Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH:19]1(C=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[C:27](O)(=O)C.[BH3-]C#N.[Na+]>CN1C(=O)N(C)CC1.CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH3:27])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=CC1CCCCC1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: CN(c1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12)C1CCCCC1

Procedure:
Analogously to Example 34, 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 168 mg (1.5 mmol) of cyclo-hexanecarbaldehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) and then reacted with 440 mg (7 mmol) of NaCNBH3. Stirring in DIPE yields 4-(3-chloro-phenylamino)-3-(cyclohexyl-methyl-amino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 188-190° C.; HPLC: tRet(grad20-100/20)=12.8; FAB-MS: (M+H)+=357.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1.[H][H]>CN(C)C=O.C(OCC)C.C(O)(=O)C>[Cl:21][C:20]1[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:16][CH:17]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:19]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride in mineral oil (5.28 g) in dry dimethylformamide (50 ml) at 0° C. was added a solution of diethyl malonate (10 ml) in dry dimethylformamide (25 ml) and the mixture was stirred for 30 minutes. A solution of 2,3-dichloro-5-(trifluoromethyl)pyridine (9.8 ml) in dry dimethylformamide (10 ml) was added dropwise and the mixture warmed with stirring to 22° C. over 18 hours. Acetic acid (7.5 ml) in diethyl ether (20 ml) was added dropwise and the mixture was stirred until hydrogen evolution had ceased. The mixture was diluted with diethyl ether (600 ml) and then water washed (3×200 ml). The organic extract was dried (MgSO4) and evaporated onto flash silica. Chromatography over silica eluting with 0-20% diethyl ether in light petroleum (b.p. 40-60° C.) gave the title compound. 1H N.M.R. (CDCl3) δ(ppm) 1.28 (6H, t, 2×CH3CH2), 4.30 (4H, q, 2×CH2CH3), 5.24 (1H, s, CH(CO2Et)2), 7.96 (1H, s, py-H), 8.74 (1H, s, py-H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1.O.C(OCC)(=O)C>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:18]1[N:17]=[C:16]([C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[N:12]2[CH:13]=[CH:14][N:15]=[C:10]([Cl:9])[C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc2c(Cl)nccn12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1nc(Br)c2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
N-Bromosuccinimide (24.69 mmol, 4.4 g) was added to a stirred solution of (S)-benzyl 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (24.94 mmol, 8.9 g) in DMF (145 mL). The reaction was stirred 3 h at rt. The mixture was poured (slowly) in a stirred mixture of water (145 mL), ethyl acetate (145 mL) and brine (145 mL). The mixture was then transferred into a separating funnel and extracted. The water layer was extracted with 2×145 mL ethyl acetate. The combined organic layers were washed with 3×300 mL water, 300 mL brine, dried over sodium sulfate, filtered and evaporated. The product was purified using silica gel chromatography (ethyl acetate/heptane=3/1 v/v %) to give 8.95 g of (S)-benzyl 2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (82.3%).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[CH:4][C:5]2[CH:6]([CH3:15])[CH2:7][CH:8](C)[C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CN([CH:20]=[O:21])C.[H-].[Na+].I[CH3:25]>O>[Br:1][C:2]1[C:3]([O:21][CH3:20])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:25])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CN(C)C=O
Reactant: CC1CC(C)C(C)(C)c2cc(Br)c(O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
7 g (24.7 mmol) of 3-bromo-2-hydroxy-5,6,7,8-tetrahydro-5,5,8,6-tetramethylnaphthalene and 40 ml of DMF are introduced into a three-necked flask under a stream of nitrogren. 890mg (29.6 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. 1.7 ml (27 mmol) of iodomethane are then added and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 7.3 g (99%) of the expected product are collected in the for of an oil which crystallizes slowly. Melting point 77-8° C.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[N:25][CH:26]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.08 min; Mass spectrum (ESI+): m/z=423 [M+H]+.
Reaction SMILES: [C:1](=[O:22])(OCCCCCCCCCCCCCCCCCC)[NH2:2].CC(O)C.[NH2:27][CH2:28][CH2:29][CH:30]([NH2:33])[CH2:31][CH3:32].O=C=[N:36]C1CC(C)(C)CC(C)(CN=C=O)C1>CCCCCCC.C1(C)C(C)=CC=CC=1>[NH2:27][CH2:28][CH2:29][CH:30]([NH2:33])[CH2:31][CH3:32].[NH2:36][C:1]([NH2:2])=[O:22]
Reactant: CCCCCCCCCCCCCCCCCCOC(N)=O
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: CCC(N)CCN
Solvent: Cc1ccccc1C
Solvent: CC(C)O
Solvent: CCCCCCC
Product: NC(N)=O

Procedure:
To a solution of 4.4 grams of polyoctadecyl carbamate-co-vinyl acetate having 50 mole % octadecyl carbamate (prepared in xylene at 40 percent solids as described above) and 1.58 grams of polyvinyl butyral (available under the trade designation "BUTVAR" B72 from Monsanto Company, St. Louis, Mo.) in a solvent mixture of 178.6 grams of 2-propanol, 20.6 grams of xylene and 59.9 grams of heptane was added 0.40 grams of 5,000 Mn polydimethylsiloxane diamine (PDMS, prepared following U.S. Pat. No. 5,512,650) and 0.50 grams of 1,3-diaminopentane (available under the trade designation "DYTEK" EP from DuPont) with stirring at 25° C. Next, 1.10 grams of isophorone diisocyanate (IPDI available from Huls or Bayer) was added at 25° C. with stirring and a slow nitrogen purge. The mixture was stirred for 30 minutes, and, in the presence of the polyoctadecyl carbamate-co-vinyl acetate and the polyvinyl butyral, the IPDI reacted with the PDMS diamine and the 1,3-diaminopentane to form a polydiorganosiloxane urea-containing component with 20 weight % PDMS and 80 weight % 1,3-diaminopentane/IPDI. The final product mixture was a homogeneous, hazy, approximately 3% solids solution of a polymer component (polyoctadecyl carbamate-co-vinyl acetate), a polydiorganosiloxane urea-containing component and polyvinyl butyral in a 55:25:20 solids weight ratio.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:17][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CCCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCCNC1CCc2ccc(OC)cc2C1
Yield: 61 %

Procedure:
A solution of 7-methoxy-2-tetralone (32 mmol. 5 g), n-propylamine (60 mmol. 5 mL), acetic acid (60 mmol. 4 mL), molecular sieves 3A (5 g) in ethanol (25 mL) was stirred at room temperature for 2.5 hrs. The solution was filtered on paper in a Paar bottle and the reduction was carried out with PtO2 (100 mg) as the catalyst, under 30 PSI of hydrogen. When the pressure dropped to 6 PSI (30 min.), the catalyst was removed by elution onto a column (celite 545) with chloroform. The eluent was concentrated under vacuum. The residue, a brown oil, was converted to solid by formation of hydrogen chloride salt in ether/HCl. Several recrystallizations in ether/methanol (60/40) afforded the final product (1) as white crystals (4.28 g, 61% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:24])[CH2:19]2)=[N:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([CH:20]3[CH2:21][CH2:22][N:18]([C:15]4[CH:16]=[CH:17][N:12]=[CH:13][N:14]=4)[CH2:19]3)=[O:24])[CH2:26][CH2:27]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(C1CCN(c2ccncn2)C1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccncn2)C1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 2 h
Yield: 56.1 %

Procedure:
4-Bromophenylsulphonyl chloride (129 mg) was added at ambient temperature to a stirred solution of 1-[1-(4-pyrimidinyl)pyrrolidin-3-ylcarbonyl]piperazine (130 mg) in THF (8 ml) containing triethylamine (0.14 ml). The mixture was stirred for 2 hours then evaporated. The residue was treated with water (16 ml) and dichloromethane (30 ml) added. Aqueous was separated and re-extracted with dichloromethane (20 ml). The combined organic phases were washed with saturated brine (2×10 ml), dried and evaporated. The residue was purified by chromatography on neutral alumina eluting with dichloromethane/methanol (99/1 v/v) to give, as a colourless solid, 1-(4-bromophenylsulphonyl)-4-[1-(4-pyrimidinyl)pyrollidin-3-ylcarbonyl]piperazine (134 mg), mp 94-6°;
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH2:23]([Br:25])[CH3:24].P(=O)(O)(O)O>C1(C)C(C)=CC=CC=1>[Br-:25].[CH2:23]([P+:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=1)([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH3:24]
Reactant: CCBr
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1C
Product: CC[P+](c1ccc(C)cc1)(c1ccc(C)cc1)c1ccc(C)cc1
Product: [Br-]
Temperature: 30 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 15 gms (0.0473 mole) of tri-p-tolyl phosphine and 40 gms of xylene. The slurry is heated to 30° C., then 7 gms (0.0642 mole) of ethyl bromide is added. This reaction mass is heated to 45° C. in 1.17 hours and maintained for 21.4 hours, then cooled to 65° C. and maintained for 2.47 hours, then heated to 90° C., then maintained for 2.42 hours at that temperature, then cooled to 25° C. Then 1.5 gm (0.0138 mole) of ethyl bromide is added and maintained at 25° C. for 0.75 hour, then heated to 45° C. and maintained at that temperature for 16.58 hours, then heated to 70° C. and maintained at that temperature for 1.5, then cooled to 48° C. and the resulting phosphonium salt collected by filtration. After vacuum drying, there is obtained 12.8 gms of catalyst which has a melting point of 213°-220° C. and a chemical shift of 24.6 ppm (phosphoric acid reference).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>O1CCCC1>[CH:13]1([CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:35])=[CH:7][CH:6]=2)[C:9]([OH:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.4 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid (130 mg, 0.56 mmol) in tetrahydrofuran (10 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.23 mL, 1.34 mmol) and nicotinoyl chloride hydrochloride (99 mg, 0.54 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 90/10 ethyl acetate/heptane) afforded 3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionic acid (40.9 mg, 21.7%) as a yellow solid: mp 160-163° C.; EI-HRMS m/e calcd for C21H23NO3 (M+) 337.1677, found 337.1670.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1>S(Cl)(Cl)=O.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A stirred suspension of 4-bromo-3-methylbenzoic acid (15 g, 69.0 mmol) in thionyl chloride (60 mL) was heated at reflux for 2 h and then concentrated under reduced pressure. The residual acyl chloride was dissolved in dichloromethane (300 mL) and added to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (7.2 g, 72.0 mmol) and pyridine (16.8 mL, 207.0 mmol) in dichloromethane (450 mL) at −20° C. The reaction mixture was allowed to warm to room temperature overnight and then washed with 1 M aqueous potassium carbonate solution. The aqueous solution was extracted with dichloromethane. The organic extracts were concentrated under reduced pressure. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes as eluent to afford the title product as a pale yellow oil (17.81 g, 69.0 mmol, 100% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.BrCCCOC1C=CC(OC(F)(F)F)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[CH:44]=[C:43]([O:45][CH2:46][CH:47]=[C:48]([Cl:50])[Cl:49])[CH:42]=[C:41]([CH3:51])[C:40]=1[OH:52]>CN(C)C=O.C(OCC)C>[Cl:38][C:39]1[CH:44]=[C:43]([O:45][CH2:46][CH:47]=[C:48]([Cl:49])[Cl:50])[CH:42]=[C:41]([CH3:51])[C:40]=1[O:52][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1
Reactant: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Reactant: FC(F)(F)c1ccc(OCCCBr)cc1
Agent: FC(F)(F)Oc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
First, 0.35 g of 1-(3-bromopropyloxy)-4-trifluoromethylbenzene (prepared in the same manner as described above for 1-(3-bromopropyloxy)-4-trifluoromethoxybenzene) and 0.2 g of potassium carbonate were dissolved in 100 ml of N,N-dimethylformamide, to which 0.3 g of 2-chloro-6-methyl-4-(3,3-dichloro-2-propenyloxy)phenol was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was mixed with 200 ml of diethyl ether, washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.50 g of 3-chloro-4-[3-(4-trifluoromethylphenoxy) propyloxy]-5-methyl-1-(3,3-dichloro-2-propenyloxy)benzene (94% yield), nD23.0 1.5330.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3ccccc3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
To a solution of example 41 (0.130 g, 0.265 mmoles) in dichloromethane (26 ml), BBr3 (1M in dichloromethane, 2.6 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as light yellow solid (0.070 g, 56% yield). MP: 212-216° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.78(s,1H), 8.24(d, J=7.5 Hz, 1H), 8.05(d, J=7.9 Hz, 1H), 7.85(t, J=8.4 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.53(t, J=7.7 Hz, 1H), 7.36-7.02 (m, 9H), 6.90(d, J=8.2 Hz, 1H), 6.03(q, J=6.9 Hz, 1H), 1.91(d, J=7.3 Hz, 3H). Mass: 476.17(M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])[CH3:3].[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:36][CH2:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][NH2:35])[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1>>[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:36][CH2:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][NH:35][C:8](=[O:9])[C:7]3[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=3)[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 56.9 %

Procedure:
Using the general method of Example 92, 3,5-di-(1,1dimethylethyl)-4-hydroxybenzoyl chloride (0.47 g, 1.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 248-250° C. Analysis: Calculated for C30H40N6O2: % C, 69.74; % H, 7.80; % N, 16.27; Found: % C, 69.65% H, 7.69; % N, 16.42. HRMS (EI) calcd for C30H40N6O2 (M+) 516.3212 found 516.3226
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6](CCl)=[CH:5][CH:4]=1)=[CH2:2].[NH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][Si:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].[CH3:28]O>>[CH:2]([CH2:28][N:14]([CH2:13][CH2:12][NH2:11])[CH2:15][CH2:16][CH2:17][Si:18]([O:25][CH2:26][CH3:27])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:1][C:3]1[CH:4]=[CH:5][CH:6]=[CH:9][CH:10]=1
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CCO[Si](CCCNCCN)(OCC)OCC
Reactant: CO
Product: CCO[Si](CCCN(CC=Cc1ccccc1)CCN)(OCC)OCC
Reaction time: 1 h
Yield: 69.4 %

Procedure:
14 g (0.1 mol) of 4-vinylbenzyl chloride is added with stirring and at +20° C. under nitrogen atmosphere to a solution of N-(2-aminoethyl)-3-aminopropyltriethoxysilane (26.4 g, 0.1 mol) in methanol (40 g). The temperature of the mixture is raised to reflux and maintained until the reactants have been consumed completely (3 hours). After the temperature of the reaction mixture has returned to +20° C., the methanol is evaporated and the residue is taken up in 50 mL of toluene. The salts are filtered. 15 g of potassium carbonate is added to the filtrate to neutralize the residual ammonium hydrochloride. After stirring at +20° C. for 1 hour, the salts are filtered and the solvent is evaporated under vacuum. 26.4 g of the desired product are then isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:8]([C:18]([OH:20])=[O:19])=[C:9]([CH3:17])[N:10](COCC)[C:11]=1[CH3:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39]Br.[ClH:41].[C:42]1([C:48]2([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CC(C)=O.C1(C)C=CC=CC=1.O>[ClH:41].[CH3:12][C:11]1[NH:10][C:9]([CH3:17])=[C:8]([C:18]([O:20][CH2:37][CH2:38][CH2:39][N:51]2[CH2:50][CH2:49][C:48]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:53][CH2:52]2)=[O:19])[CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: CCOCN1C(C)=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C1C
Reactant: BrCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2 g of (+)-5-ethoxycarbonyl-1-ethoxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid are dissolved in 25 ml of acetone, and 1.5 g of finely powdered potassium carbonate, 7.5 ml of 1,3-dibromopropane and a spatula tip of [18]crown-6 are added. The mixture is stirred vigorously for 20 h at room temperature, after which the solution is filtered off from the solid, the filtrate is evaporated in vacuo and the excess 1,3-dibromopropane is distilled off under high vacuum. 15 ml of concentrated formic acid are added to the residue while cooling with ice; stirring is then carried out at room temperature until a clear solution has formed (about 15-20 minutes). The formic acid is distilled off in vacuo, the residue is dissolved in 30 ml of dichloromethane and the solution is washed with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated again. The crystalline residue is triturated with diisopropyl ether, filtered off under suction, washed with diisopropyl ether and dried. 2.2 g are obtained and are heated at the boil, without further purification, with 1.32 g of 4,4-diphenylpiperidine hydrochloride and 2 g of potassium carbonate in a mixture of 20 ml of toluene and 4 ml of water for 30 h. After cooling, the phases are separated. The organic phase is washed twice with water and evaporated. The residue is chromatographed over a silica gel column using 95:5 chloroform/ethanol as the mobile phase. The chromatographically pure fractions are collected and evaporated. The residue is dissolved in dichloromethane, 2 ml of a saturated solution of hydrogen chloride in ether are added and the mixture is immediately evaporated in vacuo. Two portions of 20 ml of dichloromethane are distilled off, after which the residue is triturated with ether, filtered off under suction and dried. 2.65 g of the title compound which decomposes from 142° C. and has [α]22D =+18.9° (c=1, methanol) are obtained.