Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:10].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:10]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1

Procedure:
A solution of 4-chlorobenzyl 2,4-dichlorophenyl ketone (4.5 g, 14.4 mmol) and dimethyl-formamide dimethylacetal (7.7 mL, 58 mmol) in DMF (60 mL) was heated at 75° C. for 20 h. The volatiles were removed in vacuo to provide the crude product which was used directly in the next step. HPLC/MS: 354 (M+1), 356 (M+3); Rt=3.47 min.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:19])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[S:28])=[CH:25][CH:24]=1>>[Cl:19][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:27](=[S:28])[C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:31][CH:30]=1)([C:3]#[N:4])[CH3:20])[C:14]=2[O:15][CH2:16][CH2:17][CH3:18]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CCCOc1c2ccc(Cl)cc2nn1CC(C)(N)C#N
Product: CCCOc1c2ccc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-3-propoxy-2H-indazol-2-yl)-2-methylpropionitrile (104 mg, described in Example 135) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (88 mg, 46%). MS (ES): M/Z [M+H]=497. 1H NMR: (400 MHz, CHLOROFORM-d): 1.14 (t, J=7.4 Hz, 3H), 1.90 (s, 3H), 1.92-2.04 (m, 2H), 4.51 (d, J=14.2 Hz, 1H), 4.56-4.70 (m, 2H), 4.82 (d, J=14.2 Hz, 1H), 6.92 (dd, J=9.1, 1.7 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.62 (dd, J=9.1, 0.5 Hz, 1H), 7.79 (dd, J=8.3 Hz, 2H), 7.91-7.99 (m, 2H) and 9.17 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])([F:23])[F:22]>>[Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([S:24]([C:21]([F:23])([F:20])[F:22])(=[O:26])=[O:25])=[CH:28][CH:29]=4)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Product: O=S1(=O)N=C(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)c2ccc(-c3ncccc3Cl)cc21

Procedure:
The title compound was prepared by reacting the product of Example 1B (0.1521 g, 0.52 mmol) with 4-aminophenyl trifluoromethyl sulphone (0.1417 g, 0.63 mmol) using the procedure as described in Example 1C. MS (ESI+) m/z 454 (M-47)+; (ESI−) m/z 500 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.58 (dd, J=8.3, 4.6 Hz, 1H), 8.18 (m, 1H), 8.28 (m, 3H), 8.39 (m, 3H), 8.65 (d, J=8.1 Hz, 1H), 8.72 (dd, J=4.6, 1.5 Hz, 1H), 11.42 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11]Br)[N:6]=1)=[O:4].[I:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:20][C:17]2[CH:18]=[CH:19][C:14]([I:13])=[CH:15][CH:16]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(CBr)n1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cccc(COc2ccc(I)cc2)n1
Yield: 61.3 %

Procedure:
6-Bromomethyl-pyridine-2-carboxylic acid methyl ester (2.27 g, 9.9 mmol; from Step 2 above) was dissolved in acetone (50 mL) and 4-iodophenol (2.37 g, 10.8 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added, followed by finely ground potassium carbonate (1.54 g, 11.2 mmol). The mixture was heated overnight at 60 degrees, and it was then cooled and filtered. The solid was washed with acetone and the filtrate was concentrated to dryness. Ethyl acetate (100 mL) was added and the solution was washed twice with 2 M NaOH, with water, and with brine. The solution was dried (magnesium sulfate), filtered and evaporated to give the crude product. This was dissolved in acetone (approximately 25 mL) with warming, and water (approximately 20 mL) was added. An oil came out of solution and it crystallized. The mixture was heated to redissolve the solid and the solution was seeded with a crystal of the product to give crystals of the product. The recrystallization was repeated to give 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid methyl ester (2.24 g, 62%) as a white crystalline solid. Mass spectrum m/z 370.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[C:32]1([S:42]([Cl:45])(=[O:44])=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[ClH:45].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:42]([C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)(=[O:44])=[O:43])=[C:3]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: Cl
Product: O=S(=O)(Nc1cc(N2CCCNCC2)ccc1NS(=O)(=O)c1cccc2ccccc12)c1ccccc1

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 1-naphthalenesulfonylchloride (61 mg, 0.27 mmol) to give 56 mg as purple solid. M+1 537.2 Calcd 537.15. 1HNMR δ 8.67-8.64 (m, 1H), 8.10 (d, 1H), 8.02-7.98 (m, 1H), 7.89 (dd, 1H), 7.77-7.38 (m, 8H), 6.46 (d, 1H), 6.26 (d, 1H), 6.14 (dd, 1H), 3.54 (app t, 2H), 3.36-3.31 (m, 2H), 3.17 (app t, 2H), 2.05-1.96 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1C=CN=C1.[N+:19]([CH:22]=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][S:24]1)([O-:21])=[O:20]>C(COC)OC.C(Cl)Cl>[N+:19]([C:22](=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][S:24]1)[C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:9])([O-:21])=[O:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])C=C1NCCCS1
Agent: Cn1ccnc1
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(C(=C1NCCCS1)[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution/suspension of 20.4 g of p-nitrobenzoyl chloride in 25 ml of monoglyme was added dropwise at 5°-10° to a solution of 9.09 g of N-methylimidazole in 75 ml of monoglyme and the mixture was stirred for an additional 30 minutes at 5°-10°, after which was added dropwise (same temperature) a solution/suspension of 16.0 g of tetrahydro-2-(nitromethylene)-2H-1,3-thiazine in 25 ml of monoglyme, after which the stirred mixture was allowed to warm to room temperature and stirred for 96 hours. The mixture then was taken up in methylene chloride, washed with water and saturated sodium chloride solution, dried (Na2SO4) and the solvent evaporated under reduced pressure to give an oil which was chromatographed on florosil using methylene chloride as eluent to give a gum, which was washed with ether to give 17, as a yellow solid, m.p.: 158°-160.5°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]=[CH2:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27].CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]1[O:27][CH2:21]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC(Cc1ccccc1)C1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a stirred solution of 2-benzyloxycarbonylamino-1-phenyl-3-butene (1.43 g, 5.08 mmoles) in 20 mL of CH2Cl2 was added 3-chloroperoxybenzoic acid (2.19 g, 60%, 7.62 mmoles) in several portions, and the mixture was stirred at room temperature for 30 hrs. After addition of EtOAc (60 mL), the mixture was washed with saturated NaHCO3 and brine, and the organic layer was dried over Na2SO4. Evaporation of the solvent afforded an oily residue. The crude product was purified by column chromatography on silica gel with elution by 2:8 EtOAc-hexane to give pure 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@@H:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][OH:23]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[OH:23][CH2:22][C@@H:21]([NH:20][C:14](=[O:16])[C:13]1[CH:18]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[OH:19])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(N[C@H](CO)Cc1ccccc1)c1cc(OCc2ccccc2)ccc1O
Reaction time: 72 h
Yield: 50 %

Procedure:
In a flask equipped with a reflux condenser and a magnetic stirring bar are dissolved the methyl 5-benzyloxy-2-hydroxybenzoate and one equivalent of 2-(S)-amino-3-phenyl-1-propanol in dry dimethyl formamide. The flask is immersed in an oil bath at 75° C. and left to stir for 72 hours. The solvent is evaporated and the residue is isolated-through the use of a silica gel column using a mixture of ethyl acetate and hexane as eluent. In this fashion is obtained in 50% yield, N-{(S)-1-hydroxy-3-phenyl-2-propyl}-5-benzyloxy-2-hydroxybenzamide.
Reaction SMILES: [C:1]1([CH:7]([C:11](=O)[CH3:12])[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]([C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][OH:24])[CH:19]=[CH:20][CH:21]=1)[NH2:15].Cl>>[CH3:12][C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([CH3:9])[N:14]([C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][OH:24])[CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CC(=O)C(C(C)=O)c1ccccc1
Reactant: NNc1cccc(CCO)c1
Agent: Cl
Product: Cc1nn(-c2cccc(CCO)c2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-phenyl-2,4-pentanedione and 2-(3-hydrazinophenyl)ethanol (WO 94/07896) hydrochloride: MS (ESI) m/z 293 [M+H]+, 1H-NMR (CDCl3) δ 7.44-7.22 (9H, m), 3.87 (2H, t, J=6.0 Hz), 2.67 (2H, t, J=6.0 Hz), 2.33 (3H, s), 2.15 (3H, s).
Reaction SMILES: CO[C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([NH:10][N:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])[S:9][C:5]=2[CH:4]=1.C(#N)CC#N.O.[NH2:25][NH2:26].[CH2:27]([OH:29])C>>[CH3:27][O:29][C:18]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][N:11]=[C:12]3[C:13]([NH2:14])=[N:26][N:25]=[C:15]3[NH2:16])=[N:7][C:6]=2[CH:17]=1
Reactant: NN
Reactant: CCO
Reactant: COc1ccc2nc(NN=C(C#N)C#N)sc2c1
Solvent: N#CCC#N
Solvent: O
Product: COc1ccc2sc(NN=C3C(N)=NN=C3N)nc2c1
Temperature: 25 °C

Procedure:
4-[(5-methoxybenzothiazol-2-yl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 2-[(6-methoxybenzothiazol-2-yl)hydrazono]malononitrile (200 mg), which was derived from 2-amino-6-methoxybensothiazole (1.17 g) and malononitrile (0.82 g), and hydrazine hydrate (0.2 mL) in ethanol. Solids had not formed after heating the reaction at 40° C. for 2 hrs. The solution was allowed to cool to ambient temperature and concentrated. The product was obtained after column chromatography purification (80 mg, 35%).
Reaction SMILES: OC1C=C(N2C3C=CN=CC=3N=C2)SC=1C(OC)=O.[OH:20][C:21]1[CH:25]=[C:24]([N:26]2[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[S:23][C:22]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53]([F:56])([F:55])[F:54]>CN(C)C=O>[N:28]1[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[N:26]([C:24]2[S:23][C:22]([C:35]([O:37][CH3:38])=[O:36])=[C:21]([O:20][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]([F:54])([F:55])[F:56])[CH:25]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 7.92 g of an isomeric mixture of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate (example C1) and 4.77 g of K2CO3 and 8.23 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene in 60 ml N,N-dimethylformamide yield compound B1a and compound B1b.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:27][C:26]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=2[F:24])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1nccnc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1F)c1nccnc1Cl
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a mixture of 3-chloropyrazine-2-carboxylic acid (Tyger Scientific, 500 mg, 3.15 mmol) in methylene chloride (30 mL) and DMF (0.1 mL) was added oxalyl chloride (593 mg, 4.7 mmol). After stirring 30 min the reaction mixture was concentrated in vacuo. The residue was taken up in acetonitrile (12 mL) and was treated with triethylamine (920 mg, 9.1 mmol) and 2,4-difluoroaniline (430 mg, 3.3 mmol) and stirred 30 min. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over anhydrous MgSO4, and then concentrated in vacuo. The resulting solid was recrystallized (ethyl acetate/hexanes) to give the amide (455 mg, 53%) as a solid. MS(ESI+) m/z 270 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18](OCCCCCCCCCCCC)[CH:17]=[CH:16][C:14]=2[N:15]=1.NC1N[C:36]2[C:42]([C:43]3C=CC=CC=3)=[CH:41]C=CC=2N=1.NC1N(CCCC)C2C=CC=CC=2N=1.NC1N(C2C=CC=CC=2)C2C=CC=CC=2N=1.NC1N(C(OC)=O)C2C=CC=CC=2N=1>>[N:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:11]=1[NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][C:5]([C:42]([CH3:43])([CH3:36])[CH3:41])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2cccc(-c3ccccc3)c2[nH]1
Reactant: CCCCCCCCCCCCOc1ccc2nc(N)[nH]c2c1
Agent: CCCCn1c(N)nc2ccccc21
Agent: COC(=O)n1c(N)nc2ccccc21
Agent: Nc1nc2ccccc2n1-c1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2nc3ccccc3[nH]2)cc1

Procedure:
Following the above procedure, using as reactants benzoyl chloride and equivalent quantities of 2-amino-5-dodecyloxybenzimidazole, 2-amino-4-phenylbenzimidazole, 2-amino-1-(n-butyl)benzimidazole, 2-amino-1-phenylbenzimidazole, or 2-amino-1-(methoxycarbonyl)benzimidazole, there is obtained as a product, N-(5-dodecyloxybenzimidazol-2-yl)-4-benzamide, N-(4-phenylbenzimidasol-2-yl)-4-benzamide, N-(1-n-butyl) benzimidazol-2-yl)-4-benzamide, N-(1-phenyl)benzimidazol-2-yl)-4-benzamide, or N-(1-methoxycarbonyl)benzimidazol-2-yl)-4-benzamide, respectively.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17]C(=O)OC(C)(C)C)[CH2:11]3)=[CH:6][C:5](=[O:25])[NH:4]1)[CH3:2].F[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH2:17])[CH2:11]3)=[CH:6][C:5]([O:25][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:4]1)[CH3:2]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CCn1[nH]c(=O)cc1-c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1ccc2c(c1)CC(N)C2
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 56.7 %

Procedure:
A mixture of tert-butyl [5-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-2-yl]carbamate (28 mg, 0.082 mmol) in DMSO (1 mL) was treated with fluoro-4-(trifluoromethyl)benzene (100 mg, 0.609 mmol) and K2CO3 (20 mg, 0.15 mmol). The suspension was stirred for 40 min at 140° C. until no SM remained. Significant Boc thermolysis was observed under these conditions. The reaction was cooled, diluted with DCM, extracted with 1 N NaOH, water, dried (Na2SO4), concentrated. The residue was dissolved in 0.9 mL of DCM and 0.1 mL of TFA, then stirred for 1 hour, diluted with DCM, extracted with 1 N NaOH, water, dried (Na2SO4), and finally concentrated to give 5-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}-2,3-dihydro-1H-inden-2-amine (18 mg, 57%): MS cal'd for C21H21F3N3O [M+H]+388.2. found 388.1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12].C(O)(=O)C.C1C=CC=CC=1>O>[CH2:1]([NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 106 g of benzaldehyde, 89 g of 2-amino-2-methyl-1-propanol, 2 ml of glacial acetic acid and 500 ml of benzene is heated for 3 hours under reflux, using a water separator. After completion of the reaction, the mixture is evaporated and the residue is dissolved in 2 liters of ethanol. After adding a total of 76 g of sodium borohydride in portions over the course of 2-3 hours, continuing to stir the mixture overnight at room temperature, and working up in the usual manner, 2-benzylamino-2-methyl-1-propanol is obtained, which melts at 50°-55° C. after crystallisation from ether.
Reaction SMILES: [N:1](C1C=CC=C2C(N(CCCCN3C(=O)C4=C(N=[N+]=[N-])C=CC=C4C3=O)C(=O)C=12)=O)=[N+:2]=[N-].[N+:33]([C:36]1[CH:72]=[CH:71][CH:70]=[C:38]2[C:39]([N:41]([CH:44]([CH3:69])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]([N:55]3[C:59](=[O:60])[C:58]4=[C:61]([N+:65]([O-])=O)[CH:62]=[CH:63][CH:64]=[C:57]4[C:56]3=[O:68])[CH3:54])[C:42](=[O:43])[C:37]=12)=[O:40])([O-])=O.[N-:73]=[N+:74]=[N-].[Na+]>>[N:33]([C:36]1[CH:72]=[CH:71][CH:70]=[C:38]2[C:39]([N:41]([CH:44]([CH3:69])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]([N:55]3[C:59](=[O:60])[C:58]4=[C:61]([N:65]=[N+:73]=[N-:74])[CH:62]=[CH:63][CH:64]=[C:57]4[C:56]3=[O:68])[CH3:54])[C:42](=[O:43])[C:37]=12)=[O:40])=[N+:1]=[N-:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(CCCCCCCCC(C)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCCCN1C(=O)c3cccc(N=[N+]=[N-])c3C1=O)C2=O
Agent: [Na+]
Product: CC(CCCCCCCCC(C)N1C(=O)c2cccc(N=[N+]=[N-])c2C1=O)N1C(=O)c2cccc(N=[N+]=[N-])c2C1=O
Yield: 80 %

Procedure:
The method of preparation is analogous to that described under (a), 8 g (0.014 mol) of 1,10-bis-(3-nitrophthalimidyl)-1,10-dimethyldecane and 2.36 g (0.035 mol) of sodium azide being used. Yield: 80% of theory. The reaction product is obtained in the form of a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[F:14][C:15]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C(OCC)(=O)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:15]=2[F:14])=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: NCc1ccc(I)cc1F
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(I)cc1F)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A mixture of 4-bromo-2-nitrobenzoic acid (3.0 g) and N,N'-carbonyldiimidazole (2.37 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 4 hours. To this mixture was added a solution of 2-fluoro-4-iodobenzylamine (3.37 g) in tetrahydrofuran (10 ml), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed successively with water, aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed in vacuo and the crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-bromo-N-(2-fluoro-4-iodobenzyl)-2-nitrobenzamide (4.88 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].O>CN(C=O)C>[C:17]1([CH2:16][CH2:15][CH2:14][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8]2=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Br)cc2CCN1CCCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline (2.82 g, 12.5 mmol) in DMF (80 ml) is added 1-bromo-3-phenylpropane (2.89 ml, 18.75 mmol), KI (200 mg, 1.25 mmol) and NaH (600 mg, 25 mmol). The reaction mixture is stirred for 3 hours and subsequently poured into H2O (300 ml). The resulting emulsion is extracted with EtOAc (2×150 mL) and the organic phase washed with 2N HCl (1×200 mL), H2O (1×200 mL), saturated NaHCO3 solution (1×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 9:1 hexane/EtOAc) to give 2-(3-phenylpropyl)-6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH:26]([OH:28])[CH3:27])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH:26]([OH:28])[CH3:27])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: CC(O)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(1-hydroxyethyl)pyrazol-1-yl]piperidine-1-carboxylate (0.17 g) dissolved in dichloromethane (1 ml) was treated with trifluoroacetic acid (2 ml) and stirred at room temperature for 2 hours. The resulting mixture was evaporated to dryness and the residual trifluoroacetic acid was removed by azeotropic distillation with toluene under vacuum to afford the crude product. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and the yellow foam was triturated with acetonitrile and re-evaporated to dryness to afford 1-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]ethanol (0.110 g) as a solid. NMR Spectrum: (DMSOd6): 1.43 (d, 1.5H), 1.44 (d, 1.5H), 1.74-1.86 (m, 1H), 1.93-2.03 (m, 2H), 2.03-2.09 (m, 1H), 2.09-2.17 (m, 1H), 2.56-2.64 (m, 1H), 3.01-3.08 (m, 1H), 3.10-3.18 (m, 1H), 4.10-4.20 (m, 1H), 4.78-4.87 (m, 1H), 5.21 (d, 0.5H), 5.22 (d, 0.5H), 7.40-7.48 (m, 2H), 7.63 (bs, 2H), 7.77 (dd, 1H), 7.84 (dd, 1H), 8.04 (s, 0.5H), 8.11 (s, 0.5H), 7.51 (d, 0.5H), 7.52 (d, 0.5H), 7.56 (d, 0.5H), 7.57 (d, 0.5H); Mass spectrum: M+H+ 405.