Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:21][C:22]1[C:23]([CH2:56][CH2:57][N:58]2[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]2)=[CH:24][C:25]([O:54][CH3:55])=[C:26]([NH:28][C:29]2[N:34]=[C:33]([C:35]3[N:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]4=[N:37][C:36]=3[C:44]3[CH:45]=[C:46]([CH:51]=[CH:52][CH:53]=3)[C:47](OC)=[O:48])[CH:32]=[CH:31][N:30]=2)[CH:27]=1.CO>C1COCC1>[F:21][C:22]1[C:23]([CH2:56][CH2:57][N:58]2[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]2)=[CH:24][C:25]([O:54][CH3:55])=[C:26]([NH:28][C:29]2[N:34]=[C:33]([C:35]3[N:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]4=[N:37][C:36]=3[C:44]3[CH:45]=[C:46]([CH:51]=[CH:52][CH:53]=3)[C:47]([NH:4][C:3]3[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=3[F:10])=[O:48])[CH:32]=[CH:31][N:30]=2)[CH:27]=1
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(F)c(CCN4CCCCC4)cc3OC)n2)c1
Reactant: Nc1c(F)cc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCN2CCCCC2)c(F)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cc(F)cc4F)c3)nc3ccccn23)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To 2,4,6-trifluoroaniline (127 mg, 1 mmol) was added 1N NaHMDS in THF (0.9 mL, 0.9 mmol). The mixture stirred for 15 min at rt. Methyl 3-{3-[2-({5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]phenyl}amino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl}benzoate (Example 128, step A) (100 mg, 0.172 mmol) in 3 mL of dry THF was added. The mixture stirred at rt for 30 minutes. 1 mL of MeOH was added followed by 1 g of silica gel. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (74 mg, 0.11 mmol, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 9.44 (d, J=6.96 Hz, 1H), 8.20-8.26 (m, 4H), 7.99 (dt, J=7.83, 1.40 Hz, 1H), 7.74-7.78 (m, 2H), 7.62 (d, J=8.97 Hz, 1H), 7.48 (t, J=7.78 Hz, 1H), 7.31-7.36 (m, 1H), 6.91 (td, J=6.87, 1.28 Hz, 1H), 6.72-6.78 (m, 3H), 6.60 (d, J=5.13 Hz, 1H), 3.90 (s, 3H), 2.78-2.84 (m, 2H), 2.53-2.58 (m, 2H), 2.44-2.53 (m, 4H), 1.58-1.65 (m, J=5.59, 5.59, 5.59, 5.59 Hz, 4H), 1.46 (d, J=5.13 Hz, 2H). MS (ESI): 696 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][C:33]([CH:36]2[O:40][CH2:39][CH2:38][O:37]2)=[CH:34][CH:35]=1)CCC>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:31]4[O:32][C:33]([CH:36]5[O:40][CH2:39][CH2:38][O:37]5)=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: c1ccc(Oc2ccc(Nc3ccnc4cc(-c5ccc(C6OCCO6)o5)ccc34)cc2)cc1
Yield: 68.1 %

Procedure:
(4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was treated with 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16 g) and tetrakis(triphenylphosphine)palladium(0) (0.26 g) in dimethylacetamide (20 ml) in accordance with Procedure B. Purification via column chromatography, eluting with ethyl acetate, followed by trituration with diethylether afforded a yellow solid (1.4 g); δH [2H6] DMSO 9.10 (1H, s), 8.45 (2H, m), 8.13 (1H, s), 7.96 (1H, d), 7.41 (4H, m), 7.22 (1H, d), 7.20-7.03 (5H, m), 6.83 (1H, d), 6.75 (1H, d), 6.02 (1H, s), 4.13 (2H, m), 4.01 (2H, m); m/z 451 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C@:8]([CH3:22])([C@H:9]4[C@@:13]([CH2:15][CH:16]=3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C1COCC1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH3:22])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@]1(C)C2=CC[C@@]2(C)[C@H]1CC[C@@H]2O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@]1(C)[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@H]21

Procedure:
75 mg of 3-methoxy-8β-methyl-estra-1,3,5(10),9(11)-tetraen-17β-ol (7a) was dissolved in a solvent mixture that consists of 3.5 ml of THF and 1.5 ml of methanol and stirred with 75 mg of palladium (10%, on magnesium carbonate) for 3.75 hours at room temperature under hydrogen atmosphere. Then, the reaction solution was filtered on Celite, the filtrate was evaporated to the dry state in a rotary evaporator, and the thus obtained TLC-uniform, foamy product (74 mg, 98%) was used without further purification in the next stage.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[CH:3]=[N:2]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][C:12]=1[CH2:24][S:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[C:26]([S:25][CH2:24][C:12]1[CH:13]=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[CH:16][C:11]=1[CH2:10][N:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[CH:3]=[N:2]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: N#CCc1cn[nH]c1
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cn1cc(CC#N)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(1H-Pyrazol-4-yl)-acetonitrile (0.19 g, 1.77 mmol) and N-(4-bromomethyl-3-tert-butylsulfanylmethyl-phenyl)-2,2-dimethyl-propionamide (0.20 g, 0.55 mmol) were combined in MeCN. Cesium carbonate (0.95 g, 2.90 mmol) was added, and the reaction was stirred for 45 minutes at room temperature. The mixture was worked-up and purified by silica gel chromatography to give the title compound.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20]C)=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.Cl.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([OH:20])=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1cccc(OCOC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1cccc(O)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
Methyl 2-(4-(3-(methoxymethoxy)phenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (60 mg; 0.143 mmol) was dissolved in methanol (1.5 mL) and 12N hydrochloric acid (10 μL; 0.120 mmol) was added. The mixture was heated at 60° C. for 3 h until the deprotection was finished (monitored by TLC). The mixture was basified with an excess 10N sodium hydroxide solution and stirred in a sealed tube at 80° C. for 18 h. The volatiles were removed under reduced pressure, the residue was dissolved in water and acidified with a 6N hydrochloric acid solution. The precipitate was filtered, washed with water and dried under reduced pressure over phosphorus pentoxide to give 37 mg (71%) of the title compound as a yellowish solid. ESI/APCI(+): 363 (M+H). ESI/APCI(−): 723 (2M−H).
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
A mixture of 2-phenylprop-1-ene (14.16 g, 0.12 mol), N-bromosuccinimide (13.5 g, 72 mmol) and α,α'-azoisobutyronitrile (1.5 mg) in carbon tetrachloride (7.5 mL) was placed in a pre-heated oil bath at 170° C. (the internal temperature rose to 110° C.). The slurry was stirred vigorously at this temperature for 2 h. and was then allowed to cool to ambient temperature. The mixture was filtered, washing with carbon tetrachloride, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane to give the title compound as an oil (320 mg). 1H NMR (250 MHz, CDCl3) δ(7.85-7.81 (2 H, m), 7.75-7.63 (3 H, m), 5.89 (1 H, s), 5.82 (1 H, s), and 4.72 (2 H, s).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH2:33]([CH:35]1[O:37][CH2:36]1)Cl>O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:33][CH:35]2[CH2:36][O:37]2)[CH:3]=1
Reactant: ClCC1CO1
Reactant: O=c1c2cc3ccccc3cc2oc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc3ccccc3cc2oc2cc(OCC3CO3)cc(O)c12
Yield: 10.8 %

Procedure:
1,3-dihydroxy-12H-benzo[b]xanthen-12-one (0.1 g, 0.36 mmol) synthesized in Step 1 of Example 18, K2CO3 (0.2 g, 1.44 mmol), and DMF (5 mL) were added to a dry round-bottom flask, and epichlorohydrin (0.19 g, 2.16 mmol) was added thereto with stirring using a syringe. The reaction mixture was stirred under a nitrogen atmosphere (75° C., overnight). After the reaction was completed, water was added to the reaction mixture which was then extracted twice with ethyl acetate. The organic layer was combined, washed with brine and dried over anhydrous Na2SO4. This liquid was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give the title compound (13 mg, 10.8%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=3)[CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[OH-].[Na+]>Br.C(O)(=O)C>[Cl:1][C:2]1[C:3]([NH:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=3)[CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1ncnc(NC2CCc3cc(OC)ccc3C2)c1Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1ncnc(NC2CCc3cc(O)ccc3C2)c1Cl

Procedure:
A solution of 5.8 g (18 mmol) of 5-chloro6-ethyl4-(6-methoxytetralin-2-ylamino)pyrimidine in 22 ml of 48% HBr and 4.5 ml of acetic acid was heated for 4 hours at 110° C. After the mixture had cooled, it was brought to pH=8 with sodium hydroxide solution and extracted with dichloromethane. After the dichloromethane phase had been dried, concentrated and washed with toluene, 4.8 g (88% of theory) of colorless crystals were obtained (m.p. 178° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10]([Cl:26])=[CH:11][C:12]([F:25])=[C:13]([N:15]3[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]3)[CH:14]=2)=[N:6][CH:7]=1.Cl.[N:28]([O-])=O.[Na+].[F:32][B-:33]([F:36])([F:35])[F:34].[Na+]>O>[F:32][B-:33]([F:36])([F:35])[F:34].[Cl:26][C:10]1[CH:11]=[C:12]([F:25])[C:13]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:22])[F:23])[C:17]([CH3:24])=[N:16]2)=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[CH:3][C:2]([N+:1]#[N:28])=[CH:7][N:6]=1
Reactant: Cc1nn(-c2cc(Oc3ccc(N)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: Cc1nn(-c2cc(Oc3ccc([N+]#N)cn3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
To a stirred mixture of 3.9 g (0.010 mole) of 1-[5-(5-aminopyridin-2-yloxy)-4-chloro-2-fluorophenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 10 mL of water was added 5.0 mL of concentrated hydrochloric acid. The mixture was cooled in an ice water bath, and a solution of 0.76 g (0.011 mole) of sodium nitrite in 1.4 mL of water was added portionwise. The resultant mixture was stirred at 0° C. for 30 minutes, and a solution of 1.5 g (0.014 mole) of sodium tetrafluoroborate in 5 mL of water was added portionwise. An additional 5 mL of water was added, and the reaction mixture was stirred at 0° C. for 45 minutes. The mixture was filtered, and the filter cake was rinsed with ice water followed by diethyl ether. The filter cake was dried under reduced pressure to yield 4.7 g of 2-[2-chloro-4 -fluoro-5-(4-difluoromethyl-4,5-dihydro -3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]pyridine-5-diazonium tetrafluoroborate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]([C:8]2[C:9]([CH2:10][OH:11])=[CH:13][CH:14]=[CH:15][CH:16]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCc1ccccc1C(O)c1ccc(Cl)cc1

Procedure:
A mixture of 55 g (0.3M) of 2-(4-chlorobenzoyl) benzoic acid, 5 ml of concentrated sulphuric acid and 500 ml of methanol was heated under reflux for 3 hours. The mixture was evaporated and the residue was taken up in dichloromethane washed with water then aqueous sodium bicarbonate. The dichloromethane was dried and evaporated. The residue was then reduced with lithium aluminium hydride in an analogous manner to that described in Example X1 to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:39](=[O:40])[CH2:38][CH2:37][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(C(=O)OC)cc3)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(=O)OC)cc3)C(=O)CCC3CCCC3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure E using methyl 4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]benzoate and 3-cyclopentylpropanoyl chloride as a colorless oil (71%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.54-7.39 (m, 4H), 7.30-7.06 (m, 6H), 4.61 (d, J=11.3 Hz, 2H), 4.48 (d, J=11.7 Hz, 2H), 3.91 (m, 3H), 2.61 (t, J=7.7 Hz, 2H), 2.41 (m, 2H), 1.79-1.66 (m, 4H), 1.65-1.43 (m, 7H), 1.40-1.28 (m, 2H), 1.14-1.00 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). M+ (ESI): 536.4. HPLC, Rt: 6.42 min (Purity: 99%).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18].C(=O)(O)[O-].[Na+]>>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]c(Cl)nc12
Reactant: CN(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCNc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-4-nitro-1H-benzimidazole (300 mg) and N,N-dimethylethylenediamine (2 ml) were stirred at 80° C. for 8 hours. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution and extracted with a mixture of chloroform and methanol. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The resiude was washed with diisopropyl ether to give 2-[[2-(dimethylamino)ethyl]amino]-4-nitro-1H-benzimidazole (113 mg).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([OH:8])=[O:7].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]>ClCCl>[N+:6]([O:9][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCCCBr
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C(O)CCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
Concentrated sulphuric acid 96% (1.24 mL, 2.0 eq) was added dropwise to fuming nitric acid 100% (0.97 mL, 2.0 eq) at 0° C. After 10 minutes of stirring at 0° C., a solution of 1 (2.00 g, 1.0 eq) in dichloromethane (20.0 mL) was added dropwise. The reaction mixture was stirred from 0° C. to RT for 3 hours and quenched with water (30.0 mL). The organic layer was washed with water (20.0 mL) and brine (20.0 mL), dried over magnesium sulphate, filtered off and concentrated under vacuum. The residue was adsorbed on silica gel and purified by flash chromatography [Biotage®, dichloromethane/methanol 100/0→97/3 (10CV*), 97/3 (5CV)] affording compound 2 as a colourless liquid (1.47 g, yield=58%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][NH:7]1)(=[O:3])[CH3:2].[N+:12]([C:15]1[CH:33]=[CH:32][C:18]([CH2:19][O:20][C:21](SC2N=C(C)C=C(C)N=2)=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC)CC)C>O.O1CCCC1.C(OCC)(=O)C>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([N:7]2[CH2:8][C@H:9]([OH:11])[CH2:10][C@H:6]2[CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:22])=[CH:32][CH:33]=1)([O-:14])=[O:13]
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(=O)OC[C@@H]1C[C@@H](O)CN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-2-acetoxymethyl-4-hydroxypyrrolidine (22.66 g) in water (100 ml), a solution of S-p-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (34.45 g) in tetrahydrofuran (453 ml) was added at room temperature, followed by addition of triethylamine (22.54 ml). The resulting mixture was stirred at the same temperature for 30 minutes and diluted with ethyl acetate. The reaction mixture was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution and dried over magnesium sulfate, followed by removal of the solvent. The residue was purified by silica gel column chromatography to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-acetoxymethyl4-hydroxypyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1.[CH:21]1C=C(Cl)C=[C:23]([C:28]([O:30]O)=[O:29])[CH:22]=1>C(Cl)Cl>[C:28]([CH2:23]/[CH:22]=[CH:21]/[C:15]1[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:19][CH:18]=[C:17]([CH3:20])[N:16]=1)([OH:30])=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CCCCOc2ccc(C)nc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCCOc2ccc(C)nc2/C=C/CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-E-2-Carboxymethylethenyl)-3-[4-(4-methoxyphenyl) butyloxy]-6-methylpryidine (13.6 g, 38.2 mmol) was dissolved in dry CH2Cl2 (100 mL) and cooled to 0° C. To this was added 50% mCPBA (13.2 g, 38.3 mmol) in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 h at room temperature. The reaction was poured into aqueous NaHCO3 and the product extracted into CH2Cl2. The organic extract was washed with H2O and brine and dried (MgSO4). The crude product was obtained as a yellow solid and was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:118][C:119]([CH3:139])=[CH:120][CH2:121][CH2:122]/[C:123](/[CH3:138])=[CH:124]/[CH2:125][CH2:126]/[C:127](/[CH3:137])=[CH:128]/[CH2:129][S:130][CH2:131][C@H:132]([NH2:136])[C:133]([OH:135])=[O:134]>C(Cl)Cl>[CH3:4][C:2]([CH3:1])([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16](=[O:18])[NH:136][C@H:132]([C:133]([OH:135])=[O:134])[CH2:131][S:130][CH2:129]/[CH:128]=[C:127](\[CH3:137])/[CH2:126][CH2:125]/[CH:124]=[C:123](\[CH3:138])/[CH2:122][CH2:121][CH:120]=[C:119]([CH3:139])[CH3:118])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-phenylglycine (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes and S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (118 mg, 21%) to yield Compound N-5. 1H-NMR (500 MHz, CD3OD): δ 1.47 (s, 9H), 1.62 (s, 6H), 1.69 (s, 6H), 1.99 (t, J=7.0 Hz, 2H), 2.03-2.13 (m, 6H), 2.81 (dd, J=8.1, 13.9 Hz, 1H), 3.01 (dd, J=6.8, 12.1 Hz, 1H), 3.16 (dd, J=7.6, 13.2 Hz, 1H), 3.26 (dd, J=8.5, 13.4 Hz), 4.62 (bt, J=5.5), 5.09-5.12 (m, 2H), 5.22 (t, J=7.9 Hz, 1H), 7.29-7.37 (m, 3H), 7.46 (d, J=7.3 Hz, 2H). 13C-NMR (125 MHz, CD3OD): δ 16.2, 16.3, 25.9, 27.3, 27.8, 28.7, 30.3, 33.4, 33.5, 40.8, 40.9, 53.6, 59.9, 81.1, 121.6, 125.2, 125.5, 128.6, 129.1, 129.7, 132.1, 136.3, 139.1, 140.5, 158.3, 173.0, 173.4; ES-MS: mass calcd for
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH2:14][C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[CH2:14][C:15]1([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:6]
Reactant: CNCC1(N2CCN(C)CC2)CCCCC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: CN1CCN(C2(CN(C)C(=O)c3ccc(Cl)c(Cl)c3)CCCCC2)CC1
Yield: 23.5 %

Procedure:
A solution of 3,4-dichlorobenzoylchloride (0.61 g.,) in benzene (10 ml) was added dropwise over 25 mins. to a stirred solution of 1-[1-(methylaminomethyl)cylcohexyl]-4-methyl piperazine (1) (0.65 g.). The mixture was then heated on a steambath for 1 hr. and the mixture was evaporated to dryness. The residue was dissolved in hot light petroleum (60°-80°) and decolourised with charcoal. The solid which separated was crystallised from light petroluem (60°-80°) to give 3,4-Dichloro-N-methyl-N-[[1-(4-methyl-1-piperazinyl)cyclohexyl]methyl]benzamide (0.27 g., 23%) m.p. 126°-129°.