Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Reactant: Nc1ccc(I)cn1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(N)nc3)cn2n1

Procedure:
The title compound, off white solid, MS: m/e=292.1 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 5-iodopyridin-2-amine.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[O-2].[Ca+2].[H][H]>[Pd].CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][CH:2]=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(N2CCN(c3ccc(Cl)nn3)CC2)cc1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: COc1ccc(N2CCN(c3cccnn3)CC2)cc1
Yield: 63.2 %

Procedure:
A mixture of 7.3 parts of 3-chloro-6-[4-(4-methoxyphenyl)-1-piperazinyl]pyridazine, 2 parts of calcium oxide and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated. The residue was crystallized from 2-propanol, yielding 4.1 parts (63.2%) of 3-[4-(4-methoxyphenyl)-1-piperazinyl]pyridazine; mp. 133.4° C. (compound 272).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(C(C)=O)C(C)C.O>[C:19]1([CH2:18][N:3]2[CH2:4][CH2:5][S:1][C:2]2=[O:6])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCS1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C1SCCN1Cc1ccccc1
Yield: 55.2 %

Procedure:
A mixture containing 3.09 g (0.03 mol) of 2-thiazolidinone, 11.2 g of potassium carbonate, 1.8 g of potassium hydrogen carbonate, 0.5 ml of water, 30 ml of methyl isobutyl ketone and 3.0 ml (0.033 mol) of benzyl bromide is refluxed for 7 hours. After cooling down, the reaction mixture is washed twice with 30 ml of water each, the organic phase is dried and evaporated. The yellow oily product (which solidifies on standing) may be purified by column chromatography (by using Kieselgel 60 of 230-400 mesh as sorbent and chloroform as eluent) to give 3.2 g (55.2%) of the title compound, m.p.: 50°-51° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[N:6]=[CH:5]2
Reactant: Clc1c(Br)ccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1c(Br)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a mixture of 5-bromo-4-chloro-1H-indazole (8.0 g, 34.6 mmol) and 3,4-dihydro-2H-pyran (8.72 g, 0.104 mol) in dry dichloromethane (200 mL) was added p-TsOH (0.657 g, 3.46 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. Upon completion, saturated aqueous NaHCO3 (100 mL) was added slowly to the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜3% EtOAc in petroleum ether) affording the title compound (8.9 g). 1H NMR (300 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.71 (m, 2H), 5.88 (dd, 1H), 3.89-3.84 (m, 1H), 3.79-3.73 (m, 1H), 2.42-2.32 (m, 1H), 2.05-1.95 (m, 2H), 1.75-1.70 (m, 1H), 1.60-1.54 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](Cl)=[O:9].[CH3:22][NH:23][CH3:24]>O1CCCC1.O>[CH3:22][N:23]([CH3:24])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=2[F:1])[CH:6]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (2.2 g) in tetrahydrofuran (8 ml) was added dropwise to a stirred solution of dimethylamine (50% in water; 2 ml) in water (10 ml) at 5° C. The mixture was stirred for 30 minutes at 5° C. and for 1 hour at room temperature. The mixture was concentrated and extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure. The residue (2.4 g) was solidified with a mixture of hexane and ethanol to give pale brown powder of N,N-dimethyl-3-(2,4-difluorophenoxy)-4-nitrobenzamide (2.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[N:19]=[C:18]([CH3:20])[O:17][N:16]=2)[CH:5]=[C:6]([CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C([Li])CCC.[F:26][C:27]([F:34])([F:33])[C:28](OCC)=[O:29].B(F)(F)F>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[N:19]=[C:18]([CH3:20])[O:17][N:16]=2)[CH:5]=[C:6]([CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:28](=[O:29])[C:27]([F:34])([F:33])[F:26]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#CCCCOc1c(C)cc(-c2noc(C)n2)cc1C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C)c(OCCCC#CC(=O)C(F)(F)F)c(C)c2)no1
Temperature: -70 °C
Reaction time: 5 h

Procedure:
A solution of 2.0 g 3-[3,5-dimethyl-4-(3-ethinylpropoxy)phenyl]-5-methyl-1,2,4-oxadiazole, prepared by a procedure similar to that described in Example 1(b), in 50 mls anhydrous tetrahydrofuran in an argon atmosphere was chilled to about -70° C. To this solution there was added 3.7 mls butyl lithium followed by ethyl trifluoroacetate and, after ten minutes, 1.5 mls boron trifluoride ethereate. The solution was stirred for five hours at -70° C. and then overnight without cooling, quenched with 20 mls aqueous ammonium chloride solution, diluted with water and extracted with ethyl ether. The ethyl ether extracts were dried (Na2SO4) and concentrated in vacuo. The residue was subjected to column chromatography (silica gel; 20:80 to 40:60 ethyl ether/hexane) to give 497 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[I:11]N1C(=O)CCC1=O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cn1
Yield: 89.5 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.3 g, 2 mmol) (Frontier Cat. No. Z13659) and N-iodosuccinimide (0.53 g, 2.3 mmol) in N,N-dimethylformamide (2 mL) was stirred at 80° C. for 1 h. After cooling it was concentrated and the residue was treated with methanol. The white solid was collected by filtration to afford the desired product (0.5 g). LCMS (M+H)+=279.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH3:26][O:27][CH2:28][CH2:29][OH:30].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:30][CH2:29][CH2:28][O:27][CH3:26])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COCCO
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COCCOc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. EI-MS m/e (%): 360 (M+, 100), 302 (36), 287 (28), 259 (32), 43 (42).
Reaction SMILES: [NH2:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][S:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:4]2[S:3][CH:2]([NH2:1])[NH:6][C:5]2=[O:7])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: NC1NC(=O)CS1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: NC1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)S1
Temperature: 100 °C

Procedure:
A solution containing 0.58 g (0.005 mol) of 2-aminothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 24 h at 100° C. The product was filtered and washed with ethanol. Yield 1.2 g (86%), mp 250° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: OCCOCCCCCCBr
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.067 g) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 222 mg) and the mixture was stirred at 200 for 15 min. A solution of 2-[(6-bromohexyl)oxy]ethanol (1.157 g) in DMF (1 ml) was added and the mixture was stirred at 20° for 3.5 h. Phosphate buffer solution (pH 6.5, 20 ml) and water (30 ml) were added. The mixture was extracted with EtOAc (2×20 ml) and the combined extracts were washed with water (30 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (1.42 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:50]5[CH2:51][CH2:52][N:47]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=6)[CH2:48][CH2:49]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (0.5 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.32 g), 4-(2-pyridyl)piperazine (0.39 g) and 4-(dimethylamino)pyridine (0.05 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol®. and the eluate evaporated to dryness to provide the desired title compound (0.30 g) as a pale yellow amorphous solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[OH:16]>C(O)(=O)C>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:5](=[O:7])[CH3:6])=[CH:11][C:10]=1[OH:16]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)c(O)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
Acetic anhydride (3.0 mL, 42.0 mmol) was added to a solution of 4-chloro-3-hydroxy aniline (4.0 g, 28 mmol) in acetic acid (20 mL), and the reaction was refluxed for 5 mins. The reaction mixture was cooled to room temperature and the product was solidified. It was filtered off and washed with water (10 mL) and dried to obtain the product 17a in 93% yield (4.8 g) as a creamy white solid. There was no need for further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: Clc1ccc(Br)cc1
Reactant: COc1ccc2c(Cl)ccnc2c1
Product: COc1ccc2c(Cl)cc(-c3ccc(Cl)cc3)nc2c1

Procedure:
The title compound, m. p. 153-155° C., MS: m/e=305 (M+H+), was prepared from 4-chloro-7-methoxy-quinoline and 1-bromo-4-chlorobenzene.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:16])([F:15])[O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.C([O:19][C:20](=O)[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[C:24]([Cl:29])=[N:23][CH:22]=1)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:29][C:24]1[C:25]([C:27]#[N:28])=[CH:26][C:21]([C:20]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([O:7][C:6]([F:15])([F:16])[F:5])=[CH:9][CH:10]=2)=[O:19])=[CH:22][N:23]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cnc(Cl)c(C#N)c1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution trimethylaluminium 2 M in toluene (20.77 mL, 41.5 mmol) was added to a stirred solution of 4-(trifluoromethoxy)aniline (2.247 mL, 16.62 mmol) in toluene (150 mL) under an argon atmosphere. After 30 min, a solution of 6-chloro-5-cyanonicotinic acid ethyl ester (3.5 g, 16.62 mmol) in toluene (10 mL) was added and the RM was stirred at 25° C. for 1 h. After cooling to 5° C., the RM was treated dropwise with a solution of sat. aq. NH4Cl (50 mL) and EtOAc (50 mL) was added. The mixture was stirred for 60 min, filtered over Hyflo® and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 30% EtOAc) and recrystallized from n-hexane/DCM to afford the title compound as a yellow crystalline solid. m.p. 198-200° C., HPLC (Condition 4) tR=6.24 min, UPLC-MS (Condition 8) tR=1.14 min, m/z=340.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.15-7.34 (m, 2H), 7.67 (d, J=8.99 Hz, 2H), 8.02 (br. s, 1H), 8.53 (d, J=2.35 Hz, 1H), 9.05 (d, J=2.35 Hz, 1H).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9].[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[C:12]([O:14]CC)=O.S(=O)(=O)(O)O>C(O)C>[O:14]=[C:12]([CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCC(C)=O
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCCC(=O)CC(=O)C(=O)OCC
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To refluxing solution of sodium ethoxide (51.2 g, 0.75 mmol) in ethanol (170 ml) was added dropwise over 30 minutes a solution of 2-pentanone (59 g, 0.68 mol) in diethyl oxalate (99 g, 0.68 mol). The resulting turbid yellow mixture was refluxed further for 2 hours, cooled to room temperature, poured over 500 g ice with stirring and adjusted to pH 1-2 with concentrated sulfuric acid (~40 ml). The organic phase was extracted with benzene (3×300 ml), washed once with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, before being filtered, concentrated, and fractionally distilled at 0.1 mm Hg to give 48.2 g (38%) of the title compound as a yellow liquid; b.p. 85°-95° C.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]([OH:28])[CH2:15][NH:16][CH2:17][CH2:18][NH:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27].Cl.[CH4:30]>C(O)=O>[ClH:1].[ClH:1].[N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:12][CH2:13][CH:14]([OH:28])[CH2:15][NH:16][CH2:17][CH2:18][NH:19][C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[C:5]=2[NH:4][CH:30]=1
Reactant: Cc1cccc(C)c1NCCNCC(O)COc1cccc(N)c1N
Reactant: C
Agent: Cl
Solvent: O=CO
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2nc[nH]c12

Procedure:
A solution of 21.5 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy}-benzene trihydrochloride in 150 ml. formic acid is boiled under reflux for 6 hours. After evaporating the reaction mixture in a vacuum, the residue obtained is taken up in 200 ml. 2N hydrochloric acid, boiled under reflux for 4 hours, mixed with active charcoal and filtered while hot. The filtrate is evaporated to dryness and the residue then recrystallized. There are obtained 3.5 g. (17.4% of theory) of the desired compound: m.p. 128°-131° C.
Reaction SMILES: N1(C[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.NC1CCN(C[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)CC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:9]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(Cc5ccccc5)CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-p-tolyloxy-1H-indole-2-carboxylic acid (137) (850 mg, 3.2 mmol) and 4-amino-N-benzylpiperidine (605 mg, 3.2 mmol) are dissolved in 5 ml of DMF and after addition of TBTU (1.2 g, 3.5 mmol) and ethyldiisopropylamine (2.2 ml, 12.8 mmol) the mixture is stirred at room temperature for 2 h. Then the mixture is evaporated at high vacuum. The residue is dissolved in ethyl acetate and washed with saturated NaHCO3-solution and brine. The organic layers are dried over Na2SO4, filtrated and evaporated under reduced pressure.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[C:14]([O:18][C:19]([N:21]1[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:22]1[CH:23]=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:22]1[CH:23]([OH:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
2.0M Phenylmagnesium bromide-tetrahydrofuran solution (22.8 ml, 45.6 mmol) was added dropwise to a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (10 g, 30.4 mmol) in tetrahydrofuran (200 ml) at -78° C. in a nitrogen stream. The reaction solution was allowed to gradually warm and then stirred at room temperature for 3 hours. After addition of water, this reaction solution was concentrated in vacuo. The resulting residue was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300 heptane:ethyl acetate 4:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-hydroxybenzyl)pyrrolidine (11.98 g, yield: 96.8%) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11].O>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a solution of 1-bromo-4-ethylbenzene (7 g, 37.8 mmol) in 9 mL concentrated H2SO4 at −20° C. was added a mixture of H2SO4 (3.74 g, 41.9 mmol) and HNO3 (2.64 g, 41.9 mmol). The mixture was stirred at −20° C. for 2 h. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give that tile compound (3 g, 34%).
Reaction SMILES: [Br:1][C:2]([Br:22])=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN.[ClH:26]>CO>[ClH:26].[C:16]1([C:3](=[C:2]([Br:1])[Br:22])[CH2:4][NH2:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(=C(Br)Br)c1ccccc1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: NCC(=C(Br)Br)c1ccccc1

Procedure:
Treatment of 1,1-dibromo-2-phenyl-3-phthalimidopropene (421 mg) with hydrazine hydrate (55 mg) and methanol (6 ml) followed by 50% aqueous hydrochloric acid as described in Example 19 D gives 2-phenyl-3,3-dibromoallylamine hydrochloride (175 mg): colorless needles; m.p. 243°-244°;
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[Br:1][C:2]1[C:3]([S:11][C:12]2[N:13]([CH2:23][C:24]3([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[CH2:26][CH2:25]3)[C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Reactant: Clc1ccc(C2(CBr)CC2)cc1
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CC1(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared from 8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)-9H-purin-6-ylamine and 1-(-bromomethyl-cyclopropyl)-4-chloro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(6-Bromo-benzo[1,3]dioxol-5-ylsulfanyl)-9-[1-(4-chloro-phenyl)-cyclopropylmethyl]-9H-purin-6-ylamine: 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.24 (d, J=9.3 Hz, 2H), 7.19 (s, 1H), 714 (d, J=8.6 Hz, 2H), 6.93 (s, 1H), 6.08 (s, 2H) 4.49 (s, 2H), 1.41-1.35 (m, 2H), 0.95-0.91 (m, 2H); LC-MS [M+H]+ 531.8.