Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].ClC([O:19][CH2:20][CH2:21]Cl)=O.Cl>COCCOC.O>[OH:19][CH2:20][CH2:21][NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccccc1NCCO
Temperature: 80 °C

Procedure:
60.1 g of calcium carbonate are added to a solution of 138.1 g of 2-nitroaniline in 360 g of monoethylene glycol dimethylether and 60 g of water. 150.0 g of 2-chloroethyl chloroformate are then metered in at 80° C. and the reaction is brought to completion by subsequent stirring at 80° C. 100 g of water and 8.7 g of 35% strength hydrochloric acid are then added, up to a pH of 1, and the lower aqueous phase is separated off. The upper organic phase is diluted with 90 g of monoethylene glycol dimethylether, and 370.6 g of a 50% strength potassium hydroxide solution are added at 15° C. The reaction mixture is then heated to 85° C. and subsequently stirred at 85° C. for 4 hours. Thereafter, 250 g of water are added and the lower salt-containing aqueous phase is separated off. First 500 g of water and then 9 g of 10% strength sulphuric acid are added to the yellow-red organic phase, up to a pH of 8.5. After the monoethylene glycol dimethyl ether has been distilled off and the residue has been cooled to 10° C., the product is obtained in the form of yellow-red crystals.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:2][C:3]#[N:4])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: N#CCBr
Reactant: COc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCN(CC#N)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.9 %

Procedure:
A mixture of bromoacetonitrile (0.70 mL, 10 mmol), 4-(3-methoxyphenyl)piperidine (1.74 g, 9.1 mmol) and K2CO3 (1.3 g) in MeCN was stirred at room temperature for 3 days. The reaction mixture was partitioned between CH2Cl2 and H2O, and the organic extract was dried (Na2SO4). The solvent was then removed in vacuo to afford [4-(3-methoxyphenyl)-1-piperidinyl]acetonitrile as an amber oil (2.03 g, 97%): MS (DCl) m/z 231 (MH+). Anal. Calcd. for C14H18N2O.0.5 H2O: C, 70.27; H, 8.00; N, 11.71. Found: C, 70.12; H, 7.67; N, 11.87.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]1[C:50]2([CH2:55][CH2:54][CH:53]([CH2:56][OH:57])[CH2:52][CH2:51]2)[CH2:49][CH2:48]1>>[Cl:17][C:18]1[C:19]([O:57][CH2:56][CH:53]2[CH2:52][CH2:51][C:50]3([CH2:49][CH2:48][CH2:47]3)[CH2:55][CH2:54]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1CCC2(CCC2)CC1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCC3(CCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with spiro[3.5]nonan-7-ylmethanol, the title compound was obtained as a colorless solid (0.26 g, 47%): 1H NMR (300 MHz, CDCl3) δ 8.61 (br s, 1H), 8.05 (d, J=8.4 Hz, 1H), 6.65 (d, J=13.5 Hz, 1H), 3.82 (d, J=6.3 Hz, 2H), 3.01 (s, 6H), 1.89-1.65 (m, 11H), 1.35-1.04 (m, 4H); MS (ES−) m/z: 431.2, 433.2 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[C:4]([F:14])[CH:3]=1.Cl.Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.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>CN(C=O)C>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][C:4]([F:14])=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:19]2
Reactant: O=C(O)c1cc2cc(F)cc(Br)c2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(Br)c2o1
Reaction time: 0.33 h

Procedure:
143 mg (0.55 mmol) of 5-fluoro-7-bromo-1-benzofuran-2-carboxylic acid (Example 4A), 100 mg (0.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 229.14 mg (0.6 mmol) of HATU, 234 mg (1.81 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted by general method C. DMF is removed under reduced pressure, and the crude product is dissolved in 1N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. 181 mg (98% of theory) of the title compound are isolated.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH2:21])=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[S:31])[NH2:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(C(N)=O)cn(CC3CCCCC3)c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.5 %

Procedure:
A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide (prepared from 7-methoxyindole as described in Example 1; 5.10 g, 17.8 mmol), Lawesson's reagent (7.92 g, 19.6 mmol), and toluene (150 ml) was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with dichloromethane to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (3.58 g). A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (200 mg, 0.66 mmol), 1,3-dichloroacetone (126 mg, 0.99 mmol), and ethanol (2.0 ml) was stirred at 60° C. for 1 h. The reaction mixture was concentrated in vacuo, and the obtained residue was mixed with 5% aqueous sodium carbonate (100 ml). The resulting mixture was extracted with dichloromethane (4×100 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 25% (v/v) ethyl acetate in n-heptane to give 3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (200 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Product: O=C1N(c2ccc(C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133 step 3) and 1-bromo-4-(trifluoromethyl)benzene as white crystalline solid. MS (m/e): 356.146 [(M-H2O)H+].
Reaction SMILES: C(OC(=O)[N:7]([CH2:24][CH3:25])[CH2:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][C:13]2[NH:17][C:18]([CH:21]=[O:22])=[C:19]([CH3:20])[C:12]=2[C:11]1=[O:23])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:24]([NH:7][CH2:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][C:13]2[NH:17][C:18]([CH:21]=[O:22])=[C:19]([CH3:20])[C:12]=2[C:11]1=[O:23])[CH3:25]
Reactant: CCN(CCN1CCCc2[nH]c(C=O)c(C)c2C1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCCN1CCCc2[nH]c(C=O)c(C)c2C1=O

Procedure:
Ethyl-[2-(2-formyl-3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-5-yl)-ethyl]-carbamic acid tert-butyl ester 62f (43 mg, 0.118 mmol) was dissolved in 10 ml of dichloromethane under stirring, and added with trifluoroacetic acid (272 μl, 3.55 mmol) to the solution and stirred for 15 minutes in an ice-water bath. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound 5-(2-ethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 62j to be used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([F:42])=[CH:23][N:22]=1>>[F:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Product: CNC(=O)CN1CCc2cc(Nc3ncc(F)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product was isolated as a pale yellow solid (0.044 g, 48%). MP: 82-124° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.29 (d, 1H, J=8.6 Hz), 8.16 (s, 1H), 7.93-7.90 (m, 1H), 7.40 (s, 1H), 7.36-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.63 (s, 1H), 6.56-6.53 (m, 1H) 6.53-6.48 (m, 1H), 3.93-3.84 (m, 10H), 3.17-3.09 (m, 6H), 2.92-2.82 (m, 7H), 2.74-2.65 (m, 4H). MS: 566.30 (MH)+.
Reaction SMILES: [Cl-:1].[NH4+:2].CO[C:5]1[CH2:6][CH:7]([CH2:10][CH2:11][CH3:12])[CH2:8][N:9]=1>C(O)C>[Cl-:1].[CH2:10]([CH:7]1[CH2:8][NH:9][C:5](=[NH2+:2])[CH2:6]1)[CH2:11][CH3:12]
Reactant: CCCC1CN=C(OC)C1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Product: CCCC1CNC(=[NH2+])C1
Yield: 76.7 %

Procedure:
Ammonium chloride (110 mg, 2.06 mmol) was added to a solution of 5-methoxy-3-propyl-3,4-dihydro-2H-pyrrole (306 mg, 2.17 mmol) in ethanol (12 ml) and the mixture was heated to reflux for 4 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure to yield a crude product of the title compound (257 mg) as a white solid. 1H-NMR (DMSO-d6) δ(ppm) 0.86 (3H, t, J=7.2 Hz), 1.12-1.52 (4H, m), 2.34-2.60 (1H and DMSO, m), 2.78-2.93 (1H, m), 3.05-3.22 (2H, m), 3.54-3.70 (1H, m)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5](OC)=[O:6].[CH2:11]1COC[CH2:12]1.C([Mg]Br)C>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(OCC)C.O>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5]1([OH:6])[CH2:12][CH2:11]1
Reactant: C1CCOC1
Reactant: COC(=O)CC(OC)OC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: COC(CC1(O)CC1)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 1.0 L RBF containing methyl 3,3-dimethoxypropanoate (17.6500 g, 119 mmol) was added THF (150 ml) and diethyl ether (150 ml), and the mixture was allowed to stir at 0° C. for 15 min. At this time, tetra-isopropoxy titanium (6.98 ml, 23.8 mmol) was added in one portion before the dropwise addition of ethylmagnesium bromide (99.3 ml, 298 mmol) via syringe. The reaction was allowed to warm to 23° C. and stir for 14 hours before being re-chilled to 0° C. After 5 min at this temp, water (15 ml) was added and a solid formed. Diethyl ether (200 ml) was added and the quenched reaction was stirred for 10 min before filtering through a plug of magnesium sulfate. The filtrate was dried with additional magnesium sulfate, filtered and concentrated to give a colorless oil. The crude material was used directly in the next reaction.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.BrC1C(=O)NC2C=CC=CC=2CC1.C1(=O)C2C(=CC=CC=2)CCC1.[N-:38]=[N+:39]=[N-].[Na+]>>[N:1]([CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1)=[N+:38]=[N-:39]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C1CCCc2ccccc21
Agent: O=C1Nc2ccccc2CCC1Br
Agent: [Na+]
Product: [N-]=[N+]=NC1CCc2ccccc2NC1=O

Procedure:
In U.S. Pat. No. 4,873,235, W. H. Parsons et al. describes the synthesis of 3-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one by reacting 3-bromo-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, which is synthesized by bromination of 1-tetralone, followed by reaction with sodium azide to form 3-azido-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. Subsequent hydrogenation of the azido group e.g. by reaction with sodium cyanoborohydride or in the presence of hydrogen on a suitable catalyst leads to 3-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH:9]=[N:10][O:11][CH3:12])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[CH:16]([O-])=[O:17].[Na+]>CN(C)C=O.O>[CH:16]([C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH:9]=[N:10][O:11][CH3:12])=[O:7])=[C:4]([CH3:15])[CH:3]=1)=[O:17]
Reactant: O=C[O-]
Reactant: CON=CNC(=O)c1ccc(Br)cc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=CNC(=O)c1ccc(C=O)cc1C
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
In a solution of 0.20 g of 4-bromo-N-(methoxyiminomethyl)-2-methyl benzoic acid amide in 5 ml of N,N-dimethylformamide, 0.065 g of sodium formate and 0.026 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under carbon monoxide atmosphere at 120° C. for 1.5 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and poured in 30 mL of water, and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (gradient of 1:3 to 1:1) to obtain 0.071 g of the aimed product as colorless oily substance.
Reaction SMILES: C[C:2]([CH3:4])=[O:3].[OH-:5].[Ca+2:6].[OH-]>C(O)(=O)C>[C:2]([O-:5])(=[O:3])[CH3:4].[Ca+2:6].[C:2]([O-:5])(=[O:3])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)=O
Agent: [Ca+2]
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
Furthermore, acetone can be synthesized by pyrolyzing cellulose in a wood material to give acetic acid, neutralizing the acetic acid with calcium hydroxide to give calcium acetate, and then pyrolyzing the calcium acetate. Since acetic acid is generated by oxidation of ethanol during the fermentation in the synthesis of bioethanol, the acetic acid can be utilized to synthesize acetone through the same process as above.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>C(#N)C>[CH3:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:29]1
Reactant: CC1CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC1CCCN(C[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)C1
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.20 g, 0.5 mmol), 3-methylpiperidine (0.35 ml, 3 mmol) and ACN (2 ml) was heated under microwave radiation at 120° C. for 30 min. Purification on flash column chromatography (Isooctane/EtOAc/MeOH). Yield: 0.097 g, 85%. The amine was converted to the fumaric acid salt and crystallized from MeOH/(i-Pr)2O. M.p. 159° C. MS m/z (rel. intensity, 70 eV) 325 (M+, 1), 113 (83), 112 (bp), 69 (43), 55 (46). [α]=+50° (MeOH).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:19][CH:18]=1.Cl>C1COCC1.CCCCCC>[C:17]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:18]=[CH:19][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A dispersion of sodium hydride in a mineral oil (60%) (0.22 mol) was treated with hexane under N2 flow to remove the oil and then dispensed in THF (100 ml) under N2 flow. Ethyl (diethylphosphono)acetate (0.22 mol) was added dropwise. The mixture was stirred for 30 minutes until the gas development has stopped. A mixture of (1,1′-biphenyl)-4-ylphenylmethanone (0.2 mol) in THF (100 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, then stirred and refluxed for 17 hours, cooled, poured out into HCl 10% and ice and extracted three times with DCM. The combined organic layer was washed once with a saturated K2CO3 solution, twice with H2O and once with a saturated NaCl solution, then dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc/hexane 1/1/98). Two pure fractions were collected and their solvents were evaporated. Fraction 2 was crystallized from 2-propanol. The precipitate was filtered off and dried. The mother layer was evaporated and combined with fraction 1, yielding 45 g of ethyl 3-[(1,1′-biphenyl)4-yl]-3-phenyl-2-propenoate (interm. 18).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
4-Nitrobenzoic acid (1.00 g, 6.00 mmol), tert-butyl 1-piperazinecarboxylate (1.10 g, 6.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.70 g, 9.00 mmol) and N-methylmorpholine (1.30 ml, 12.00 mmol) were dissolved in dichloromethane (10 ml) and the reaction mixture stirred at 20° C. for 5 h. The reaction was then washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-50% EtOAc in hexane gradient to afford tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (1.88 g, 5.60 mmol, 94%) as a white solid. LCMS (1) Rt: 2.01 min; m/z (ES+) No M+H+, but 280 (-tBu) and 236 (-Boc).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[ClH:1].[NH:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[CH2:14][N:11]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:13]=[N:12]1
Reactant: [N-]=[N+]=NCc1nc2ccccc2[nH]1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3nc4ccccc4[nH]3)nn2)c[nH]1
Yield: 59 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.091 g, 0.576 mmol) was reacted with 2-azidomethyl-1H-benzimidazole, which was synthesized using previously reported methods (Hiales et al., Synthesis 1978, 4, 313-315), (0.120 g, 0.691 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(1H-Benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-ylmethyl]1Himidazol-2-ylamine dihydrochloride (0.125 g, 59%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.01 (s, 1H), δ 7.58 (d, 2H), δ 7.31 (t, 2H), δ 6.44 (s, 1H), δ 5.98 (s, 2H) δ 3.84 (s, 2H) ppm; 13C (75 MHz, CD3OD) δ 135.6, 124.7, 123.7, 123.5, 122.8, 112.8, 112.3, 108.4, 83.6, 78.9, 74.0, 73.2, 44.2, 19.3 ppm; HRMS (ESI) calcd for C14H14N8(M+) 295.1414, found 295.1420.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[CH:42][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:45])[F:46])=[CH:42][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(-c3nc4cc(C(F)(F)F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(-c3nc4cc(C(F)(F)F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(1-methyl-5-trifluoromethyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.