Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]([CH3:24])=[C:8]([CH3:25])[N:7]=1>CO>[CH3:3][O:2][N:4]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]([CH3:24])=[C:8]([CH3:25])[N:7]=[C:6]([NH2:5])[C:11]=2[N:12]=[C:13]1[CH2:21][CH2:22][CH3:23])[CH3:19]
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCC(C)=O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCC(C)=NOC
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
Methoxylamine hydrochloride (0.57 g, 6.8 mmol) was added to a solution of 5-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridine-1-yl)pentan-2-one (1.31 g, 4.5 mmol) in methanol (30 mL) and stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (150 mL), washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under reduced pressure to afford 1.33 g of crude material. The crude material was purified by HPFC (silca gel, CMA 0-40% in chloroform) and dried overnight at 70° C. at 28 psi (1.9×105 Pa) to afford 0.75 g of 5-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridine-1-yl)pentan-2-one O-methyloxime as an off-white powder, mp 144.0-145.5° C. 1H NMR (300 MHz, DMSO-d6) δ 5.58 (s, 2H), 4.23 (t, J=8.1 Hz, 2H), 3.74 (s, H), 3.71 (s, H), 2.77 (t, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 2.25 (t, J=7.5 Hz, 2H), 1.80 (m, J=7.5 Hz, 8H), 1.00 (t, J=6.9 Hz, 3H; MS (APCI) m/z 318 (M+H)+; Anal. calcd for C20H26N6O2: C, 64.32; H, 8.57; N, 22.06. Found: C, 64.19; H, 8.86; N, 22.32.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20]O)[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:23].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20][Br:23])[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: BrCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 120 °C
Yield: 70 %

Procedure:
To a solution of [3-(4-benzyloxyphenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.052 g, 0.17 mmol) in toluene (5 ml) was added PBr3 (0.027 ml, 0.26 mmol) and the resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.043 g, 68%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:9][OH:10])[C:5]([F:8])=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](Cl)=[O:26])[C@H:21]([CH2:28][CH3:29])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[CH2:9][O:10][C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:18])[CH2:20][C@H:21]1[CH2:28][CH3:29])=[O:26]
Reactant: OCc1c(F)ccc(Br)c1F
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(Br)c1F

Procedure:
The compound was prepared from (3-bromo-2,6-difluoro-phenyl)-methanol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedures described in Example 121 and 54 to give the product as a colorless oil (9.22 g); MS (ISP): 480.3, 482.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:34]1[CH2:33][CH2:32][CH2:31]CC2.BrCC1CC1.O>C(O)C>[CH:33]1([CH2:34][O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH2:25][CH3:26])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:31][CH2:32]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1
Agent: BrCC1CC1
Solvent: CCO
Solvent: O
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCC3CC3)c2)n1

Procedure:
A 0.2 g quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2 and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml of ethanol, and 0.14 g of (bromomethyl)cyclopropane was added thereto. The mixture was heated and refluxed overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.18 g of white powdery N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[C:7]([Cl:20])[CH:6]=[CH:5][C:4]1=2.C(N(CC)CC)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O.CN(C)C=O>[Cl:20][C:7]1[CH:6]=[CH:5][C:4]2[CH:3]([NH:2][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]=2[CH:8]=1
Reactant: NC1c2ccc(Cl)cc2-c2[nH]c(=O)c3nccn3c21
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)NC1c2ccc(Cl)cc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 0.5 g of 10-amino-7-chloro-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride suspended in 8 ml of dimethyl sulphoxide is added dropwise 0.45 ml of triethylamine, followed by a solution of 0.9 ml of phenyl isocyanate in 2 ml of dimethylformamide. The reaction medium is stirred for 2 hours at a temperature in the region of 20° C. and the precipitate formed is filtered off, washed with water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 50° C. 0.15 g of 7-chloro-10-(3-phenylureido)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, in the form of a white solid the melting point of which is greater than 260° C. (Analysis C20H14ClN5O2 ·0.6 DMF·0.8 H2O % calculated C: 61.31; H: 3.60; Cl: 9.05; N: 17.87; % found C: 61.1; H: 3.5; Cl: 9.4; N: 17.7).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C[CH:14]=[CH:15][CH2:16][NH2:17].[CH3:18]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:17][CH2:16][C:15]([CH3:18])=[CH2:14]
Reactant: CC=CCN
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: C=C(C)CNCc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-5-nitrobenzaldehyde (25 g) in EtOH (200 mL) was added 3-methylallylamine (10.6 g, 1.1 eq). HOAc (9 g) was added to the solution. The mixture was stirred at 20˜25° C. for 3 h. NaBH(OAc)3 (43 g, 1.5 eq) was added in one portion at ˜5° C. The mixture was warmed to RT in 30 min and stirred for 1 h. The EtOH was removed under reduced pressure and saturated Na2CO3 aqueous solution (200 mL) was added. The mixture was extracted with toluene (100 mL). To the toluene solution was added 5 N HCl in IPA (20 mL) at ˜5° C. in 1 h. The mixture was stirred for 1 h. The solids were filtered off, and dried under vacuum.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]1([NH:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:38][N:39]([CH:41]=O)C>[Cu].O>[CH:24]1[CH:25]=[CH:26][C:21]([N:27]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([N:39]([C:41]4[CH:32]=[CH:31][C:30]5[C:35](=[CH:36][CH:37]=[CH:28][CH:29]=5)[CH:34]=4)[C:38]4[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=4)=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:22][CH:23]=1
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Reactant: CN(C)C=O
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc(N(c2ccc(-c3ccc(N(c4ccccc4)c4ccc5ccccc5c4)cc3)cc2)c2ccc3ccccc3c2)cc1
Yield: 72.4 %

Procedure:
25.1 g (61.5 mmol) of 4,4′-diiodobiphenyl, 2.14 g of poly(ethylene glycol) PEG-6000 that was available from Wako Pure Chemical Industries, Ltd., 17.1 g (0.124 mol) of potassium carbonate and 15.7 g (247 mmol) of powdered copper were added to 32.4 g (148 mmol) of N-phenyl-2-naphthylamine. It was heated at 200 degrees Centigrade. It was determined for tracing by the high-speed liquid chromatography. And it was stirred and refluxed for 12 hours until no peaks of starting materials and intermediates were determined. DMF and water were added thereto to disperse. It was filtrated and washed with water. Precipitated crystals were purified by silica gel column chromatography to obtain 26.2 g of beta-NPD that is represented by Compound Example 5 at 72.4% yield.
Reaction SMILES: [F:1][C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].C1C(=O)N([I:36])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N>[F:1][C:2]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:36])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([F:4])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
(R)-4-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (865 mg, 2.22 mmol) and NIS (550 mg, 2.45 mmol, 1.1 eq.) were dissolved in CH3CN (5 mL). Then CF3COOH (76 mg, 0.67 mmol, 0.3 eq.) was added to the mixture dropwise at 0° C. The mixture was warmed to 15° C. and stirred for another 1 h. Then the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using PE/EA (1/1) as eluent to give the title compound as a slight red solid (1.02 g, 90%). EDI-MS (M+1): 515.8. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, 1H), 7.73 (d, 2H), 7.48 (dd, 1H), 7.18 (d, 1H), 6.49 (s, 1H), 4.45-4.40 (m, 2H), 4.33-4.30 (m, 1H), 2.27-2.25 (m, 2H), 2.03-2.01 (m, 2H), 1.84 (s, 3H), 1.65-1.24 (m, 8H).
Reaction SMILES: C([O-])(=O)[C:2]([CH3:4])=[O:3].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H:35]([N:37]5C=C(C(N)=O)C[CH:39]=[CH:38]5)[C@H:34]([OH:46])[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C([O-])(=O)C(C)[OH:53].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[N:37]([CH2:4][CH2:2][OH:3])([CH2:35][CH2:34][OH:46])[CH2:38][CH2:39][OH:53]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: CC(=O)C(=O)[O-]
Reactant: CC(O)C(=O)[O-]
Product: OCCN(CCO)CCO

Procedure:
pyruvate + NADH LDH LDH lactate + NAD
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O-:17])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2)(=[O:21])=[O:20].[CH3:31][C:32]([O-])([CH3:34])[CH3:33].[Na+]>O1CCOCC1.CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:32]([CH3:34])([CH3:33])[CH3:31])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=1)[CH:26]=[CH:25]2)(=[O:21])=[O:20]
Reactant: O=C([O-])N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1
Yield: 74.4 %

Procedure:
To a mixture of 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) (0.440 g, 1.4 mmol) and 5-(methylsulfonyl)-1H-indole (intermediate-21) (0.261 g, 1.3 mmol) in anhydrous dioxane (5 mL), 2-(2′-Di-tert-butylphosphine) biphenylpalladium(II)acetate (0.130 g, 0.281 mmol) and NaOtBu (sodium tert.butoxide) (0.312 g, 0.960 mmol) were added. The resultant reaction mixture was refluxed for 4-5 h. The reaction mixture was filtered over celite and filtrate was concentrated in vacuo. The residue was purified by flash column chromatography to give tert-butyl 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidine-1-carboxylate (0.337 g, 50%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:51][CH2:52][C:53]1[O:57][C:56]([C:58]2[CH:63]=[CH:62][C:61]([C:64]3[C:69]([CH3:70])=[CH:68][CH:67]=[C:66]([C:71]([NH:73][CH:74]4[CH2:76][CH2:75]4)=[O:72])[CH:65]=3)=[CH:60][CH:59]=2)=[N:55][N:54]=1>CN(C=O)C>[CH:74]1([NH:73][C:71]([C:66]2[CH:65]=[C:64]([C:61]3[CH:62]=[CH:63][C:58]([C:56]4[O:57][C:53]([CH2:52][NH:51][C:5](=[O:7])[CH2:4][CH:1]5[CH2:2][CH2:3]5)=[N:54][N:55]=4)=[CH:59][CH:60]=3)[C:69]([CH3:70])=[CH:68][CH:67]=2)=[O:72])[CH2:76][CH2:75]1
Reactant: O=C(O)CC1CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)CC3CC3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Cyclopropylacetic acid (8.6 mg) and HATU (33 mg) in DMF (1 ml) were stirred for 10 minutes at room temperature. To this solution was added HOBt (11.6 mg), DIPEA (.0.45 ml) and 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in DMF (2 ml) and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue dissolved in DCM and washed with water (2×4 ml). The organic phase was reduced to dryness and the residue purified by bond-elut (SCX, 5 g) eluting with methanol and methanolic ammonia. The methanolic ammonia fraction was further purified by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4′-(5-{[(cyclopropylacetyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][C:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]34[O:29][CH2:28][C:25]([CH3:30])([CH2:26][O:27]3)[CH2:24][O:23]4)=[C:16]([CH3:31])[CH:15]=2)=[C:9]([CH3:11])[CH:10]=1)CCC.[F:40][C:41]1[CH:48]=[C:47](Br)[CH:46]=[CH:45][C:42]=1[C:43]#[N:44].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCCC1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[F:40][C:41]1[CH:48]=[C:47]([C:6]2[S:7][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]45[O:23][CH2:24][C:25]([CH3:30])([CH2:26][O:27]4)[CH2:28][O:29]5)=[C:16]([CH3:31])[CH:15]=3)=[C:9]([CH3:11])[CH:10]=2)[CH:46]=[CH:45][C:42]=1[C:43]#[N:44]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)c(CCc2ccc(OCC34OCC(C)(CO3)CO4)c(C)c2)s1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: Cc1cc(CCc2sc(-c3ccc(C#N)c(F)c3)cc2C)ccc1OCC12OCC(C)(CO1)CO2

Procedure:
A mixture of tributyl[4-methyl-5-(2-{3-methyl-4-[(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methoxy]phenyl}ethyl)thien-2-yl]stannane (intermediate 100, 0.037 g) and 2-fluoro-4-bromobenzonitrile (0.011 g) in tetrahydrofuran (2 ml) was treated with palladium bis(dibenzylideneacetone) (0.0035 g) and trifuranyl phosphine (0.0013 g) and the resulting mixture stirred at reflux for 3 hours. The solvent was removed and the residue purified by Biotage® chromatography using a mixture of petroleum ether:ethyl acetate (4:1) as eluent to give the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=2)=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>C1COCC1.CCOCC>[NH2:1][CH2:4][C:5]1[O:9][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:11]=2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reaction time: 24 h
Yield: 0.1 %

Procedure:
121.5 mg of 3-(5-azidomethylfuran-2-yl)-1-benzyl-indazole (0,369 mmol) and 102 mg of triphenylphosphine (0.389 mmol) were stirred in 1 ml of THF for 3.5 hours. 10 μl of water were then added. After 24 hours, ether and aqueous HCl, 0.3M, were added to the reaction mixture. The solid which had been filtered off and the aqueous phase were combined, rendered alkaline with NaOH, 2M, and extracted with ether. The organic phase was washed with a little water and then with a sodium chloride solution, dried over sodium sulphate and concentrated. 79.9 mg of a yellow oil were obtained.
Reaction SMILES: BrC1SC(N[C:8](=[O:10])C)=NN=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]2[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=[C:21]2[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][CH:8]=[O:10])[CH2:15][CH2:16]2)=[CH:28][CH:29]=1
Reactant: CC(=O)Nc1nnc(Br)s1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 4.4 parts of N-(5-bromo-1,3,4-thiadiazol-2-yl)acetamide, 7.3 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 3.18 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 80°-90° C. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1.7 parts of N-[2-[4-[[1[(4fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl] ethyl]formamide; mp. 153.2° C. (intermediate 156).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)[C:5]([O:7][CH3:8])=[O:6].[CH3:25][O-].[Na+].CI>CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)([CH3:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[O-]
Reactant: COC(=O)C(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-propanedioic acid dimethyl ester (37 mmol) in dry MeOH (0.25 L) at 0° C. under argon was added a solution of 25% NaOMe in MeOH (8.56 mL, 37.4 mmol). The mixture was stirred for 30 min at 0° C. MeI (3.56 mL, 56.6 mmol) was added. The mixture was refluxed for 42 h, cooled, and concentrated. The residue was partitioned between H2O and Et2O. The Et2O extracts were washed with H2O, dried, and concentrated to an oil. This oil was purified by silica chromatography to give the title compound: TLC Rf=0.50 (CH2Cl2); MS (ESI+) m/z 371.1; 1H NMR (CDCl3, 300 MHz) δ 9.63 (1H), 7.44 (1H), 7.05 (1H), 6.97 (1H), 3.82 (6H), 3.44 (2H), 2.94 (2H), 1.93 (3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:23])[C:18]([OH:20])=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: COC(=O)C(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of methyl 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]sulfonyl}-2-methylpropanoate (1.65 g, 4.06 mmol) in methanol (7.5 mL) and THF (7.5 mL) is added 2N aqueous NaOH solution at room temperature. The reaction is stirred for 3 h, then acidified with 2N aqueous HCl solution to pH 4 and concentrated under reduced pressure. The residue is partitioned between water (75 mL) and DCM (75 mL). The acidic aqueous layer is extracted with DCM (50 mL×2) and the combined organic extracts are dried over Na2SO4, filtered and the filtrated is concentrated under reduced pressure to afford 1.31 g of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethyl-propyl)-1H-benzoimidazol-5-yl]sulfonyl}-2-methylpropanoic acid. Yield: 82%, ES-MS: 393 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[N+:17]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[NH2:17]
Reactant: [H][H]
Reactant: COc1cccc(/C=C/c2ccccc2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CCc2ccccc2)c1N
Reaction time: 18 h
Yield: 105.6 %

Procedure:
2.25 g of 1-methoxy-2-nitro-3-[(E)-2-phenylvinyl]benzene are added to 0.18 g of palladium-on-charcoal (10%) suspended in 90 ml of methanol, and placed under 4 bar of hydrogen. After 18 hours, the reaction medium is filtered through talc and the filtrate is concentrated to give 2.115 g of the expected product.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[H][H]>CO.[Pd]>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(N2CCN(C3CC3)CC2)cc1
Yield: 99.4 %

Procedure:
To a solution of 1-cyclopropyl-4-(4-nitro-phenyl)-piperazine (1.24 g, 5.00 mmol) in methanol (25 mL) was added Pd/C (10%, 100 mg) and trifluoroacetic acid (1.0 mL). The mixture was stirred under 1 atm of hydrogen (balloon) overnight, filtered and concentrated. To the residue was added water and 1N aq. NaOH to adjust the PH>11. The mixture was extracted ethyl acetate, and the organic layer was dried over Na2SO4, concentrated to give the title compound (1.08 g, 100%) as a brown oil. MS (ES+): m/z=218.1.