example 33. 1H NMR (DMSO-d6) δ 8.35 (dd, 1H, J=10.7, 3.1 Hz), 8.09 (d, 1H, J=9.2 Hz), 7.85 (d, 1H, J=5.6 Hz), 7.31-7.15 (m, 1H), 6.54 (dd, 1H, J=17.8, 11.7 Hz), 6.24 (br s, 2H), 6.20 (d, 1H, J=5.6 Hz), 5.71 (d, 1H, J=17.8 Hz), 5.46 (d, 1H, J=11.7 Hz); MS(ESI+): m/z 276.17 (M+H)+.
Reaction SMILES: C([C:3]1[N:4]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[C:5]([CH:9]=[O:10])=[C:6](C)[N:7]=1)C.N1C2C(=CC=CC=2)[CH2:24][C:23]1=O>CO.[OH-].[K+]>[CH2:23]([C:14]1[CH:13]=[C:12]([CH2:11][N:4]2[C:5]([CH:9]=[O:10])=[CH:6][N:7]=[CH:3]2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])[CH3:24]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCc1nc(C)c(C=O)n1Cc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(Cn2cncc2C=O)ccc1C(=O)O

Procedure:
A solution of the above ester from Example 11D in MeOH (4 mL) and 4N KOH (1.3 mL) was stirred at room temperature for 18 hours. MeOH was removed, the residue was treated with water, and the solution was adjusted to pH 5. It was extracted with EtOAc and the extract was dried and evaporated to give a pale yellow solid which was used as is for condensation with oxindole.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].C(NC(C)C)(C)C.[Li].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:29])(=O)=O)=CC=1>O1CCCC1>[F:29][CH:2]([CH3:3])[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCC(=O)c1ccccc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(F)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 85 %

Procedure:
1 millimole propiophenone in tetrahydrofuran was dropped into a stirred solution of lithium diisopropylamine in 2 milliliters tetrahydrofuran at -78° C. After 1 hour of stirring, a solution of 1.2 millimoles N-fluorobenzenesulfonimide prepared according to Example 1 above in 3 milliliters tetrahydrofuran was dropped into the reaction mixture and stirring was continued at -78° C. The temperature of the reaction mixture was allowed to rise to 25° C., stirring was continued for 1 hour, and the reaction was quenched by pouring the mixture into saturated ammonium chloride solution. The mixture was neutralized with 1N hydrogen chloride solution and extracted with dichloromethane and the organic phase was washed with water. 2-fluoropropiophenone was obtained in 85% yield.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([C@@:7]1([CH3:34])[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C@@H:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C@@H:27]([CH:30]([CH3:32])[CH3:31])[CH:28]=[O:29])[C:8]1=[O:33])[CH:5]=[CH2:6]>C1COCC1>[CH2:4]([C@@:7]1([CH3:34])[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C@@H:10]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:9]([CH:27]([CH:30]([CH3:31])[CH3:32])[C@@H:28]([OH:29])[CH3:1])[C:8]1=[O:33])[CH:5]=[CH2:6]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)C(C)C)C1=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C(C)C)[C@H](C)O)C1=O
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (1.4 mL, 1.960 mmol, 1.4 M in 1:3 THF:toluene) was added by syringe to a solution under nitrogen of pre-dried (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutanal (Example 261, Step 1,286 mg, 0.624 mmol) in THF (6.5 mL) at 0° C. The ice bath was removed. After 2 h, the solution was recooled to 0° C. and quenched by careful addition of saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0 to 40% ethyl acetate in hexanes. Fractions containing the desired product were combined and re-purified to give the title compound as a mixture of diastereomeric alcohols) as a white foam. MS (ESI) m/z=474 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:5][CH:4]=1)[CH3:2].[CH3:14][CH:15]1OC(C)OC(C)O1>>[CH2:14]([C:4]1[NH:5][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH3:8])[C:3]=1[CH2:1][CH3:2])[CH3:15]
Reactant: CC1OC(C)OC(C)O1
Reactant: CCOC(=O)c1[nH]cc(CC)c1C
Product: CCOC(=O)c1[nH]c(CC)c(CC)c1C

Procedure:
As in Example 32 but using 3-ethyl-4-methyl-5-carbethoxy-pyrrole and paraldehyde. Colourless prisms (64%), m.p. 71°-73° (lit. 8) 73°-74°). Anal. Calc. for C12H19NO2 : C, 68.86; H, 9.15; N, 6.67. Found: C, 68.71; H, 9.11; N, 6.84.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH:40]([F:42])[F:41].[BrH:43]>C(#N)C.CCOC(C)=O.O.[Cu]Br>[Br:43][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH:40]([F:42])[F:41]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Sodium nitrite (0.12 g, 1.75 mmol) was added to a 0° C. solution of 6-(N-(4-amino-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.87 g, 1.59 mmol) in acetonitrile (10 ml) and aq HBr (48%) (10 mL). The reaction mixture was stirred for 30 min at 0° C. and copper (I) bromide (0.27 g, 1.91 mmol) was added. The reaction mixture was stirred at 75° C. for 2 h and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.38 g, 39%) as a white foam. LCMS (m/z, ES+)=607, 609 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15](=[O:21])[N:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])#[N:29]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:16]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[C:15](=[O:21])[N:14]([CH:22]3[CH2:23][CH2:24][N:25]([S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:28]#[N:29])(=[O:38])=[O:37])[CH2:26][CH2:27]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C23CCCC3)cc1OC
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C#N)CC3)C(=O)C23CCCC3)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)-2,3-diazaspiro[4.4]non-3-en-1-one hydrochloride (compound B10*HCl) and 2-cyanobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([NH2:15])=[CH:8][C:7]=1[CH3:16])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.O>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([NH:15][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)=[CH:8][C:7]=1[CH3:16])[CH3:2]
Reactant: CCOC(=O)Nc1c(C)cc(N)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 75 %

Procedure:
(4-Amino-2-methyl-6-nitro-phenyl)-carbamic acid ethyl ester (0.50 g) and 4-trifluoromethyl-benzaldehyde (0.29 mL) were dissolved in ethanol (10 mL) and refluxed for 16 h. The reaction mixture was poured into water (75 mL) and the precipitate collected by filtration. Sodium cyanoborohydride (0.3 g) and acetic acid (0.5 mL) were added to the precipitate dispersed in methanol (10 mL) and stirred for 60 minutes. The reaction mixture was filtered, water (50 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (100 mL) to furnish 0.47 g (75% yield) of the title compound as a yellow solid. LC-MS (m/z) 398 (MH+); tR=3.18, (UV, ELSD) 86%, 94%. 1H NMR (500 MHz, DMSO-d6): 1.20 (1,3H), 2.10 (s, 3H), 4.05 (m, 2H), 4.45 (m, 2H), 6.75 (m, 1H), 6.90 (m, 1H), 7.55 (m, 2H), 7.73 (m, 2H), 8.75 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1)C.C1COCC1.[OH-].[Na+]>>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])=[C:8]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:9]=1)([O-:15])=[O:14]
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1-n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc([N+](=O)[O-])cc1-n1cccc1
Yield: 80.1 %

Procedure:
(4-Nitro-2-pyrrol-1-yl-phenoxy)-acetic acid ethyl ester (15 g, 0.052 mol), THF (100 mL, 1 mol), and Sodium hydroxide (10 mL, 0.5 mol) were stirred at rt for 6 h. The reaction mixture was concentrated, diluted with H2O, and washed with EtOAc. The aqueous layer was neutralized and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford 10.92 g (80%) of a yellow oil which solidified upon standing.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]2=3)=[O:10])=[CH:4][CH2:3]1.[H][H]>C(O)C.[Pt]=O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]2=3)=[O:10])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CC=C(CC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CN1CCC(CC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1
Yield: 91.6 %

Procedure:
3.5 g (0.01 mol) of 5,10-dihydro-5-[(1-methyl-1,2,5,6-tetrahydro-4-pyridinyl)acetyl]-11H-dibenzo[b,e][1,4]diazepin-11-one were dissolved in 100 ml of ethanol and hydrogenated in the presence of 0.5 g of platinum oxide at ambient temperature and under a pressure of 3 bar. After the uptake of hydrogen had ended, the catalyst was filtered out and the remaining mixture concentrated by evaporation in vacuo. The residue was purified by column chromatography (NM silica gel 60; 0.063-0.2 mm particle size; eluent; ethyl acetate/methanol=9:1) and 3.2 g (91% of theory) of 5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-dibenzo[b,e][1,4]diazepin-11-one was obtained, which was identical, according to thin layer chromatography, elementary analysis and IR spectrum, to the product obtained using the method of Example 4.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:14]2[N:15]([CH3:40])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([N:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]2[CH2:38][CH3:39])[N:17]=3)([O:12][CH3:13])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:30]1[N:29]([C:18]2[N:17]=[C:16]3[C:21]([N:22]=[C:14]([C:10]4([O:12][CH3:13])[CH2:11][NH:8][CH2:9]4)[N:15]3[CH3:40])=[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:19]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1)[CH3:39]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-methoxyazetidine-1-carboxylic acid tert-butyl ester (109 mg, 0.20 mmol) in DCM (2 mL) was added TFA (1 mL) and the resulting mixture allowed to stir for 1.5 h at r.t. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH affording 2-(2-Ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine as an oil (72 mg, 80%). LCMS: (method A): RT 1.86 min [M+H]+ 449.2
Reaction SMILES: [CH2:1](N(CC)CC)C.[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22]([N:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:31][CH2:32][OH:33])[C:23]4[CH2:29][NH:28][CH2:27][CH2:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1.CI>CN(C=O)C>[CH3:1][N:28]1[CH2:27][CH2:26][C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:8][CH:9]=[N:10][CH:11]=4)=[CH:14][CH:15]=3)[N:21]=[C:22]([N:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:31][CH2:32][OH:33])[C:23]=2[CH2:29]1
Reactant: CCN(CC)CC
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
Triethylamine (0.038 ml, 0.27 mmol) was added to 2-((2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (0.058 g, 0.14 mmol, Example 1) in DMF (2 mL). Methyl iodide (9.28 μl, 0.15 mmol) was added and the reaction mixture was stirred for 1 h at 25° C. The solution was concentrated under reduced pressure and the product purified by preparative HPLC to give 2-((6-methyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (0.022 g, 36.7%). MS (ESI+)/(ESI−) m/z 443/441
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:32])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][NH2:42])=[CH:35][CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][CH2:41][CH2:40][CH2:39][C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)=[O:32])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reactant: NCCCc1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCc2ccncc2)c2ccc(OC)cc2)cc1
Yield: 92.7 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.647 g) and 4-pyridinepropanamine (0.204 g) in tetrahydrofuran (5 mL) was stirred for 3 hours at room temperature. After the usual work up, the crude product was purified by HPLC (ethyl acetate) and then was crystallized from ethyl acetate to provide 0.595 g of (E)-5,5-bis(4-methoxyphenyl)-N-[3-(4-pyridinyl)propyl]-2,4-pentadienamide, mp 90°-92° C.